Permeability skin barrier

Although SC water is relentlessly lost to the environment by perspiratio insensibilis (about 2-8 ml/mVh at rest) (Forslind 1994 Rudikoff 1998), an almost constant amount of water is retained both inside the protein-rich keratinocytes (20%) and in the intercellular space (10%) (Imokawa et al. 1991). A highly specialized and dynamic permeability skin barrier controls the movement of water across the SC as well as the penetration of environmental chemical, physical and biological hazards (Kerscher et al. 1991 Cork 1997), allowing the body to suffer little change while encountering the different environments that are a part of daily life (Spencer 1988). 

Dry skin and its complications are very frequent problems in several occupational settings, although they are often underestimated and seldom included in the lists of occupational skin diseases. In order to understand how dry skin develops, how the main environmental factors induce it and how we can prevent or treat this condition, we have to understand the constitution and physiology of the permeability skin barrier. 

The permeability skin barrier, a highly specialized structure responsible for retaining skin moisture, is localized mainly at the stratum corneum (Rudikoff 1998) however, its formation begins deeper in the epidermis and its constituents are progressively modified during the process of keratinization until they reach their highest efficiency in the five layers of the stratum compactum (Rawlings et al. 1994). The modified keratinocytes - the corneocytes - and the intercellular complex lipid matrix in which they are embedded form this specialized structure, which Elias compared to a bricks and mortar model, in which the corneocytes are the bricks and the lipid matrix the mortar (Elias 1983). 

Many QSPR models rely on some sort of idealized theoretical model for the transport of a molecule through the skin barrier. The descriptors necessary for predicting skin permeability—usually molecular weight and the octanol-water... 

Won Lim, S. etal. The effect of ursolic and oleanolic acid on permeability barrier function and epidermal keratinocyte differentiation via PPAR alpha. Abstract 83, J. Skin. Barrier. Res., 83,5, 2003. 

Structure of SC and its lipid content affect the permeability barrier function. Visualization studies revealed that the penetration route across the SC resides in the intercellular tortuous pathway between the corneocytes. This implies that SC lipids play a key role in the skin barrier function.27 Another major controlling element in barrier homeostasis seems to be the epidermal Calcium ion.28... 

Another factor to consider is that patients with endogenous skin disease are frequently more susceptible to cosmetic reactions. One reason is that patients with preexisting skin disease may have skin barrier dysfunction, with consequent increased permeability. Skin hyper-reactivity in atopic patients, particularly, has been gathering interest in recent years. Epidemiologic associations between atopic dermatitis and irritant dermatitis are now supported by skin bioengineering data.25... 

These testosterone systems illustrate two different approaches to solve the problem of inadequate percutaneous absorption rate. In the former case, the patch must be applied to the body s most permeable skin site, the scrotum (which has been shown to be at least five times more permeable than ary other site). In the latter, the difficulty is resolved by creating a transdermal formulation which includes excipients to reduce barrier function. Neither solution is ideal scrotal application is clearly not preferred from a patient compliance standpoint on the other hand, permeation enhancers, by their very nature, tend to be irritating (and the more effective they are, the greater the irritation they provoke). This general problem, which presently limits the application of transdermal delivery, is now discussed in more detail. 

Unlike iontophoresis, which acts on the transporting molecules and ions, US has been shown to act on the skin barrier itself The effects of sonophoresis depend on the "quality" of the barrier that is subject to US treatment thus, barriers which are intrinsically more permeable will be more liable to physical perturbation by US and vice versa. This may explain why the most successful attempts at the US-assisted extraction of glucose across the skin involved the use of a surfactant or chemical enhancer to better "normalize" the increased transport effects observed. One of the challenges in pretreatment-type sonophoresis is that the degree of skin permeability must be determined prior to drug placement. 

Some fatty acids, especially unsaturated fatty acids, are well-known skin penetration enhancers. It is also known that many fatty acids possess antimicrobial activity. The topical activity of the anti-viral drug acyclovir is hampered by its inadequate permeability through the skin barrier. Some reports have shown that fatty acid extract of cod liver oil as well as the extract in the form of an ointment show effective antiviral properties against herpes simplex virus (HSV-1) (37). 

