Pharmaceutical dosage form

• US 8,383,152 B2
• Filed: 01/23/2009
• Issued: 02/26/2013
• Est. Priority Date: 01/25/2008
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Jans, Eugeen Marie Jozef, Voorspoels, Jody Firmin Marceline, Faure, Anne, Arkenau-Maric, Elisabeth, Bartholomus, Johannes, Galia, Eric, Kiekens, Filip Ren Irena, Barnscheid, Lutz, Frevel, Marc, Ziegler, Iris, Schssele, Andrea
• Primary Examiner(s): Sasan, Aradhana
• Application Number:
  US12/358,415
• Publication Number:
  US 20090202634A1
• Time in Patent Office: 1,495 Days
• Field of Search: 424/468, 424/464, 424/474, 514/654
• US Class Current: 424/468
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• 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 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: Y10T 428/24479 including variation in thickness

Abstract

The invention relates to a pharmaceutical dosage form, preferably with controlled release of a pharmacologically active compound (A) contained therein, the pharmaceutical dosage form very preferably being tamper-resistant and most preferably having a breaking strength B₁ of at least 500 N in direction of extension E₁ and having a breaking strength B₂ of less than 500 N in direction of extension E₂.

Claims

1. A pharmaceutical dosage form with controlled release of a pharmacologically active compound (A) contained therein, the pharmaceutical dosage form having a first breaking strength (B₁) of at least 500 N in a first direction of extension (E₁) and having a second breaking strength (B₂) of less than 500 N in a second direction of extension (E₂).

2. A pharmaceutical dosage form according to claim 1, having a shape comprising a longitudinal axis and two opposite longitudinal edges, a transversal axis perpendicular to the longitudinal axis and two opposite transversal edges, a front side, an opposite back side and a circumferential rim between said front and back side, wherein the front side and/or the back side comprise a basis area and wherein the front side and/or the back side comprise at least one bulge which extends above said basis area, said at least one bulge being present at and/or adjacent to at least a section of one or both longitudinal edges and/or at and/or adjacent to at least a section of one or both transversal edges and/or between both longitudinal edges and both transversal edges.

3. The pharmaceutical dosage form according to claim 2, which is a tablet having an oblong shape.

4. The pharmaceutical dosage form according to claim 2, wherein the front side and the back side each comprise at least one bulge at least along a section at and/or adjacent to both longitudinal edges and/or at least along a section at and/or adjacent to both transversal edges.

5. The pharmaceutical dosage form according to claim 2, wherein said front side and said back side comprise an at least essentially continuous bulge at and/or adjacent to at least two thirds of both opposite longitudinal edges.

6. The pharmaceutical dosage form according to claim 2, wherein one or both longitudinal edges are essentially straight over at least a major part of their length and/or wherein one or both transversal edges are curved over a major part of their length.

7. The pharmaceutical dosage form according to claim 2, wherein the front side and/or the back side comprise an essentially circumferential bulge at and/or adjacent to the circumferential edge of the front side and/or the back side of said pharmaceutical dosage form.

8. The pharmaceutical dosage form according to claim 2, wherein said pharmaceutical dosage form has an oblong form, and in its oblong form comprises at and/or adjacent to major portions of both opposite longitudinal edges of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge at and/or adjacent to major portions of both opposite longitudinal edges of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge at and/or adjacent to the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge at and/or adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form.

9. The pharmaceutical dosage form according to claim 8, wherein said pharmaceutical dosage form in its oblong form comprises at major portions of both opposite longitudinal edges of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge at major portions of both opposite longitudinal edges of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge at the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge at the circumferential edge of both the front side and the back side of said pharmaceutical dosage form.

10. The pharmaceutical dosage form according to claim 8, wherein said pharmaceutical dosage form in its oblong form comprises adjacent to major portions of both opposite longitudinal edges of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge adjacent to major portions of both opposite longitudinal edges of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of the frontside of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form.

