Development of liposomal bupivacaine using a transmembrane pH gradient

• Main Author: Mowat, Jeffrey John
• Language: English
• Published: 2009
• Online Access: http://hdl.handle.net/2429/3972

There is a clear clinical requirement for longer acting local anaesthetics, 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 following local administration. In this thesis, a transmembrane pH gradient was employed to efficiently encapsulate bupivacaine within large unilamellar vesicles. The rate and extent of bupivacaine uptake into large unilamellar vesicles exhibiting a pH gradient (interior acidic) were determined and compared to drug association with control liposomes that did not exhibit a proton gradient. Subsequent studies examined the kinetics of bupivacaine release from the liposome systems in vitro. Using the Guinea Pig cutaneous wheal model, the rate of clearance of the liposome carrier was monitored following intradermal administration employing a radiolabeled lipid marker and the duration of nerve blockade produced by free and liposomal bupivacaine compared. Intraperitoneal injections of bupivacaine encapsulated in pH gradient vesicles, control (no pH gradient vesicles) and free drug were completed in mice to determine the relative toxicities. While bupivacaine is rapidly and efficiently accumulated within liposomes exhibiting a pH gradient (interior acidic), little uptake was seen for control vesicles. Using an in vitro model of drug clearance, liposomally encapsulated bupivacaine was found to be released more slowly and over a longer period of time compared to either the free drug or bupivacaine associated with control (no pH gradient liposomes). In the Guinea Pig cutaneous wheal model, over 85% of the liposomal carrier was found to remain at the site of administration over two days and the sustained drug release afforded by liposomes exhibiting a pH gradient resulted in a threefold increase in the duration of nerve blockade compared to either the free drug or bupivacaine in the presence of control (no pH gradient) liposomes. In the toxicity study, bupivacaine encapsulated in pH gradient vesicles showed a greater than fourfold increase in safety compared to the use of the free drug and control (no pH gradient) vesicles. The present results clearly establish that large unilamellar vesicles exhibiting a pH gradient can efficiently encapsulate bupivacaine and subsequently provide a sustained release system that greatly increases the duration of neural blockade and, in addition, reduces the toxicity.