Sustained release of levobupivacaine from temperature-sensitive injectable hydrogel for long-term local anesthesia in postoperative pain management

Postoperative pain is a major concern for most of the surgical patients, and an inadequate postoperative pain control may cause a series of complications. With an effective pain control and lesser side effects, local anesthetics are preferred for use in postoperative pain management. However, the action duration of current local anesthetics is too short to meet the requirements of postoperative analgesia. In this study, an injectable levobupivacaine (LB)-loaded thermo-sensitive hydrogel system based on biodegradable poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide) (PLEL) was developed for long-acting local anesthetic, in which the soluble charged cation form of LB (LB HCl) was partly alkalified to the poorly soluble base form (LB base). This hybrid LB loaded PLEL system (hLB/PLEL) is a free flowable liquid at room temperature and changes into a semi-solid hydrogel once injection in response to the physiological temperature. Then, the dissolved LB HCl could release firstly from the hydrogel contributing to a quick work, and the insoluble LB base dissolved and released gradually as the decrease of the pH during the biodegradation of PLEL hydrogel, resulting in a long-term LB release in local. The drug release behavior, pharmacokinetic, and biocompatibility of the thermo-sensitive hLB/PLEL were studied in vitro and in vivo. The anesthetic effects of hLB/PLEL system were evaluated in the rat models of sciatic nerve block, subcutaneous infiltration anesthesia and postoperative pain as well. This hLB/PLEL system generated a significantly prolonged analgesic effect in rat models, which produced approximately 7 times longer duration than 0.75% LB HCl and effectively relieved the spontaneous pain for 3 days. In general, the presented hLB/PLEL system can not only achieve a fast-acting but also sustainably release LB to block the nerve and significantly extend the effect of local analgesia, which means a promising candidate for long-acting postoperative pain management.