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 > 1000). The liposomes were then characterized for size distribution; drug-to-phospholipid ratio; in vitro release profile at 4 degree, 21 degree C, and 37 degree 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 2439 +/- 544 nm, with a drug-to-phospholipid ratio of 1.8, fivefold greater than results previously reported. In vitro release was slowest at 4 degree 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.
Grant
Gilbert J
GJ
Department of Anesthesiology, New York University School of Medicine, New York, New York 10016, USA. gilbert.grant@med.nyu.edu
Barenholz
Yechezkel
Y
Bolotin
Elijah M
EM
Bansinath
Mylarrao
M
Turndorf
Herman
H
Piskoun
Boris
B
Davidson
Elyad M
EM
D000328:Adult; D000645:Ammonium Sulfate / Q000737:chemistry; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002045:Bupivacaine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D006801:Humans; D007271:Injections, Intradermal; D008081:Liposomes; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D010316:Particle Size
D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes; D000645:Ammonium Sulfate; D002045:Bupivacaine