Stratum corneum diffusion

Diffusivity (I)) is a temperature-dependent parameter (Equation (2)) that essentially describes the mobility of a penetrating molecule within the stratum corneum. Diffusivity can be affected by a variety of factors, including the physical size of a penetrant and its potential interactions with the stratum corneum (through hydrogen bonding, electrostatic forces, etc.). 

At the other end of the spectrum, however, in transdermal systemic delivery, the molecular attributes required are rather different. In this case, compounds are required to partition into the relatively lipophilic stratum corneum, diffuse rapidly across the stratum corneum and partition easily into the more hydrophilic viable epidermis and dermis prior to vascular removal. The intrinsic requirements of compounds for transdermal delivery are, therefore, a medium polarity (a log octanol-water partition coefficient of 1-3), a low molecular volume and a lack of potential to bind to skin components (e.g., via hydrogen bonding). 

Skin. The skin s unique molecular transport and barrier properties pose a challenge for transdermal dmg dehvery. Diffusion of dmgs through the stratum corneum, the outer layer primarily responsible for the skin s limited permeabUity, varies by dmg, by skin site, and among individuals. Until recently, virtuaUy aU dmgs appHed to skin were topical treatments. 

Sweating, the other powerful heat loss mechanism actively regulated by the thermoregulatory center, is most developed in humans. With about 2,6 million sweat glands distributed over the skin and neurally controlled, sweat secretion can vary from 0 to 1 I7(h m ). The other, lesser, passive evaporative process of the skin is from the diffusion of water. The primary resistance to this flow is the stratum corneum or outermost 15 pm of the skin. The diffusion resistance of the skin is high in comparison to that of clothing and the boundary layer resistance and as a result makes water loss by diffusion fairly stable at about 500 grams/day. 

Fig. 2.3.9 A time series of profiles showing the is shown by the lowest trace. The inset shows ingress from right (stratum corneum) to left the advance of the glycerine front against the (viable epidermis) of glycerine into human skin square root of time from which Fickian in vitro. The skin before application of glycerine diffusion is inferred.

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. 

Estimated diffusion coefficients in the stratum corneum are up to 10,000 times smaller than found... 

To illustrate the above point, take the set of largest values given for the diffusion coefficients found in Table 8, that is, 10-9 cm2/s for the stratum corneum, 10-7 cm2/s for sebum, and 10-6 cm2/s for the viable tissue, and convert them to cm2/h. Conversion of these from reciprocal seconds to reciprocal hours eventually leads to permeability coefficients that are more easily compared with literature values (P in units of cm/h) When these values are substituted into Eq. (7) along with... 

These diffusivities are estimates obtained by in vitro experiment (stratum corneum) or by comparison with small tissues in which diffusivities have been measured (all others). They do not account for regional variations across the body surface, so on both counts must be considered highly approximate. 

Model interpretation takes a different bent when minimum values for the respective diffusion coefficients are incorporated in the steady-state model, i.e., 1013 cm2/s for the stratum corneum and 10 9 cm2/s for the follicular shunt route. Inserting these values, everything else held constant, suggests there should be a substantial upgrading of the importance of the transfollicular contribution. Data with steroids seem to indicate, however, that the transepidermal route retains a dominant position in the steady state even in this case. 

First, consider the transepidermal (TE) route. The solute molecules diffuse across the stratum corneum and the viable tissues located above the capillary bed. Considering the stratum corneum and the viable tissues as two diffusion barriers in series, the total resistance is given by... 

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. 

However, the validity of a similar assumption has to be questioned, in case the skin has previously been treated with a topically applied formulation [126], Opinions differ, whether the distinct curvature of the steady-state stratum corneum concentration gradient, reported in literature, may be an artifact of a wrong depth scale, since such a behavior cannot be reasonably explained by the established diffusion theory. 

