Permeability of pure enantiomers of ketorolac through human cadaver skin.
The permeability of pure enantiomers of ketorolac acid, a potent non-narcotic analgesic, through human cadaver skin was evaluated. The melting temperature of each enantiomer was 20 degrees C higher than that of the racemic compound. As expected, the solubility of the racemic compound in water and isopropyl alcohol/water/isopropyl myristate (IPA/water/IPM, 50:50:1.5) was roughly 2 times higher than that of the enantiomers. The permeability of the enantiomers through poly(ethylenevinyl acetate) (EVA) synthetic membrane and human cadaver skin was determined with a side-by-side diffusion cell. The skin flux of the racemic compound was about 1.5 times higher than those of the enantiomers. On the other hand, no significant differences in the intrinsic permeability coefficient of the racemic compound and the enantiomers in the EVA membrane and human cadaver skin was observed. An excellent agreement between the predicted and experimental flux ratio of the racemic compound and enantiomer in the EVA membrane and cadaver skin was observed. The IPA/water/IPM (50:50:1.5) provided the highest in vitro skin flux of the S enantiomer among the three vehicle formulations studied. The skin flux of the active pure S enantiomer was ca. 34% higher than that of the 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 calculated from the pharmacokinetic parameters was about 32 micrograms/cm2/h from a 25 cm2 transdermal patch, which was readily achievable from the IPA/water/IPM (50:50:1.5) ternary vehicle system.
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D066298:In Vitro Techniques; D020910:Ketorolac; D008566:Membranes / Q000378:metabolism; D010539:Permeability; D012869:Skin Absorption / Q000502:physiology*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014046:Tolmetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014046:Tolmetin; D020910:Ketorolac