Scratching the surface: skin permeation. (part 1)

Scratching the Surface: Skin Permeation

This is the first of a series of twelve articles on the skin sorption and permeation of active compounds. The articles, written by a distinguished group of scientists, will discuss methodology, applicable models, and the factors of importance in skin permeation. Professor Joel Zatz, chairman of the department of Pharmaceutics at Rutgers University, is general editor of the series.

These articles are designed to cover basic concepts as well as newer developments. The literature of skin permeation is expanding rapidly because of exciting advances in drug delivery through the skin. There is growing recognition of the importance of measurements of skin uptake and absorption in the development of topical dermatological and cosmeceutical products. Information on percutaneous absorption is also relevant to the toxicology of compounds and products that come in contact with the skin.

The next few articles will deal with biological factors in skin penetration, applications of percutaneous absorption data to toxicology and the details of in vitro measurement. Future topics include in vivo measurement, factors affecting skin sorption, and optimizing skin availability of topical products.

Although early investigators thought that the skin was totally impermeable, we now realize that a few substances overcome the resistance of the epidermis rather easily, and most make steady, slow progress through the skin. The literature of skin transport has been growing rapidly (one might say this subject area is in a state of flux) because of its many applications.

It is also now possible to get better, more precise information on the uptake and transcutaneous movement of molecules than in the past. With the introduction of sensitive analytical techniques and improvement in study methods, we can often quantitate the sometimes infinitesimal amounts of various substances that manage to get into and through the skin.

The skin barrier is constantly put to the test. Whether swimming in the ocean or walking through an ocean of air, whether because of spills or sprays, the skin is bombarded by minute amounts of many chemical agents. Then we have products deliberately put on the skin: dermatologicals to modify skin function, cosmetics to beautify, transdermals to treat some distant organ. Finally, individuals may repeatedly come into contact at their workplace with potentially toxic materials at concentrations thousands of times those encountered by the general population.

Overview of the skin barrier

Although the skin excretes wastes, receives sensory stimuli and helps regulate body temperature, its principal function is to separate and protect the sensitive protoplasmic jelly of the body's interior from an environment that can be very harsh. The skin prevents intrusion of microbes, chemicals and various forms of radiation, and keeps body fluids and tissues from spilling out.

It is remarkable that the principal resistance to permeation of most, though not all, substances resides in the paper-thin outer layer of skin called the stratum corneum, or horny layer. This stratum, generated by the underlying cells of the epidermis, is most conveniently thought of as a separate layer when skin permeation is under discussion.

The horny layer is a compact amalgam of dried, dead, elongated cells (corneocytes), the end product of differentiation of cells produced in the viable epidermis. Keratin, deposited within the corneocytes, provides strength and chemical resistance. Most of the lipoidal material present is found between the compressed cells in the form of neutral lipids.[1]

The horny layer is a rather dry tissue, although the actual moisture content depends on the ambient relative humidity. At low humidity, the water associated with keratin and other proteins is tightly bound and therefore oriented, so that the tissue has a low effective dielectric constant. Within the cells are low molecular weight hydrophilic substances (such as amino acids and sugars) that are sometimes collectively referred to as natural moisturizing factor (NMF).

Resistance to transport through the horny layer depends on the properties and arrangement of its alternating hydrophilic and hydrophobic layers, as well as their thickness, all of which vary from species to species and even from place to place on the same individual. Additional variables are the local concentration of hair follicles and sweat glands; these provide possible alternate pathways for diffusion.

Experimentally, large permeation differences have been demonstrated depending on skin location.[2] Although relative rates are to some extent a function of the permeant, we can generalize and rank permeability of body sites as follows:

genitals [is greater than] head areas [is greater than] trunk [is …