Encased tamper resistant controlled release dosage forms

• US 8,808,740 B2
• Filed: 12/21/2011
• Issued: 08/19/2014
• Est. Priority Date: 12/22/2010
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Huang, Haiyong Hugh
• Primary Examiner(s): Desai, Anand
• Assistant Examiner(s): MERCIER, MELISSA S
• Application Number:
  US13/333,560
• Publication Number:
  US 20120164220A1
• Time in Patent Office: 972 Days
• Field of Search: None
• US Class Current: 424/469
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• 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 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

In certain embodiments, the present invention is directed to a solid controlled release dosage form comprising: a core comprising a first portion of an opioid analgesic dispersed in a first matrix material; and a shell encasing the core and comprising a second portion of the opioid analgesic dispersed in a second matrix material; wherein the amount of opioid analgesic released from the dosage form is proportional within 20% to elapsed time from 8 to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 C.

Claims

1. A solid controlled release dosage form comprising:

a core comprising a first portion of an opioid analgesic dispersed in a first controlled release matrix material; and

a shell encasing the core and comprising a second portion of the opioid analgesic dispersed in a second controlled release matrix material;

wherein the amount of opioid analgesic released from the dosage form is proportional within 20% to elapsed time from 8 to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°

C.

2. The solid controlled release dosage form of claim 1, wherein the core is a compressed tablet.

3. The solid controlled release dosage form of claim 1, wherein the shell is a compression coating.

4. The solid controlled release dosage form of claim 1, wherein the first controlled release matrix material comprises polyethylene oxide.

5. The solid controlled release dosage form of claim 1, wherein the second controlled release matrix material comprises polyethylene oxide.

6. The solid controlled release dosage form of claim 1, wherein both the first controlled release matrix material and the second controlled release matrix material comprise polyethylene oxide.

7. The solid controlled release dosage form of claim 6, wherein the polyethylene oxide in the second controlled release matrix material has a higher viscosity than the polyethylene oxide in the first controlled release matrix material.

8. The solid controlled release dosage form of claim 4, wherein the first controlled release matrix material comprises polyethylene oxide having an average molecular weight from about 300,000 to about 10,000,000.

9. The solid controlled release dosage form of claim 5, wherein the second controlled release matrix material comprises polyethylene oxide having an average molecular weight from about 1,000,000 to about 10,000,000.

10. The solid controlled release dosage form of claim 1, wherein the weight ratio of the core to the shell is from about 1:

0.5 to about 1;

5.

11. The solid controlled release dosage form of claim 4, wherein the weight ratio of the first portion of opioid analgesic to polyethylene oxide in the first controlled release matrix material is from about 1:

0.5 to about 1;

100.

12. The solid controlled release dosage form of claim 5, wherein the weight ratio of the second portion of opioid analgesic to polyethylene oxide in the second controlled release matrix material is from about 1:

2 to about 1;

200.

13. The solid controlled release dosage form of claim 1, wherein the opioid analgesic in the first portion is the same as the opioid analgesic in the second portion.

14. The solid controlled release dosage form of claim 1, wherein the opioid analgesic in the first portion is different than the opioid analgesic in the second portion.

15. The solid controlled release dosage form of claim 1, wherein the ratio of opioid analgesic in the core to the ratio of opioid analgesic in the shell is from about 1:

1 to about 10;

1.

16. The solid controlled release dosage form of claim 1, wherein the opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and mixtures thereof.

17. The solid controlled release dosage form of claim 16, wherein the opioid analgesic is selected from the group consisting of codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and mixtures thereof.

18. The solid controlled release dosage form of claim 17, wherein the opioid analgesic is selected from the group consisting of hydrocodone, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and mixtures thereof.

19. The solid controlled release dosage form of claim 18, wherein the opioid analgesic is hydrocodone bitartrate.

20. The solid controlled release dosage form of claim 19, wherein total amount of hydrocodone bitartrate in the dosage form is from about 0.5 mg to about 1250 mg.

21. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 10% to elapsed time from 8 to 24 hours.

22. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 5% to elapsed time from 8 to 24 hours.

23. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 20% to elapsed time from 8 to 18 hours.

24. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 20% to elapsed time from 8 to 12 hours.

25. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 20% to elapsed time from 12 to 24 hours.

26. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 20% to elapsed time from 12 to 18 hours.

27. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 10% to elapsed time from 8 to 18 hours.

28. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 10% to elapsed time from 8 to 12 hours.

29. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 10% to elapsed time from 12 to 24 hours.

30. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 10% to elapsed time from 12 to 18 hours.

31. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 5% to elapsed time from 8 to 18 hours.

32. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 5% to elapsed time from 8 to 12 hours.

33. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 5% to elapsed time from 12 to 24 hours.

34. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released is proportional within 5% to elapsed time from 12 to 18 hours.

35. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 2 hours is less than about 25%.

36. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 4 hours is from about 10% to about 30%.

37. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 8 hours is from about 20% to about 60%.

38. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 12 hours is from about 40% to about 90%.

39. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 18 hours is greater than about 70%.

40. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 2 hours is less than about 20%.

41. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 4 hours is from about 10% to about 20%.

42. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 8 hours is from about 20% to about 40%.

43. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 12 hours is from about 40% to about 65%.

44. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 18 hours is greater than about 80%.

45. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 2 hours is less than about 15%.

46. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 4 hours is from about 20% to about 30%.

47. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 8 hours is from about 45% to about 60%.

48. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 12 hours is from about 70% to about 90%.

49. The solid controlled release dosage form of claim 1, wherein the amount of opioid analgesic released at 18 hours is greater than about 90%.

50. The solid controlled release dosage form of claim 6, wherein the dosage form is cured at a temperature of at least the softening point of the polyethylene oxide for at least 1 minute.

51. The solid controlled release dosage form of claim 50, wherein the dosage form is cured at a temperature of at lease about 60°

C.

52. The solid controlled release dosage form of claim 1, wherein the core and the shell are visually indistintinguishable.

53. The solid controlled release dosage form of claim 1, wherein the core and the shell have a CIE L*A*B* value within 10% of each other.

54. The solid controlled release dosage form of claim 1, wherein the dosage form can be flattened without breaking, wherein the thickness of the dosage form after flattening corresponds to no more than about 60% of the thickness of the dosage form before flattening.

55. The solid controlled release dosage form of claim 54, wherein the amount of opioid analgesic released at 0.5 hour from a flattened dosage form deviates no more than about 20% points from a non-flattened dosage form as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°

C.

56. The solid controlled release dosage form of claim 18, that provides a C₂₄/C_max ratio of hydrocodone of about 0.55 to about 1.0 after administration.

57. The solid controlled release dosage form of claim 56, wherein the C₂₄/C_max ratio is about 0.55 to about 0.85.

58. The solid controlled release dosage form of claim 56, wherein the C₂₄/C_max ratio is about 0.55 to about 0.75.

59. The solid controlled release dosage form of claim 56, wherein the C₂₄/C_max ratio is about 0.60 to about 0.70.

60. The solid controlled release dosage form of claim 18, that provides a T_max (h) of hydrocodone from about 4 to about 20 hours after administration.

61. The solid controlled release dosage form of claim 60, wherein the T_max (h) is about 6 to about 12 hours.

62. The solid controlled release dosage form of claim 60, wherein the T_max (h) is about 8 to about 10 hours.

63. The solid controlled release dosage form of claim 60, wherein the T_max (h) is about 4 to about 10 hours.

64. The solid controlled release dosage form of claim 60, wherein the T_max (h) is about 8 to about 14 hours.

65. The solid controlled release dosage form of claim 60, wherein the T_max (h) is about 14 to about 20 hours after administration of the dosage form.

66. The solid controlled release dosage form of claim 56, wherein the administration is a first administration to a healthy subject.

67. The solid controlled release dosage form of claim 56, wherein the administration is a first administration to a population of healthy subjects.

68. The solid controlled release dosage form of claim 56, wherein the administration is steady state administration to a healthy subject.

69. The solid controlled release dosage form of claim 56, wherein the administration is steady state administration to a population of healthy subjects.

70. The solid controlled release dosage form of claim 18, that contains about 20 mg hydrocodone or a pharmaceutically acceptable salt thereof.

71. The solid controlled release dosage form of claim 18, that contains about 120 mg hydrocodone or a pharmaceutically acceptable salt thereof.

72. The solid controlled release dosage form of claim 18, that provides a mean AUC (ng*h/mL) after administration of about 250 to 400 per each 20 mg hydrocodone included in the dosage form.

73. The solid controlled release dosage form of claim 70, that provides a mean AUC (ng*h/mL) after administration of about 250 to about 400.

74. The solid controlled release dosage form of claim 71, that provides a mean AUC (ng*h/mL) after administration of about 1500 to about 2400.

75. The solid controlled release dosage form of claim 18, that provides a mean C_max (ng/mL) after administration of about 10 to about 30 per each 20 mg hydrocodone included in the dosage form.

76. The solid controlled release dosage form of claim 70, that provides a mean C_max (ng/mL) after administration of about 10 to about 30.

77. The solid controlled release dosage form of claim 71, that provides a mean C_max (ng/mL) after administration of about 60 to about 180.

