Sequestration compounds for treatment of substance use disorder and uses thereof
Described herein are i) sequestering agents and ii) central nervous system (CNS) active agents for the treatment of intoxication due to toxic agents such as drugs of abuse, and associated symptoms. Also disclosed herein, are a cucurbituril and naloxone for use in the treatment of opioid overdoses through sequestering and excretion of the bound molecule of interest through the urine. Also provided herein, are kits and methods of treatment of the disclosure.
1 . A method of treating intoxication, overdose, or a symptom thereof due to at least one opioid in a human subject, the method comprising administering a therapeutically effective amount of:
i) a sequestration agent or a pharmaceutically acceptable salt thereof in an amount sufficient to sequester the at least one opioid, wherein the sequestration agent is an acyclic cucurbituril; and
ii) an opioid receptor antagonist or a pharmaceutically acceptable salt thereof;
wherein the sequestration agent and the opioid receptor antagonist are administered simultaneously, or
wherein the sequestration agent and opioid receptor antagonist are administered sequentially, wherein the opioid receptor antagonist is administered first.
2 . The method of claim 1 , wherein the sequestration agent and the opioid receptor antagonist are administered in one pharmaceutical composition.
3 . The method of claim 2 , wherein the pharmaceutical composition is a liquid dosage form.
4 . The method of claim 2 , wherein the pharmaceutical composition is in a form suitable for oral, intravenous, intramuscular, subcutaneous, intramedullary, intrathecal, intraperitoneal, intranasal, ophthalmic, pulmonary, transmucosal, transdermal, or topical administration.
5 . The method of claim 1 , wherein the sequestration agent and opioid receptor antagonist are administered in different pharmaceutical compositions.
6 . The method of claim 1 , wherein the sequestration agent and opioid receptor antagonist are administered simultaneously.
7 . The method of claim 1 , wherein the sequestration agent and opioid receptor antagonist are administered sequentially, wherein the opioid receptor antagonist is administered first.
8 . The method of claim 7 , wherein the sequestration agent is administered less than 5 minutes after the opioid receptor antagonist.
9 . The method of claim 1 , wherein the sequestration agent is Compound A, or a pharmaceutically acceptable salt thereof
10 . The method of claim 1 , wherein the opioid receptor antagonist is a mu opioid receptor antagonist.
11 . The method of claim 1 , wherein the opioid receptor antagonist is selected form the group consisting of naloxone, pentazocine, nalbuphine, diprenorphine, methylnaltrexone, naloxegol, alvimopan, naltrexone, nalmefene, buprenorphine, and pharmaceutically acceptable salts thereof.
12 . The method of claim 11 , wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.
13 . The method of claim 12 , wherein the naloxone or pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition, the pharmaceutical composition comprising from about 0.01% by weight to about 20% by weight of the naloxone or pharmaceutically acceptable salt thereof.
14 . The method of claim 1 , wherein
i) the sequestration agent is Compound A, or a pharmaceutically acceptable salt thereof
and
ii) the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.
15 . The method of claim 1 , wherein the opioid is selected a group consisting of fentanyl, fentanyl analogs, carfentanil, sufentanil, acetylfentanyl, alfentanil, heroin, morphine, oxycodone, codeine, hydrocodone, oxymorphone, and any pharmaceutically acceptable salts, and any combinations thereof.
16 . The method of claim 15 , wherein the sequestration agent binds to the opioid with a K a of at least 1×10 3 M −1 .
17 . The method of claim 1 , wherein the opioid receptor antagonist binds to the opioid with a K a of at least 1×10 3 M −1 .
18 . The method of claim 1 , wherein the sequestration agent binds to the opioid receptor antagonist with a K a of at least 1×10 3 M −1 .
19 . The method of claim 1 , wherein Compound A or a pharmaceutically acceptable salt thereof is administered at about 1 mg/kg to about 2,000 mg/kg.
20 . The method of claim 1 , wherein the opioid receptor antagonist is naloxone or a pharmaceutically acceptable salt thereof, wherein the naloxone or pharmaceutically acceptable salt thereof is administered at about 0.1 μg/kg to about 1,000 μg/kg.
21 . The method of claim 1 , wherein the administration is orally, intravenously, intramuscularly, subcutaneously, intramedullary, intrathecally, intraperitoneally, intranasal, ophthalmic, pulmonary, transmucosal, transdermal, or topically.
22 . The method of claim 1 , further comprising monitoring the human subject to determine whether a subsequent administration of an opioid antagonist is needed.
23 . The method of claim 22 , wherein the monitoring comprises measuring the human subject for abnormal heartrate, respiratory rate, appetite, cognitive capacity, or any combination thereof.
24 . The method of claim 1 , wherein treating intoxication, overdose, or a symptom thereof in said human subject comprises alleviating opioid intoxication or overdose in said human subject.
25 . The method of claim 24 , wherein said alleviating comprises restoration of normal respiration rate, wherein said normal respiration rate comprises at 12 to 20 breaths per minute.
26 . The method of claim 24 , wherein said alleviating comprises restoration of appetite.
27 . The method of claim 24 , wherein said alleviating comprises preventing opioid renarcotization.
28 . The method of claim 1 , further comprising at least a second administration of said opioid receptor antagonist.
29 . The method of claim 28 , wherein the at least second administration of said opioid receptor antagonist comprises at least 1, 2, 3, or 4 dose over 8 hours.
30 . The method of claim 1 , wherein administering said opioid receptor antagonist comprises administering at least 0.4 mg over 8 hours.