US-12617807-B2 - Long lasting opioid reversal using hydrogen peroxide-induced release in blood

Abstract

Naloxone variants that are both long lasting and responsive are disclosed. One version of the compound has a boron ester functional group and the antagonist compound is capable of a sustained release of antagonist based on reaction with hydrogen peroxide. In addition, a method of treating opioid overdose is disclosed. The method involves administering a therapeutically effective amount of the formulation described above to a patient in need thereof. Administration occurs either intranasally, sublingually or intranasally and sublingually, wherein if administration occurs intranasally and sublingually administration occurs simultaneously, sequentially or concomitantly.

Inventors

• Edward Merino
• Steve Davidson
• Priyangika Senevirathne

Assignees

• UNIVERSITY OF CINCINNATI

Dates

Publication Date

20260505

Application Date

20220401

Claims (4)

1. 1 . A modified opioid receptor antagonist compound having the following structure: or a pharmaceutically acceptable salt thereof.
2. 2 . A modified opioid receptor antagonist compound having the following structure: or a pharmaceutically acceptable salt thereof.
3. 3 . A method of treating opioid overdose comprising administering a therapeutically effective amount of the compound of claim 1 to a patient in need thereof, wherein administration occurs either intranasally, sublingually or intranasally and sublingually, wherein if administration occurs intranasally and sublingually administration occurs simultaneously, sequentially or concomitantly.
4. 4 . A method of treating opioid overdose comprising administering a therapeutically effective amount of the compound of claim 2 to a patient in need thereof, wherein administration occurs either intranasally, sublingually or intranasally and sublingually, wherein if administration occurs intranasally and sublingually administration occurs simultaneously, sequentially or concomitantly.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Ser. No. 63/169,416, filed Apr. 1, 2021, and PCT application PCT/US22/23095, which applications are hereby incorporated by reference in their entirety. TECHNICAL FIELD The present invention relates generally to the field of opioid receptor antagonists. BACKGROUND OF THE INVENTION Opioid overdose is a significant problem that is rising in the US. For example, the rate of opioid overdose death was 13.3 deaths per 100,000 persons in 2016. Ohio has been particularly impacted with a rate three times the national average and greater than 30% annual increases in opioid overdoses for the last four years. One clear issue has been the lack of treatment options. Biochemically, treatment for opioid overdose reversal are opioid receptor antagonists. The most widely used is naloxone, which is most commonly administered intravenously for rapid action and more recently, through nasal sprays. The structure of naloxone is shown in FIG. 1. Naloxone binds to the various opioid receptors (μ, δ, κ) with affinities of 1-15 nM and blocks opioid-induced activation on the same receptors. Unfortunately, naloxone is metabolically instable. Because of naloxone's instability it can lose effectiveness within ˜1 hr and often leads to a second overdose event. Especially problematic is that much of the illicit use of opioids now entails synthetic opioids, like fentanyl, that have stronger affinity and longer residence time once bound. As such, a dose of naloxone is metabolized before the receptor's site is open. This causes the need of multiple doses of naloxone and possible death. Thus, there is a strong need for chemical technologies to combat opioid overdose and addiction. SUMMARY OF THE INVENTION The present invention addresses that need with a novel modified opioid receptor antagonist compound. In one embodiment, the compound has a boron ester functional group and the antagonist compound is capable of a sustained release of antagonist based on reaction with hydrogen peroxide. In another embodiment, a method of treating opioid overdose is disclosed. The method involves administering a therapeutically effective amount of the formulation described above to a patient in need thereof. Administration occurs either intranasally, sublingually or intranasally and sublingually, wherein if administration occurs intranasally and sublingually administration occurs simultaneously, sequentially or concomitantly. In one embodiment, the modified opioid receptor antagonist compound has the following structure: or a pharmaceutically acceptable salt thereof. In another embodiment of the present invention, the modified opioid receptor antagonist compound has a boronic acid functional group and the compound is capable of a sustained release of antagonist based on reaction with hydrogen peroxide. In another embodiment, a method of treating opioid overdose is disclosed. The method involves administering a therapeutically effective amount of the formulation described above to a patient in need thereof. Administration occurs either intranasally, sublingually or intranasally and sublingually, wherein if administration occurs intranasally and sublingually administration occurs simultaneously, sequentially or concomitantly. In one embodiment, the modified opioid receptor antagonist compound has the following structure: or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing summary, as well as the following detailed description of preferred embodiments of the application, will be better understood when read in conjunction with the appended drawings. FIG. 1 shows the chemical structure of naloxone. FIG. 2 is a graph showing increasing amounts of opioids induce higher levels of hydrogen peroxide. FIG. 3 shows the chemical structure of naloxone, with a red circle indicating the phenol group. FIG. 4 shows the synthetic pathway for PS-NPD-1. FIG. 5 shows the chemical process whereby PS-NPD-1 releases naloxone in the blood as it is exposed to hydrogen peroxide. FIG. 6 is the chemical structure of PS-NPD-2. FIG. 7 is a graph showing that PS-NPD-2 produces higher concentrations of naloxone in the blood of mice. FIG. 8 is a graph showing that, at 2 hours, NPD-2 results in more naloxone in mice blood compared to naloxone. FIG. 9A is an illustration of the experimental process for Example 3. FIG. 9B is table of compounds administered to the subjects as described in Example 3. FIG. 9C is a graph showing oxidative stress after opioid/antagonist treatment. FIG. 10 is graph showing the effect of NPD-2 for a rescue of a mouse from opioid-induced respiratory failure and death. FIG. 11 is a schematic of the experimental design of Example 5. FIG. 12 is a graph showing the results of Example 5, where the prodrug of the present invention led to a higher number of surviving animals than naloxone after a supplemental opioid is given to mimic ren