Controlled Release Formulations of Opioids

• US 20130022646A1
• Filed: 04/09/2012
• Published: 01/24/2013
• Est. Priority Date: 02/09/2010
• Status: Abandoned Application

• Current Assignee: Qrxpharma Ltd.
• Original Assignee: Qrxpharma Ltd.
• Inventors: Rudnic, Edward M., Vachon, Michael, Pace, Gary W.
• Application Number:
  US13/442,849
• Publication Number:
  US 20130022646A1
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

Pharmaceutical formulations containing opioid components that each has a release profile. The components may provide immediate or controlled release of the opioid. The invention is also directed to methods of controlling release of one or more opioid compounds and methods of treating pain.

Claims

1. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:

(a) the controlled release component comprises one or more cores;

(b) the controlled release component comprises oxycodone;

(c) the pharmaceutical formulation comprises a steady state plasma concentration profile of the oxycodone having a fluctuation index of about 90% or less; and

(d) the pharmaceutical formulation, when containing a total dose of about 20 mg of oxycodone and administered at a dosing interval of 12 hours, will produce an AUC_ss,τ

that is about 100 ng*h/mL to about 550 ng*h/mL.

2. The pharmaceutical formulation of claim 1, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone and administered at a dosing interval of 12 hours, C_ss,max of oxycodone is about 10 ng/mL to about 50 ng/mL.

3. The pharmaceutical formulation of claim 1, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone and administered at a dosing interval of 12 hours, t_ss,max of oxycodone is about 1 hour to about 10 hours.

4. The pharmaceutical formulation of claim 1, wherein when the pharmaceutical formulation contains a different total dose of oxycodone than about 20 mg, AUC_ss,τ

of oxycodone at the different total dose is proportional to AUC_ss,τ

of oxycodone at 20 mg.

5. The pharmaceutical formulation of claim 2, wherein when the pharmaceutical formulation contains a different total dose of oxycodone than about 20 mg, C_ss,max of oxycodone at the different total dose is proportional to C_ss,max of oxycodone at 20 mg.

6. The pharmaceutical formulation of claim 1, wherein the controlled release component further comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.

7. The pharmaceutical formulation of claim 6, wherein the controlled release component comprises morphine or salts thereof.

8. The pharmaceutical formulation of claim 7, wherein the morphine is in the form of morphine sulfate and the oxycodone is in the form of oxycodone hydrochloride.

9. The pharmaceutical formulation of claim 1, in the form of a tablet or capsule.

10. The pharmaceutical formulation of claim 9, wherein the form is a tablet.

11. The pharmaceutical formulation of claim 1, wherein the controlled release component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.

12. The pharmaceutical formulation of claim 11, wherein the controlled release component is in the form of a beadlet.

13. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation further comprises an abuse deterrent component.

14. The pharmaceutical formulation of claim 13, wherein the abuse deterrent component comprises a core comprising one or more materials that are both hydrophilic and hydrophobic.

15. The pharmaceutical formulation of claim 14, wherein the material that is both hydrophilic and hydrophobic is acrylic acid cross-linked with allyl ethers of polyalcohols.

16. The pharmaceutical formulation of claim 15, wherein the acrylic acid cross-linked with allyl ethers of polyalcohols is a carbomer.

17. The pharmaceutical formulation of claim 13, wherein the abuse deterrent component comprises a coating.

18. The pharmaceutical formulation of claim 13, wherein the abuse deterrent component further comprises an alkalizing agent.

19. The pharmaceutical formulation of claim 18, wherein the alkalizing agent is meglumine.

20. The pharmaceutical formulation of claim 13, wherein the abuse deterrent component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.

21. The pharmaceutical formulation of claim 20, wherein the abuse deterrent component is in the form of a beadlet.

22. The pharmaceutical formulation of claim 1, further comprising one or more fillers or diluents, one or more hydrophilic polymers, one or more disintegrants, and one or more lubricants.

23. The pharmaceutical formulation of claim 22, wherein the one or more fillers or diluents comprises microcrystalline cellulose.

