Extended-release injectable gel for multi-day treatment of postoperative pain - Principal Investigator: Overstreet, Derek J. Abstract Sonoran Biosciences, Inc. SBIR PA-23-230: Phase II Over 14 million patients undergoing surgical procedures in the US annually require treatment of moderate-to-severe postoperative pain lasting at least three days. The goal of this project is to enable opioid- free treatment of pain in these patients using an injectable extended-release gel-forming formulation of bupivacaine. Currently available alternatives have inadequate efficacy beyond 24 hr, leaving a window of time when pain emerges and is frequently treated with opioids. Prescription opioid use poses serious risks of adverse events to patients and is contributing to the ongoing nationwide opioid crisis. An extended-release local anesthetic acting for three days or more would have considerable impact by simplifying postoperative recovery, avoiding opioid-related adverse events, eliminating a common pathway to new and persistent opioid use, and preventing unsafe storage of unused oral opioids. Achieving analgesic efficacy using an extended-release local anesthetic requires supplying effective drug concentrations in a volume of tissue surrounding the surgical site. Competing delivery technologies fail to accomplish this, despite apparently well-timed release kinetics, due to one of two inherent limitations. First, materials applied in the surgical wound space, such as organic polymer solutions and solid implants, must rely on diffusion into surrounding tissue resulting in limited distribution. Alternatively, liquid-based systems such as liposomes or prodrugs can be injected into a sufficient volume of tissue, but are susceptible to washout, leading to off-target release. We have developed a proprietary extended release carrier, SB Gel, which can be injected as an aqueous solution and forms a soft gel upon contact with tissue. This combination of injectability and retention at the injection site enables SB Gel to sustain a sufficient volume of tissue with effective local anesthetic concentrations and avoid washout. In a Phase I SBIR project, we established the feasibility of SBG004, a formulation of SB Gel with 4 wt% bupivacaine. Preliminary data indicate that SBG004 provides extended release in vivo for 7 days, outperformed plain local anesthetics and current extended release competing products in soft and hard tissue models of pain for 72-96 hr, and is well-tolerated both locally and systemically, including low Cmax at high doses. We now propose to complete a Phase II project to continue the development of SBG004. In Aim 1, we will collect further data comparing SBG004 against competing products, including data on weight-bearing behavior after knee surgery and the concentrations of local anesthetic provided in surrounding tissue. In Aim 2, we will conduct dose range-finding toxicity studies in two species to estimate a maximum tolerated dose and inform the design of definitive IND-enabling studies. In Aim 3, we will manufacture a batch of SBG004 at 500 unit scale for use in IND-enabling studies. In Aim 4, we will complete a GLP toxicity study and a GLP cardiopulmonary safety study which fulfill regulatory requirements and inform the design of future clinical studies.
