# An Orally Administered Misuse Deterrent Opioid Prodrug for Treatment of Acute Pain

## TL;DR

This paper introduces a new opioid prodrug designed to prevent misuse by requiring specific conditions for activation, offering a safer option for treating acute pain.

## Contribution

The development of a novel oxycodone prodrug with three covalent misuse deterrent layers that resist common subversion methods.

## Key findings

- The prodrug is resistant to degradation by acidic and basic pH, household chemicals, and enzyme supplements.
- The prodrug shows analgesic effects in mice only after oral administration, not intraperitoneal injection.
- The dual-enzyme requirement for activation suggests strong misuse deterrent properties.

## Abstract

Opioids are a powerful class of medicines due to their
ability
to alleviate acute pain. However, the use of prescription opioids
has led to an epidemic in the United States. Many efforts to combat
this are ongoing, including the preparation of misuse deterrent opioid
formulations, some of which can be subverted using common household
chemicals. Herein, the development of an oxycodone-containing peptide
prodrug is reported that contains three covalent misuse deterrent
protective layers. This prodrug is resistant to degradation in the
presence of acidic and basic pH conditions, common household chemicals,
and enzyme supplements. After optimization of the peptide sequence,
the lead prodrug is composed of a branched lysine residue coupled
to a tert-butyl-protected tyrosine that is not naturally
recognized by digestive enzymes. There is a necessary sequence of
protecting group removal and then subsequent enzymatic peptide cleavages
that trigger cyclization of a self-immolative linker to release the
opioid agonist, oxycodone. The prodrug has analgesic properties in vivo in mice only after oral administration and not by
intraperitoneal injection, which suggests that this prodrug may have
misuse deterrent properties. The specificity for dual-enzyme release
and the resulting in vivo studies warrant further
examination of this prodrug scaffold for its potential as a misuse
deterrent alternative to treat acute pain.