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Last Updated: September 21, 2021

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Claims for Patent: 9,549,923


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Summary for Patent: 9,549,923
Title:Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and uses thereof
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.
Inventor(s): Mickle; Travis (Celebration, FL), Guenther; Sven (Coralville, IA), Mickle; Christal (Celebration, FL), Chi; Guochen (Coralville, IA), Kanski; Jaroslaw (Blacksburg, VA), Martin; Andrea K. (Fincastle, VA), Bera; Bindu (Blacksburg, VA)
Assignee: KemPharm, Inc. (Celebration, FL)
Application Number:14/817,581
Patent Claims: 1. A composition comprising 13.34 mg benzoate-hydrocodone hydrochloride conjugate, wherein the conjugate has the following structure: ##STR00025##

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.sub.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.sub.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.sub.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.sub.0-0.083 h of hydrocodone of about 11.30 h.times.pg/mL.+-.14.14 h.times.pg/mL when administered intranasally to a human.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

21. The composition of claim 1, wherein the conjugate results in the mean t.sub.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.sub.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.sub.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.sub.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.sub.0-0.5 h of hydrocodone of about 4,767 h.times.pg/mL.+-.2,313 h.times.pg/mL when administered intranasally to a human.

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

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

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

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

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

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

33. The composition of claim 22, wherein the conjugate results in the mean t.sub.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: ##STR00026##

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.sub.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.sub.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.sub.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.sub.0-0.5 h of hydrocodone of about 12,530 h.times.pg/mL.+-.7,213 h.times.pg/mL when administered orally to a human.

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

41. The composition of claim 35, wherein the conjugate results in the mean AUC.sub.0-2 h of hydrocodone of about 95,850 h.times.pg/mL.+-.29,510 h.times.pg/mL when administered orally to a human.

42. The composition of claim 35, wherein the conjugate results in the mean AUC.sub.0-4 h of hydrocodone of about 172,200 h.times.pg/mL.+-.39,550 h.times.pg/mL when administered orally to a human.

43. The composition of claim 35, wherein the conjugate results in the mean AUC.sub.0-8 h of hydrocodone of about 269,000 h.times.pg/mL.+-.51,840 h.times.pg/mL when administered orally to a human.

44. The composition of claim 35, wherein the conjugate results in the mean AUC.sub.0-24 h of hydrocodone of about 382,100 h.times.pg/mL.+-.81,260 h.times.pg/mL when administered orally to a human.

45. The composition of claim 35, wherein the conjugate results in the mean AUC.sub.inf of hydrocodone of about 392,800 h.times.pg/mL.+-.86,300 h.times.pg/mL when administered orally to a human.

46. The composition of claim 35, wherein the conjugate results in the mean t.sub.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: ##STR00027##

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.sub.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.sub.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.sub.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.sub.0-0.5 h of hydrocodone of about 26,900 h.times.pg/mL.+-.14,770 h.times.pg/mL when administered orally to a human.

53. The composition of claim 48, wherein the conjugate results in the mean AUC.sub.0-1 h of hydrocodone of about 88,750 h.times.pg/mL.+-.42,380 h.times.pg/mL when administered orally to a human.

54. The composition of claim 48, wherein the conjugate results in the mean AUC.sub.0-2 h of hydrocodone of about 193,400 h.times.pg/mL.+-.66,470 h.times.pg/mL when administered orally to a human.

55. The composition of claim 48, wherein the conjugate results in the mean AUC.sub.0-4 h of hydrocodone of about 353,500 h.times.pg/mL.+-.97,670 h.times.pg/mL when administered orally to a human.

56. The composition of claim 48, wherein the conjugate results in the mean AUC.sub.0-8 h of hydrocodone of about 566,900 h.times.pg/mL.+-.128,200 h.times.pg/mL when administered orally to a human.

57. The composition of claim 48, wherein the conjugate results in the mean AUC.sub.0-24 h of hydrocodone of about 811,900 h.times.pg/mL.+-.175,100 h.times.pg/mL when administered orally to a human.

58. The composition of claim 48, wherein the conjugate results in the mean AUC.sub.inf of hydrocodone of about 842,100 h.times.pg/mL.+-.190,800 h.times.pg/mL when administered orally to a human.

59. The composition of claim 48, wherein the conjugate results in the mean t.sub.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: ##STR00028##

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.sub.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.sub.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.sub.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.sub.0-0.5 h of hydrocodone of about 37,140 h.times.pg/mL.+-.22,750 h.times.pg/mL when administered orally to a human.

66. The composition of claim 61, wherein the conjugate results in the mean AUC.sub.0-1 h of hydrocodone of about 121,900 h.times.pg/mL.+-.65,280 h.times.pg/mL when administered orally to a human.

67. The composition of claim 61, wherein the conjugate results in the mean AUC.sub.0-2 h of hydrocodone of about 263,500 h.times.pg/mL.+-.103,300 h.times.pg/mL when administered orally to a human.

68. The composition of claim 61, wherein the conjugate results in the mean AUC.sub.0-4 h of hydrocodone of about 487,500 h.times.pg/mL.+-.154,300 h.times.pg/mL when administered orally to a human.

69. The composition of claim 61, wherein the conjugate results in the mean AUC.sub.0-8 h of hydrocodone of about 816,300 h.times.pg/mL.+-.208,800 h.times.pg/mL when administered orally to a human.

70. The composition of claim 61, wherein the conjugate results in the mean AUC.sub.0-24 h of hydrocodone of about 1, 217,00 h.times.pg/mL.+-.296,800 h.times.pg/mL when administered orally to a human.

71. The composition of claim 61, wherein the conjugate results in the mean AUC.sub.inf of hydrocodone of about 1,272,000 h.times.pg/mL.+-.326,500 h.times.pg/mL when administered orally to a human.

72. The composition of claim 61, wherein the conjugate results in the mean t.sub.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.sub.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.sub.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.sub.max) and mean overall hydrocodone exposure (AUC.sub.last and AUC.sub.inf) after oral administration to a human from about 80% to about 125% when compared to an equimolar dose of hydrocodone bitartrate.

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