Evaluation of skin permeation and accumulation profiles of ketorolac fatty esters

• Published in: Journal of pharmacy & pharmaceutical sciences Vol. 10; no. 3; p. 278
• Main Authors: Bhandari, Krishna Hari, Newa, Madhuri, Yoon, Sung Il, Kim, Jung Sun, Kim, Dae-Duk, Kim, Jung Ae, Yoo, Bong Kyo, Woo, Jong-Soo, Lyoo, Won Seok, Choi, Jun Young, Lim, Hyun Tae, Lee, Jae H, Choi, Han Gon, Yong, Chul Soon
• Format: Journal Article
• Language: English
• Published: Canada 2007
• Subjects: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Chromatography, High Pressure Liquid; Drug Stability; Esters - pharmacokinetics; Hydrogen-Ion Concentration; Hydrolysis; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Ketorolac - analogs & derivatives; Ketorolac - chemical synthesis; Ketorolac - chemistry; Ketorolac - pharmacokinetics; Mice; Permeability; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Skin - metabolism; Skin Absorption; Structure-Activity Relationship
• ISSN: 1482-1826

Classic penetration enhancement/retardation methods for improved dermal drug delivery primarily focus on co-applied chemicals aided alterations in skin accumulation/permeation profile, and in many cases, this has been achieved by compromising the systemic absorption/toxicities of penetrant/enhancer/retarder. In this study, higher dermal accumulation without systemic absorption of ketorolac and its fatty esters (esters) will be achieved by synthesizing lipophilic fatty ester soft prodrugs of ketorolac. Ketorolac decenoate (C10:1), dodecenoate (C12:1) and palmitoleate (C16:1) were synthesized and evaluated for their lipophilicity, enzymatic hydrolysis, chemical stabilities, and skin permeation and accumulation profiles using the combination of common permeation enhancing techniques such as the use of lipophilic receptor solution, enhancer pretreatment of skins, removal of stratum corneum and delipidization of skins etc. Esters were highly lipophilic, chemically stable, enzymatically unstable in hairless mouse skin/liver homogenates and impermeable into the receptor solution. Higher dermal accumulation, absence of skin permeation, relative enzymatic stability in whole skins during permeation study and the pharmaceutical stability of esters could delineate a preliminary possibility for designing safer dermal agents with minimum potential for systemic absorption without the co-application of permeation enhancers or retarders.