Oxymorphone controlled release formulations

• US 8,329,216 B2
• Filed: 06/29/2006
• Issued: 12/11/2012
• Est. Priority Date: 07/06/2001
• Status: Active Grant

• Current Assignee: Endo Pharmaceuticals Incorporated (Endo International PLC)
• Original Assignee: Endo Pharmaceuticals Incorporated (Endo International PLC)
• Inventors: Kao, Haui-Hung, Baichwal, Anand R., McCall, Troy, Lee, David
• Primary Examiner(s): CHANNAVAJJALA, LAKSHMI SARADA
• Application Number:
  US11/427,438
• Publication Number:
  US 20070098794A1
• Time in Patent Office: 2,357 Days
• Field of Search: None
• US Class Current: 424/464
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

The invention pertains to a method of relieving pain by administering a controlled release pharmaceutical tablet containing oxymorphone which produces a mean minimum blood plasma level 12 to 24 hours after dosing, as well as the tablet producing the sustained pain relief.

Claims

1. An oral controlled release oxymorphone formulation, comprising:

a. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt of oxymorphone; and

b. a hydrophilic material,

wherein upon oral administration of the formulation to a subject in need of an analgesic effect;

(i) the formulation provides detectable blood plasma levels of 6-OH oxymorphone and oxymorphone;

(ii) the blood plasma levels of 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours after administration;

(iii) the blood plasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio of area under the curve (AUC_{(0 to inf)}) of blood plasma level versus time for 6-OH oxymorphone compared to oxymorphone in a range of about 0.5 to about 1.5;

(iv) the duration of the analgesic effect is through at least about 12 hours after administration; and

(v) the blood plasma levels of oxymorphone exhibit two or three peaks within about 12 hours after administration.

2. The formulation of claim 1 wherein the hydrophilic material is selected from the group consisting of a gum, a cellulose ether, an acrylic resin, a protein-derived material, and mixtures thereof.

3. The formulation of claim 1 wherein the hydrophilic material is a gum selected from the group consisting of a heteropolysaccharide gum, a homopolysaccharide gum, and mixtures thereof.

4. The formulation of claim 3 wherein the gum is selected from the group consisting of xanthan, tragacanth, acacia, karaya, alginates, agar, guar, hydroxypropyl guar, carrageenan, locust bean, and mixtures thereof.

5. The formulation of claim 1 wherein the hydrophilic material is a cellulose ether selected from the group consisting of a hydroxyalkyl cellulose, a carboxyalkyl cellulose, and mixtures thereof.

6. The formulation of claim 1 wherein the hydrophilic material is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and mixtures thereof.

7. The formulation of claim 1 wherein the hydrophilic material comprises at least one of:

i. a heteropolysaccharide;

or

ii. a heteropolysaccharide and a cross-linking agent capable of cross-linking the heteropolysaccharide;

or

iii. a mixture of (i), (ii) and a polysaccharide gum.

8. The formulation of claim 7 wherein the heteropolysaccharide is a water soluble polysaccharide containing two or more kinds of sugar units and having a branched or helical configuration.

9. The formulation of claim 7 wherein the heteropolysaccharide is selected from the group consisting of xanthan gum, deacylated xanthan gum, carboxymethyl ether xanthan gum, propylene glycol ester xanthan gum and mixtures thereof.

10. The formulation of claim 7 wherein the cross-linking agent is a homopolysaccharide gum.

11. The formulation of claim 1 further comprising a hydrophobic polymer.

12. A method of treating pain in a subject in need thereof, the method comprising the step of administering to the subject the formulation of claim 1.

13. A pharmaceutical tablet prepared by:

a. mixing oxymorphone or a pharmaceutically acceptable salt of oxymorphone and controlled release granules comprising a hydrophilic material and one or more optional excipients; and

b. directly compressing the mixture of (a) to form the tablet,

wherein upon placement of the tablet in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test.

14. The tablet preparation of claim 13 wherein the hydrophilic material is selected from the group consisting of a gum, a cellulose ether, an acrylic resin, a protein-derived material, and mixtures thereof.

15. The tablet preparation of claim 13 wherein the hydrophilic material is a gum selected from the group consisting of a heteropolysaccharide gum, a homopolysaccharide gum, and mixtures thereof.

16. The tablet preparation of claim 13 wherein the hydrophilic material is a cellulose ether selected from the group consisting of a hydroxyalkyl cellulose, a carboxyalkyl cellulose, and mixtures thereof.

17. The tablet preparation of claim 13 wherein the hydrophilic material is hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and mixtures thereof.

