PERMEABILITY OF PURE ENANTIOMERS OF KETOROLAC THROUGH HUMAN CADAVER SKIN

The permeability of pure enantiomers of ketorolac acid, a potent non-n arcotic analgesic, through human cadaver skin was evaluated. The melti ng temperature of each enantiomer was 20 degrees C higher than that of the racemic compound. As expected, the solubility of the racemic comp ound in water and isopropyl alcohol/water/isopropyl myristate (IPA/wat er/lPM, 50:50:1.5) was roughly 2 times higher than that of the enantio mers, The permeability of the enantiomers through poly(ethylenevinyl a cetate) (EVA) synthetic membrane and human cadaver skin was determined with a side-by-side diffusion cell. The skin flux of the racemic comp ound was about 1.5 times higher than those of the enantiomers. On the other hand, no significant differences in the intrinsic permeability c oefficient of the racemic compound and the enantiomers in the EVA memb rane and human cadaver skin was observed. An excellent agreement betwe en the predicted and experimental flux ratio of the racemic compound a nd enantiomer in the EVA membrane and cadaver skin was observed. The I PA/water/lPM (50:50:1.5) provided the highest in vitro skin flux of th e S enantiomer among the three vehicle formulations studied. The skin flux of the active pure S enantiomer was ca. 34% higher than that of t he impure S enantiomer in the racemic mixture. Furthermore, about 14% intersubject variability in the in vitro skin flux of the S enantiomer was observed. The required skin flux of the S enantiomer as calculate d from the pharmacokinetic parameters was about 32 mu g/cm(2)/h from a 25 cm(2) transdermal patch, which was readily achievable from the IPA /water/lPM (50:50:1.5) ternary vehicle system.