Hexyl Aminolaevulinate Is a More Effective Topical Photosensitiser Precursor than Methyl Aminolaevulinate and 5-Aminolaevulinic Acids When Applied in Equimolar Doses

Aminolaevulinic acid (ALA) is known to poorly penetrate into thick lesions, such as nodular basal cell carcinomas. Short chain ALA esters, possessing increased lipophilicity relative to their hydrophilic parent, have previously been shown to be highly efficient at inducing protoporphyrin IX (PplX) production in cell culture, at equimolar concentrations. In contrast, in vitro skin permeation and in vivo animal studies, which up to now have compared prodrugs on a % w/w basis, have failed to demonstrate such benefits. For the first time, equimolar concentrations of ALA, methyl-ALA (m-ALA) and hexyl-ALA (h-ALA) have been incorporated into an o/w cream preparation. In vitro penetration studies into excised porcine skin revealed that increased levels of h-ALA, compared to ALA and m-ALA were found in the upper skin layers, at all drug loadings studied. Topical application of the formulations to nude murine skin in vivo, revealed that creams containing h-ALA induced significantly higher levels of peak PplX fluorescence (F_max = 289.0) at low concentrations compared to m-ALA (F_max = 159.2) and ALA (F_max = 191.9). Importantly, this study indicates that when compared on an equimolar basis, h-ALA has improved skin penetration, leading to enhanced PpIX production compared to the parent drug and m-ALA. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3486–3498, 2010