11. The pharmaceutical dosage form according to claim 8, wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form.

12. The pharmaceutical dosage form according to claim 2, wherein the front side and/or the back side comprise, in addition to at least one bulge on the front side and/or the back side, at least one indentation.

13. The pharmaceutical dosage form according to claim 12, wherein the front and the back side comprise at least one indentation.

14. The pharmaceutical dosage form according to claim 13, wherein the indentation(s) in the front side and the back side are at least once at least partially off-set.

15. The pharmaceutical dosage form according to claim 13, wherein all the indentations of the front side and all the indentations of the back side are at least partially off-set.

16. The pharmaceutical dosage form according to claim 13, wherein at least one indentation of the front side and at least one indentation of the back side are positioned in a congruent manner.

17. The pharmaceutical dosage form according to claim 16, wherein all indentations of the front side and all indentations of the back side are positioned in a congruent manner.

18. The pharmaceutical dosage form according to claim 12, wherein the indentations have a cylindrical or cube-like or cuboid-like shape or the shape of a half-sphere.

19. The pharmaceutical dosage form according to claim 2, comprising one or more hydrophilic polymers.

20. The pharmaceutical dosage form according to claim 19, wherein the one or more hydrophilic polymers are hydroxypropyl methyl cellulose and/or hydroxypropyl cellulose.

21. The pharmaceutical dosage form according to claim 19, further comprising pregelatinized starch.

22. The pharmaceutical dosage form according to claim 2, wherein the length of the pharmaceutical dosage form does not exceed 30 mm.

23. The pharmaceutical dosage form according to claim 2, having an average thickness over the basis areas of the front and the back side of about at least 1 mm.

24. The pharmaceutical dosage form according to claim 2, wherein the bulge extends perpendicular from the basis area of the front side and/or from the basis area of the back side in average from about 0.5 mm to about 2 mm.

25. The pharmaceutical dosage form according claim 2, having a length in the range of about 5 mm to about 30 mm, a width in the range of about 5 mm to about 15 mm, and a thickness over the basis areas in the range of about 1 mm to about 6 mm.

26. The pharmaceutical dosage form according to claim 2, further comprising at least partially a coating.

27. The pharmaceutical dosage form according to claim 1, which is tamper-resistant and has a retarded release profile for pharmaceutical application as an oral dosage form, comprising at least one pharmaceutically active ingredient with potential for abuse, and having a shape comprising a longitudinal axis and two opposite longitudinal edges, a transversal axis perpendicular to the longitudinal axis and two opposite transversal edges, a front side, an opposite back side and a circumferential rim between said front and back side, wherein the front side and/or the back side comprise a basis area and wherein the front side and/or the back side comprise at least one bulge which extends above said basis area, said at least one bulge being present at and/or adjacent to at least a section of one or both longitudinal edges and/or at and/or adjacent to at least a section of one or both transversal edges and/or between both longitudinal edges and both transversal edges.

28. The pharmaceutical dosage form according to claim 27, which is a tablet having an oblong shape.

29. The pharmaceutical dosage form according to claim 27, wherein the front side and the back side each comprise at least one bulge at least along a section at and/or adjacent to both longitudinal edges and/or at least along a section at and/or adjacent to both transversal edges.

30. The pharmaceutical dosage form according to claim 27, wherein said front side and said back side comprise an at least essentially continuous bulge at and/or adjacent to at least two thirds of both opposite longitudinal edges.

31. The pharmaceutical dosage form according to claim 27, wherein one or both longitudinal edges are essentially straight over at least a major part of their length and/or wherein one or both transversal edges are curved over a major part of their length.

32. The pharmaceutical dosage form according to claim 27, wherein the front side and/or the back side comprise an essentially circumferential bulge at and/or adjacent to the circumferential edge of the front side and/or the back side of said pharmaceutical dosage form.

33. The pharmaceutical dosage form according to claim 27, wherein said pharmaceutical dosage form has an oblong form, and in its oblong form comprises at and/or adjacent to major portions of both opposite longitudinal edges of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge at and/or adjacent to major portions of both opposite longitudinal edges of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge at and/or adjacent to the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge at and/or adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form.

