Stratum corneum, penetrant diffusion

Pugh WJ, Degim IT, Hadgraft J (1996) Epidermal permeability-penetrant structure relationships 4. QSAR of permeant diffusion across human stratum corneum in terms of molecular weight, H-bonding and electronic charge. Int J Pharm 197 203-211. 

Emollients are often added to cream formulations to modify either the characteristics of the pharmaceutical vehicle or the condition of the skin itself to promote penetration of the active ingredient to act either locally or systemically. The stratum corneum, being keratinized tissue, behaves as a semipermeable artificial membrane, and drug molecules can penetrate by passive diffusion. The rate of drug movement depends on the drug concentration in the vehicle, its aqueous solubility, and the oil/ water partition coefficient between the stratum corneum and the product s vehicle. Commonly used emollients include glycerin, mineral oil, petrolatum, isopropyl pal-mitate, and isopropyl myristate. 

If skin is placed in a water bath under controlled conditions [14] the primary barrier to transdermal delivery, the epidermal membrane comprising the stratum corneum and viable epidermis, can be readily removed and used to analyze the penetration and diffusion of materials. Figure 18.3a and Figure 18.3b show the appearance of human breast epidermal membrane, with epidermis facing uppermost, following application of the cylindrical dry-etch and pyramidal wet-etch silicon microneedles, respectively. In each case the microneedles are clearly shown to pierce the stratum corneum and viable epidermis to facilitate controlled access of molecules to the target region of skin. 

In defining a model for percutaneous absorption it is necessary to identify the route by which a drug molecule crosses the skin. For all but the most lipophilic materials, the principal barrier to penetration is the stratum corneum. There are, however, a number of routes a diffusing drug molecule can take in traversing this outermost layer of the epidermis. These are depicted schematically in Figure 1. 

The major barrier of the skin is the outermost dead layer, the stratum corneum. A number of routes of penetration of a drug, across this region can be identified. First, the appendages, the pilosebaceous and eccrine glands, form a potential shunt route across the stratum corneum. The relative surface area of these is very small (<0.1%) and there has been little conclusive evidence to suggest that this is a major route. Second, the penetrant could diffuse across the entire stratum corneum through the dead cells, the corneocytes. A large surface area is available but the... 

To improve topical therapy, it is advantageous to use formulation additives (penetration enhancers) that will reversibly and safely modulate the barrier properties of the skin. Fick s first law of diffusion shows that two potential mechanisms are possible. The two constants that could be altered significantly are the diffusion coefficient in the stratum corneum and the concentration in the outer regions of the stratum corneum. Thus, one of mechanisms of action of an enhancer is for it to insert itself into the bilayer structures and disrupt the packing of the adjacent lipids, thereby, reducing the microviscosity. The diffusion coefficient of the permeant will increase This effect has been observed using ESR and fluorescence spectroscopy [16,17]. 

In addition to movement through shunts, polar substances may diffuse through the outer surface of the protein filaments of the hydrated stratum corneum, while nonpolar molecules dissolve in and diffuse through the nonaqueous lipid matrix between the protein filaments. The rate of percutaneous absorption through this intercellular lipid pathway is correlated to the partition coefficient of the penetrant, as presented above in Fick s law. 

B. Diffusion Routes Across the Stratum Corneum in the Presence of Penetration Enhancers... 

The precise mode of interaction between lipid vesicles and skin remains unclear. There is considerable doubt about the ability of whole vesicles to permeate intact stratum corneum. The majority of evidence suggests that vesicles can penetrate the outer cell layers of the stratum corneum where desmosomal linkages have become disrupted and presumably, the keratinocytes are less tightly bound and surrounded by a mixture of intercellular lipid and sebum. However, continuing diffusion of vesicles through the approximately 60 nm intercellular space of the deeper layers of the stratum corneum seems unlikely. Current thinking suggests... 

Transdermal delivery is a case in point. The skin, particularly the stratum corneum presents a formidable barrier to diffusion. Materials used to enhance its permeability have ranged from simple solvents such as ethanol or propylene glycol to aromatic chemicals such as terpenoids. Such penetration enhancers appear to work by disrupting the lipid domains in the stratum... 

The dermal penetration coefficient Kp in this simplest case depends on both the partitioning of the chemical from its vehicle (usually water) into the stratum corneum, and its diffusion through the stratum corneum. Both of these quantities can be estimated from a chemical s properties or structure. Partitioning from water into the stratum corneum can be estimated from a chemical s octanol-water partition coefficient, Kow Diffusion through the stratum corneum is dependent on the molecular volume of the chemical, which is in turn a function of its molecular weight (MW). Perhaps the most widely used expression of the dependence of stratum corneum permeability on readily available physicochemical properties is the Potts-Guy equation ... 

For compounds that have either a very low diffusion coefficient or a very low lipid-water partition coefficient, the lipid barrier of the stratum corneum is a formidable impediment to penetration through the skin. However, for such compounds it has been observed that there is no longer a correlation between skin permeation and lipid solubility further, there also appears to be little dependence on molecular weight. It has therefore been hypothesized that such compounds make use of an alternative, low-permeability, and essentially aqueous pathway through the stratum corneum. Although direct physical evidence for such pores is lacking, the notion of a... 

Chemical absorption pathways can hypothetically involve both intercellular and intracellular passive diffusion across the epidermis and dermis and/or transappendageal routes, via hair follicles and sweat pores. Most available research has concentrated on the stratum corneum as the primary barrier to absorption, although the viable epidermis and dermis can also contribute resistance to the percutaneous penetration of specific chemical classes, for... 

Consequently, eliminating aU or part of the stratum corneum drastically enhances the absorption of physical and chemical agents that could not have penetrated an intact protective stratum corneum. The ability of a product to penetrate the skin also depends on how it interacts with the corneocytes and the intercellular matrix. At the same molecular weight, a proteolytic product will penetrate the skin more readily than a product that is not proteolytic. The more liposoluble a molecule is, the greater its partition between the vehicle and the skin barrier and as a result its ability to penetrate is improved. Another factor to be taken into account is how solvents interact ethanol diffuses better in the stratum corneum when it is mixed with oil rather than water. How well hydrated the stratum corneum is also plays an essential role in the skin s absorption capacity. When the stratum corneum is hydrated, products can be absorbed up to 10 times more efficiently. Hydration swells... 

We have numerous defense mechanisms to protect us, and complex physiological reactions can repair most of the damage caused by photons. Some of the light from the sun is reflected off the fatty layer covering the corneocytes. The outermost layers of the stratum corneum also reflect Kght, and the photons that manage to penetrate this layer are diffused as they reflect off the different layers of cells. 

Terminally differentiated keratinocytes of the stratum corneum are known as comeocytes and are largely devoid of normal cellular functions, being predominantly composed of protein (keratin). The ultrastructure of the stratum corneum is described by the brick and mortar model (Elias, 1983 Figure 3). The functional implication of this architecture is that some skin penetrants must diffuse via a long and tortuous route between adjacent comeocytes, thus reducing their rate of absorption. This is known as the intercellular route. In contrast, some chemicals may diffuse equally through both comeocytes and the lipid mortar, resulting in a transcellular route. 

The molecular packing of the lipid matrix effectively sets an upper limit on the physical size of molecules that may penetrate the stratum corneum (Figure 4). This is referred to as the rule of 500 (Bos and Meinardi, 2000) since few substances with a molecular weight above 500 Da are capable of passive diffusion through the skin (see Table 1). 

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