Synthesis and evaluation of Ketorolac ester prodrugs for transdermal delivery

• Published in: Journal of pharmaceutical sciences Vol. 92; no. 5; pp. 1008 - 1017
• Main Authors: Doh, Hea-Jeong, Cho, Won-Jea, Yong, Chul-Soon, Choi, Han-Gon, Kim, Jung Sun, Lee, Chi-Ho, Kim, Dae-Duk
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.05.2003; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Administration, Cutaneous; alkyl ester prodrug; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cyclooxygenase Inhibitors - administration & dosage; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - pharmacokinetics; Drug Stability; Esters; In Vitro Techniques; ketorolac; Ketorolac - administration & dosage; Ketorolac - chemical synthesis; Ketorolac - pharmacokinetics; Male; Medical sciences; Permeability; Pharmacology. Drug treatments; Prodrugs - administration & dosage; Prodrugs - chemical synthesis; Prodrugs - pharmacokinetics; Rats; Rats, Sprague-Dawley; Skin Absorption; Solubility; Structure-Activity Relationship; transdermal delivery; ketorolac; transdermal delivery; alkyl ester prodrug; Transdermal system; Rat; Ketorolac; Rodentia; Permeation; Solubility; Lipophily; Partition coefficient; Permeability; Prodrug; Non steroidal antiinflammatory agent; Ester; Vertebrata; Mammalia; Animal; Skin; Property structure relationship; Propanediol; Chemical synthesis
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10353

Alkyl esters of ketorolac were synthesized as potential prodrugs for transdermal delivery and evaluated to determine the relationship between their skin permeation characteristics and their physicochemical properties. Solubility of the prodrugs in various vehicles was determined at room temperature while lipophilicity was obtained as 1-octanol/water partition coefficients (logP) and capacity factors (k′) using HPLC. Metabolism of the prodrugs to ketorolac was studied both in rat skin homogenate and in plasma. Rat skin permeation characteristics of the prodrugs saturated in propylene glycol were investigated using the Keshary-Chien permeation system at 37°C. An increase in logP and capacity factor values of the prodrugs were observed in proportion to their alkyl chain length. Good linear relationship between the logP values and capacity factor was observed (r2=0.92). Prodrugs were rapidly degraded to ketorolac both in the skin homogenate and in plasma following a first-order kinetics. To determine accurate amounts of prodrug permeated, both the prodrug and parent drug concentration in the receptor solution were determined in mole units. The skin permeation rate of the alkyl ester prodrugs was significantly higher with a shorter lag time than that of ketorolac. The permeation rate of ketorolac reached maximum in its 1-propyl ester form as 46.61 nmol/cm2/h, and a parabolic relationship was observed between the permeation rate and the logP values of the prodrugs. Alkyl ester prodrugs of ketorolac having optimum lipophilicity could improve the transdermal delivery of ketorolac.