Predicting skin permeability of neutral species and ionic species

The skin forms an extremely efficient barrier between internal organs and the external environ-ment, but also provides an attractive administration route. Skin permeability (as log Kp) is a critical parameter for estimating transdermal delivery of chemicals in contact with the skin in pharma-ceutics and cosmetics. Given the fact that measurement of log Kp is quite time-consuming and laborious, various mathematical models based on understanding of the fundamental mechanisms underlying skin permeation have been proposed to estimate the otherwise unavailable log Kp. However, there has been no model up to now for prediction of log Kp of ionic species. In order to solve this problem, we proposed and investigated two potential solutions in this study: one is the Potts-Guy model on the basis of partition parameters in liposome-water systems and molecular volume (MV), and the other is the extended linear free-energy relationship (LFER), which can be used to predict biological membrane permeability of ionic species. In this study, the compounds with a broad structural diversity were selected and their reten-tion factors were measured in liposome electrokinetic chromatography (LEKC), where cerasomes composed mainly of the stratum corneum (SC) lipids and liposomes (POPC80/PS20) were used as the pseudo-stationary phases, respectively. These two negatively charged membrane systems and a neutral immobilized artificial membrane (IAM) system from literature as a surrogate for neutral liposome-water partition were compared with various organic solvent-water partitioning systems using LFERs. It was observed that liposomes display a greatly different chemical environment from those of organic solvents, and no organic solvent can thus provide a general model for lipo-somes in partition processes. What is more, the correlation between the skin-water partition and organic solvent/liposome-water partitions was also investigated. The results show that cerasome exhibits a better chemical similarity with the skin as compared to phospholipid liposomes and all organic solvents. Further, the cerasome-water partition correlates better to skin permeation than other liposome-water partitions and microsomal binding. This is probably due to the unique struc-tures of ceramides that occur in SC and consequently in cerasomes. The log Kp values of nine acid anions and nine base cations were measured in this study. The data were used to construct a LFER equation for skin permeation of neutral species and ionic spe-cies, together with experimental log Kp for both species in literature. The resulting equation, with a R2 value of 0.861 and a SD value of 0.462 log units, can be used to predict log Kp for neutral species and ionic species, as well as partly ionized solutes. The predicted values for the passive permeation of the sodium ion and the tetraethylammonium ion are in good accord with the exper-imental values. It was found that neutral acids and bases are much more permeable than their ion-ized forms, and that the ratio depends on the actual structure. Using the cerasome-water partition as a substitute for the skin-water partition, the effect of ionization of solutes on skin permeation was separated to those on partition and diffusion processes. The poor permeability of ionic species is largely due to slow diffusion through the SC, especially for base cations. In addition, the Potts-Guy model based on the retention factors obtained in cerasome electro-kinetic chromatography (EKC) and MV was discussed. It was found that such a model cannot be applied to predict log Kp for ionic species because MV fails to account for their diffusion through the SC, even empirically. In conclusion, LFER is a very useful tool for predicting skin permeation, not only for neutral species but also for ionic species, whereas the Potts-Guy model may be useful for neutral species but is not applicable for ionic species.