Bupivacaine lipid microparticles were prepared and evaluated as a parenteral sustained-release
dosage form for
postoperative pain management.
Bupivacaine free base was incorporated into a molten
tristearin matrix and
lipid micro-particles were subsequently formed from this molten mixture by a spray-congealing process. A 3%
injectable bupivacaine lipid microparticle
suspension was prepared by dispersing 30%
bupivacaine lipid microparticles in an aqueous medium containing
carboxymethylcellulose (CMC),
mannitol, and
Tween 80. Upon room temperature storage, the fluid
suspension gradually changed into a nonflowing semisolid (gelation) as a result of crystal growth of
bupivacaine. However,
suspensions prepared with
bupivacaine lipid microparticles that were previously annealed at an elevated temperature remained fluid upon long-term storage. Differential scanning calorimetry (DSC), x-ray
powder diffraction (XRPD), and isoperibol
solution calorimetry were used to investigate the changes in the solid-state properties of
tristearin and
bupivacaine in the
lipid microparticles before and after the heat treatment. The DSC and XRPD results indicate that after 24 hours of heating at 40 degrees C,
tristearin was completely converted from the unstable alpha form to the stable beta form. Using the isoperibol
solution calorimetric method,
bupivacaine was found to transform into a more stable form after the
lipid microparticles were heated at 60 degrees C for 24 hours. The generation of the unstable solid forms of
tristearin and
bupivacaine was attributed to the resolidification of both components from the molten mixture during the spray-congealing process.