The aim was to prepare intravenous fat emulsions (IFEs) of ketorolac (KTL) ester prodrugs and to investigate the pharmacokinetics and pharmacodynamics of these formulations. Three prodrugs of KTL (KTL-IS, KTL-AX and KTL-BT) were synthesized as a means to increase the lipid solubility of KTL. All KTL prodrugs with higher Log P values presented increased tendency to partition into a blank IFE using extemporaneous addition method - the encapsulation efficiency of KTL-IS IFE and KTL-BT IFE was more than 97%. The particle sizes and zeta potentials of these two formulations were comparable to that of the blank IFE. PK studies in rabbits showed significant larger AUC0-8h (646.969 ± 154.326 mg/L•h-1 for KTL-IS IFE and 559.426 ± 103.057 mg/L•h-1 for KTL-BT IFE) than that of ketorolac tromethamine (KTL-T) injectable (286.968 ± 63.045 mg/L•h-1) and approximately 2-fold increases in the elimination t1/2 over KTL-T. In a rat postoperative pain model, the paw withdrawal thresholds and the paw withdrawal latency after I.V. KTL prodrug IFEs were significantly higher than that after I.V. KTL-T at 3~4 h. Effective controlling of acute postoperative pain in a longer duration can be achieved by using non-addictive ketorolac derivatives intraveneous emulsions.
Keywords: Intravenous fat emulsion; Ketorolac; Pharmacodynamics; Pharmacokinetics; Prodrug.
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