Once-a-day, oral, controlled-release, oxycodone dosage forms

• US 20050106249A1
• Filed: 10/28/2004
• Published: 05/19/2005
• Est. Priority Date: 04/29/2002
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Hwang, Stephen, Modi, Nishit B., Shivanand, Padmaja
• Application Number:
  US10/977,403
• Publication Number:
  US 20050106249A1
• Time in Patent Office: Days
• US Class Current: 424/469
• 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 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Abstract

Oxycodone formulations are provided which produce substantially flat in vivo steady state plasma profiles. Tolerance levels associated with such profiles and tolerance levels associated with biphasic profiles are shown not to be statistically different. The substantially flat in vivo steady state plasma profiles are produced by dosage forms having substantially zero order in vitro release profiles. Such release profiles produce low single dose in vivo C_max levels which can reduce the probability of adverse side effects.

Claims

1. A controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

said formulation providing (a) a mean, single dose, maximum plasma concentration C_max and (b) a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC_0-48 which satisfy the relationships;

3.5×

10<sup>−

4</sup> liter<sup>−

1</sup>≦

C_max/D≦

6.8×

10<sup>−

4</sup> liter<sup>−

1</sup>, and
7.6×

10<sup>−

3</sup> hour/liter≦

AUC_0-48/D≦

16.7×

10<sup>−

3</sup> hour/liter,

wherein said formulation provides pain relief for about 24 hours or more after administration to the patient.

2. The formulation of claim 1 wherein C_max and AUC_0-48 are determined using plasma samples from individuals to whom one or more opioid antagonists have been administered.

3. The formulation of claim 1 wherein C_max and AUC_0-48 are determined using plasma samples from individuals to whom naltrexone has been administered.

4. The formulation of claim 1 wherein C_max and AUC_0-48 are determined using plasma samples from individuals who have not been administered an opioid antagonist.

5. The formulation of claim 1 wherein C_max and AUC_0-48 are determined using plasma samples from individuals who have not been administered naltrexone.

6. The formulation of claim 1, 2, or 4 wherein said formulation provides a mean, single dose, time to maximum plasma concentration T_max which satisfies the relationship:

T_max>

17 hours;

7. The formulation of claim 6 wherein T_max satisfies the relationship:

T_max>

18 hours.

8. The formulation of claim 6 wherein T_max satisfies the relationship:

T_max>

19 hours.

9. The formulation of claim 1, 2, or 4 wherein said formulation provides a mean, single dose, time to maximum plasma concentration T_max, and D, C_max, and T_max satisfy the relationship:

C_max/(T_max·

D)≦

3×

10<sup>−

4</sup> (liter·

hour)<sup>−

1</sup>.

10. The formulation of claim 9 wherein D, C_max, and T_max satisfy the relationship:

2×

10<sup>−

5</sup> (liter·

hour)<sup>−

1</sup>≦

C_max/(T_max·

D)≦

6×

10<sup>−

5</sup> (liter·

hour)⁻

.

11. The formulation of claim 1, 2, or 4 wherein said formulation provides mean, single dose, areas under a plasma concentration-time curve for 0-12 hours AUC_0-12 and for 12-24 hours AUC_12-24 which satisfy the relationship:

AUC_12-24/AUC_0-12>

1.0.

12. The formulation of claim 11 wherein AUC_0-12 and AUC_12-24 satisfy the relationship:

AUC_12-24/AUC_0-12>

1.5.

13. The formulation of claim 11 wherein AUC_0-12 and AUC_12-24 satisfy the relationship:

AUC_12-24/AUC_0-12>

1.7.

14. The formulation of claim 11 wherein AUC_0-12 and AUC_12-24 satisfy the relationship:

AUC_12-24/AUC_0-12>

2.0.

15. The formulation of claim 1, 2, or 4 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

16. The formulation of claim 15 where D is about 20 mg and W is about 0.05.

17. A controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

wherein;

(a) the formulation provides a mean, single dose, plasma concentration profile that increases substantially monotonically over 24 hours or more;

(b) the formulation provides a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC_0-48 which satisfies the relationship;

7.6×

10<sup>−

3</sup> hour/liter≦

AUC_0-48/D<

16.7×

10<sup>−

3</sup> hour/liter; and

(c) the formulation provides pain relief for about 24 hours or more after administration to the patient.

