Synthesis, physicochemical properties and in vitro permeation studies of new ketorolac ester derivatives

Curr Drug Deliv. 2007 Jul;4(3):205-10. doi: 10.2174/156720107781023893.

Abstract

Six new 1-alkylazacycloalkan-2-one esters of ketorolac (1-6) were synthesized and evaluated as potential dermal prodrugs. In vitro experiments were carried out to evaluate their chemical and enzymatic stability and permeation through excised human skin. Furthermore, partition coefficients n-octanol-water of ketorolac and its esters were determined to obtain information about their lipophilicity. Esters 1-6 showed increased lipophilicity compared to the parent drug, good stability in phosphate buffer pH 7.4, and were readily hydrolyzed in human plasma. Results from in vitro percutaneous absorption studies showed that, among all esters synthesized, only for esters 2 and 4 did a higher cumulative amount of drug penetrate through the skin, compared with that obtained after topical application of ketorolac.

MeSH terms

  • Administration, Cutaneous
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics*
  • Aza Compounds
  • Drug Stability
  • Esters
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • In Vitro Techniques
  • Ketorolac / analogs & derivatives
  • Ketorolac / chemical synthesis*
  • Ketorolac / chemistry
  • Ketorolac / pharmacokinetics*
  • Permeability
  • Prodrugs
  • Skin / drug effects
  • Skin / metabolism
  • Skin Absorption
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Aza Compounds
  • Esters
  • Prodrugs
  • Ketorolac