Effective management of acute postoperative pain using intravenous emulsions of novel ketorolac prodrugs: in vitro and in vivo evaluations

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. [Display omitted]