18. The formulation of claim 17 wherein AUC_0-48 and the mean, single dose, plasma concentration profile are determined using plasma samples from individuals to whom one or more opioid antagonists have been administered.

19. The formulation of claim 17 wherein AUC_0-48 and the mean, single dose, plasma concentration profile are determined using plasma samples from individuals to whom naltrexone has been administered.

20. The formulation of claim 17 wherein AUC_0-48 and the mean, single dose, plasma concentration profile are determined using plasma samples from individuals who have not been administered an opioid antagonist.

21. The formulation of claim 17 wherein AUC_0-48 and the mean, single dose, plasma concentration profile are determined using plasma samples from individuals who have not been administered naltrexone.

22. The formulation of claim 17, 18, or 20 wherein the mean, single dose, plasma concentration profile comprises a first rising phase and a second phase, where the slope of the first rising phase is greater than the magnitude of the slope of the second phase.

23. The formulation of claim 22 wherein the transition between the first rising phase and the second phase occurs between 12 and 16 hours.

24. The formulation of claim 23 wherein the first rising phase comprises a first subphase and a second subphase, where the first subphase rises faster than the second subphase.

25. The formulation of claim 24 wherein the transition between the first subphase and the second subphase occurs between 1 and 3 hours.

26. The formulation of claim 17, 18, or 20 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

27. The formulation of claim 26 where D is about 20 mg and W is about 0.05.

28. A controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

said formulation providing (a) a mean, single dose, 12 hour plasma concentration C₁₂ and (b) a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC_0-48 which satisfy the relationships;

2.7×

10<sup>−

4</sup> liter<sup>−

1</sup><

C₁₂/D≦

5.7×

10<sup>−

4</sup> liter<sup>−

1</sup>, and
7.6×

10<sup>−

3</sup> hour/liter≦

AUC_0-48/D≦

16.7×

10<sup>−

3</sup> hour/liter,

wherein said formulation provides pain relief for about 24 hours or more after administration to the patient.

29. The formulation of claim 28 wherein C₁₂ and AUC_0-48 are determined using plasma samples from individuals to whom one or more opioid antagonists have been administered.

30. The formulation of claim 28 wherein C₁₂ and AUC_0-48 are determined using plasma samples from individuals to whom naltrexone has been administered.

31. The formulation of claim 28 wherein C₁₂ and AUC_0-48 are determined using plasma samples from individuals who have not been administered an opioid antagonist.

32. The formulation of claim 28 wherein C₁₂ and AUC_0-48 are determined using plasma samples from individuals who have not been administered naltrexone.

33. The formulation of claim 28, 29, or 31 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

34. The formulation of claim 33 where D is about 20 mg and W is about 0.05.

35. A controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

said formulation providing mean, steady state, areas under a plasma concentration-time curve for 0-6 hours AUC_0-6, 6-12 hours AUC_6-12, 12-18 hours AUC_12-18, 18-24 hours AUC_18-24, and 0-24 hours AUC_0-24 which satisfy the relationships;

AUC_0-6/AUC_0-24>

0.18,
AUC_6-12/AUC_0-24>

0.18,
AUC_12-18/AUC_0-24>

0.18, and
AUC_18-24/AUC_0-24>

0.18,

wherein said formulation provides pain relief for about 24 hours or more after administration to the patient.

36. The formulation of claim 35 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24 and AUC_0-24 are determined using plasma samples from individuals to whom one or more opioid antagonists have been administered.

37. The formulation of claim 35 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24 and AUC_0-24 are determined using plasma samples from individuals to whom naltrexone has been administered.

38. The formulation of claim 35 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24 and AUC_0-24 are determined using plasma samples from individuals who have not been administered an opioid antagonist.

39. The formulation of claim 35 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24 and AUC_0-24 are determined using plasma samples from individuals who have not been administered naltrexone.

40. The formulation of claim 35, 36, or 38 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24, and AUC_0-24 satisfy the relationships:

AUC_0-6/AUC_0-24>

0.20,
AUC_6-12/AUC_0-24>

0.20,
AUC_12-18/AUC_0-24>

0.20, and
AUC_18-24/AUC_0-24>

0.20.

41. The formulation of claim 35, 36, or 38 wherein the magnitude of the difference between any two of AUC_0-6/AUC_0-24, AUC_6-12/AUC_0-24, AUC_12-18/AUC_0-24, and AUC_18-24/AUC_0-24 is less than or equal to 0.05.

