Alpha-hydroxy carboxylic acid and derivatives and other GRAS-based prodrugs of opioids and uses thereof
View Patent ↗The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to opioids in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.
1. An opioid prodrug of any of the following formulae where the prodrug moiety X is attached covalently to the opioid molecule,
or a pharmaceutically acceptable salt thereof,
wherein X is an alpha-hydroxy carboxylic acid selected from the group consisting of lactic acid, tartaric acid, malic acid, citric acid, mandelic acid, pantoic acid, panthothenic, 2-hydroxy glutaric acid, 3-hydroxy glutaric acid, and other poly-hydroxy carboxylic acids derived from sugars and carbohydrates.
2. The opioid prodrug of claim 1 wherein the opioid is hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, or buprenorphine.
3. The opioid prodrug of claim 2 wherein the prodrug moiety X is chemically/covalently attached to hydrocodone or hydromorphone at their 6 th position oxygen atoms as a ketone enolate ester.
4. An opioid prodrug compound of formula
wherein OP comprises an opioid selected from the group consisting of hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, and buprenorphine, X comprises a prodrug covalently attached to the opioid, and
is selected from the group consisting of
5. A pharmaceutical composition comprising one or more of the opioid prodrugs according to claim 4 and one or more pharmaceutically acceptable excipient.
6. An oral pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 4 , wherein the compound is a pharmaceutically acceptable salt form.
8. A method of treating pain comprising orally administering the composition of claim 6 to a patient.
9. The opioid prodrug of claim 1 , wherein X is malic acid.
10. The opioid prodrug of claim 1 , wherein the opioid is hydrocodone.
11. The opioid prodrug of claim 1 , wherein X is malic acid and the opioid is hydrocodone.
12. The opioid prodrug compound of claim 4 , wherein the opioid prodrug compound of formula
is represented by any one of formulae