R. Lieckfeldt, J. Villalain, J. C. Gomez-Fernandez, and G. Lee. Diffusivity and structural polymorphism in some model stratum corneum lipid systems. Biochim. Biophys. Acta Biomembr. 1150 182-188 (1993). 

Because of the possible effects of active and carrier-mediated processes and metabolic biotransformation, the issue of tissue viability is important for in vitro buccal mucosal experiments. The barrier nature of the buccal mucosa resides in the upper layers of the epithelium, where unlike in the stratum corneum, the cells contain a variety of functional organelles [119, 122, 125, 150], and so tissue viability may be an important component of the barrier function of the tissue. Various methods have been employed to assess the viability of excised buccal mucosa, including measurement of biochemical markers, microscopic methods, and linearity of transport data [42], While biochemical methods, including measurement of adenosine 5 -triphosphate (ATP) levels and utilization of glucose, provide information on the metabolic activity of the tissue, this does not necessarily relate to the barrier function of the tissue. In excised rabbit buccal mucosa, levels of ATP were measured and found to decline by 40% in 6 h, and this correlated well with transmission electron microscopic evaluation of the tissue (intact superficial cells) [32], In addition, the permeability of a model peptide was unaltered up to 6 h postmortem, but at 8 h, a significant change in permeability was observed [32], These investigators therefore claimed that excised rabbit buccal mucosa could be used for diffusion studies for 6 h. 

Roberts et al. criticized the attempts to predict permeabilities since permeability is the result of two processes, partitioning and diffusion [40], Therefore, instead of following the approach of Potts and Guy, Roberts et al. tried to find a predictive model for each of these processes separately. For the partitioning step they found a Collander-type linear relationship (Eq. 11) between the logarithms of the stratum corneum-water and the octanol-water partition coefficients with a high correlation coefficient (r2 = 0.839) ... 

To determine the molecular properties influencing the diffusion process they investigated the relationship between experimental stratum corneum-water partition coefficients and permeability data for 45 compounds. Rearrangement of the logarithmic form of Eq. 4 led to... 

The success of the Potts-Guy equation led many authors to advocate a single mechanism as the rate determining step for permeation through the skin barrier for all or at least a wide range of solutes diffusion was assumed to occur primarily via the interkeratinocyte lipids of the stratum corneum, a mixture of ceramides, fatty acids, and sterols. While from a macroscopic point of view these lipids may be modeled as a bulk solvent, on a microscopic scale they... 

Substituting hx = 3.6 cm and K ip/w = K - into Eq. 28 Johnson et al. calculated solute lateral diffusion coefficients in stratum corneum bilayers from macroscopic permeability coefficients. Measurements with highly ionized or very hydrophilic compounds were not performed because of the possible transport along a nonlipoidal pathway. Comparison of the computed Aat values with experimentally determined data for fluorescent probes in extracted stratum corneum lipids [47] showed a highly similar curve shape. The diffusion coefficient for the lateral transport showed a bifunctional size dependence with a weaker size dependence for larger, lipophilic compounds (> 350 Da), than... 

Combining the equation for the diffusion coefficient with a Collander-type expression for the lipid-water partition coefficient resulted in an expression for calculating the permeability across the stratum corneum ... 

It has been established that in analogy to Ohm s law the overall resistance to diffusion of a multilayer laminate is given simply by the sum of the separate resistances of the layers (Figure 20.2). For example, the total resistance of skin being composed of stratum corneum, viable epidermis, and dermis may be expressed as... 

In an early, quite elaborate model for the diffusion through the stratum corneum, Michaels et al. derived an equation for diffusion through a two-dimensional brick-and-mortar structure [50], In this model, stratum corneum permeability for a given compound depended only on two parameters one was the product of the partition coefficient between the protein and the donor phase /fprot/donor and the diffusion coefficient in the protein phase >Prot the other was the product of the partition coefficient between the lipid and protein phases Aip/prot and the ratio of the diffusion coefficients in the two phases... 

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