Effect of excipient composition on the biocompatibility of bupivacaine-containing microparticles at the sciatic nerve.

Abstract

Microparticulate formulations are often used for experimental prolongation of nerve blockade. Here we examine the effect of excipient composition on the biocompatibility of bupivacaine-containing microparticles. Lipid-protein-sugar particles (LPSPs) composed of 3% (1.3-microm diameter) and 60% (4.7-microm diameter) (w/w) dipalmitoylphosphatidylcholine (DPPC) were produced by spray drying, containing 10% (w/w) bupivacaine. Rat sciatic nerve blocks with 75 mg of particles produced statistically similar durations of sensory nerve block [3% (w/w) DPPC particles: 301 min; 60% (w/w) DPPC particles: 321 min]. Examination of tissues 1 day after injection revealed large particle deposits and acute inflammation in animals that received 60% (w/w) DPPC particles. There were no visible deposits in those that received 3% (w/w) DPPC particles, and microscopic inflammation was reduced. The difference between groups was similar 4 days after injection. Two weeks after injection, there was no particulate mass in either group, and inflammation had largely resolved. In both groups, moderately severe myotoxicity was seen 1 and 4 days after injection but had largely resolved by 2 weeks. In summary, reduction in particles' DPPC content greatly improved biocompatibility without compromising duration of nerve blockade; the improvement was probably attributable to the enhanced rate of particle resorption.