34. The pharmaceutical dosage form according to claim 33, wherein said pharmaceutical dosage form in its oblong form comprises at major portions of both opposite longitudinal edge of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge at major portions of both opposite longitudinal edge of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge at the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge at the circumferential edge of both the front side and the back side of said pharmaceutical dosage form.

35. The pharmaceutical dosage form according to claim 33, wherein said pharmaceutical dosage form in its oblong form comprises adjacent to major portions of both opposite longitudinal edge of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge adjacent to major portions of both opposite longitudinal edge of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge adjacent to the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form.

36. The pharmaceutical dosage form according to claim 33, wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form.

37. The pharmaceutical dosage form according to claim 27, wherein the front side and/or the back side comprise, in addition to at least one bulge on the front side and/or the back side, at least one indentation.

38. The pharmaceutical dosage form according to claim 37, wherein the front and the back side comprise at least one indentation.

39. The pharmaceutical dosage form according to claim 38, wherein the indentation(s) in the front side and the back side are at least once at least partially off-set.

40. The pharmaceutical dosage form according to claim 38, wherein all the indentations of the front side and all the indentations of the back side are at least partially off-set.

41. The pharmaceutical dosage form according to claim 37, wherein at least one indentation of the front side and at least one indentation of the back side are positioned in a congruent manner.

42. The pharmaceutical dosage form according to claim 41, wherein all indentations of the front side and all indentations of the back side are positioned in a congruent manner.

43. The pharmaceutical dosage form according to claim 37, wherein the indentations have a cylindrical or cube-like or cuboid-like shape or the shape of a half-sphere.

44. The pharmaceutical dosage form according to claim 27, comprising a polyalkylene oxide.

45. The pharmaceutical dosage form according to claim 27, comprising at least one cellulose ether derivative.

46. The pharmaceutical dosage form according to claim 45, wherein the cellulose ether derivative is hydroxy propyl methyl cellulose.

47. The pharmaceutical dosage form according to claim 44, wherein the polyalkylene oxide is polyethylene oxide.

48. The pharmaceutical dosage form according to claim 47, wherein the polyethylene oxide has a molecular weight in the range of about 2,000,000 g mol⁻

1 to about 7,000,000 g mol<sup>−

1</sup>.

49. The pharmaceutical dosage form according to claim 27, wherein the pharmaceutical dosage form further comprises a polyalkylene glycol.

50. The pharmaceutical dosage form according to claim 49, wherein the polyalkylene glycol is polyethylene glycol.

51. The pharmaceutical dosage form according to claim 27, wherein the pharmaceutically active ingredient with potential for abuse is a pain-killing drug.

52. The pharmaceutical dosage form according to claim 51, wherein the pharmaceutically active ingredient is tapentadol.

53. The pharmaceutical dosage form according to claim 27, comprising at least one pharmaceutically active ingredient with potential for abuse;

at least one polyalkylene oxide), at least one cellulose ether derivative; and

at least one polyalkylene glycol; and

optionally an additive.

54. The pharmaceutical dosage form according to claim 53, wherein the active ingredient with potential for abuse is present in an amount of at least 5 weight percent;

poly(alkylene oxide) is present in an amount of at least 15 weight percent;

cellulose ether derivative is present in an amount of at least 5 weight percent; and

polyalkylene glycol, is present in an amount of at least 5 weight percent.

55. The pharmaceutical dosage form according to claim 27, wherein the length of the pharmaceutical dosage form does not exceed 30 mm.

56. The pharmaceutical dosage form according to claim 27, having an average thickness over the basis areas of the front and the back side of about at least 1 mm.

57. The pharmaceutical dosage form according to claim 27, wherein the bulge extends perpendicular from the basis area of the front side and/or from the basis area of the back side in average from about 0.5 mm to about 2 mm.

58. The pharmaceutical dosage form according to claim 27, having a length in the range of about 5 mm to about 30 mm, a width in the range of about 5 mm to about 15 mm, and a thickness over the basis areas in the range of about 1 mm to about 6 mm.

