Deep tissue accumulation and systemic absorption is not the aim of local topical medication. Unfortunately, most of the disorders requiring such medication are found in the area of high permeation flux and in most cases, stratum corneum (SC) barrier resistance is decreased allowing their easier permeation in order to attain plasma levels that could be sufficient to elicit adverse reactions.1) There have been many attempts to develop a suitable approach to minimize their systemic absorption and the resulting adverse effects. More recently, there has been interest in agents that may be used in topical formulations to prevent the permeation of active ingredients or excipients.2) But, not all of these permeation retardants have yet been proven to be commercially viable and pharmaceutically suitable and in many cases, retardation has been achieved by compromising systemic and local toxicities of the retarders.3) Therefore, it would be an advantage if the systemic absorption of topical agents could be minimized irrespective of the sites or altered skin barrier function without the co-application of other chemical retarders.It is a well known fact that the permeability barrier properties of skin are mediated by a series of lipid multilayers segregated within SC interstices, and their hydrophobic nature and tortuous, extracellular localization restrict the transport of most compounds across the SC. 4) When this barrier is acutely perturbed by removing lipids with organic solvents, detergents, or tape stripping; a sequence of biological responses is initiated including accelerated epidermal lipid synthesis 5-7) that replenishes the skin lipid content which contribute to rapidly restore the skin barrier function.8) The specific requirement for epidermal lipids to create the barrier has also been delineated using the specific inhibitors of the rate-limiting enzymes of lipid synthesis, [9][10][11][12] and such selective inhibition of the synthesis of one or more of SC lipids increased SC permeability to epicutaneously applied drugs.13) Topical application of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA)-the rate limiting enzymes of fatty acid synthesis-immediately after barrier disruption inhibited the early stages of barrier recovery due to deletion of the target lipid from the extracellular membranes. But, the barrier recovery was normalized, and abnormalities in lamellar body and SC membrane structure were corrected by the co-application of palmitate (C16:0 fatty ester) with TOFA, indicating that the delay was due to the deficiency in bulk lipids.9-12) In addition, previous studies about the role of SC lipids as the determinant of the permeability barrier to the drug penetration reported an inverse correlation between the solute penetration and the total SC lipid weight (neither the number of cell layers nor the thickness of the SC correlated with the observed differences in permeability), 14,15) and showed that the enhanced epidermal lipid synthesis in SC or providing exogenous lipids resulted into a more efficient ba...
The aim was to evaluate the skin permeation and accumulation profiles of a highly lipophilic fatty ester using the combination of various permeation enhancing techniques to study the potential of highly lipophilic fatty esters as local topical agents. Permeation and accumulation profiles of ketorolac stearate (C18:0) were studied using solubility improved formulation, supersaturated solution of permeant in enhancer vehicle, lipophilic receptor solution, enhancer pretreatment, and the removal of stratum corneum and delipidization of skins. Impermeability and minimal skin accumulation of ketorolac stearate could delineate a preliminary possibility for designing safer topical agents without systemic absorption.
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