Development and characterization of a sustained release formulation of lidocaine using liposomes exhibiting a transmembrane pH gradient
Creators: name: Mok, Miranda Jane
Publisher: name: University of British Columbia
Year: 2009

description: Longer acting local anaesthetics which will provide prolonged nerve blockade are required for adequate management of both acute and chronic pain. It has been suggested that liposomes represent a potentially useful vehicle for sustained drug release following local administration. Thus, the aim of this thesis was to develop and characterize liposomal lidocaine by employing a transmembrane pH gradient to efficiently encapsulate lidocaine into large unilamellar vesicles (LUVs). The rate and extent of lidocaine uptake into LUVs exhibiting a pH gradient were determined and compared to drug association with control (no pH gradient) liposomes. While lidocaine was rapidly and efficiently accumulated into liposomes exhibiting a pH gradient, little uptake was seen for control vesicles. The in vitro release kinetics of lidocaine from liposomes were studied and the drug was shown to be slowly released from the carrier with drug efflux being controlled by the applied proton gradient. In addition, it was demonstrated that the rate of lidocaine release from pH gradient-loaded liposomes was only slightly increased in the presence of plasma. Using an in vivo model, the rates of clearance of lidocaine and the lipid carrier were monitored employing radiolabeled markers following intradermal administration. In the guinea pig cutaneous wheal model, the liposomal carrier was found to be cleared slowly from the site of administration, such that greater than 85% of the administered lipid dose remained at 48 hours. Similarly, clearance of liposomally encapsulated lidocaine from the site of administration was relatively slow compared to that of free drug. The guinea pig cutaneous wheal model was again used to investigate the efficacy of the liposomal local anaesthetic formulation. The sustained drug release afforded by liposomes exhibiting a pH gradient resulted in a two-fold increase in the duration of nerve blockade compared to free drug. A similar increase in duration of action was seen when these two formulations were compared in the presence of the vasoconstrictive agent, adrenaline (1:200,000). The results of the in vitro release kinetics showed that a significant amount of local anaesthetic remained within the liposomes after 24 hours, yet full recovery from nerve blockade was seen between 5-6 hours. As a result of this finding, the clearance and efficacy of smaller sized liposomes (200 nm vs. 600 nm) were determined using the guinea pig cutaneous wheal model. Again, only slow clearance of liposomes was observed, but encapsulated lidocaine was cleared much faster from the site of injection from 200 nm vesicles compared to the kinetics observed for 600 nm vesicles. However, the smaller sized vesicles did not provide longer nerve blockade compared to the 600 nm vesicles. The relative acute toxicities of free and liposomal lidocaine were also examined using intraperitoneal injections into mice to determine the CD5 0 . Liposomally encapsulated lidocaine was far superior in providing a large margin of safety in contrast to free drug or no pH gradient liposomal lidocaine, since liposomally encapsulated lidocaine did not elicit any convulsions nor was it lethal. Clearly, the present results demonstrate that large unilamellar vesicles exhibiting a pH gradient can efficiently encapsulate lidocaine and provide a controlled drug release system. These systems reduce the rate of local anesthetic clearance following administration, resulting in a significant increase in duration of neural blockade and reduction of toxicity.