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:
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 the mean AUC 0-2 h of hydrocodone of about 95,850 h×pg/mL±29,510 h×pg/mL when administered orally to a human.
42. The composition of claim 35 , wherein the conjugate results in the mean AUC 0-4 h of hydrocodone of about 172,200 h×pg/mL±39,550 h×pg/mL when administered orally to a human.
43. The composition of claim 35 , wherein the conjugate results in the mean AUC 0-8 h of hydrocodone of about 269,000 h×pg/mL±51,840 h×pg/mL when administered orally to a human.
44. The composition of claim 35 , wherein the conjugate results in the mean AUC 0-24 h of hydrocodone of about 382,100 h×pg/mL±81,260 h×pg/mL when administered orally to a human.
45. The composition of claim 35 , 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.
46. The composition of claim 35 , 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.
47. A composition comprising 53.36 mg benzoate-hydrocodone hydrochloride conjugate, wherein the conjugate has the following structure:
48. The composition of claim 47 further comprising 2600 mg acetaminophen.
49. The composition of claim 48 , 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.
50. The composition of claim 48 , wherein the conjugate results in the mean T max of hydrocodone of about 1.05 hours when administered orally to a human.
51. The composition of claim 48 , 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.
52. The composition of claim 48 , wherein the conjugate results in the mean AUC 0-0.5 h of hydrocodone of about 26,900 h×pg/mL±14,770 h×pg/mL when administered orally to a human.
53. The composition of claim 48 , wherein the conjugate results in the mean AUC 0-1 h of hydrocodone of about 88,750 h×pg/mL±42,380 h×pg/mL when administered orally to a human.
54. The composition of claim 48 , wherein the conjugate results in the mean AUC 0-2 h of hydrocodone of about 193,400 h×pg/mL±66,470 h×pg/mL when administered orally to a human.
55. The composition of claim 48 , wherein the conjugate results in the mean AUC 0-4 h of hydrocodone of about 353,500 h×pg/mL±97,670 h×pg/mL when administered orally to a human.
56. The composition of claim 48 , wherein the conjugate results in the mean AUC 0-8 h of hydrocodone of about 566,900 h×pg/mL±128,200 h×pg/mL when administered orally to a human.
57. The composition of claim 48 , wherein the conjugate results in the mean AUC 0-24 h of hydrocodone of about 811,900 h×pg/mL±175,100 h×pg/mL when administered orally to a human.
58. The composition of claim 48 , 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.
59. The composition of claim 48 , 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.
60. A composition comprising 80.04 mg benzoate-hydrocodone conjugate, wherein the conjugate has the following structure:
61. The composition of claim 60 further comprising 3900 mg acetaminophen.
62. The composition of claim 61 , 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.
63. The composition of claim 61 , wherein the conjugate results in the mean T max of hydrocodone of about 1.05 hours when administered orally to a human.
64. The composition of claim 61 , 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.
65. The composition of claim 61 , wherein the conjugate results in the mean AUC 0-0.5 h of hydrocodone of about 37,140 h×pg/mL±22,750 h×pg/mL when administered orally to a human.
66. The composition of claim 61 , wherein the conjugate results in the mean AUC 0-1 h of hydrocodone of about 121,900 h×pg/mL±65,280 h×pg/mL when administered orally to a human.
67. The composition of claim 61 , wherein the conjugate results in the mean AUC 0-2 h of hydrocodone of about 263,500 h×pg/mL±103,300 h×pg/mL when administered orally to a human.
68. The composition of claim 61 , wherein the conjugate results in the mean AUC 0-4 h of hydrocodone of about 487,500 h×pg/mL±154,300 h×pg/mL when administered orally to a human.
69. The composition of claim 61 , wherein the conjugate results in the mean AUC 0-8 h of hydrocodone of about 816,300 h×pg/mL±208,800 h×pg/mL when administered orally to a human.
70. The composition of claim 61 , wherein the conjugate results in the mean AUC 0-24 h of hydrocodone of about 1, 217,00 h×pg/mL±296,800 h×pg/mL when administered orally to a human.
71. The composition of claim 61 , 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.
72. The composition of claim 61 , 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.
73. An abuse-deterrent oral formulation comprising:
the composition of claim 1 wherein intranasal administration to a human results in mean peak hydrocodone plasma concentrations (C max ) from about 60% to about 69%, and in mean cumulative hydrocodone exposure (AUC) from about 10% to about 14% between 0 to 1 hour postdose, from about 42% to about 52% between 0 and 2 hours postdose, from about 60% to about 68% between 0 and 4 hours postdose, from about 70% to about 76% between 0 and 8 hours postdose, from about 73% to about 83% between 0 and 12 hours postdose and from about 76% to about 83% between 0 and 24 hours postdose when compared to an equimolar dose of hydrocodone bitartrate.
74. An abuse-deterrent oral formulation comprising:
the composition of claim 22 wherein intranasal administration to a human results in mean peak hydrocodone plasma concentrations (C max ) from about 96% to about 109%, and in mean cumulative hydrocodone exposure (AUC) from about 44% to about 60% between 0 to 1 hour postdose, from about 75% to about 87% between 0 and 2 hours postdose, from about 84% to about 92% between 0 and 4 hours postdose, from about 86% to about 93% between 0 and 8 hours postdose, and from about 86% to about 93% between 0 and 24 hours postdose when compared to an equimolar dose of hydrocodone bitartrate.
75. An abuse-deterrent oral formulation comprising:
a therapeutic dose of benzoate-hydrocodone hydrochloride conjugate 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.