Liposomal bupivacaine. Extended duration nerve blockade using large unilamellar vesicles that exhibit a proton gradient.

BACKGROUND: There is a clinical requirement for longer-acting local anesthetics, particularly for the management of post-operative and chronic pain. In this regard, liposomes have been suggested to represent a potentially useful vehicle for sustained drug release after local administration. In the current study, the authors used a transmembrane pH gradient to efficiently encapsulate bupivacaine within large unilamellar vesicles. They report on the kinetics of drug uptake and release and the duration of nerve blockade.
METHODS: The rate and extent of bupivacaine uptake into large unilamellar vesicles that exhibit a pH gradient (interior acidic) were determined and compared to drug association with control liposomes that did not exhibit a proton gradient. In subsequent studies, researchers examined the kinetics of bupivacaine release from these liposome systems in vitro. Using the guinea pig cutaneous wheal model, the rate of clearance of the liposome carrier was monitored after intradermal administration, using a radiolabelled lipid marker, and the duration of nerve blockade produced by free and liposomal bupivacaine was compared.
RESULTS: Bupivacaine was rapidly and efficiently accumulated within liposomes that exhibited a pH gradient (interior acidic) with trapping efficiencies of 64-82% of total drug, depending on the initial bupivacaine:phospholipid ratio. Little uptake was seen, however, for control vesicles that did not exhibit a transmembrane proton gradient. Using an in vitro model of drug clearance, liposomally encapsulated bupivacaine was found to be slowly released for a longer period of time compared with either the free drug or bupivacaine associated with control (no pH gradient liposomes). In the guinea pig cutaneous wheal model, more than 85% of the liposomal carrier was found to remain at the site of administration for 2 days. The sustained drug release afforded by liposomes that exhibited a pH gradient resulted in an increase in the duration of nerve blockade of as much as threefold compared with either the free drug or bupivacaine in the presence of control (no pH gradient) liposomes. Recovery of half maximal response (R2.5) after administration of 0.75% free bupivacaine, for example, was approximately 2 h, whereas the same dose of bupivacaine in pH gradient liposomes exhibited a R2.5 of approximately 6.5 h.
CONCLUSIONS: Large unilamellar vesicles that exhibit a pH gradient can efficiently encapsulate bupivacaine and subsequently provide a sustained-release system that greatly increases the duration of neural blockade.