24. The pharmaceutical formulation of claim 22, wherein the one or more hydrophilic polymers comprises a carbomer.

25. The pharmaceutical formulation of claim 22, wherein the one or more disintegrants comprises croscarmellose sodium.

26. The pharmaceutical formulation of claim 22, wherein the one or more lubricants comprises magnesium stearate.

109. A method of controlling release of one or more compounds having opioid receptor agonist activity for absorption in a human, wherein the method comprises administering the pharmaceutical formulation of claim 1, 27, 53, 79, or 105.

110. A method of treating pain in a human, comprising administering the pharmaceutical formulation of claim 1, 27, 53, 79, or 105.

27. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:

(a) the controlled release component comprises one or more cores;

(b) the controlled release component comprises oxycodone; and

(c) the pharmaceutical formulation, when containing a total dose of about 20 mg of oxycodone, C_max is about 5 ng/mL to about 15 ng/mL following a single administration of the pharmaceutical formulation.

28. The pharmaceutical formulation of claim 27, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone, t_max of oxycodone is about 4 hours to about 24 hours following a single administration of the pharmaceutical formulation.

29. The pharmaceutical formulation of claim 27, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone, AUC_t of oxycodone is about 70 ng*h/mL to about 352 ng*h/mL following a single administration of the pharmaceutical formulation.

30. The pharmaceutical formulation of claim 27, wherein when the pharmaceutical formulation contains a different total dose of oxycodone than about 20 mg, C_max of oxycodone at the different total dose is proportional to C_max of oxycodone at 20 mg.

31. The pharmaceutical formulation of claim 29, wherein when the pharmaceutical formulation contains a different total dose of oxycodone than about 20 mg, AUC_t of oxycodone at the different total dose is proportional to AUC_t of oxycodone at 20 mg.

32. The pharmaceutical formulation of claim 27, wherein the controlled release component further comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.

33. The pharmaceutical formulation of claim 32, wherein the controlled release component comprises morphine or salts thereof.

34. The pharmaceutical formulation of claim 33, wherein the morphine is in the form of morphine sulfate and the oxycodone is in the form of oxycodone hydrochloride.

35. The pharmaceutical formulation of claim 27, in the form of a tablet or capsule.

36. The pharmaceutical formulation of claim 35, wherein the form is a tablet.

37. The pharmaceutical formulation of claim 27, wherein the controlled release component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.

38. The pharmaceutical formulation of claim 37, wherein the controlled release component is in the form of a beadlet.

39. The pharmaceutical formulation of claim 27, wherein the pharmaceutical formulation further comprises an abuse deterrent component.

40. The pharmaceutical formulation of claim 39, wherein the abuse deterrent component comprises a core comprising one or more materials that are both hydrophilic and hydrophobic.

41. The pharmaceutical formulation of claim 40, wherein the material that is both hydrophilic and hydrophobic is acrylic acid cross-linked with allyl ethers of polyalcohols.

42. The pharmaceutical formulation of claim 41, wherein the acrylic acid cross-linked with allyl ethers of polyalcohols is a carbomer.

43. The pharmaceutical formulation of claim 39, wherein the abuse deterrent component comprises a coating.

44. The pharmaceutical formulation of claim 39, wherein the abuse deterrent component further comprises an alkalizing agent.

45. The pharmaceutical formulation of claim 44, wherein the alkalizing agent is meglumine.

46. The pharmaceutical formulation of claim 39, wherein the abuse deterrent component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.

48. The pharmaceutical formulation of claim 27, further comprising one or more fillers or diluents, one or more hydrophilic polymers, one or more disintegrants, and one or more lubricants.

49. The pharmaceutical formulation of claim 48, wherein the one or more fillers or diluents comprises microcrystalline cellulose.

50. The pharmaceutical formulation of claim 48, wherein the one or more hydrophilic polymers comprises a carbomer.

51. The pharmaceutical formulation of claim 48, wherein the one or more disintegrants comprises croscarmellose sodium.

52. The pharmaceutical formulation of claim 48, wherein the one or more lubricants comprises magnesium stearate.

47. The pharmaceutical formulation of 46, wherein the abuse deterrent component is in the form of a beadlet.

53. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:

(a) the controlled release component comprises one or more cores;

(b) the controlled release component comprises morphine;

(c) the pharmaceutical formulation comprises a steady state plasma concentration profile of the morphine having a fluctuation index of about 90% or less; and

(d) the pharmaceutical formulation, when containing a total dose of about 30 mg of morphine and administered at a dosing interval of 12 hours, will produce an AUC_ss,τ

that is about 60 ng*h/mL to about 240 ng*h/mL.