42. The formulation of claim 41 wherein the magnitude of the difference between each of:

AUC_0-6/AUC_0-24 and AUC_6-12/AUC_0-24,

AUC_6-12/AUC_0-24 and AUC_12-18/AUC_0-24,

AUC_12-18/AUC_0-24 and AUC18-24/AUC_0-24, and

AUC_18-24/AUC_0-24 and AUC_0-6/AUC_0-24

is less than or equal to 0.03.

43. The formulation of claim 35, 36, or 38 wherein the magnitude of the difference between each of:

AUC_0-6/AUC_0-24 and AUC_6-12/AUC_0-24,

AUC_6-12/AUC_0-24 and AUC_12-18/AUC_0-24,

AUC_12-18/AUC_0-24 and AUC_18-24/AUC_0-24, and

AUC_18-24/AUC_0-24 and AUC_0-6/AUC_0-24

is less than or equal to 0.03.

44. The formulation of claim 35, 36, or 38 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

45. The formulation of claim 44 where D is about 20 mg and W is about 0.05.

46. A controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

said formulation having an in vitro release profile in which;

(a) 0-20% of the dose is released in 0-2 hours;

(b) 30-65% of the dose is released in 0-12 hours; and

(c) 80-100% of the dose is released in 0-24 hours;

wherein the release profile is determined using a USP Type VII bath indexer in a constant temperature water bath at 37°

C. and wherein said formulation provides pain relief for about 24 hours or more after administration to the patient.

47. The formulation of claim 46 wherein 33-63% of the dose is released in 0-12 hours.

48. The formulation of claim 46 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

49. The formulation of claim 48 where D is about 20 mg and W is about 0.05.

50. A controlled-release oxycodone formulation for once-a-day oral administration to human patients comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

wherein;

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

51. The formulation of claim 50 wherein W is less than about 0.10.

52. The formulation of claim 50 wherein W is less than or equal to about 0.05.

53. The formulation of claim 50 where D is about 20 mg and W is about 0.05.

54. A method of treating pain in humans comprising orally administering to a human patient on a once-a-day basis a controlled-release dosage form comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

said dosage form providing (a) a mean, single dose, maximum plasma concentration C_max and (b) a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC_0-48 which satisfy the relationships;

3.5×

10<sup>−

4</sup> liter⁻

≦

C_max/D≦

6.8×

10<sup>−

4</sup> liter<sup>−

1</sup>, and
7.6×

10<sup>−

3</sup> hour/liter≦

AUC_0-48/D≦

16.7×

10<sup>−

3</sup> hour/liter,

wherein the dosage form provides pain relief for about 24 hours or more after administration to the patient.

55. The method of claim 54 wherein C_max and AUC_0-48 are determined using plasma samples from individuals to whom one or more opioid antagonists have been administered.

56. The method of claim 54 wherein C_max and AUC_0-48 are determined using plasma samples from individuals to whom naltrexone has been administered.

57. The method of claim 54 wherein C_max and AUC_0-48 are determined using plasma samples from individuals who have not been administered an opioid antagonist.

58. The method of claim 54 wherein C_max and AUC_0-48 are determined using plasma samples from individuals who have not been administered naltrexone.

59. The method of claim 54, 55, or 57 wherein the dosage form provides a mean, single dose, time to maximum plasma concentration T_max which satisfies the relationship:

T_max>

17 hours.

60. The method of claim 59 wherein T_max satisfies the relationship:

T_max>

18 hours.

61. The method of claim 59 wherein T_max satisfies the relationship:

T_max>

19 hours.

62. The method of claim 54, 55, or 57 wherein the dosage form provides a mean, single dose, time to maximum plasma concentration T_max, and D, C_max, and T_max satisfy the relationship:

C_max/(T_max·

D)≦

3×

10<sup>−

4</sup> (liter·

hour)<sup>−

1</sup>.

63. The method of claim 62 wherein D, C_max, and T_max satisfy the relationship:

2×

10<sup>−

5</sup> (liter·

hour)<sup>−

1</sup>≦

C_max/(T_max·

D)≦

6×

10<sup>−

5</sup> (liter·

hour)<sup>−

1</sup>.

