James Ronald Lawter

Chiral β-blockers for transdermal delivery

Abstract An investigation of the role of drug chirality on transport through the skin was conducted. It was shown that the ratio of enantiomer to racemate flux through the skin can be predicted from thermal analysis data. The melting temperature-membrane transport (MTMT) concept and an equation for calculating the enantiomer / racemic flux ratio through the skin, which uses the thermal characteristics of the compound, are presented. The concept predicts a significant difference in skin transport rates in those cases where there are large differences in melting temperatures between the pure enantiomers and racemate. Thermal analysis was carried out for threeβ-blocker chiral molecules: atenolol, alprenolol and propranolol. Propranolol free base showed a difference between racemate and enantiomer melting points of 21°C. By using the MTMT model, the predicted ratio of enantiomer / racemic fluxes through the skin was found to be 3.2. This predicted ratio was confirmed in experiments conducted on Testskin™ and human cadaver skin with solutions of propranolol base isomers and racemic compound in propylene glycol. The 3-fold greater skin permeation of the S-(−)-enantiomer vs the racemic compound, along with the 2 orders of magnitude greater pharmacological effect reported for this isomer, make this enantiomer the candidate of choice for transdermal delivery of propranolol.