title: Iontophoretic transport kinetics of ketorolac in vitro and in vivo: demonstrating local enhanced topical drug delivery to muscle.
abstract: The objective of the study was to investigate the iontophoretic delivery kinetics of ketorolac (KT), a highly potent NSAID and peripherally-acting analgesic that is currently indicated to treat moderate to severe acute pain. It was envisaged that, depending on the amounts delivered, transdermal iontophoretic administration might have two distinct therapeutic applications: (i) more effective and faster local therapy with shorter onset times (e.g. to treat trauma-related pain/inflammation in muscle) or (ii) a non-parenteral, gastrointestinal tract sparing approach for systemic pain relief. The first part of the study investigated the effect of experimental conditions on KT iontophoresis using porcine and human skin in vitro. These results demonstrated that KT electrotransport was linearly dependent on current density - from 0.1875 to 0.5mA/cm(2) - (r(2)>0.99) and drug concentration - from 5 to 20mg/ml (r(2)>0.99). Iontophoretic permeation of KT from a 2% hydroxymethyl cellulose gel was comparable to that from an aqueous solution with equivalent drug loading (584.59±114.67 and 462.05±66.56μg/cm(2), respectively). Cumulative permeation (462.05±66.56 and 416.28±95.71μg/cm(2)) and steady state flux (106.72±11.70 and 94.28±15.47μg/cm(2)h), across porcine and human skin, were statistically equivalent confirming the validity of the model. Based on the results in vitro, it was decided to focus on topical rather than systemic applications of KT iontophoresis in vivo. Subsequent experiments, in male Wistar rats, investigated the local enhancement of KT delivery to muscle by iontophoresis. Drug biodistribution was assessed in skin, in the biceps femoris muscle beneath the site of iontophoresis ('treated muscle'; TM), in the contralateral muscle ('non-treated muscle'; NTM) and in plasma (P). Passive topical delivery and oral administration served as negative and positive controls, respectively. Iontophoretic administration for 30min was superior to passive topical delivery for 1h and resulted in statistically significant increases in KT levels in the skin (91.04±15.48 vs. 20.16±8.58μg/cm(2)), in the biceps femoris at the treatment site (TM; 6.74±3.80 vs. <LOQ), in the contralateral site (NTM; 1.26±0.54 vs. <LOQ) and in plasma (P; 8.58±2.37μg/ml vs. <LOD). In addition to increasing bioavailability, iontophoretic administration of KT showed clear selectivity for local delivery to the biceps femoris at the treatment site - the TM:NTM ratio was 5.26±1.45, and the TM:P and NTM:P ratios were 0.75±0.32 and 0.14±0.04, respectively. Furthermore, the post-iontophoretic concentration of KT in the 'treated' biceps femoris muscle and the muscle:plasma ratio were also superior to those following oral administration of a 4mg/kg dose (6.74±3.80 vs. 0.62±0.14μg/g and 0.75±0.32 vs. 0.14±0.03, respectively). In conclusion, the results demonstrate that iontophoresis of ketorolac enables local enhanced topical delivery to subjacent muscle; this may have clinical application in the treatment of localised inflammation and pain.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, 30 Quai Ernest Ansermet, 1211 Geneva, Switzerland; Faculdade de Ciências da Saúde, Universidade de Brasília, Campus Universitário Darcy Ribeiro, s/n 70910-900 Brasília, Brazil.
authors.forename: Taís
authors.initials: T
authors.lastname: Gratieri
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, 30 Quai Ernest Ansermet, 1211 Geneva, Switzerland; Faculty of Pharmacy, University of Barcelona, Joan XXIII, s/n 08028 Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Pujol-Bello
authors.affiliation: Faculdade de Ciências da Saúde, Universidade de Brasília, Campus Universitário Darcy Ribeiro, s/n 70910-900 Brasília, Brazil.
authors.forename: Guilherme M
authors.initials: GM
authors.lastname: Gelfuso
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, University of São Paulo, Av do Café, s/n 14040-903 Ribeirão Preto, Brazil.
authors.forename: Joel G
authors.initials: JG
authors.lastname: de Souza
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, University of São Paulo, Av do Café, s/n 14040-903 Ribeirão Preto, Brazil.
authors.forename: Renata F V
authors.initials: RF
authors.lastname: Lopez
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, 30 Quai Ernest Ansermet, 1211 Geneva, Switzerland. Electronic address: yogi.kalia@unige.ch.
authors.forename: Yogeshvar N
authors.initials: YN
authors.lastname: Kalia
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007478:Iontophoresis / Q000379:methods; D020910:Ketorolac / Q000008:administration & dosage* / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine; D014018:Tissue Distribution
chemical_list: D020910:Ketorolac
keywords: Iontophoresis; Ketorolac; Local enhanced effect; Muscle; NSAID; Topical delivery