An injectable in situ gel formed by ropivacaine with small lipid molecules to achieve long-term postoperative analgesia.

Abstract

Although local anesthetics (LA) are non-addictive and effective in managing postoperative pain, their short-term effects limit their clinical utility. In this study, we constructed an in situ gel injection formulation with stearic acid-ropivacaine hydrophobic ion-pair (HIP) and glycerol monoglyceride (SA-ROP-GMS) for multiday postoperative pain management. As an in situ gel, SA-ROP-GMS avoids the burst release effect common to water-soluble small molecule drugs in liposomes and hydrogels. Meanwhile, the hydrophobic ion-pair formed by ropivacaine and stearic acid contributes to the gel's stabilization and slow-release properties. In vivo evaluation of mouse models of pain demonstrated that the formulation provided multiday analgesia. And the absence of systemic toxicity of SA-ROP-GMS was verified by histological and blood biochemical studies. This study demonstrated the safety and efficacy of an injectable ropivacaine formulation based on in situ gel. The materials used in SA-ROP-GMS are safe and easy to obtain, and the preparation process is simple and fast, providing a convenient and effective strategy for the development of single-dose long-acting local anesthetic products, which is of great significance for postoperative pain management. STATEMENT OF SIGNIFICANCE: More than 80% of patients experience severe postoperative pain, and poor pain control reduces recovery satisfaction while increasing the risk of chronic pain. In this study, we constructed an injectable in situ gel using all-small-molecule excipients for slow-release drug delivery for the first time. We designed a method to form a lipid drug coupling between ropivacaine and stearic acid (SA-ROP HIP), which was then combined with glyceryl monostearate (SA-ROP-GMS). SA-ROP-GMS maintained analgesia for nearly 10 days in a single dose, significantly improving ease of administration and patient compliance. In addition, the auxiliary ingredients used in this study are biocompatible and inexpensive. This formulation follows the trend of regional anesthesia and provides a new solution for postoperative pain management.