https://purehost.bath.ac.uk/ws/files/227909/Guy_IJP_2011_418_1_115.pdf

Mathematical models of skin permeability: An overview

Evaluation of solute permeation through the stratum corneum: lateral bilayer diffusion as the primary transport mechanism.

The structure and function of the skin common skin disorders and their topical treatment basic mathematical principles in skin permeation skin transport methods for studying percutaneous absorption formulation strategies for modulating skinpermeation formulation and development of dermatological dosage forms bioequivalence of dermal and transdermal formulations scale-up of dermatological dosage forms a case for multivariate optimization and product homogeneity transdermal drug deliverysystems safety considerations for dermal and transdermal products transdermal delivery and cutaneous reactions.

Dermatological And Transdermal Formulations

Modes of action of terpene penetration enhancers in human skin; Differential scanning calorimetry, small-angle X-ray diffraction and enhancer uptake studies

Permeability coefficients (P

 m
 ) across planar egg lecithin/decane bilayers and bulk hydrocarbon/water partition coefficients (K
w→hc) have been measured for 24 solutes with molecular volumes, V, varying by a factor of 22 and P

 m
 values varying by a factor of 107 to explore the chemical nature of the bilayer barrier and the effects of permeant size on permeability. A proper bulk solvent which correctly mimics the microenvironment of the barrier domain was sought. Changes in P

 m
 /Kw→hc were then ascribed to size-dependent partitioning and/or size-dependent diffusivity. The diffusion coefficient-size dependency was described by D
barrier = D

 0
 /V

 n
 . When n-decane was used as a reference solvent, the correlation between log P

 m
 /K
w→hc and log V was poor (r = 0.56) with most of the lipophilic (hydrophilic) permeants lying below (above) the regression line. Correlations improved significantly (r = 0.87 and 0.90, respectively) with more polarizable solvents, 1-hexadecene and 1,9-decadiene. Values of the size selectivity parameter n were sensitive to the reference solvent (n = 0.8 ± 0.3, 1.2 ± 0.1 and 1.4 ± 0.2, respectively, for decane, hexadecene, and decadiene). Decadiene was selected as the most suitable reference solvent. The value for n in bilayer transport is higher than that for bulk diffusion in decane (n = 0.74±0.10), confirming the steep dependence of bilayer permeability on molecular size. Statistical mechanical theory recently developed by the authors suggests that a component of this steep size dependence may reside in size-dependent solute partitioning into the ordered chain region of bilayers. This theory, combined with the above diffusion model, yielded the relationship, P

 m
 /K
W→hc=D

 0
 exp(™αV)V

 n
 . A fit of the experimental data to this model gave the best fit (r=0.93) with α = 0.0053±0.0021 and n=0.8 ± 0.3, suggesting that both diffusion and partitioning mechanisms may play a role in determining the size dependence of lipid bilayer permeabilities.

The relationship between permeant size and permeability in lipid bilayer membranes.

The uptake of a series of hydrocortisone esters varying in lipophilicity from water into untreated and delipidized human stratum corneum has been determined. The partition coefficients of solutes into fully hydrated stratum corneum are postulated to represent the separate contributions of three structurally distinct domains—the extractable lipids, protein, and the solvent domain. The solvent domain was assumed to have the properties of bulk water. The relative affinities of the protein and lipid domains of stratum corneum for solutes varying in structure were determined by comparing solute uptake in untreated and delipidized stratum corneum. Partitioning into the extracted lipids was also examined. Solute uptake into stratum corneum may be governed by the protein domain, the lipid domain, or a combination of the two, depending on solute lipophilicity. Due to differences in the selectivity of the two domains, a change in uptake mechanism occurs with increasing solute lipophilicity from protein-dominated uptake for hydrophilic solutes to lipid domain-dominated uptake for lipophilic solutes. The stratum corneum lipid content, which varies dramatically from individual to individual (3–46% in this study), is an important determinant of the affinity of the stratum corneum for highly lipophilic solutes but has no effect on the uptake of hydrophilic solutes.

Man-Cheong Fung

Papers

The role of protein and lipid domains in the uptake of solutes by human stratum corneum.

Hydrolysis and Solvent-Dependent 2′→5′ and 3′→5′ Acyl Migration in Prodrugs of 9-β-d-Arabinofuranosyladenine