Oxymorphone controlled release formulations

1. An analgesically effective controlled release pharmaceutical composition for oral delivery, comprising about 5 mg to about 80 mg oxymorphone or a pharmaceutically acceptable salt of oxymorphone and a controlled release matrix with a release rate profile designed to provide an adequate blood plasma level of oxymorphone over at least 12 hours to provide sustained pain relief over this same period wherein:

(a) oxymorphone is the sole active ingredient in the composition;

(b) the controlled release matrix comprises a hydrophilic material which forms a gel upon exposure to gastrointestinal fluid, 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; and

(c) upon oral administration of the composition to a subject in need of an analgesic effect the blood plasma level of oxymorphone displays two or three peaks over the first 12 hours after administration,

wherein 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.

2. The composition of claim 1 wherein the hydrophilic material is a polysaccharide.

3. The composition 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.

4. The composition 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.

5. The composition of claim 4 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.

6. The composition 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.

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

8. The composition of claim 1 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 composition of claim 1 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 composition of claim 1 wherein the cross-linking agent is a homopolysaccharide gum.

11. The composition of claim 10 wherein the homopolysaccharide gum is locust bean gum.

12. The composition of claim 1 further comprising a filler selected from the group consisting of sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, and mixtures thereof.

13. The composition of claim 1 wherein upon oral administration of a single dose thereof the oxymorphone C max is at least about 50% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.

14. The composition of claim 1 wherein the composition comprises about 40 mg oxymorphone, and wherein the oxymorphone C max is about 58% higher when the composition is administered to the subject under fed as compared to fasted conditions.

15. The composition of claim 1 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.

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

17. The composition of claim 1 wherein the controlled release matrix further comprises a hydrophobic polymer.

18. The composition of claim 17 wherein the hydrophobic polymer is selected from hydrophobic cellulosic materials, polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, waxes, shellac, and hydrogenated vegetable oils.

19. The composition of claim 17 wherein the hydrophobic polymer comprises an alkyl cellulose.

20. The composition of claim 1 further comprising a cationic cross-linking agent.

21. The composition of claim 20 wherein the cationic cross-linking agent is an alkali metal sulfate, chloride, borate, bromide, citrate, acetate or lactate or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate or lactate.

22. The composition of claim 20 wherein the cationic cross-linking agent is selected from calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate and sodium fluoride.

23. The composition of claim 20 wherein the cationic cross-linking agent is present in an amount of about 0.5% to about 16%, by weight of the composition.

24. The composition of claim 1 wherein the weight ratio of heteropolysaccharide to oxymorphone is in the range of about 10:1 to about 1:10.

25. The composition of claim 1 wherein the oxymorphone is present in an amount of about 20 mg.

26. The composition of claim 1 wherein the controlled release delivery system comprises about 10% to about 99% of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum, about 1% to about 20% of a cationic crosslinking agent, and about 0% to about 89% of an inert diluent, by total weight of the controlled release delivery system.

27. The composition of claim 1 wherein the controlled release delivery system comprises about 10% to about 75% of a gelling agent, about 2% to about 15% of a cationic crosslinking agent, and about 30% to about 75% of an inert diluent, by total weight of the controlled release delivery system.

28. The composition of claim 1 wherein the controlled release delivery system comprises about 30% to about 75% of a gelling agent, about 5% to about 10% of a cationic cross linking agent, about 15% to about 65% of an inert diluent, by total weight of the controlled release delivery system.

29. An analgesically effective controlled release pharmaceutical composition for oral delivery, comprising about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt of oxymorphone and a controlled release matrix with a release rate profile designed to provide an adequate blood plasma level of oxymorphone over at least 12 hours to provide sustained pain relief over this same period wherein oxymorphone is the sole active ingredient in the composition, and wherein 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.

30. The composition of claim 29 wherein the controlled release matrix comprises a hydrophilic material.

31. The composition of claim 30 wherein the hydrophilic material is a polysaccharide.

32. The composition of claim 30 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.

33. The composition of claim 30 wherein the hydrophilic material is a gum selected from the group consisting of a heteropolysaccharide gum, a homopolysaccharide gum, and mixtures thereof.

34. The composition of claim 33 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.

35. The composition of claim 30 wherein the hydrophilic material is a cellulose ether selected from the group consisting of a hydroxyalkyl cellulose, a carboxyalkyl cellulose, and mixtures thereof.

