Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and use thereof
View Patent ↗The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydrocodone (morphinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs/compositions of hydrocodone, including benzoates and heteroaryl carboxylic acids, which have a decreased potential for abuse of hydrocodone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.
1. A composition comprising acetaminophen and a conjugate, wherein the conjugate is benzoate-hydrocodone (Bz-HC) having the following structure:
2. The composition of claim 1 , wherein the conjugate is used to treat narcotic or opioid abuse; to reduce narcotic or opioid withdrawal; to treat moderate to severe pain; to reduce oral, intranasal or intravenous drug abuse; or to provide oral, intranasal or parenteral drug abuse resistance.
3. The composition of claim 1 , wherein the conjugate exhibits an improved AUC and rate of release over time when compared to unconjugated hydrocodone over the same time period; exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone; or has reduced side effects when compared with unconjugated hydrocodone.
4. The composition of claim 1 , wherein the conjugate is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oral powder, a solution, an oral film, a thin strip, a slurry, and a suspension.
5. The composition of claim 1 , wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone.
6. The composition of claim 1 , wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and C max when compared to an equivalent molar amount of unconjugated hydrocodone.
7. The composition of claim 1 , wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and a lower C max when compared to an equivalent molar amount of unconjugated hydrocodone.
8. The composition of claim 1 , wherein the conjugate is a salt.
9. The composition of claim 8 , wherein the salt is a hydrochloride/chloride.
10. The composition of claim 1 , further comprising a biologically acceptable carrier.
11. The composition of claim 1 , wherein upon administration, active hydrocodone is released from the conjugate through first-pass metabolism.
12. A method for treating pain in an individual in need thereof comprising the step of orally administering a pharmaceutically effective amount of a composition comprising acetaminophen and a conjugate, wherein the conjugate is benzoate-hydrocodone (Bz-HC) having the following structure:
13. The method of claim 12 , wherein the conjugate exhibits an improved AUC and rate of release over time when compared to unconjugated hydrocodone over the same time period; exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone; or has reduced side effects when compared with unconjugated hydrocodone.
14. The method of claim 12 , wherein the composition is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oral powder, a solution, an oral film, a strip, a slurry, and a suspension.
15. The method of claim 12 , wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone.
16. The method of claim 12 , wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and C max when compared to an equivalent molar amount of unconjugated hydrocodone.
17. The method of claim 12 , wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and a lower C max when compared to an equivalent molar amount of unconjugated hydrocodone.
18. The method of claim 12 , wherein the composition is used for treating pain mediated by binding of an opioid primarily to μ opioid receptors of the patient.
19. The method of claim 18 , wherein the conjugate binds reversibly to the μ opioid receptors of the patient.
20. The method of claim 18 , wherein the conjugate binds reversibly to the μ opioid receptors of the patient without a CNS depressive effect.
21. The method of claim 12 , wherein the composition also reduces narcotic or opioid abuse.
22. The method of claim 12 , wherein the composition also reduces narcotic or opioid withdrawal.
23. The method of claim 12 , wherein the composition also reduces oral, intranasal or intravenous narcotic or opioid abuse.
24. The method of claim 12 , wherein the composition also provides oral, intranasal or parenteral non corticoid opioid abuse resistance.
25. A pharmaceutical kit comprising a specified amount of individual doses in a package containing a pharmaceutically effective amount of acetaminophen and a conjugate, wherein the conjugate is benzoate-hydrocodone (Bz-HC) having the following structure:
26. The pharmaceutical kit of claim 25 , wherein the kit further comprises instructions for use of the kit in a method for treating pain.
27. The pharmaceutical kit of claim 25 , wherein the kit further comprises instructions for use of the kit in a method for treating narcotic or opioid withdrawal symptoms.
28. The pharmaceutical kit of claim 25 , wherein the kit further comprises instructions for use of the kit in a method for reducing narcotic or opioid abuse.
29. The pharmaceutical kit of claim 25 , wherein the specified amount of individual doses comprise from about 1 to about 100 individual dosages.
30. The pharmaceutical kit of claim 25 , wherein the individual doses comprise at least about 0.5 mg of the conjugate.