Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and uses 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 13.34 mg benzoate-hydrocodone hydrochloride conjugate, wherein the conjugate has the following structure:
wherein the conjugate is provided in a gel formulation.
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 gel formulation further comprises a soft gel.
4. The composition of claim 1 further comprising 650 mg acetaminophen.
5. A composition comprising 26.68 mg benzoate-hydrocodone hydrochloride conjugate, wherein the conjugate has the following structure:
wherein the conjugate is further provided in a gel formulation.
6. The composition of claim 5 further comprising 1300 mg acetaminophen.
7. The composition of claim 6 , 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.
8. The composition of claim 6 , wherein the conjugate results in the mean T max of hydrocodone of about 1.17 hours when administered orally to a human.
9. The composition of claim 6 , 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.
10. The composition of claim 6 , wherein the conjugate results in the mean AUC 0-0.5h of hydrocodone of about 12,530 h×pg/mL±7,213 h×pg/mL when administered orally to a human.
11. The composition of claim 6 , wherein the conjugate results in the mean AUC 0-1h of hydrocodone of about 42,520 h×pg/mL±20,200 h×pg/mL when administered orally to a human.
12. The composition of claim 6 , wherein the conjugate results in the mean AUC 0-2h of hydrocodone of about 95,850 h×pg/mL±29,510 h×pg/mL when administered orally to a human.
13. The composition of claim 6 , wherein the conjugate results in the mean AUC 0-4h of hydrocodone of about 172,200 h×pg/mL±39,550 h×pg/mL when administered orally to a human.
14. The composition of claim 6 , wherein the conjugate results in the mean AUC 0-8h of hydrocodone of about 269,000 h×pg/mL±51,840 h×pg/mL when administered orally to a human.
15. The composition of claim 6 , wherein the conjugate results in the mean AUC 0-24h of hydrocodone of about 382,100 h×pg/mL±81,260 h×pg/mL when administered orally to a human.
16. The composition of claim 6 , wherein the conjugate results in the mean AUC inf of hydrocodone of about 392,800 h×pg/mL±86,300 h×pg/mL when administered orally to a human.
17. The composition of claim 6 , wherein the conjugate results in the mean t 1/2 of hydrocodone of about 4.99 hours±0.79 hours when administered orally to a human.
18. A composition comprising 53.36 mg benzoate-hydrocodone hydrochloride conjugate, wherein the conjugate has the following structure:
wherein the conjugate is provided in a gel formulation.
19. The composition of claim 18 further comprising 2600 mg acetaminophen.
20. The composition of claim 19 , wherein the conjugate results in the mean C max of hydrocodone of about 147,000 pg/mL±54,100 pg/mL when administered orally to a human.
21. The composition of claim 19 , wherein the conjugate results in the mean T max of hydrocodone of about 1.05 hours when administered orally to a human.
22. The composition of claim 19 , 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.
23. The composition of claim 19 , wherein the conjugate results in the mean AUC 0-0.5h of hydrocodone of about 26,900 h×pg/mL±14,770 h×pg/mL when administered orally to a human.
24. The composition of claim 19 , wherein the conjugate results in the mean AUC 0-1h of hydrocodone of about 88,750 h×pg/mL±42,380 h×pg/mL when administered orally to a human.
25. The composition of claim 19 , wherein the conjugate results in the mean AUC 0-21 , of hydrocodone of about 193,400 h×pg/mL±66,470 h×pg/mL when administered orally to a human.
26. The composition of claim 19 , wherein the conjugate results in the mean AUC 0-4h of hydrocodone of about 353,500 h×pg/mL±97,670 h×pg/mL when administered orally to a human.
27. The composition of claim 19 , wherein the conjugate results in the mean AUC 0-8h of hydrocodone of about 566,900 h×pg/mL±128,200 h×pg/mL when administered orally to a human.
28. The composition of claim 19 , wherein the conjugate results in the mean AUC 0-4h of hydrocodone of about 811,900 h×pg/mL±175,100 h×pg/mL when administered orally to a human.
29. The composition of claim 19 , wherein the conjugate results in the mean AUC inf of hydrocodone of about 842,100 h×pg/mL±190,800 h×pg/mL when administered orally to a human.
30. The composition of claim 19 , wherein the conjugate results in the mean t 1/2 of hydrocodone of about 4.92 hours±0.95 hours when administered orally to a human.
31. A composition comprising 80.04 mg benzoate-hydrocodone conjugate, wherein the conjugate has the following structure:
wherein the conjugate is provided in a gel formulation.
32. The composition of claim 31 further comprising 3900 mg acetaminophen.
33. The composition of claim 31 , wherein the conjugate results in the mean C max of hydrocodone of about 208,000 pg/mL±87,300 pg/mL when administered orally to a human.
34. The composition of claim 31 , wherein the conjugate results in the mean T max of hydrocodone of about 1.05 hours when administered orally to a human.
35. The composition of claim 31 , wherein the conjugate results in the range of T max of hydrocodone from about 0.6 hours to about 4.15 hours when administered orally to a human.
36. The composition of claim 31 , wherein the conjugate results in the mean AUC 0-0.5h of hydrocodone of about 37,140 h×pg/mL±22,750 h×pg/mL when administered orally to a human.
37. The composition of claim 31 , wherein the conjugate results in the mean AUC 0-1h of hydrocodone of about 121,900 h×pg/mL±65,280 h×pg/mL when administered orally to a human.
38. The composition of claim 31 , wherein the conjugate results in the mean AUC 0-2h of hydrocodone of about 263,500 h×pg/mL±103,300 h×pg/mL when administered orally to a human.
39. The composition of claim 31 , wherein the conjugate results in the mean AUC 0-4h of hydrocodone of about 487,500 h×pg/mL±154,300 h×pg/mL when administered orally to a human.
40. The composition of claim 31 , wherein the conjugate results in the mean AUC 0-8h of hydrocodone of about 816,300 h×pg/mL±208,800 h×pg/mL when administered orally to a human.
41. The composition of claim 31 , wherein the conjugate results in the mean AUC 0-24h of hydrocodone of about 1, 217, 00 h×pg/mL±296,800 h×pg/mL when administered orally to a human.
42. The composition of claim 31 , wherein the conjugate results in the mean AUC inf of hydrocodone of about 1,272,000 h×pg/mL±326,500 h×pg/mL when administered orally to a human.
43. The composition of claim 31 , wherein the conjugate results in the mean t 1/2 of hydrocodone of about 5 hours±1.79 hours when administered orally to a human.
44. An abuse-deterrent oral formulation comprising:
a therapeutic dose of benzoate-hydrocodone conjugate hydrochloride wherein the conjugate is provided in a gel formulation that results in mean peak hydrocodone plasma concentrations (C max ) and mean overall hydrocodone exposure (AUC last and AUC inf ) after oral administration to a human from about 80% to about 125% when compared to an equimolar dose of hydrocodone bitartrate.
45. The composition of claim 5 , wherein the gel formulation further comprises a soft gel.
46. The composition of claim 18 , wherein the gel formation further comprises a soft gel.
47. The composition of claim 31 , wherein the gel formation further comprises a soft gel.