A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia

Background: Currently available local anesthetics have relatively brief durations of action. An ultralong-acting local anesthetic would benefit patients with acute and chronic pain. The authors prepared and characterized a novel liposomal bupivacaine formulation using remote loading of bupivacaine along an ammonium sulfate gradient and assessed its efficacy in humans. Methods: A large multivesicular liposomal bupivacaine formulation was prepared by subjecting small unilamellar vesicles to successive freeze-and-thaw cycles. Bupivacaine hydrochloride was then remotely loaded into the liposomes along an ammonium sulfate gradient ([(NH4)2SO4)]intraliposome/ [(NH4)2SO4)]medium > 1,000). The liposomes were then characterized for size distribution; drug-to-phospholipid ratio; in vitro release profile at 4°, 21°, and 37°C; sterility; and pyrogenicity. Six subjects each received six intradermal injections in the lower back with 0.5 ml of 0.5, 1.0, and 2% liposomal bupivacaine; 0.5% standard bupivacaine; saline; and “empty” liposomes. Duration of analgesia was assessed using pinprick testing of the skin directly over the injection sites. Results were compared using the log-rank test. Results: The mean large multivesicular vesicle size was 2,439 544 nm, with a drug-to-phospholipid ratio of 1.8, fivefold greater than results previously reported. In vitro release was slowest at 4°C. The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively. Neither saline nor “empty” liposomes produced analgesia. Conclusions: This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain. SUBOPTIMAL treatment of pain results in needless human suffering, and pain-related physiologic derangements are associated with medical complications, may delay hospital discharge, and may increase healthcare costs. 1 Systemic analgesics, such as opioids, produce many untoward effects, including ileus, urinary retention, somnolence, pruritus, nausea, and vomiting. The fear of respiratory depression and of inducing addiction often inhibits healthcare providers from administering sufficient drug, resulting in unrelieved pain. Unlike systemic analgesics, local anesthetics reliably relieve pain while avoiding systemic side effects. However, currently available local anesthetics have relatively brief durations of action, so the analgesic benefit is evanescent. An ultralong-acting local anesthetic would be of great help in managing acute and chronic pain, but no such agent is yet available for clinical use. The search for the elusive ultralong-acting local anesthetic has aptly been likened to the search for the Holy Grail. 2