Non steady-state descriptions of drug permeation through stratum corneum. I. The biphasic brick-and-mortar model.

PURPOSE: The diffusion equation should be solved for the non-steady-state problem of drug diffusion within a two-dimensional, biphasic stratum corneum membrane having homogeneous lipid and corneocyte phases. METHODS: A numerical method was developed for a brick-and-mortar SC-geometry, enabling an explicit solution for time-dependent drug concentration within both phases. The lag time and permeability were calculated. RESULTS: It is shown how the barrier property of this model membrane depends on relative phase permeability, corneocyte alignment, and corneocyte-lipid partition coefficient. Additionally, the time-dependent drug concentration profiles within the membrane can be observed during the lag and steady-state phases. CONCLUSIONS: The model SC-membrane predicts, from purely morphological principles, lag times and permeabilities that are in good agreement with experimental values. The long lag times and very small permeabilities reported for human SC can only be predicted for a highly-staggered corneocyte geometry and corneocytes that are 1000 times less permeable than the lipid phase. Although the former conclusion is reasonable, the latter is questionable. The elongated, flattened corneocyte shape renders lag time and permeability insensitive to large changes in their alignment within the SC. Corneocyte/lipid partitioning is found to be fundamentally different to SC/donor partitioning, since increasing drug lipophilicity always reduces both lag time and permeability.

Apparent pKa of the fatty acids within ordered mixtures of model human stratum corneum lipids.

PURPOSE: The apparent pKa of the fatty acids within hydrated (30% w/w) model human stratum corneum (SC) lipid mixtures should be measured. METHODS: The degree of ionisation of the fatty acids was calculated as a function of pH using Fourier transform infra-red spectroscopy. The relative intensity of the stretching bands of the unionized and ionized carboxylic groups was determined and fitted to the relevant expression for ionic equilibrium of a monoprotic acid. The pKa was then calculated for increasing proportion of unsaturated fatty acid in the lipid mixture. RESULTS: Values for pKa in the range 6.2-7.3 were found, increasing with greater proportion of oleic acid. These are some 1.5-3 pH units higher than the pKas of fatty acids in molecular solution. CONCLUSIONS: As there exists a pH-gradient across the SC, the degree of ionisation will also vary. In the innermost SC layers, a pH of 7 will produce 90% ionization of the fatty acids and head-group repulsion will be great. At the SC surface, the pH of 5 will cause almost minimal head-group repulsion, tending to increase crystallinity and promote a bilayer structure.

Diffusivity and structural polymorphism in some model stratum corneum lipid systems.

Mixtures of model stratum corneum lipids were prepared in water from cholesterol, six fatty acids and ceramides. The influence of composition on the polymorphism of these mixtures and also on the diffusivity of a model drug within them, Dlip, was determined. The former was obtained from X-ray diffraction and Fourier transform infrared spectrometry, and the latter from a diffusional release model. An L beta structure was formed for the composition approximating that of the extracellular lipids in intact human abdominal stratum corneum. Dlip was independent of water content in the range 20-40% w/w, with the bilayers showing one dimensional swelling without lateral expansion. Although removal of the ceramides did not result in a significant alteration in Dlip, crystalline cholesterol now appeared. The ceramides were, therefore, necessary for solubilization within the fatty acid bilayers of the large proportion of cholesterol present in the lipid fraction of intact SC. They were also responsible for a thermal L alpha-HII transition observed at approx. 68 degrees. At the concentration in which it exists in intact SC, cholesterol also had only a minimal effect on Dlip, but was necessary to suppress HII phase formation within the fatty acids and ensure an L beta structure. All lipid mixtures that had an L beta structure presented a diffusional barrier approx. 1 order of magnitude greater than that of an unstructured, isotropic lipid mixture. HII structures formed at cholesterol/fatty acid proportions less than approx 8:92 mol% and appeared more permeable than L beta ones. All the results indicate that the diffusional barrier within the model lipid mixtures is guaranteed essentially by the presence of an L beta phase. Although the ceramides and cholesterol exert no intrinsic influence on the magnitude of Dlip, their presence in necessary for the existence of an L beta phase at 33 degrees that is free of both crystalline cholesterol and HII character.