Prevention of renarcotization from synthetic opioids

PROJECT SUMMARY/ABSTRACT In October 2017, the U.S. Government declared the current opioid epidemic the worst drug crisis in American history. Synthetically derived opioids such as fentanyl and fentanyl-derivatives have been at the forefront of this public health emergency, exhibiting the highest year-to-year contribution to overdose deaths. While the mu opioid receptor (MOR) antagonist naloxone has proven invaluable as an opioid overdose antidote, naloxone suffers from a very short duration of action (half-life ~ 1hr.) and has been found to be less effective against newer, long acting opioids including fentanyl (half-life ~7-10 hrs.). This leads to a highly lethal and increasingly prevalent phenomenon known as “renarcotization”, wherein an overdose patient revived with naloxone can re-enter an overdose state from residual fentanyl in the body. To counter renarcotization, naloxone must be given repeatedly and at significantly higher doses than fentanyl. This approach may be achievable in a hospital; however, renarcotization is often not recognized outside a medical setting and can lead to death. Thus, there is a critical need to develop a long acting MOR antagonist formulation that can address renarcotization by providing the multi-hour protection. The goal of this Phase I STTR project is to reformulate naloxone using FDA approved microencapsulation technology into a long acting injectable (LAI) that can provide 12-24 hrs. of sustained antagonist activity in vivo. Other attempts to address this issue by chemically modifying naloxone are likely to suffer significant regulatory and technical risk. Consegna’s innovation is to employ its proprietary Computational Drug Delivery™ software, called ADSR™, to perform in silico formulation optimization as well as to predict its in vitro dissolution and in vivo pharmacokinetic behavior. Approval can be sought thru the 505(b)(2) accelerated regulatory pathway to gain near-term entry into the market since the naloxone molecule is not modified and efficacy is not at risk. This new long acting naloxone formulation, named CP216, will utilize an innovative design to address both primary and secondary overdose (renarcotization) situations thru a combination of free form naloxone for immediate effect and microencapsulated naloxone for sustained protection. Our hypothesis is that sustained release of naloxone from microparticles, coupled with an immediate release of free naloxone, can provide the therapeutics levels needed to reverse the overdose and prevent renarcotization. To test this hypothesis, 1) design an appropriate microparticle formulation and assess the formulation’s payload and release behavior in vitro, 2) evaluate the pharmacokinetics in an animal model, and 3) complete a Quality-by-Design assessment for a Chemistry, Manufacturing, and Controls package. Consegna believes this project has a significant potential to lead to the first safe and effective product to address renarcotization, and will lead to a positive impact on public health.PROJECT NARRATIVE There were more than 72,000 drug overdose deaths in 2017, most involving opioids. The goal of this STTR Phase I project is to create a better antidote for opioid overdose and address a critical unmet medical need. While naloxone is an effective opioid overdose antidote, it does not last long enough to be effective for synthetic opioids such as fentanyl that have a long half-life. We plan to create a formulation that continuously releases naloxone at therapeutic levels long enough to prevent renarcotization.