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This is the first report of the delivery of carbenoxolone through the skin.A rational development pathway for the optimal formulation of this compound is described.New data indicates different mechanisms of interaction of penetration enhancers with the skin which has not been observed previously.Carbenoxolone (CEX), a semi-synthetic derivative of glycyrrhetinic acid, has previously been used as a disodium salt for the management of dyspepsia and peptic ulcer because of its anti-inflammatory properties. Although glycyrrhetinic acid is available in pharmaceutical and personal care products for skin care, the topical use of the free acid form of CEX, has not previously been reported. In this work we investigated the percutaneous penetration of CEX. Solubility and permeability studies were conducted using a range of solvents or skin permeation enhancers (SPEs) commonly used for skin delivery. Binary combinations of dimethyl isosorbide (DMI) and Transcutol™ (TC) with isopropyl myristate (IPM) were effective in promoting skin permeation of CEX although individual solvents were not. Alternative fatty acid esters to IPM were subsequently investigated with the most promising formulation consisting of TC and propylene glycol laurate (PGL). Interestingly, propylene glycol monolaurate (PGML) did not demonstrate comparable efficacy when combined with TC. A ternary formulation consisting of TC, PGL and IPM demonstrated the best permeation enhancement of CEX compared with all other vehicles. The findings confirm (i) the feasibility of promoting CEX penetration across the skin (ii) the synergistic effect of combinations of solvents and SPEs on dermal and transdermal delivery (iii) the necessity for more fundamental studies to explain the differential effects of fatty acid esters on the skin barrier.