18. The tablet preparation of claim 13 wherein the hydrophilic material comprises at least one of:

i. a heteropolysaccharide;

or

ii. a heteropolysaccharide and a cross-linking agent capable of cross-linking the heteropolysaccharide;

or

iii. a mixture of (i), (ii) and a polysaccharide gum.

19. The tablet preparation of claim 18 wherein the heteropolysaccharide is a water soluble polysaccharide containing two or more kinds of sugar units and having a branched or helical configuration.

20. The tablet preparation of claim 19 wherein the heteropolysaccharide is selected from the group consisting of xanthan gum, deacylated xanthan gum, carboxymethyl ether xanthan gum, propylene glycol ester xanthan gum and mixtures thereof.

21. A pharmaceutical tablet prepared by:

a. mixing oxymorphone or a pharmaceutically acceptable salt of oxymorphone and one or more controlled release excipients; and

b. forming the tablet,

wherein upon placement of the tablet in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test; and

wherein upon oral administration to a human subject the tablet alleviates pain for 12 to 24 hours.

22. The tablet of claim 21 wherein about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 4 hours in the test, and at least about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test.

23. The tablet of claim 21 wherein at least 27%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test, at least 40%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 2 hours in the test, at least 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 3 hours in the test, at least 64%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 5 hours in the test, at least 70%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 6 hours in the test, at least 79%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 8 hours in the test, at least 85%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test, and at least 89%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 12 hours in the test.

24. The tablet of claim 21, wherein at least 27%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test.

25. The tablet of claim 21, wherein at least 40%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 2 hours in the test.

26. The tablet of claim 21, wherein at least 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 3 hours in the test.

27. The tablet of claim 21, wherein at least 64%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 5 hours in the test.

28. The tablet of claim 21, wherein at least 70%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 6 hours in the test.

29. The tablet of claim 21, wherein at least 79%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 8 hours in the test.

30. The tablet of claim 21, wherein at least 85%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test.

31. A method for treating pain in a human subject in need of acute or chronic pain relief, comprising the steps of:

(a) Providing a solid oral dosage form of a controlled release oxymorphone formulation with a release rate profile designed to provide adequate blood plasma levels over at least 12 hours to provide sustained pain relief over this same period comprising about 5 mg to about 80 mg oxymorphone or a pharmaceutically acceptable salt thereof wherein oxymorphone is the sole active ingredient, and wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test; and

(b) administering a single dose of the dosage form to the subject,

wherein the oxymorphone C_max is at least 50% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.

32. The method of claim 31 wherein the dosage form comprises about 40 mg oxymorphone or a pharmaceutically acceptable salt thereof, and wherein the oxymorphone C_max is about 58% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.

33. The method of claim 31 wherein the dosage form comprises about 20 mg oxymorphone or a pharmaceutically acceptable salt thereof.

34. The method of claim 31 wherein the dosage form comprises about 20 mg to about 40 mg oxymorphone hydrochloride.

35. The method of claim 31 wherein the difference in the oxymorphone area under the curve (AUC_(0-inf) between fed and fasted conditions is less than 20%.

36. The method of claim 35 wherein the difference in AUC_(0-inf) between fed and fasted conditions is about 18%.

37. The method of claim 31 wherein upon oral administration of the dosage form to the subject under fed or fasting conditions:

(i) the dosage form provides detectable blood plasma levels of 6-OH oxymorphone and oxymorphone;

(ii) the blood plasma levels of 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours after administration; and

(iii) the blood plasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio of AUC_(0-inf) of blood plasma level versus time for 6-OH oxymorphone compared to oxymorphone in a range of about 0.5 to about 1.5.

38. A method for treating pain in a human subject in need of acute or chronic pain relief, comprising the steps of:

(a) Providing a solid oral dosage form comprising about 5 mg to about 80 mg oxymorphone or a pharmaceutically acceptable salt thereof in a controlled release delivery system with a release rate profile designed to provide adequate blood plasma levels over at least 12 hours to provide sustained pain relief over this same period, wherein oxymorphone is the sole active ingredient, and wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test, about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 4 hours in the test, and at least about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test; and

(b) administering a single dose of the dosage form to the subject,

wherein the oxymorphone C_max is at least 50% higher when the dosage form is administered to the subject under fed versus fasted conditions.

39. The method of claim 38 wherein the oxymorphone C_max is at least about 58% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.

40. The method of claim 38 wherein the difference in the oxymorphone area under the curve AUC_(0-inf) between fed and fasted conditions is less than 20%.

41. The method of claim 40 wherein the difference in AUC_(0-inf) between fed and fasted conditions is about 18%.

42. The method of claim 38 wherein upon oral administration of the dosage form to the subject under fed or fasting conditions:

(i) the dosage form provides detectable blood plasma levels of 6-OH oxymorphone and oxymorphone;

(ii) the blood plasma levels of 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours after administration; and

(iii) the blood plasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio of AUC_(0-inf) of blood plasma level versus time for 6-OH oxymorphone compared to oxymorphone in a range of about 0.5 to about 1.5.

