Ketorolac amide prodrugs for transdermal delivery: stability and in vitro rat skin permeation studies

Abstract

Various amide prodrugs of ketorolac were synthesized and their rat skin permeation characteristics were determined. The solubility of the prodrugs in propylene glycol (PG) was determined at 37 degrees C while lipophilicity was obtained as 1-octanol/water partition coefficient (log P) and capacity factor (k') using HPLC. Stability of the prodrugs in rat skin homogenate, plasma and liver homogenate was investigated to observe the enzymatic degradation. Rat skin permeation characteristics of the prodrugs saturated in PG were investigated using the Keshary-Chien permeation system at 37 degrees C. The log P value of the prodrugs increased up to 4.28 with the addition of various alkyl chain to ketorolac which has a log P of 1.04. Good linear relationship between log P and capacity factor was observed (r(2) = 0.89). Amide prodrugs were converted to ketorolac only in rat liver homogenate. However, the skin permeation rate of amide prodrugs did not significantly increase, probably due to their low aqueous solubility. Chemical modification of the ketorolac amide prodrug and/or the selection of proper vehicle to increase aqueous solubility would be necessary for an effective transdermal delivery of ketorolac. (c) 2005 Elsevier B.V. All rights reserved.