Synthesis of Piperazinylalkyl Ester Prodrugs of Ketorolac and their In Vitro Evaluation for Transdermal Delivery

Abstract

Ketorolac, an NSAID, has low intrinsic permeation capacity through the skin. In this work, seven piperazinylalkyl ester prodrugs of ketorolac were synthesized to enhance its skin permeation. The chemical hydrolysis and the stability in human serum at 37°C were investigated in buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs were chemically more stable at pH 5.0 than at pH 7.4 with prodrug 8 being the most stable (t_1/2 = 119.75 h and 11.97 h at pH 5 and 7.4, respectively). The prodrugs' t_1/2 in human serum ranged from 0.79 to 3.92 min. The prodrugs' aqueous solubility was measured in buffer solution at pH 5.0 and 7.4 and Log P_app was measured by partitioning between buffer solution (pH 5.0 and 7.4) and n-octanol. The prodrugs were more lipophilic than ketorolac at pH 7.4. Skin permeation of ketorolac and prodrug 8, the most stable chemically, through rat skin was studied at pH 5.0 and 7.4. Prodrug 8 enhanced permeation by 1.56- and 11.39-fold at pH 5 and 7.4, respectively. This is attributed to higher lipophilicity at pH 7.4 and higher aqueous solubility at pH 5 compared to ketorolac.

Keywords:

• Ketorolac
• prodrug
• piperazine
• transdermal delivery
• synthesis

ACKNOWLEDGMENTS

This work was funded by a grant from the Deanship of Research, Jordan University of Science and Technology. We thank Professor Jarkko Rautio for his help and support, Mr. Farouq Al-Zoughoul for his tremendous help with the HPLC analysis, and Dr. Mutasem Taha for his valuable suggestions. We also thank Al-Hikma Pharmaceuticals for providing ketorolac raw material.