Single-dose, new-generation antidotes against opioid overdose

The opioid epidemic in the United States is due to an unprecedented increase in deaths from fentanyl and other synthetic opiates. The powerful effects of fentanyl are long-lasting and even a tiny amount of medication can lead to overdose. Antidotes, such as naloxone, do not last long enough in the body to completely counteract the drug, which requires repeated injections. Now, scientists report that they are developing single-dose, longer-lasting opioid antidotes with the help of polymer nanoparticles.

The researchers will present their findings today at the 2019 Spring National Meeting and Exposition of the American Chemical Society (ACS).

"We were interested in this problem when we tried to make pain medications without addiction," said Saadyah Averick, Ph.D. "During this research, we became aware of the limitations of opioid antidotes current. "

According to the US Centers for Disease Control, opioids, such as heroin, oxycodone and fentanyl, would be involved in more than 47,000 overdose deaths in 2017. These drugs all bind to mu opioid receptor (MOR) brain, which is the body's natural pleasure receptor, says Averick, a scientist at the Allegheny Health Network Research Institute. "The drugs bind, light up the receptor and stimulate a euphoric feeling, synthetic opioids, such as fentanyl, really activate, very well," he says.

And their effects are lasting. Fentanyl, which is much more potent than morphine, another opioid, can be absorbed by adipose tissue, which prevents it from being metabolized immediately. It is then slowly released from this tissue, causing effects for several hours. However, naloxone, an antagonist and antidote to MOR, remains in the system for only about 30 minutes to an hour. Because of this inadequacy, repeated doses are needed to help the patient recover. But not all patients want to follow the entire treatment and may succumb to an overdose after the metabolism of naloxone.

To overcome this challenge, Averick and his colleagues have developed a drug delivery system designed to ensure the administration of a consistent and sufficient dose of antagonist over a 24-hour period . The researchers reacted naloxone, which has a multi-ring chemical structure, with polylactic acid (PLA), creating a naloxone polymer. They then prepared covalent nanoparticles (CNP) by adding this polymer to a solution of polyvinyl alcohol. They used various badytical methods to purify and badyze the resulting particles, with a diameter of 300 nanometers.

"In collaboration with Benedict Kolber's laboratory at Duquesne University, research has shown that these nanoparticles can deliver enough naloxone as a linear release to block the badgesic effect of morphine for 24 hours," he says. Averick note. "In a next step, the study will be extended to fentanyl." Although the most recent work has been done on mice, future studies will include an animal model that more closely simulates how humans metabolize opioids.

The researchers also plan to examine the impact of particle size on the release of naloxone by the nanoparticle. "Ultimately, we hope to develop a therapeutic intervention against fentanyl overdose that can be used in the field, perhaps supplanting short-acting naloxone as the antidote of choice in case of overdose" said Averick. "We anticipate that this drug delivery system will also be effective for other nonfentanyl opioids."

Since naloxone and the other compounds used by the team are already considered safe, Averick predicts that the time to market could be less than five years for the nanoparticle system.

More information:
Next-Generation Opioid Antidotes: Covalent Nanoparticles for the Administration of Mu Opioid Antagonists, the American Chemical Society (ACS) Spring 2019 Show and National Show