43. The method of claim 38 wherein the system further comprises a hydrophilic material.

44. The method of claim 43 wherein the hydrophilic material is selected from the group consisting of a gum, a cellulose ether, an acrylic resin, a protein-derived material, and mixtures thereof.

45. The method of claim 44 wherein the hydrophilic material is a gum selected from the group consisting of xanthan, tragacanth, acacia, karaya, alginates, agar, guar, hydroxypropyl guar, carrageenan, locust bean, and mixtures thereof.

46. The method of claim 43 wherein the hydrophilic material is a cellulose ether selected from the group consisting of a hydroxyalkyl cellulose, a carboxyalkyl cellulose, and mixtures thereof.

47. The method of claim 43 wherein the hydrophilic material is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and mixtures thereof.

48. The method of claim 43 wherein the hydrophilic material comprises at least one of:

a. a heteropolysaccharide;

or

b. a heteropolysaccharide and a cross-linking agent capable of cross-linking the heteropolysaccharide;

or

c. a mixture of (a), (b) and a polysaccharide gum.

49. An analgesically effective controlled release pharmaceutical composition for oral delivery, comprising:

a. a controlled release delivery system with a release rate profile designed to provide adequate blood plasma levels over at least 12 hours to provide sustained pain relief over this same period; and

b. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt of oxymorphone, wherein oxymorphone is the sole active ingredient,

wherein upon oral administration of a single dose of the composition to a human subject, the oxymorphone C_max is at least 50% higher when the dose is administered to the subject under fed as compared to fasted conditions, and wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test.

50. The composition of claim 49 wherein upon oral administration thereof the oxymorphone AUC_(0-inf) is no more than 20% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.

51. The composition of claim 49 wherein the dosage form comprises about 40 mg oxymorphone, and wherein the oxymorphone C_max is about 58% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.

52. The composition of claim 49 wherein the controlled release delivery system comprises a heteropolysaccharide and an agent capable of cross-linking the heteropolysaccharide in presence of gastrointestinal fluid.

53. The composition of claim 52 wherein the heteropolysaccharide and the agent capable of cross-linking the heteropolysaccharide are present in a weight ratio of about 1:

3 to about 3;

1.

54. The composition of claim 49 wherein about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 4 hours in the test, and at least about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test.

55. An analgesically effective controlled release pharmaceutical composition for oral delivery, comprising:

a. a controlled release delivery system with a release rate profile designed to provide adequate blood plasma levels of oxymorphone and 6-hydroxy-oxymorphone over at least 12 hours to provide sustained pain relief over this same period; and

b. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt of oxymorphone, wherein oxymorphone is the sole active ingredient,

wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test.

56. The composition of claim 55, wherein upon oral administration of a single dose of the composition to a human subject, the oxymorphone C_max is at least 50% higher when the dose is administered to the subject under fed as compared to fasted conditions.

57. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 27%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test, at least 40%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 2 hours in the test, at least 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 3 hours in the test, at least 64%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 5 hours in the test, at least 70%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 6 hours in the test, at least 79%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 8 hours in the test, at least 85%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test, and at least 89%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 12 hours in the test.

58. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 27%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test.

59. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 40%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 2 hours in the test.

60. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 3 hours in the test.

61. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 64%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 5 hours in the test.

62. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 70%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 6 hours in the test.

63. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 79%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 8 hours in the test.

64. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 85%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test.

65. The composition of claim 55, wherein the composition is in the form of a tablet and wherein at least 89%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 12 hours in the test.

66. An analgesically effective controlled release pharmaceutical composition for oral delivery, comprising:

a. a controlled release delivery system with a release rate profile designed to provide adequate blood plasma levels over at least 12 hours to provide sustained pain relief over this same period; and

b. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt of oxymorphone, wherein oxymorphone is the sole active ingredient,

wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test, and wherein upon oral administration of the composition to a human subject, the blood plasma levels of oxymorphone comprise one or more peaks.

67. The composition of claim 66 wherein the blood plasma levels comprise two peaks.

68. The composition of claim 66 wherein upon oral administration of the composition to a subject in need of an analgesic effect:

(i) the composition provides detectable blood plasma levels of 6-OH oxymorphone and oxymorphone;

(ii) the blood plasma levels of 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours after administration; and

(iii) the blood plasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio of area under the curve (AUC_{(0 to inf)}) of blood plasma level versus time for 6-OH oxymorphone compared to oxymorphone in a range of about 0.5 to about 1.5.

