title: 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 degrees 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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan. drqandil@just.edu.jo
authors.forename: Amjad
authors.initials: A
authors.lastname: Qandil
authors.forename: Soraya
authors.initials: S
authors.lastname: Al-Nabulsi
authors.forename: Bashar
authors.initials: B
authors.lastname: Al-Taani
authors.forename: Bassam
authors.initials: B
authors.lastname: Tashtoush
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D020910:Ketorolac / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D010539:Permeability; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism*; D012995:Solubility
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010879:Piperazines; D011355:Prodrugs; D020910:Ketorolac