Stratum corneum drug diffusivity

The percutaneous absorption or the transdermal delivery of a drug occurs in the following manner. Initially a topically applied drug is absorbed into the stratum corneum and diffuses through that layer of skin into the epidermis and then into the dermis where drug... 

Temperature influences skin permeability in both physical and physiological ways. For instance, activation energies for diffusion of small nonelectrolytes across the stratum corneum have been shown to lie between 8 and 15 kcal/mole [4,32]. Thus thermal activation alone can double the rate skin permeability when there is a 10°C change in the surface temperature of the skin [33], Additionally, blood perfusion through the skin in terms of amount and closeness of approach to the skin s surface is regulated by its temperature and also by an individual s need to maintain the body s 37° C isothermal state. Since clearance of percuta-neously absorbed drug to the systemic circulation is sensitive to blood flow, a fluctuation in blood flow might be expected to alter the uptake of chemicals. No clear-cut evidence exists that this is so, however, which seems to teach us that even the reduced blood flow of chilled skin is adequate to efficiently clear compounds from the underside of the epidermis. 

The intercellular route is considered to be the predominantly used pathway in most cases, especially when steady-state conditions in the stratum corneum are reached. In case of intercellular absorption, substance transport occurs in the bilayer-structured, continuous, intercellular lipid domain within the stratum corneum. Although this pathway is very tortuous and therefore much longer in distance than the overall thickness of the stratum corneum, the intercellular route is considered to yield much faster absorption due to the high diffusion coefficient of most drugs within the lipid bilayer. Resulting from the bilayer structure, the intercellular pathway provides hydrophilic and lipophilic regions, allowing more hydrophilic substances to use the hydrophilic and more lipophilic substances to use the lipophilic route. In addition, it is possible to influence this pathway by certain excipients in the formulation. 

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. 

Based on Eq. (4.4), the enhancement factor E is defined as the enhancement on the maximum flux J"max of a drug across skin by increasing the (kinetic) diffusivity and/or the (thermodynamic) solubility in the stratum corneum.79 Thus... 

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. 

From Figure 2, it is apparent that there is also a partitioning step as the drug diffuses from the stratum corneum to the viable tissue, this can be described by a backward rate constant, kj. Empirically it has been shown that the ratio kg/k2 can be related to the octanol-water (pH 7.4) partition coefficient of the drug divided by... 

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... 

The rate of diffusion of a topically applied toxicant across the rate-limiting stratum corneum is directly proportional to the concentration gradient across the membrane, the lipid/water partition coefficient of the drug, and the diffusion coefficient for the compound being studied. This can be summarized by Fick s law of diffusion in the equation... 

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