Liu Xiaowei, Zhao Ruihan, Xu Peijie, Qian Jianqiang, Zhang Peiyan, Xie Xudong, Ling Yong, Ge Qimin, Chen Yong
School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, China.
School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
Pharmaceutics. 2024 Dec 30;17(1):37. doi: 10.3390/pharmaceutics17010037.
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. A novel -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. The structure of ROP-ST was ascertained with clear H 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. The injectable oil-based depot formulation of -acyloxymethyl prodrug of ROP may provide a new opportunity of long-acting local analgesia for postoperative pain.
开发新型长效局部麻醉剂注射剂对于有效控制术后急性疼痛是必要的。本研究的目的是制备一种罗哌卡因（ROP）前药（硬脂酰氧基罗哌卡因，ROP-ST）的油基注射剂，并研究注射给药后的药代动力学和药效学。合成了一种新型的ROP -酰氧基甲基前药，即ROP-ST，并对其理化性质如log P、溶解度和稳定性进行了表征。制备了基于大豆油的ROP-ST长效注射剂，并采用“倒杯”法评估了ROP-ST的体外释放情况。在大鼠肌肉注射该制剂后，研究了其药代动力学特征和组织滞留特性。通过测量爪部退缩阈值，采用von Frey单丝试验评估镇痛效果。通过清晰的1H NMR归属和准确的质荷比确定了ROP-ST的结构。ROP-ST的高Log P值（9.16）表明其水溶性极低，但该前药在与血浆或肝酯酶接触时具有生物可降解性。在大鼠中肌肉注射ROP-ST油溶液可提供显著更长的平均驻留时间，且ROP没有非常明显的血浆峰。在大鼠术后疼痛模型中，将ROP-ST油溶液注射到右踝关节坐骨神经附近可有效控制术后疼痛至少72小时。ROP的-酰氧基甲基前药的油基注射长效制剂可能为术后疼痛的长效局部镇痛提供新的机会。