64. The method of claim 54, 55, or 57 wherein the dosage form provides mean, single dose, areas under a plasma concentration-time curve for 0-12 hours AUC_0-12 and for 12-24 hours AUC_12-24 which satisfy the relationship:

AUC_12-24/AUC_0-12>

1.0.

65. The method of claim 64 wherein AUC_0-12 and AUC_12-24 satisfy the relationship:

AUC_12-24/AUC_0-12>

1.5.

66. The method of claim 64 wherein AUC_0-12 and AUC_12-24 satisfy the relationship:

AUC_12-24/AUC_0-12>

1.7.

67. The method of claim 64 wherein AUC_0-12 and AUC_12-24 satisfy the relationship:

AUC_12-24/AUC_0-12>

2.0.

68. The method of claim 54, 55, or 57 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

69. The method of claim 68 where D is about 20 mg and W is about 0.05.

70. A method of treating pain in humans comprising orally administering to a human patient on a once-a-day basis a controlled-release dosage form comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

wherein;

(a) the dosage form provides a mean, single dose, plasma concentration profile that increases substantially monotonically over 24 hours or more;

(b) the dosage form provides a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC_0-48 which satisfies the relationship;

7.6×

10<sup>−

3</sup> hour/liter≦

AUC_0-48/D≦

16.7×

10<sup>−

3</sup> hour/liter; and

(c) the dosage form provides pain relief for about 24 hours or more after administration to the patient.

71. The method of claim 70 wherein AUC_0-48 and the mean, single dose, plasma concentration profile are determined using plasma samples from individuals to whom one or more opioid antagonists have been administered.

72. The method of claim 70 wherein AUC_0-48 and the mean, single dose, plasma concentration profile are determined using plasma samples from individuals to whom naltrexone has been administered.

73. The method of claim 70 wherein AUC_0-48 and the mean, single dose, plasma concentration profile are determined using plasma samples from individuals who have not been administered an opioid antagonist.

74. The method of claim 70 wherein AUC_0-48 and the mean, single dose, plasma concentration profile are determined using plasma samples from individuals who have not been administered naltrexone.

75. The method of claim 70, 71, or 73 wherein the mean, single dose, plasma concentration profile comprises a first rising phase and a second phase, where the slope of the first rising phase is greater than the magnitude of the slope of the second phase.

76. The method of claim 75 wherein the transition between the first rising phase and the second phase occurs between 12 and 16 hours.

77. The method of claim 76 wherein the first rising phase comprises a first subphase and a second subphase, where the first subphase rises faster than the second subphase.

78. The method of claim 77 wherein the transition between the first subphase and the second subphase occurs between 1 and 3 hours.

79. The method of claim 70, 71, or 73 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

80. The method of claim 79 where D is about 20 mg and W is about 0.05.

81. A method of treating pain in humans comprising orally administering to a human patient on a once-a-day basis a controlled-release dosage form comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

said dosage form providing (a) a mean, single dose, 12 hour plasma concentration C₁₂ and (b) a mean, single dose, area under a plasma concentration-time curve for 0-48 hours AUC₀₄₈ which satisfy the relationships;

2.7×

10<sup>−

4</sup> liter<sup>−

1</sup>≦

C₁₂/D≦

5.7×

10<sup>−

4</sup> liter<sup>−

1</sup>, and
7.6×

10<sup>−

3</sup> hour/liter≦

AUC_0-48/D≦

16.7×

10<sup>−

3</sup> hour/liter,

wherein said dosage form provides pain relief for about 24 hours or more after administration to the patient.

82. The method of claim 81 wherein C₁₂ and AUC_0-48 are determined using plasma samples from individuals to whom one or more opioid antagonists have been administered.

83. The method of claim 81 wherein C₁₂ and AUC_0-48 are determined using plasma samples from individuals to whom naltrexone has been administered.

84. The method of claim 81 wherein C₁₂ and AUC_0-48 are determined using plasma samples from individuals who have not been administered an opioid antagonist.

85. The method of claim 81 wherein C₁₂ and AUC_0-48 are determined using plasma samples from individuals who have not been administered naltrexone.

