A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia

Anesthesiology. 2004 Jul;101(1):133-7. doi: 10.1097/00000542-200407000-00021.


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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Ammonium Sulfate / chemistry
  • Anesthetics, Local / administration & dosage*
  • Anesthetics, Local / adverse effects
  • Anesthetics, Local / therapeutic use*
  • Bupivacaine / administration & dosage*
  • Bupivacaine / adverse effects
  • Bupivacaine / therapeutic use*
  • Chemistry, Pharmaceutical
  • Delayed-Action Preparations
  • Drug Carriers
  • Drug Compounding
  • Humans
  • Injections, Intradermal
  • Liposomes
  • Male
  • Pain Measurement / drug effects
  • Particle Size


  • Anesthetics, Local
  • Delayed-Action Preparations
  • Drug Carriers
  • Liposomes
  • Ammonium Sulfate
  • Bupivacaine