54. The pharmaceutical formulation of claim 53, wherein when the pharmaceutical formulation contains about 30 mg of morphine and administered at a dosing interval of 12 hours, C_ss,max of morphine is about 8 ng/mL to about 29 ng/mL.

55. The pharmaceutical formulation of claim 53, wherein when the pharmaceutical formulation contains about 30 mg of morphine and administered at a dosing interval of 12 hours, t_ss,max of morphine is about 1 hour to about 5 hours.

56. The pharmaceutical formulation of claim 53, wherein when the pharmaceutical formulation contains a different total dose of morphine than about 30 mg, AUC_ss,τ

of morphine at the different total dose is proportional to AUC_ss,τ

of morphine at 30 mg.

57. The pharmaceutical formulation of claim 54, wherein when the pharmaceutical formulation contains a different total dose of morphine than about 30 mg, C_ss,max of morphine at the different total dose is proportional to C_ss,max of morphine at 30 mg.

58. The pharmaceutical formulation of claim 53, wherein the controlled release component further comprises an opioid selected from the group consisting of oxycodone, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.

59. The pharmaceutical formulation of claim 58, wherein the controlled release component comprises oxycodone or salts thereof.

60. The pharmaceutical formulation of claim 59, wherein the oxycodone is in the form of oxycodone hydrochloride and the morphine is in the form of morphine sulfate.

61. The pharmaceutical formulation of claim 53, in the form of a tablet or capsule.

62. The pharmaceutical formulation of claim 61, wherein the form is a tablet.

63. The pharmaceutical formulation of claim 53, wherein the controlled release component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.

64. The pharmaceutical formulation of claim 63, wherein the controlled release component is in the form of a beadlet.

65. The pharmaceutical formulation of claim 53, wherein the pharmaceutical formulation further comprises an abuse deterrent component.

66. The pharmaceutical formulation of claim 65, wherein the abuse deterrent component comprises a core comprising one or more materials that are both hydrophilic and hydrophobic.

67. The pharmaceutical formulation of claim 66, wherein the material that is both hydrophilic and hydrophobic is acrylic acid cross-linked with allyl ethers of polyalcohols.

68. The pharmaceutical formulation of claim 67, wherein the acrylic acid cross-linked with allyl ethers of polyalcohols is a carbomer.

69. The pharmaceutical formulation of claim 65, wherein the abuse deterrent component comprises a coating.

70. The pharmaceutical formulation of claim 65, wherein the abuse deterrent component further comprises an alkalizing agent.

71. The pharmaceutical formulation of claim 70, wherein the alkalizing agent is meglumine.

72. The pharmaceutical formulation of claim 65, wherein the abuse deterrent component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.

74. The pharmaceutical formulation of claim 53, further comprising one or more fillers or diluents, one or more hydrophilic polymers, one or more disintegrants, and one or more lubricants.

75. The pharmaceutical formulation of claim 74, wherein the one or more fillers or diluents comprises microcrystalline cellulose.

76. The pharmaceutical formulation of claim 74, wherein the one or more hydrophilic polymers comprises a carbomer.

77. The pharmaceutical formulation of claim 74, wherein the one or more disintegrants comprises croscarmellose sodium.

78. The pharmaceutical formulation of claim 74, wherein the one or more lubricants comprises magnesium stearate.

73. The pharmaceutical formulation of 72, wherein the abuse deterrent component is in the form of a beadlet.

79. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:

(a) the controlled release component comprises one or more cores;

(b) the controlled release component comprises morphine;

(c) the pharmaceutical formulation, when containing a total dose of about 30 mg of morphine, C_max is about 1 ng/mL to about 11 ng/mL following a single administration of the pharmaceutical formulation.

80. The pharmaceutical formulation of claim 79, wherein when the pharmaceutical formulation contains about 30 mg of morphine, t_max of morphine is about 3 hours to about 25 hours following a single administration of the pharmaceutical formulation.

81. The pharmaceutical formulation of claim 79, wherein when the pharmaceutical formulation contains about 30 mg of morphine, AUC_t of morphine is about 60 ng*h/mL to about 433 ng*h/mL following a single administration of the pharmaceutical formulation.