Additional work, however, has addressed mechanistic aspects of the effects of low-frequency US. Cavitation and thermal effects have been postulated and, to a certain extent, characterized, but further work is clearly needed to define exactly how US interacts with the skin barrier to increase its permeability. 

Numerous reports exist to suggest that application of therapeutic ultrasound (1-3 MHz, 0-2W/cm ) does not induce any irreversible change in the skin permeability to drugs in vivo. Quantitative measurements of estradiol transport across human skin (in vitro) have also shown that application of therapeutic ultrasound (1 MHz, 2W/cm ) does not induce any statistically significant irreversible change in skin barrier properties. Similar studies have also been performed using very low-frequency ultrasound (20 kHz, 125mW/cm, 100 ms pulses applied every second) to assess whether... 

Some chemicals have prompt, destractive effects on the skin barrier. Saturated aqueous phenol, corrosive acids, and strong alkali instantly denature the stratum comeum and destroy its functionahty even as their corrosive actions stifle the hving cells beneath. Though the stratum comeum may appear normal following such damage, the skin may be only marginally less permeable than denuded tissue (35). Other chemicals are dehberately added to formulations to raise the permeabihty of skin and improve drag delivery. For obvious reasons, these are referred to as skin penetration enhancers. More will be said of these later. 

In the case of a composite membrane consisting of a skinless porous substrate and a dense film, permeability and permselectivity may be determined solely by the resistance of the denser film. Different membrane polymers may therefore be employed for the thin barrier layer and the thick support structure. This permits a combination of properties which are not available in a single material. Such membranes were initially developed for desalination by reverse osmosis where they are known as thin- or ultrathin-film composites or nonlntegrally-skinned membranes. A second type of composite membrane is utilized for gas separations. It is a composite consisting of an integrally-skinned or asymmetric membrane coated by a second, more permeable skin which is used to fill skin defects. The inventors of the latter have entitled their device a resfstanee model membrane, but the present author prefers the term coated integrally-skinned composites. 

It has been known for some time that the intercellular lipids of the stratum corneum play a very important role in the skin barrier function. This knowledge has been accumulated from systematic studies on skin permeability of compounds of varying lipophilicity (Scheuplein 1965 Roberts et al. 1977 Durrheim et al. 1980 Surber et al. 1993) and investigations of alterations in transepidermal water loss (Elias and Feingold 1992 Aszterbaum et al. 1992). Because the major route of permeation across the stratum corneum is via the intercellular lipid, the rate at which permeation occurs is largely dependent on the physicochemical characteristics of the penetrant, the most important of which is the relative ability to partition into the intercellular lamellae. 

Fares, H. M., and J. L. Zatz. 1997. Dual-probe method for assessing skin barrier integrity Effect of storage conditions on permeability of micro-Yucatan pig skin./. Soc. Cosmet. Chem. 48 175-186. 

Yoshiike, T., Aikawa, Y, Sindhvananda, J., Suto, H., Nishimura, K., Kawamoto, T, and Ogawa, H. (1993). Skin barrier defect in atopic dermatitis increased permeability of the stratum comeum using dimethyl sulfoxide and theophylline, J. Dermatol Scl, 5 92-96. 

There is today a consensus about penetration pathways through the skin barrier (Bodde et al. 1990). Under normal conditions, the corneocytes are permeable essentially only to water, which implies that the transport route for hydrophilic and hydrophobic substances is via the extracellular space of the stratum corneum. The lipids of this space are organised in bilayers stacked on top of each other. The corneocyte envelopes have long-chain ceramides covalently bound to their surfaces... 

Lipids present in the stratum comeum play a crucial role in skin function ensiuing cellular cohesion, skin barrier properties, and good healthy looking skin. Indeed, a delipidized or lipid disorganized skin is more water permeable and often has a rough, scaly, dry aspect. 

---