intemational journal of pharmaceutics ELSEV ] ER International Journal of Pharmaceutics 131 (1996) 117 129 I A lamellar matrix model for stratum corneum intercellular l~pids. II. Effect of geometry of the stratum corneum on permeation of model drugs 5-fluorouracil and oestradiol Hamid R. Moghimi, Adrian C. Williams, Brian W. Barry* Po.~tgraduate Studies in Pharmaceutical Technology, The School <~f Pharmacy, Unirersity ~?! BraEtli,'d, Brad/oral, BD 7 IDP. UK Received 26 May 1995: accepted 12 July 1995 Abstract The principal barrier to transdermal delivery of most drugs is the lamellar intercellular lipid domain of the stratum corneum (SC). The low permeability of SC in comparison to other lipid barriers is in part due to its geometry. Here, effect of geometry of the SC on permeation of 5-fluorouracil (5-FU) a model hydrophilic drug - and oestradiol (OE) -- a model lipophilic drug -- was investigated using a lamellar model matrix for SC intercellular lipids. Release studies at 32°C showed that the diffusion coefficients of 5-FU and OE in the matrix are approximately 6000-7000- and 60-260-times greater, respectively, than apparent human epidermis values, in good agreement with theoretical considerations. Release studies from 13 to 44°C revealed that 5-FU has a maximum diffusion coefficient around the main transition temperature of the matrix (35°C) in agreement with other lamellar systems reported in the literature. The diffusional activation energy of 5-FU in the matrix was 27.8 kcal tool ~ which correlates well with human epidermal data. Release experiments were then combined with permeation studies and the permeability of model drugs through the SC at 32°C was predicted from matrix data. The predicted permeability coefficients of 5-FU (5.5-18 × 10 5 cm h ~) and OE (0.07-0.24 z 10 3 cm h 1) were in agreement with human epidermis data. Our results show the effect of the SC morphology on the percutaneous absorption of drugs and illustrate that 5-FU and OE permeate the SC through intercellular lipids. Keyword~': 5-Fluorouracil; Oestradiol; Model human stratum corneum lipid: Diffusion coefficient: Permeability coefficient: Activation energy I. Introduction Before any topically applied drug can act either locally or systemically, it must permeate the bar- * Corresponding author. Tel.: + 44 1274 384761; Fax: + 44 1274 384769. rier of the skin, which is usually located at its outermost layer, the stratum corneum (Berenson and Burch, 1951). The stratum corneum (SC) is a multilayered wall-like structure in which keratin-rich cor- neocytes are embedded in an intercellular lipid- rich matrix (Fig. 1). In this two compartment 0378-5173,96515.00 cc~ 1996 Elsevier Science B.V. All rights reserved SSDI 0378-5173(95)04307-V