Abstract
To efficiently prolong analgesic effects, we developed osmotically balanced, large unilamellar liposomes (~ 6 μm in diameter) in which highly concentrated bupivacaine (up to 30 mg/mL) was encapsulated, and their sustained bupivacaine release was highly effective in relieving postoperative pain over 24 h in a rat model. Our reverse-phase evaporation method based on non-toxic alcohol, ethanol, enabled simple and cost-effective production of bupivacaine-loaded liposomes, of which osmotic pressure was readily balanced to improve the structural stability of the enlarged unilamellar liposomes along with extension of their shelf life (> a month). The in vitro release profile verified that the release duration of the bupivacaine-loaded liposomes extended up to 6 days. For the in vivo study, male Sprague–Dawley rats were used for the incisional pain model, simulating postoperative pain, and the mechanical withdrawal threshold (MWT) was measured using a von Frey filament. Compared to the control group that received intraplantar administration of normal saline, the group of liposomal bupivacaine showed that the initially increased MWT gradually decreased up to 24 h, and importantly, the analgesic effect of the liposomal bupivacaine was maintained 6 times longer than that of bupivacaine only, proving the potential of effective long-acting anesthetics.
Highlights
To efficiently prolong analgesic effects, we developed osmotically balanced, large unilamellar liposomes (~ 6 μm in diameter) in which highly concentrated bupivacaine was encapsulated, and their sustained bupivacaine release was highly effective in relieving postoperative pain over 24 h in a rat model
Unentrapped bupivacaine was washed with phosphate-buffered saline (PBS), and the bupivacaine-loaded liposomes were harvested via centrifugation
Postoperative pain control still depends on opioids, which have limited use owing to their adverse effects, including postoperative nausea and vomiting, respiratory depression, and urinary retention
Summary
To efficiently prolong analgesic effects, we developed osmotically balanced, large unilamellar liposomes (~ 6 μm in diameter) in which highly concentrated bupivacaine (up to 30 mg/mL) was encapsulated, and their sustained bupivacaine release was highly effective in relieving postoperative pain over 24 h in a rat model. Intravenous lidocaine infusion[1], incisional local anesthetic injection[5,6], and intraperitoneal instillation of local anesthetics[7] have efficiently decreased postoperative pain, nausea and vomiting, and opioid consumption These procedures have theoretical benefits; the decrease in pain intensity during surgery reduces the use of general anesthetics and the associated complications and hospital stay and increases patient satisfaction. Various methods, such as applying adjuvants (including dexamethasone and dexmedetomidine) and sustained release of local anesthetic, have been proposed and attempted to prolong the analgesic duration Among these methods, injectable liposomal suspension that encapsulates bupivacaine, called EXPAREL, has been proven to extend the acting duration of bupivacaine and approved for clinical use by the U.S FDA. A simpler and cheaper process is required to develop lipid-based, long-acting bupivacaine to overcome these drawbacks
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