Stratum corneum permeability

Confining their study to monofunctional molecules, Roberts et al. [38] compared seven different models for predicting human stratum corneum permeability coefficients. The performance of the models was assessed by the adjusted coefficient of determination r2dj and the Akaike Information Criterion (AIC) [39], Both r2dj and AIC allow for comparing models with different numbers of variables (degrees of freedom). Exclusion of polyfunctional molecules led to a comparatively small set of only 24 molecules. The previously reported... 

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... 

In 2003, Mitragotri developed a model for predicting stratum corneum permeability which included four different pathways. The overall skin permeability was described by the following equation ... 

Behne, MJ. etal., NHE1 regulates the stratum corneum permeability barrier homeostasis. Microenvironment acidification assessed with fluorescence lifetime imaging, J. Biol. Chem., 211, 47399, 2002. 

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 ... 

An additional variable that must be accounted for in derma absorption studies that may overshadow the difference between chemicals Is body site differences in absorption within a species. Regional variation in skin permeability at different body. sites may be related to skin thickne.ss, number of cell layers, cell size of the epidermis and stratum comeum, and di.stribution of hair follicles and sweat pores. Because of thick layers of stratum corneum, permeability in palmar and plantar skin is expected to be less than that in the scalp or forearm (Feldmann and Maibach, 1974). Data from several studies suggc.st that regional variation in vascular anatomy and blood flow should also be considered (Montciro-Rivicrc o/.. 1990 Qiao cf a/.. 1993). 

Ayala-Bravo, H.A., Quintanar-Guerrero, D., Naik, A., Kalia, Y.N., Comejo-Bravo, J.M., and Ganem-Quintanar, A., 2003, Effects of sucrose oleate and sucrose laureate on in vivo human stratum corneum permeability, Pharm. Res., 20, 1267—1273. 

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. 

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... 

Transdermal Administration. The development of the stratum corneum is complete at birth and is considered to have permeability similar to that of adults, except in preterm infants [81], Preterm neonates and infants have an underdeveloped epidermal barrier and are subject to excessive absorption of potentially toxic ingredients from topically applied products. 

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

K. Miyajima, S. Tanikawa, M. Asano, and K. Matsuzaki. Effects of absorption enhancers and lipid composition on drug permeability through the model membrane using stratum corneum lipids. Chem. Pharm. Bull. 42 1345-1347 (1994). 

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... 

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 ... 

For parallel permeation pathways within a single layer of such a laminate, the total permeability may be calculated as the sum of the permeabilities [49], For example, when assuming that permeation may occur through both a lipid fraction and a protein fraction of the stratum corneum, the total permeability is calculated according to Eq. 34 ... 

Estimating the geometric parameters for the model from micrographs and experimental data on the lipid content of the stratum corneum, the equation for the permeability through the stratum corneum reduced to Eq. 35 ... 

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. 

FIG. 12. Permeability of ibuprofen from different formulations via excised human stratum comeum. Redrawn from Stoye, L, Permeabilitdtsverdnderung von humanem Stratum corneum nach Applikation nicht-steroidaler Antirheumatika in verschiedenen kolloidalen Trdgersystemen, Ph.D. Thesis TU Braunschweig, 1997. 

---