59. The pharmaceutical dosage form according to claim 27, wherein said pharmaceutical dosage form is a monolith.

60. The pharmaceutical dosage form according to claim 27, which has been prepared via compression using a die and a punch from a monolithic mass obtained by melt extrusion.

61. The pharmaceutical dosage form according to claim 59, wherein said pharmaceutical dosage form has been obtained by compressing a melt extruded monolithic mass which exhibits ambient temperature.

62. The pharmaceutical dosage form according to claim 61, wherein the extruded monolithic mass has been cut prior to compression.

63. The pharmaceutical dosage form according to claim 60, wherein melt extrusion has been conducted with a twin-screw extruder.

64. The pharmaceutical dosage form according to claim 27, further comprising at least partially a coating.

65. The pharmaceutical dosage form according to claim 1, wherein E₁ is orthogonal to E₂.

66. The pharmaceutical dosage form according to claim 1, which has a main direction of extension, wherein E₂ is the main direction of extension of the pharmaceutical dosage form.

67. The pharmaceutical dosage form according to claim 1, which provides fragments when exerting a force higher than B₂ in direction of extension E₂, said fragments in turn having a breaking strength of at least 500 N in any of their directions of extension.

68. The pharmaceutical dosage form according to claim 67, wherein the volume of each fragment is at least 5% of the volume of the pharmaceutical dosage form.

69. The pharmaceutical dosage form according to claim 1, which is deformed when exerting a force in direction of extension E₂ so that, when the amount of force reaches the breaking strength B₂, deformation causes tractive forces that lead to disruption of the dosage form.

70. The pharmaceutical dosage form according to claim 1, which has released under in vitro conditions

after 0.5 h 1.0 to 35 wt.-%,

after 1 h 5.0 to 45 wt.-%,

after 2 h 10 to 60 wt.-%,

after 4 h at least 15 wt.-%,

after 6 h at least 20 wt.-%,

after 8 h at least 25 wt.-% and

after 12 h at least 30 wt.-%

of the pharmacologically active compound (A) that was originally contained in the pharmaceutical dosage form.

71. The pharmaceutical dosage form according to claim 1, which is not radially symmetric about its principal direction of extension.

72. The pharmaceutical dosage form according to claim 1, which exhibits a maximum extension of the dosage form orthogonal to a main area of extension of the dosage form spaced from a centre of mass of the dosage form parallel to said main area of extension.

73. The pharmaceutical dosage form according to claim 1, wherein a portion of its surface is convex, and another portion of its surface is concave.

74. The pharmaceutical dosage form according to claim 1, which contains a polymer (C) having a weight average molecular weight of at least 100,000 g mol⁻

1.

75. The pharmaceutical dosage form according to claim 74, wherein the polymer (C) comprises a polyalkylene oxide.

76. The pharmaceutical dosage form according to claim 1, wherein

a portion of the surface of the pharmaceutical dosage form is convex, another portion of its surface is concave;

and

the pharmacologically active compound (A) is a psychotropically acting substance; and

the content of the pharmacologically active compound (A) is at least 0.5 wt. %, based on the total weight of the dosage form; and

polymer (C) is an polyalkylene oxide having a weight average molecular weight of at least 200,000 g/mol; and

the content of polymer (C) is at least 15 wt.-%, based on the total weight of the dosage form; and

the pharmacologically active compound (A) is embedded in the polymer (C); and

the pharmaceutical dosage form is adapted for oral administration once daily or twice daily; and

the pharmaceutical dosage form is thermoformed.

77. A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a pharmaceutical dosage form according to claim 2, wherein the pharmaceutically active ingredient is selected from the group consisting of analgesics.

78. A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a pharmaceutical dosage form according to claim 27, wherein the pharmaceutically active ingredient with potential for abuse is selected from the group consisting of analgesics.

79. A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a pharmaceutical dosage form according to claim 1, wherein the pharmacologically active compound (A) is selected from the group consisting of analgesics.