86. The method of claim 81, 82, or 84 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

87. The method of claim 86 where D is about 20 mg and W is about 0.05.

88. A method of treating pain in humans comprising orally administering to a human patient on a once-a-day basis a controlled-release dosage form comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone, said dosage form providing mean, steady state, areas under a plasma concentration-time curve for 0-6 hours AUC_0-6, 6-12 hours AUC_6-12, 12-18 hours AUC_12-18, 18-24 hours AUC_18-24, and 0-24 hours AUC_0-24 which satisfy the relationships;

AUC_0-6/AUC_0-24>

0.18,
AUC_6-12/AUC_0-24>

0.18,
AUC_12-18/AUC_0-24>

0.18, and
AUC_18-24/AUC_0-24>

0.18,

wherein said dosage form provides pain relief for about 24 hours or more after administration to the patient.

89. The method of claim 88 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24and AUC_0-24 are determined using plasma samples from individuals to whom one or more opioid antagonists have been administered.

90. The method of claim 88 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24, and AUC_0-24 are determined using plasma samples from individuals to whom naltrexone has been administered.

91. The method of claim 88 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24, and AUC_0-24 are determined using plasma samples from individuals who have not been administered an opioid antagonist.

92. The method of claim 88 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24, and AUC_0-24 are determined using plasma samples from individuals who have not been administered naltrexone.

93. The method of claim 88, 89, or 91 wherein AUC_0-6, AUC_6-12, AUC_12-18, AUC_18-24, and AUC_0-24 satisfy the relationships:

AUC_0-6/AUC_0-24>

0.20,
AUC_6-12/AUC_0-24>

0.20,
AUC_12-18/AUC_0-24>

0.20, and
AUC_18-24/AUC_0-24>

0.20.

94. The method of claim 88, 89, or 91 wherein the magnitude of the difference between any two of AUC_0-6/AUC_0-24, AUC_6-12/AUC_0-24, AUC_12-18/AUC_0-24, and AUC_18-24/AUC_0-24 is less than or equal to 0.05.

95. The method of claim 94 wherein the magnitude of the difference between each of:

AUC_0-6/AUC_0-24 and AUC_6-12/AUC_0-24,

AUC_6-12/AUC_0-24 and AUC_12-18/AUC_0-24,

AUC_12-18/AUC_0-24 and AUC_18-24/AUC_0-24, and

AUC_18-24/AUC_0-24 and AUC_0-6/AUC_0-24

is less than or equal to 0.03.

96. The method of claim 88, 89, or 91 wherein the magnitude of the difference between each of:

AUC_0-6/AUC_0-24 and AUC_6-2/AUC_0-24,

AUC_6-12/AUC_0-24 and AUC_12-18/AUC_0-24,

AUC_12-18/AUC_0-24 and AUC_18-24/AUC_0-24, and

AUC_18-24/AUC_0-24 and AUC_0-6/AUC_0-24

is less than or equal to 0.03.

97. The method of claim 88, 89, or 91 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

98. The method of claim 97 where D is about 20 mg and W is about 0.05.

99. A method of treating pain in humans comprising orally administering to a human patient on a once-a-day basis a controlled-release dosage form comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

said dosage form providing pain relief for about 24 hours or more after administration to the patient and having an in vitro release profile in which;

(a) 0-20% of the dose is released in 0-2 hours;

(b) 30-65% of the dose is released in 0-12 hours; and

(c) 80-100% of the dose is released in 0-24 hours;

where the release profile is determined using a USP Type VII bath indexer in a constant temperature water bath at 37°

C.

100. The method of claim 99 wherein 33-63% of the dose is released in 0-12 hours.

101. The method of claim 99 wherein:

(a) the dose comprises a first component for immediate release and a second component for sustained release; and

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25.

102. The method of claim 101 where D is about 20 mg and W is about 0.05.

103. A method of treating pain in humans comprising orally administering to a human patient on a once-a-day basis a controlled-release dosage form comprising a dose D of:

(i) oxycodone,

(ii) one or more pharmaceutically-acceptable acid addition salts of oxycodone, or

(iii) a combination of oxycodone and one or more pharmaceutically-acceptable acid addition salts of oxycodone,

wherein;

(a) the dose comprises a first component for immediate release and a second component for sustained release;

(b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25; and

(c) the dosage form provides pain relief for about 24 hours or more after administration to the patient.

104. The method of claim 103 wherein W is less than about 0.10.

105. The method of claim 103 wherein W is less than or equal to about 0.05.

106. The method of claim 103 where D is about 20 mg and W is about 0.05.