Bupivacaine binding to pegylated liposomes

Local anesthetic drugs, such as bupivacaine, can cause severe toxicity. Lipid emulsions have been proposed and used clinically for treating such cases. Liposomes may be an alternative for overdose treatment because of their unique structures and surface charges, which allows them to act as high affinity drug "sinks" and remove bupivacaine from solution.

We conducted in vitro experiments with unilamellar and multilamellar anionic, polymer-coated liposomes to determine the amount of bupivacaine bound to liposomes in buffer solutions as a means of assessing the liposome-drug affinity. Binding experiments were also done in human serum to determine the liposomes' ability to compete with serum proteins for binding drug molecules.

Unilamellar liposomes sequestered 60%-65% and 77%-85% of bupivacaine from buffer at 1.45 and 2.9 mg lipid/mL, respectively. The increased lipid loading increased the drug uptake at all drug concentrations measured (P = 0.001, 0.002, <0.001, and 0.003 for 5, 20, 35, and 50 microM, respectively). Multilamellar liposomes bound more drug per unit mass, with 71%-90% of the total bupivacaine bound at a phospholipid concentration of 1.45 mg lipid/mL. When comparing unilamellar and multilamellar liposomes at 1.45 mg lipid/mL, the multilamellar liposomes were significantly better at 3 of the 4 drug concentrations measured (P = 0.002, 0.001, 0.001, and 0.08 for 5, 20, 35, and 50 microM, respectively). In human serum samples, unilamellar liposomes (2.9 mg lipid/mL) reduced the unbound (free) drug by 36% (P = 0.037), 56% (P = 0.022), 47% (P = 0.042), and 50% (P = 0.018) for bupivacaine concentrations of 5, 20, 35, and 50 microM, respectively.

The anionic, pegylated liposomes exhibit high binding for bupivacaine, both in buffer and in human serum. These results suggest that an IV injection of liposomes could be useful for the treatment of bupivacaine toxicity through drug redistribution.