No abstract

In the development of transdermal and topical products it is important to understand how formulation ingredients interact with the molecular components of the upper layer of the skin, the stratum corneum (SC), and thereby influence its macroscopic barrier properties. The aim here was to investigate the effect of two commonly used excipients, transcutol and dexpanthenol, on the molecular as well as the macroscopic properties of the skin membrane. Polarization transfer solid-state NMR methods were combined with steady-state flux and impedance spectroscopy measurements to investigate how these common excipients influence the molecular components of SC and its barrier function at strictly controlled hydration conditions in vitro with excised porcine skin. The NMR results provide completely new molecular insight into how transcutol and dexpanthenol affect specific molecular segments of both SC lipids and proteins. The presence of transcutol or dexpanthenol in the formulation at fixed water activity results in increased effective skin permeability of the model drug metronidazole. Finally, impedance spectroscopy data show clear changes of the effective skin capacitance after treatment with transcutol or dexpanthenol. Based on the complementary data, we are able to draw direct links between effects on the molecular properties and on the macroscopic barrier function of the skin barrier under treatment with formulations containing transcutol or dexpanthenol.

Monolayers of palmitic (C16:0) and lignoceric acid (C24:0) and their equimolar mixture were transferred to a hydrophilic mica substrate at various surface pressures and investigated by means of atomic force microscopy (AFM) in contact and lateral force modes. The first-order transition of lignoceric acid gives a plateau region, representing a liquid expanded to liquid condensed phase transition in the pressure-area isotherm. This was visualized by AFM as stripes of a condensed phase within the expanded phase, exhibiting a small height difference but a significant difference in friction. The corresponding phase transition of the palmitic acid was continuous, and no changes of the Langmuir-Blodgett films with respect to pressure were observed with AFM. Both the surface pressure-area isotherms and the direct observations of domains of irregular size and shape using the AFM showed that lignoceric and palmitic acid were immiscible. The height difference between the domains was 1.1 nm corresponding to the difference in hydrocarbon chain length of the two fatty acids.

In this study the effect of cholesterol in Langmuir-Blodgett monolayers of fatty acids of varying chain lengths was investigated by atomic force microscopy (AFM). Domain formation due to lateral phase separation was studied at different lipid compositions and surface pressures. A small amount of cholesterol is miscible with palmitic acid (C16:0) and forms a flat monolayer while excess cholesterol forms a rougher cholesterolrich phase. No miscibility was observed in monolayers of lignoceric acid (C24:0) and cholesterol. For the ternary mixed monolayer (palmitic acid, lignoceric acid, and cholesterol) the two fatty acids formed separate domains and the miscibility of cholesterol in the two phases showed behavior corresponding to that of the binary fatty acid-cholesterol systems. From the shape, size, and height differences of the domains one can conclude that the driving force to minimize the interfacial length between different phases is reduced in the presence of cholesterol. This can be attributed to line active properties of cholesterol.

The outer part of the skin, stratum corneum, is essential to the skin's barrier function. Monolayer and bulk phase behavior of stratum corneum model lipids have thus been studied. Domain formation in Langmuir-Blodgett monolayers of synthetic ceramides (C16CerIII and C24CerIII), cholesterol, and free fatty acids (lignoceric acid, C24:0, and palmitic acid, C16:0) were investigated by atomic force microscopy. Binary, ternary, and more complex lipid mixtures were examined. It was shown that small amounts of ceramide are miscible in a cholesterol-rich phase with the miscibility dependent upon the ceramide chain length. Two phases are formed at low and intermediate cholesterol concentrations. In the ceramidecholesterol monolayers, very small rectangular-shaped ceramide domains thought to be two-dimensional single ceramide crystals are formed. Small domains were also found in more complex mixtures where the fatty acid is miscible in the ceramide phase, although these domains were not as regular in shape. Binary ceramide-cholesterol as well as ternary ceramide-cholesterol-lignoceric acid bulk mixtures were also studied by X-ray diffraction. The bulk lipid miscibility is consistent with the monolayer results.