82. The pharmaceutical formulation of claim 79, wherein when the pharmaceutical formulation contains a different total dose of morphine than about 30 mg, C_max of morphine at the different total dose is proportional to C_max of morphine at 30 mg.

83. The pharmaceutical formulation of claim 79, wherein when the pharmaceutical formulation contains a different total dose of morphine than about 30 mg, AUC_t of morphine at the different total dose is proportional to AUC_t of morphine at 30 mg.

84. The pharmaceutical formulation of claim 79, wherein the controlled release component further comprises an opioid selected from the group consisting of oxycodone, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.

85. The pharmaceutical formulation of claim 84, wherein the controlled release component comprises oxycodone or salts thereof.

86. The pharmaceutical formulation of claim 85, wherein the oxycodone is in the form of oxycodone hydrochloride and the morphine is in the form of morphine sulfate.

87. The pharmaceutical formulation of claim 79, in the form of a tablet or capsule.

88. The pharmaceutical formulation of claim 87, wherein the form is a tablet.

89. The pharmaceutical formulation of claim 79, wherein the controlled release component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.

90. The pharmaceutical formulation of claim 89, wherein the controlled release component is in the form of a beadlet.

91. The pharmaceutical formulation of claim 79, wherein the pharmaceutical formulation further comprises an abuse deterrent component.

92. The pharmaceutical formulation of claim 91, wherein the abuse deterrent component comprises a core comprising one or more materials that are both hydrophilic and hydrophobic.

93. The pharmaceutical formulation of claim 92, wherein the material that is both hydrophilic and hydrophobic is acrylic acid cross-linked with allyl ethers of polyalcohols.

94. The pharmaceutical formulation of claim 93, wherein the acrylic acid cross-linked with allyl ethers of polyalcohols is a carbomer.

95. The pharmaceutical formulation of claim 91, wherein the abuse deterrent component comprises a coating.

96. The pharmaceutical formulation of claim 91, wherein the abuse deterrent component further comprises an alkalizing agent.

97. The pharmaceutical formulation of claim 96, wherein the alkalizing agent is meglumine.

98. The pharmaceutical formulation of claim 91, wherein the abuse deterrent component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.

100. The pharmaceutical formulation of claim 79, further comprising one or more fillers or diluents, one or more hydrophilic polymers, one or more disintegrants, and one or more lubricants.

101. The pharmaceutical formulation of claim 100, wherein the one or more fillers or diluents comprises microcrystalline cellulose.

102. The pharmaceutical formulation of claim 100, wherein the one or more hydrophilic polymers comprises a carbomer.

103. The pharmaceutical formulation of claim 100, wherein the one or more disintegrants comprises croscarmellose sodium.

104. The pharmaceutical formulation of claim 100, wherein the one or more lubricants comprises magnesium stearate.

99. The pharmaceutical formulation of 98, wherein the abuse deterrent component is in the form of a beadlet.

105. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:

(a) the controlled release component comprises one or more cores;

(b) the controlled release component comprises oxycodone hydrochloride and morphine sulfate;

(c) the pharmaceutical formulation, when containing a total dose of about 20 mg of oxycodone hydrochloride, C_max of oxycodone is about 5 ng/mL to about 15 ng/mL following a single administration of the pharmaceutical formulation; and

(d) the pharmaceutical formulation, when containing a total dose of about 30 mg of morphine sulfate, C_max of morphine is about 1 ng/mL to about 11 ng/mL following a single administration of the pharmaceutical formulation.

106. The pharmaceutical formulation of claim 105, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone hydrochloride and 30 mg of morphine sulfate, t_max is about 4 hours to about 24 hours for oxycodone and about 3 hours to about 25 hours for morphine following a single administration of the pharmaceutical formulation.

107. The pharmaceutical formulation of claim 105, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone hydrochloride and 30 mg of morphine sulfate, AUC_t is about 70 ng*h/mL to about 352 ng*h/mL for oxycodone and about 60 ng*h/mL to about 433 ng*h/mL for morphine following a single administration of the pharmaceutical formulation.

108. The pharmaceutical formulation of claim 105, wherein the pharmaceutical formulation further comprises an abuse deterrent component.