Prolonged analgesia from Bupisome and Bupigel formulations: from design and fabrication to improved stability

Abstract

There is a compelling need for an ultralong-acting local anesthetic. Previously, we demonstrated in mice and humans that encapsulation of bupivacaine into large multivesicular liposomes (Bupisome) prolongs drug residence time and analgesic duration at the injection site while reducing peak plasma concentration. However, we observed considerable leakage of bupivacaine from the liposomes during storage at 4 °C. This deficiency was overcome by modifying the lipid composition of Bupisome and by entrapping them in a Ca-alginate cross-linked hydrogel (Bupigel), forming stable, soft, injectable (3-5 mm) beads. Bupisome are not released from Bupigel, but their encapsulated bupivacaine is released into the bulk solution. Adding 0.5% to 2.0% free bupivacaine to the Bupigel prevented net loss of bupivacaine from the Bupisome after storage at 4 °C for 2 years, and at 37 °C enough bupivacaine was released to prolong analgesia. For injection subcutaneously into mice, the beads are drawn into a syringe, leaving the small amount of free bupivacaine behind. Both Bupisome and Bupigel formulations significantly prolonged analgesia in mice compared to standard bupivacaine, with Bupigel performing better than Bupisome.