International Journal of Pharmaceutics, 98 (1993) 173-179 0 1993 Elsevier Science Publishers B.V. All rights reserved 0378-5173/93/$06.00 173 IJP 03257 Azone@ and the formation of reversed mono- and bicontinuous lipid-water phases Johan Engblom and Sven Engstrijm Food Technology, Chemical Center, POB 124, S-221 00 Lund (Sweden) (Received 1 February 1993) (Modified version received 1.5March 1993) (Accepted 25 March 1993) Key words: Azone; Cubic phase; Hexagonal phase; Phase diagram; Skin lipid; Transdermal penetration Summary The interfacial properties of the skin penetration enhancer Azone@ were investigated as well as the effect the substance has on the phase behaviour of two bilayer forming lipid-water systems, i.e., lecithin-water and monoolein-water. Interfacial studies revealed a change in Azone packing on the water surface as the area per molecule decreased below 62 AZ. It is suggested that this change reflects a situation where the polar amide bond of Azone loses its direct contact with water and the molecule adopts a straighter conformation normal to the surface. Phase studies show that Azone promotes the formation of reversed types of lipid-water phases such as bicontinuous cubic, reversed hexagonal and reversed micellar phases. From this phase behaviour and recent literature data, we suggest that the formation of reversed types of phases should be considered as one important mechanism behind the increased skin penetration of drugs caused by lipophilic substances such as Azone. Introduction Transdermal administration of drugs suffers from the fact that the stratum corneum consti- tutes such an effective barrier. One way to over- come this problem is by using so-called penetra- tion enhancers. Several types of penetration en- hancers have been discussed in the literature, such as solvents (ethanol, propylene glycol) and amphiphilic substances (detergents, fatty acids, monoglycerides). One of the most extensively studied molecules in this respect is Azone@ (Fig. Correspondence to: J. Engblom, Food Technology, Chemical Center, POB 124, S-221 00 Lund, Sweden. 11, and it has been shown to increase the penetra- tion of drugs, both polar and non-polar, through skin (Wiechers and De Zeeuw, 1990; Wiechers, 1992). Even though Azone has been used in many studies, little has been discussed as to its and similar enhancer’s effects at a molecular level (Barry, 1987a,b; Potts et al., 1991; Schiickler et al., 1993). In this work, the inter-facial properties of Azone were investigated, as well as the effect the molecule has on two bilayer forming lipid-water systems, lecithin-water and monoolein-water. These model systems are not directly applicable to stratum corneum lipids, which have a unique composition, particularly with respect to the low concentration of phospholipids and the presence