69. The composition of claim 66 wherein upon oral administration of the composition to a subject in need of an analgesic effect the blood plasma levels of oxymorphone exhibit two or three peaks within about 12 hours after administration.

70. The composition of claim 66 wherein upon oral administration of the composition to a subject in need of an analgesic effect the blood plasma levels of oxymorphone comprise a first peak at about 3 hours after administration and a second peak at about 6-7 hours after administration.

71. The composition of claim 66 wherein the composition is in the form of a tablet and about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 4 hours in the test, and at least about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test.

72. A controlled release pharmaceutical composition comprising oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient and a controlled release matrix, comprising about 10% to about 75% (by total weight of the controlled release matrix) of a gelling agent which forms a gel upon exposure to gastrointestinal fluid;

wherein upon placement of the composition in an in vitro dissolution test comprising USP paddle method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the composition after about 1 hour in the test.

73. The pharmaceutical composition of claim 72 wherein about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released from the composition after about 4 hours in the test.

74. The pharmaceutical composition of claim 72 wherein at least 80%, by weight, of the oxymorphone or salt thereof is released from the composition after about 10 hours in the test.

75. The pharmaceutical composition of claim 72 wherein upon oral administration of the dosage form to a human subject in need of an analgesic effect, the blood plasma concentration of oxymorphone comprises one or peaks.

76. The pharmaceutical composition of claim 72 wherein upon oral administration of the dosage form to a human subject in need of an analgesic effect, the blood plasma concentration of oxymorphone comprises a first peak at about 3 hours after administration and a second peak at about 6-7 hours after administration;

and wherein

(i) the dosage form provides detectable blood plasma levels of 6-OH oxymorphone and oxymorphone;

(ii) the blood plasma levels of 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours after administration;

(iii) the blood plasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio of area under the curve (AUC_{(0 to inf)}) of blood plasma level versus time for 6-OH oxymorphone compared to oxymorphone in a range of about 0.5 to about 1.5; and

(iv) the duration of the analgesic effect is through at least about 12 hours after administration.

81. A method of treating pain in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 72 in an amount sufficient to provide the subject with about 5 mg to about 80 mg of oxymorphone or salt thereof, wherein upon oral administration of a single dose of the composition to a human subject, the composition provides an oxymorphone C_max of at least 50% higher when the dose is administered to the subject under fed as compared to fasted conditions and provides a difference in oxymorphone AUC_(0-inf) of less than 20% higher when the dose is administered to the subject under fed as compared to fasted conditions.

77. A controlled release pharmaceutical composition comprising oxymorphone or pharmaceutically acceptable salt thereof as the sole active ingredient, and a controlled release matrix comprising about 10% to about 75% (by total weight of the controlled release matrix) of a gelling agent which forms a gel upon exposure to gastrointestinal fluid;

wherein upon placement of the composition in an in vitro dissolution test comprising USP paddle method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°

C., about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the composition after about 1 hour in the test, about 45% to about 80%, by weight, of the oxymorphone or salt thereof is released from the composition after about 4 hours in the test, and at least 80%, by weight, of the oxymorphone or salt thereof is released from the composition after about 10 hours in the test,

wherein upon oral administration of a single dose of the composition to a human subject, the composition provides an oxymorphone C_max of at least 50% higher when the dose is administered to the subject under fed as compared to fasted conditions and provides a difference in oxymorphone AUC_(0-inf) of less than 20% higher when the dose is administered to the subject under fed as compared to fasted conditions.

78. The pharmaceutical composition of claim 77 wherein upon oral administration of the dosage form to a human subject in need of an analgesic effect the blood plasma level of oxymorphone displays two or three peaks over about the first 12 hours after administration;

and

(i) the dosage form provides detectable blood plasma levels of 6-OH oxymorphone and oxymorphone;

(ii) the blood plasma levels of 6-OH oxymorphone and oxymorphone peak within about 1 hour to about 8 hours after administration;

(iii) the blood plasma levels of 6-OH oxymorphone and oxymorphone exhibit a ratio of area under the curve (AUC_{(0 to inf)}) of blood plasma level versus time for 6-OH oxymorphone compared to oxymorphone in a range of about 0.5 to about 1.5; and

(iv) the duration of the analgesic effect is through at least about 12 hours after administration.

79. The pharmaceutical composition of claim 77 wherein about 58% to about 66%, by weight, of the oxymorphone or salt thereof is released from the composition after about 4 hours in the test.

80. The pharmaceutical composition of claim 77 wherein about 85% to about 96%, by weight, of the oxymorphone or salt thereof is released from the composition after about 10 hours in the test.

82. A method of treating pain in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 77 in an amount sufficient to provide the subject with about 5 mg to about 80 mg of oxymorphone or salt thereof.