An Injectable Oil-Based Depot Formulation of N-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia:...

Objectives: The development of novel long-acting injectables for local anesthetics is necessary to effectively manage the acute postoperative pain. The aim of this study was to prepare an injectable oil-based formulation of ropivacaine (ROP) prodrug (ropivacaine stearoxil, ROP-ST) and to investigate the pharmacokinetics and pharmacodynamics after injectable administration. Methods: A novel N-acyloxymethyl prodrug of ROP, i.e., ROP-ST, was synthesized and its physicochemical properties such as log P, solubility and stability characterized. A soybean oil-based depot of ROP-ST was prepared, and the in-vitro release of ROP-ST was evaluated using an "inverted-cup" method. Pharmacokinetic profiles and tissue retention properties were investigated after intramuscular administration of the formulation in rats. The analgesic efficacy was assessed via a von Frey monofilaments test by measuring the paw withdrawal thresholds. Results: The structure of ROP-ST was ascertained with clear ¹H NMR assignment and accurate mass-to-charge ratio. The high Log P value of ROP-ST (9.16) demonstrated extremely low aqueous solubility, but the prodrug is biolabile when in contact with plasma or liver esterase. Intramuscular injection of ROP-ST oil solution in rats provided a significantly higher mean residence time without a very clear plasma peak of ROP. In a postoperative pain model of rats, the injection of ROP-ST oil solution into the vicinity of the sciatic nerve in the right ankle effectively controlled the postoperative pain for at least 72 h. Conclusions: The injectable oil-based depot formulation of N-acyloxymethyl prodrug of ROP may provide a new opportunity of long-acting local analgesia for postoperative pain.