PROJECT SUMMARY/ABSTRACT The opioid overdose epidemic is killing Americans at the level of a mass casualty event – Hurricane Katrina killed 1,577 people but the death toll from opioid overdose in 2018 in California alone was 5,348. Synthetic, more potent opioids such as fentanyl and its derivatives are further increasing the numbers of deaths. Naloxone (NLX), an opioid antagonist, is the antidote for opioid overdose. NLX works by displacing opioid molecules from receptors in the body, ultimately reversing the respiratory depression. NLX is administered intravenously (IV), intramuscularly (IM), subcutaneous (SC), or intranasally. Unfortunately all commercially available dosage forms have significant shortcomings, making them challenging for pre-hospital settings. Most notably, NLX suffers from a very short plasma half-life, presenting a risk of overdose relapse if there is a very large amount of opioid in the plasma. This results in need for repeated NLX doses to be given (known as “rescue” doses) to prevent hypoxia, and this disadvantage is shared by all routes of delivery and is becoming increasingly common. Additional challenges include the need for use of needles/syringes with IV/IM/SC delivery, which is very risky in the context of a potentially combative patient; intranasal delivery is not uniformly effective, and is contraindicated in the context of intranasal damage that is often seen with use of other illicit substances. In this research we propose to overcome the shortcomings of current NLX dosage forms through development of a novel self-heating transdermal patch with microneedles. The long-term goal is to decrease pre-hospital opioid overdose deaths through development of the novel transdermal NLX dosage form. The intent is to deliver NLX quickly through the skin, aiming to achieve consistent and therapeutically relevant drug concentrations without need for rescue doses. The central hypothesis of this proposal is that NLX will rapidly and continuously absorb through epidermal micropores, and a positive correlation will exist between elevated skin temperature and the rate and extent of NLX permeation. The patch will include 3 layers: 1) dissolving microneedles, 2) a transdermal NLX gel, and 3) a heating layer. Each layer fulfills a specific function, with the combined effect of producing NLX skin permeation that can reach plasma levels appropriate for treating opioid overdose. Dissolving NLX microneedles will immediately start to deliver NLX as they dissolve, while also creating micropores to allow transdermal NLX delivery from the gel. The gel will deliver NLX through the micropores for a minimum of 2 hrs after patch application. The heating layer will rapidly generate heat upon air exposure, increasing skin temperature and thereby increasing the rate and extent of NLX absorption. The patch is intended to be applied in just one step. In Aim 1 we will optimize each patch layer in vitro to meet predetermined milestones to provide similar...