Porous Core/Dense Shell PLA Microspheres Embedded with High Drug Loading of Bupivacaine Crystals for Injectable Prolonged Release.

Objective of the study was to design an injectable microsphere preparation with high drug loading of bupivacaine for prolonged release and local anesthetic. PLA or PLGA was used as the biodegradable matrix material to fabricate microspheres with the o/w emulsification-solvent evaporation method. The characterization of bupivacaine microspheres was observed by SEM, DSC, and XRPD. The microsphere preparation and extended drug release, as well as the plasma drug concentration and sciatic nerve blockade after injection of the microsphere formulation to rats were investigated. High drug-loading microspheres of more than 70% were successfully obtained with extended drug release over 5 days in vitro depending on the type of matrix and the feed ratio of drug to polymer. SEM, DSC, and XRPD results verified a novel microsphere structure characterized as the porous core composed of PLA material and form II bupivacaine crystals and dense shell formed of PLA layer. The mechanism that bupivacaine was dissolved inside the microsphere and diffused across the dense shell was suggested for drug release in vitro. The optimized PLA microsphere formulation showed low and steady plasma drug concentration over 5 days and prolonged duration of sensory and motor blockade of sciatic nerve lasted more than 3 days. Results indicated that the porous core-shell structure of PLA microsphere formulation would provide enormous potential as an injectable depot for locally prolonged delivery of bupivacaine and control of postoperative pain.