78. The solid controlled release dosage form of claim 18, that provides a mean T_max (h) after administration of about 10 to about 20.

79. The solid controlled release dosage form of claim 18, that provides a mean T_1/2 (h) after administration of about 5 to about 10.

80. The solid controlled release dosage form of claim 18, that provides a mean T_lag (h) after administration of about 0.01 to about 0.2.

81. The solid controlled release dosage form of claim 18, wherein the mean C₂₄/C_max ratio is about 0.2 to about 0.8.

82. The solid controlled release dosage form of claim 72, wherein the administration is in the fasted state.

83. The solid controlled release dosage form of claim 18, wherein the mean AUC (ng*h/mL) after administration in the fed state is less than 20% higher than the AUC (ng*h/mL) after administration in the fasted state.

84. The solid controlled release dosage form of claim 18, wherein the mean C_max (ng/mL) after administration in the fed state is less than 80% higher than the C_max after administration in the fasted state.

85. The solid controlled release dosage form of claim 18, wherein the mean T_max (h) after administration in the fed state is within 25 of the T_max (h) after administration in the fasted state.

86. The solid controlled release dosage form of claim 18, wherein the mean T_1/2 (h) after administration in the fed state is within 8 of the T_1/2 after administration in the fasted state.

87. The solid controlled release dosage form of claim 18, wherein the mean T_lag (h) after administration in the fed state is less than 150% higher than the T_1/2 after administration in the fasted state.

95. A method of treating pain in a subject in need thereof, comprising administering to the subject a solid controlled release dosage form according to claim 1.

88. A solid controlled release dosage form comprising:

a core comprising a first portion of an opioid analgesic dispersed in a first matrix material comprising polyethylene oxide; and

a shell encasing the core and comprising a second portion of the opioid analgesic dispersed in a second matrix material comprising polyethylene oxide.

89. A solid controlled release dosage form comprising:

a compressed core comprising a first portion of an opioid analgesic dispersed in a first matrix material comprising polyethylene oxide; and

a compression coating encasing the core and comprising a second portion of the opioid analgesic dispersed in a second matrix material comprising polyethylene oxide.

90. A solid controlled release dosage form comprising:

a core comprising a first portion of an opioid analgesic dispersed in a first matrix material; and

a shell encasing the core and comprising a second portion of the opioid analgesic dispersed in a second matrix material;

wherein the amount of opioid analgesic released from the dosage form at 2 hours is less than about 25%;

the amount of opioid analgesic released from the dosage form at 4 hours is from about 10% to about 30%;

the amount of opioid analgesic released from the dosage form at 8 hours is from about 20% to about 60%;

the amount of opioid analgesic released from the dosage form at 12 hours is from about 40% to about 90%; and

the amount of opioid analgesic released from the dosage form at 18 hours is greater than about 70%;

as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°

C.

91. A solid controlled release dosage form comprising:

a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a controlled release excipient;

wherein the amount of hydrocodone or salt thereof released from the dosage form is proportional within 20% to elapsed time from 8 to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°

C.; and

the dosage form can be flattened without breaking, wherein the thickness of the dosage form after flattening corresponds to no more than about 20% of the thickness of the dosage form before flattening; and

the amount of hydrocodone or salt thereof released at 0.5 hour from a flattened dosage form deviates no more than about 20% points from a non-flattened dosage form as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°

C.

92. A solid controlled release dosage form comprising:

a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a controlled release excipient;

wherein the amount of hydrocodone or salt thereof released from the dosage form at 2 hours is less than about 25%;

the amount of hydrocodone or salt thereof released from the dosage form at 4 hours is from about 10% to about 30%;

the amount of hydrocodone or salt thereof released from the dosage form at 8 hours is from about 20% to about 60%;

the amount of hydrocodone or salt thereof released from the dosage form at 12 hours is from about 40% to about 90%; and

the amount of hydrocodone or salt thereof released from the dosage form at 18 hours is greater than about 70%;

as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°

C.; and

the dosage form can be flattened without breaking, wherein the thickness of the dosage form after flattening corresponds to no more than about 20% of the thickness of the dosage form before flattening; and

the amount of hydrocodone or salt thereof released at 0.5 hour from a flattened dosage form deviates no more than about 20% points from a non-flattened dosage form as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°

C.

93. A solid controlled release dosage form comprising:

a therapeutically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof dispersed in a controlled release excipient;

wherein the inner 60% of the dosage form contains at least 80% of the hydrocodone or salt thereof;

wherein the amount of hydrocodone or salt thereof released from the dosage form is proportional within 20% to elapsed time from 8 to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°

C.

94. The solid controlled release dosage form of claim 93, wherein the inner 50% of the dosage form contains at least 80% of the hydrocodone or salt thereof.