Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and uses thereof

Patent metadata

Field	Value
Publication number	US-9549923-B2
Application number	US-201514817581-A
Country	US
Kind code	B2
Filing date	Aug 4, 2015
Priority date	Jul 2, 2009
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

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.

First claim

The invention claimed is:

1. A composition comprising 13.34 mg benzoate-hydrocodone hydrochloride conjugate, wherein the conjugate has the following structure:

2. The composition of claim 1 , wherein the 13.34 mg benzoate-hydrocodone hydrochloride contains a molar equivalent of 9.08 mg of hydrocodone.

3. The composition of claim 1 , wherein the conjugate results in the mean C max of hydrocodone of about 25,600 pg/mL±6,390 pg/mL when administered intranasally to a human.

4. The composition of claim 1 , wherein the conjugate results in the mean T max of hydrocodone of about 2 hours±0.91 hours when administered intranasally to a human.

5. The composition of claim 1 , wherein the conjugate results in the range of T max of hydrocodone from about 0.75 hours to about 4 hours when administered intranasally to a human.

6. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-0.083 h of hydrocodone of about 11.30 h×pg/mL±14.14 h×pg/mL when administered intranasally to a human.

7. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-0.25 h of hydrocodone of about 297.9 h×pg/mL±170.3 h×pg/mL when administered intranasally to a human.

8. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-0.5 h of hydrocodone of about 1,485 h×pg/mL±667.7 h×pg/mL when administered intranasally to a human.

9. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-0.75 h of hydrocodone of about 3,831 h×pg/mL±1,726 h×pg/mL when administered intranasally to a human.

10. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-1 h of hydrocodone of about 7,714 h×pg/mL±3,597 h×pg/mL when administered intranasally to a human.

11. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-1.5 h of hydrocodone of about 17,790 h×pg/mL±7,695 h×pg/mL when administered intranasally to a human.

12. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-2 h of hydrocodone of about 28,690 h×pg/mL±10,360 h×pg/mL when administered intranasally to a human.

13. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-3 h of hydrocodone of about 49,510 h×pg/mL±13,290 h×pg/mL when administered intranasally to a human.

14. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-4 h of hydrocodone about 68,360 h×pg/mL±15,540 h×pg/mL when administered intranasally to a human.

15. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-6 h of hydrocodone of about 99,100 h×pg/mL±20,450 h×pg/mL when administered intranasally to a human.

16. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-8 h of hydrocodone of about 121,100 h×pg/mL±25,710 h×pg/mL when administered intranasally to a human.

17. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-10 h of hydrocodone of about 137,200 h×pg/mL±30,610 h×pg/mL when administered intranasally to a human.

18. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-12 h of hydrocodone of about 149,000 h×pg/mL±34,890 h×pg/mL when administered intranasally to a human.

19. The composition of claim 1 , wherein the conjugate results in the mean AUC 0-24 h of hydrocodone of about 185,500 h×pg/mL±50,470 h×pg/mL when administered intranasally to a human.

20. The composition of claim 1 , wherein the conjugate results in the mean AUC inf of hydrocodone of about 194,700 h×pg/mL±55,690 h×pg/mL when administered intranasally to a human.

21. The composition of claim 1 , wherein the conjugate results in the mean t 1/2 of hydrocodone of about 5.29 hours±0.78 hours when administered intranasally to a human.

22. The composition of claim 1 further comprising 650 mg acetaminophen.

23. The composition of claim 22 , wherein the conjugate results in the mean C max of hydrocodone of about 34,700 pg/mL±8,690 pg/mL when administered intranasally to a human.

24. The composition of claim 22 , wherein the conjugate results in the median T max of hydrocodone of about 1.23 hours when administered intranasally to a human.

25. The composition of claim 22 , wherein the conjugate results in the range of T max of hydrocodone from about 0.52 hours to about 2.23 hours when administered intranasally to a human.

26. The composition of claim 22 , wherein the conjugate results in the mean AUC 0-0.5 h of hydrocodone of about 4,767 h×pg/mL±2,313 h×pg/mL when administered intranasally to a human.

27. The composition of claim 22 , wherein the conjugate results in the mean AUC 0-1 h of hydrocodone of about 18,640 h×pg/mL±6,222 h×pg/mL when administered intranasally to a human.

28. The composition of claim 22 , wherein the conjugate results in the mean AUC 0-2 h of hydrocodone of about 50,120 h×pg/mL±12,060 h×pg/mL when administered intranasally to a human.

29. The composition of claim 22 , wherein the conjugate results in the mean AUC 0-4 h of hydrocodone about 103,200 h×pg/mL±23,210 h×pg/mL when administered intranasally to a human.

30. The composition of claim 22 , wherein the conjugate results in the mean AUC 0-8 h of hydrocodone of about 173,300 h×pg/mL±38,750 h×pg/mL when administered intranasally to a human.

31. The composition of claim 22 , wherein the conjugate results in the mean AUC 0-24 h of hydrocodone of about 264,800 h×pg/mL±67,650 h×pg/mL when administered intranasally to a human.

32. The composition of claim 22 , wherein the conjugate results in the mean AUC inf of hydrocodone of about 278,300 h×pg/mL±75,130 h×pg/mL when administered intranasally to a human.

33. The composition of claim 22 , wherein the conjugate results in the mean t 1/2 of hydrocodone of about 5.23 hours±0.87 hours when administered intranasally to a human.

34. A composition comprising 26.68 mg benzoate-hydrocodone hydrochloride conjugate, wherein the conjugate has the following structure:

35. The composition of claim 34 further comprising 1300 mg acetaminophen.

36. The composition of claim 35 , wherein the conjugate results in the mean C max of hydrocodone of about 75,100 pg/mL±25,500 pg/mL when administered orally to a human.

37. The composition of claim 35 , wherein the conjugate results in the mean T max of hydrocodone of about 1.17 hours when administered orally to a human.

38. The composition of claim 35 , wherein the conjugate results in the range of T max of hydrocodone from about 0.6 hours to about 4.12 hours when administered orally to a human.

39. The composition of claim 35 , wherein the conjugate results in the mean AUC 0-0.5 h of hydrocodone of about 12,530 h×pg/mL±7,213 h×pg/mL when administered orally to a human.

40. The composition of claim 35 , wherein the conjugate results in the mean AUC 0-1 h of hydrocodone of about 42,520 h×pg/mL±20,200 h×pg/mL when administered orally to a human.

41. The composition of claim 35 , wherein the conjugate results in

Assignees

• Kempharm Inc

Inventors

• Mickle Travis
• Guenther Sven
• Mickle Christal
• Chi Guochen
• Kanski Jaroslaw
• Martin Andrea K
• Bera Bindu

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61K31/167 Primary

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• A61K31/485 Primary

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title