title: Evaluation of skin permeation and accumulation profiles of ketorolac fatty esters.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  Esters were highly lipophilic, chemically stable, enzymatically unstable in hairless mouse skin/liver homogenates and impermeable into the receptor solution.
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, South Korea.
authors.forename: Krishna Hari
authors.initials: KH
authors.lastname: Bhandari
authors.forename: Madhuri
authors.initials: M
authors.lastname: Newa
authors.forename: Sung Il
authors.initials: SI
authors.lastname: Yoon
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Jung Ae
authors.initials: JA
authors.lastname: Kim
authors.forename: Bong Kyo
authors.initials: BK
authors.lastname: Yoo
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Woo
authors.forename: Won Seok
authors.initials: WS
authors.lastname: Lyoo
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Lim
authors.forename: Jae H
authors.initials: JH
authors.lastname: Lee
authors.forename: Han Gon
authors.initials: HG
authors.lastname: Choi
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004952:Esters / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D020910:Ketorolac / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D011355:Prodrugs; D020910:Ketorolac