CHIRAL BETA-BLOCKERS FOR TRANSDERMAL DELIVERY

An investigation of the role of drug chirality on transport through th e skin was conducted. It was shown that the ratio of enantiomer to rac emate flux through the skin can be predicted from thermal analysis dat a. The melting temperature-membrane transport (MTMT) concept and an eq uation for calculating the enantiomer/racemic flux ratio through the s kin, which uses the thermal characteristics of the compound, are prese nted. The concept predicts a significant difference in skin transport rates in those cases where there are large differences in melting temp eratures between the pure enantiomers and racemate. Thermal analysis w as carried out for three beta-blocker chiral molecules: atenolol, alpr enolol and propranolol. Propranolol free base showed a difference betw een racemate and enantiomer melting points of 21 degrees C. By using t he MTMT model, the predicted ratio of enantiomer/racemic fluxes throug h the skin was found to be 3.2. This predicted ratio was confirmed in experiments conducted on Testskin(TM) and human cadaver skin with solu tions of propranolol base isomers and racemic compound in propylene gl ycol. The 3-fold greater skin permeation of the S-(-)-enantiomer vs th e racemic compound, along with the 2 orders of magnitude greater pharm acological effect reported for this isomer, make this enantiomer the c andidate of choice for transdermal delivery of propranolol.