TY - JOUR
T1 - A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia
AU - Grant, Gilbert J.
AU - Barenholz, Yechezkel
AU - Bolotin, Elijah M.
AU - Bansinath, Mylarrao
AU - Turndorf, Herman
AU - Piskoun, Boris
AU - Davidson, Elyad M.
PY - 2004/7
Y1 - 2004/7
N2 - 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 ([(NH 4) 2SO 4)] intraliposome/[(NH 4) 2SO 4)] 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.
AB - 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 ([(NH 4) 2SO 4)] intraliposome/[(NH 4) 2SO 4)] 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.
UR - http://www.scopus.com/inward/record.url?scp=3042547606&partnerID=8YFLogxK
U2 - 10.1097/00000542-200407000-00021
DO - 10.1097/00000542-200407000-00021
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C2 - 15220782
AN - SCOPUS:3042547606
SN - 0003-3022
VL - 101
SP - 133
EP - 137
JO - Anesthesiology
JF - Anesthesiology
IS - 1
ER -