| Summary: | 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.
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