Nanodroplet Infused Analgesic-Wafer for Transmucosal Opioid-free Treatment of Subacute Oral Pain

SUMMARY Over 2 million patients visit hospital emergency departments (EDs) each year for non-traumatic dental conditions, accounting for 2.5% of ED visits, at a cost of $2 billion/year. Current methods for treating dental pain in the ED or in the home do not offer long-term management of intra-oral pain (IOP). As a result, ED providers prescribe opioids to up to 59% of the patients. To address the critical need for long-acting relief of subacute dental pain, Centrea Biopharmaceuticals has partnered with Trekka Therapeutics and researchers at the University of Minnesota to develop a novel transmucosal local anesthetic cocktail (LAC) encased in an advanced “CAPRO” polymer for programmable transmucosal release (t-LAC). Here we propose to formulate t-LAC into adhesive wafers for treatment of subacute intra-oral pain (IOP). Medical and dental providers have been urged to replace opioids with non-steroidal anti-inflammatory drugs or local regional blocks, but these treatments show limited efficacy for severe persistent IOP. Benzocaine, the most common topical analgesic for IOP, provides only mild pain relief for a short duration (<30 minutes). As a result, IOP has become a gateway to opioid abuse, misuse, and diversion, especially in adolescents and young adults. In our prior studies on post-operative pain, injection of a 5-drug LAC provided superior analgesia than the current gold standard, Exparel® (liposomal bupivacaine). Unfortunately, treatment of IOP via an injectable local block in the ED and in the home is limited by availability as well as the providers’ and patients’ lack of comfort with injectable dental blocks. Therefore, we propose to develop the t-LAC nanoparticle formulation as an easy-to-use, over-the-counter method for programmable delivery of an efficacious drug cocktail in an adhesive, intra-oral topical wafer. Our novel topical t-LAC wafer will extend delivery of analgesia to >12 hours with a single dose. We propose two Specific Aims to establish the feasibility of t-LAC for delivering three drugs to manage IOP: (Aim 1) To demonstrate the in vitro efficacy of CAPRO-based t-LAC formulations, we will load t-LAC nanodroplets onto mucoadhesive wafers and quantify the mucoadhesive strength, dissolution rate, and drug penetration in the presence of simulated saliva in a porcine gingival tissue model; (Aim 2) To show the feasibility of effective topical analgesia with t-LAC wafers, we will demonstrate the in vivo efficacy and biocompatibility in a mouse model of dental pulp injury, with comparisons to Orajel™ and plain bupivacaine. We will conduct post-mortem histopathologic studies to evaluate local tissue inflammation following the treatments. Upon successful conclusion of our Phase I work, we will pursue a Phase II grant to optimize t-LAC drug concentrations and pursue IND-enabling studies of efficacy, pharmacology, toxicity, and chemistry- manufacturing-control (CMC). We ultimately will seek a major pharmaceutical partner to commercialize the topical LAC wafers as an innovative therapy for safe, effective, and affordable management of dental pain.