Influence of excipients on two elements of the stratum corneum barrier: Intercellular lipids and epidermal tight junctions

Abstract

The skin is one of the most important organs in the human body due to its crucial role as an interface between the internal and external environments. Homeostasis and permeability of the skin barrier are regulated by a combination of several factors, biochemical and structural, in response to the external influences. The permeability barrier function is essentially fulfilled by the final product of epidermal differentiation stratum corneum (SC). Efficiency of the SC barrier depends on the composition and the correct arrangement of its principal elements: (1) corneocytes linked by corneodesmosomes and (2) intercellular lipids covalently bound to the cross-linked corneocyte envelopes and organized in a multilayered extracellular matrix. Epidermal tight junctions (TJ) present in the granular layer may constitute an additional permeability barrier and play a role during the SC barrier formation. Cross-linked TJ-like structures persisting in the SC participate in the regulation of desquamation and may also influence barrier function. Most of the excipients, e.g., solvents, emulsifiers/detergents, moisturizers, and penetration enhancers, interact with the skin barrier. The latter are designed to modify the intercellular SC domains in order to reduce resistance of barrier lipid bilayers. Several mechanisms of action are individualized (extraction, fluidization, or disorganization of the intercellular lipid matrix) and may intervene separately, depending on the nature of the excipient, although combined actions are most frequently encountered. Excipients can also interact with the extracellular loops or the membrane domain of TJ, causing internalization of the TJ strands and loss of the additional TJ barrier. In the longer term, this effect may also impact the SC formation and function.