36. The composition of claim 30 wherein the hydrophilic material is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and mixtures thereof.

37. The composition of claim 30 wherein the hydrophilic material comprises a heteropolysaccharide.

38. The composition of claim 37 further comprising a cross-linking agent capable of cross-linking the heteropolysaccharide.

39. The composition of claim 37 wherein the heteropolysaccharide is a water soluble polysaccharide containing two or more kinds of sugar units and having a branched or helical configuration.

40. The composition of claim 37 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.

41. The composition of claim 38 wherein the cross-linking agent comprises a homopolysaccharide gum.

42. The composition of claim 38 wherein the cross-linking agent is a homopolysaccharide gum.

43. The composition of claim 41 wherein the homopolysaccharide gum is locust bean gum.

44. The composition of claim 30 further comprising a filler selected from the group consisting of sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, and mixtures thereof.

45. The composition of claim 29 wherein upon oral administration thereof the oxymorphone C max is at least about 50% higher when the dosage form is administered to the subject under fed as compared to fasted conditions.

46. The composition of claim 29 wherein the composition comprises about 40 mg oxymorphone, and wherein the oxymorphone C max is about 58% higher when the composition is administered to the subject under fed as compared to fasted conditions.

47. The composition of claim 38 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.

48. The composition of claim 38 wherein the heteropolysaccharide and the agent capable of cross-linking the heteropolysaccharide are present in a weight ratio of about 1:1.

49. The composition of claim 30 wherein the controlled release matrix further comprises a hydrophobic polymer.

50. The composition of claim 49 wherein the hydrophobic polymer is selected from hydrophobic cellulosic materials, polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, waxes, shellac, and hydrogenated vegetable oils.

51. The composition of claim 49 wherein the hydrophobic polymer comprises an alkyl cellulose.

52. The composition of claim 30 further comprising a cationic cross-linking agent.

53. The composition of claim 52 wherein the cationic cross-linking agent is an alkali metal sulfate, chloride, borate, bromide, citrate, acetate or lactate or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate or lactate.

54. The composition of claim 52 wherein the cationic cross-linking agent is selected from calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate and sodium fluoride.

55. The composition of claim 52 wherein the cationic cross-linking agent is present in an amount of about 0.5% to about 16%, by weight of the composition.

56. The composition of claim 37 wherein the weight ratio of heteropolysaccharide to oxymorphone is in the range of about 10:1 to about 1:10.

57. The composition of claim 29 wherein the oxymorphone is present in an amount of about 20 mg.

58. The composition of claim 29 wherein the controlled release delivery system comprises about 10% to about 99% of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum, about 1% to about 20% of a cationic crosslinking agent, and about 0% to about 89% of an inert diluent, by total weight of the controlled release delivery system.

59. The composition of claim 29 wherein the controlled release delivery system comprises about 10% to about 75% of a gelling agent, about 2% to about 15% of a cationic crosslinking agent, and about 30% to about 75% of an inert diluent, by total weight of the controlled release delivery system.

60. The composition of claim 29 wherein the controlled release delivery system comprises about 30% to about 75% of a gelling agent, about 5% to about 10% of a cationic cross linking agent, about 15% to about 65% of an inert diluent, by total weight of the controlled release delivery system.

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

a. a controlled release delivery matrix 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, the matrix comprising a hydrophilic material, 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; 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 release rate test, about 58% to about 80%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 4 hours in the test.

62. The composition of claim 61 , wherein upon oral administration of a single dose of the composition to a human subject, the oxymorphone Cmax is at least 50% higher when the dose is administered to the subject under fed as compared to fasted conditions.

63. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, about 27% to about 33%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test, about 40% to about 48%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 2 hours in the test, about 50% to about 59%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 3 hours in the test, about 64% to about 74%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 5 hours in the test, about 70% to about 84%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 6 hours in the test, about 79% to about 92%, 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.

64. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, about 27% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test.

65. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, about 40% to about 48%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 2 hours in the test.

66. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, about 50% to about 59%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 3 hours in the test.

67. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, about 64% to about 74%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 5 hours in the test.

68. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, about 70% to about 84%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 6 hours in the test.

69. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, about 79% to about 92%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 8 hours in the test.

70. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, at least 85%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 10 hours in the test.

71. The composition of claim 61 , wherein upon placement of the composition in an in vitro release rate test, at least 89%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 12 hours in the test.