Percutaneous permeation of enantiomers and racemates of chiral drugs and prediction of their flux ratios using thermal data: A pharmaceutical perspective

Abstract

Albeit pharmacological, pharmacokinetic, and toxicological differences between enantiomeric pairs or between the pure enantiomers and racemate of chiral drugs are known to exist for decades, we are just beginning to realize that there are apparent differences between these species with respect to their percutaneous permeation as well. Such differences in permeation are likely to be enhanced when chiral drugs are formulated with chiral excipients, necessitating a careful assessment of the effect of formulation excipients on the permeation as well as the overall therapeutic outcomes. The in vitro transport data from the preclinical investigations, using laboratory animal models and/or in vitro cell culture systems, must be carefully validated in vivo as there are differences between these models and the human skin. Mathematical models such as MTMT that utilize the interdependence of certain physicochemical characteristics and percutaneous permeability have a predictive value in assessing the flux behavior of enantiomers and racemates.

Quiralidade: a outra face dos medicamentos: conceituação e contextualização

“…Contudo, se utilizarmos esse medicamento quiral para uma aplicação tópica, será que o enantiômero ativo terá a mesma eficiência se comparado ao outro enantiômero ou à forma racêmica? Estudos vêm demonstrando que a quiralidade afeta o transporte epidérmico dos medicamentos 96 . Será que as agências reguladoras irão requerer mais estudos sobre esse medicamento quiral, que é agora aplicado de modo tópico?…”

An Investigation into the Influence of Counterion on the RS‐Propranolol and S‐Propranolol Skin Permeability

“…Indeed, other than the biological activity of the single enantiomer, the chirality of the skin has to be taken into account, because differential binding of enantiomers to keratin or interactions with ceramides may give rise to differences in the permeation profiles of the enantiomers 1. In addition to the intrinsic stereoselectivity of the skin for enantiomers, extrinsic factors such as differences in physicochemical properties between enantiomers and racemate may also be implicated in enantioselective permeation 2, 3. It has been described that the stereoisomer of chiral compounds with a lower melting point than their racemates have usually higher solubility and thermodynamic activity and, consequently, greater flux through the skin than those of the racemates 4.…”