Process for forming an ingestible thin film with non-self-aggregating uniform heterogeneity

• US 7,910,031 B2
• Filed: 03/26/2009
• Issued: 03/22/2011
• Est. Priority Date: 10/12/2001
• Status: Expired due to Fees

• Current Assignee: Aquestive Therapeutics, Inc.
• Original Assignee: Monosol Rx LLC (Kuraray Company Limited)
• Inventors: Yang, Roert K., Fuisz, Joseph M., Fuisz, Richard C., Myers, Garry L.
• Primary Examiner(s): Lee; Edmund H.
• Application Number:
  US12/411,835
• Publication Number:
  US 20090182062A1
• Time in Patent Office: 726 Days
• Field of Search: None
• US Class Current: 264/172.19
• CPC Class Codes: A61J 3/00 Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: B29C 48/08 flexible, e.g. films
• CPC Class Codes: B29C 48/91 Heating, e.g. for cross linking
• CPC Class Codes: B29C 48/919 using a bath, e.g. extruding into an open bath to coagulate or cool the material
• CPC Class Codes: F26B 13/10 Arrangements for feeding, heating or supporting materials; Controlling movement, tension or position of materials heating processes F26B3/00
• CPC Class Codes: F26B 13/104 supported by fluid jets only; Fluid blowing arrangements for flotation dryers, e.g. coanda nozzles

Abstract

The invention relates to film products containing desired levels of active components and methods of their preparation. Desirably, the films disintegrate in water and may be formed by a controlled drying process, or other process that maintains the required uniformity of the film. Desirably, the films may be exposed to temperatures above that at which the active components typically degrade without concern for loss of the desired activity.

Claims

1. A process for forming an ingestible film having a substantially uniform distribution of components comprising at least one anti-emetic compound, comprising the steps of:

(a) combining a polymer component, water and at least one anti-emetic compound to form a matrix with a substantially uniform distribution of said components;

(b) forming a film from said matrix;

(c) providing a conveyor surface having top and bottom sides;

(d) feeding said film onto said top side of said surface; and

(e) drying said film within about 10 minutes or fewer by applying hot air currents to said bottom side of said conveyor surface and exposing said film to a temperature above the degradation temperature of said anti-emetic compound, wherein said degradation temperature is 70°

C. or higher.

39. The process of claim 1, wherein said drying step maintains a non-self-aggregating uniform heterogeneity of said components throughout said film.

40. The process of claim 1, wherein said film is self-supporting.

41. The process of claim 1, wherein a specific amount of said anti-emetic compound is obtained from said film by cutting said film to a predetermined size.

42. The process of claim 1, wherein a specific amount of said anti-emetic compound is obtained from said film by cutting said film to a predetermined weight.

43. The process of claim 1, wherein said drying of said film reduces the weight percent of said solvent to about 10% or less.

44. The process of claim 1, wherein said drying of said film reduces the weight percent of said solvent to about 6% or less.

45. The process of claim 1, wherein said solvent comprises a polar solvent.

46. The process of claim 45, wherein said solvent comprises a mixture of polar solvents.

47. The process of claim 1, wherein said polymer is water soluble.

48. The process of claim 1, wherein said polymer is an edible polymer.

49. The process of claim 1, wherein said polymer component, said active comprising at least one anti-emetic compound, and said solvent are each ingestible materials.

50. The process of claim 1, wherein said active comprising at least one anti-emetic compound is in the form of a particle.

51. The process of claim 1, wherein said matrix comprises an emulsion, a colloid or a suspension.

52. The process of claim 1, wherein said matrix comprises a dispersion.

53. The process of claim 1, wherein said matrix comprises at least one taste-masking agent.

54. The process of claim 1, wherein said active comprising at least one anti-emetic compound is in a controlled release form.

55. The process of claim 1, wherein said ingestible film releases said active comprising at least one anti-emetic compound over an extended period of time.

56. The process of claim 1, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through the buccal cavity of said individual.

57. The process of claim 1, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through a mucosal surface of said individual.

58. The process of claim 1, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through sublingual application.

59. The process of claim 1, wherein said ingestible film is orally administrable.

60. The process of claim 1, wherein said ingestible film has a substantially uniform thickness.

61. The process of claim 1, wherein the ingestible film has a variation of active content of less than 10% per film unit.

62. The process of claim 1, further comprising the step of forming a plurality of individual dosage units of substantially the same size, wherein the active content of individual dosage units has a variance of no more than 10%.

63. The process of claim 1, further comprising the step of deaerating said matrix.

64. The process of claim 1, wherein said matrix is formed via a process comprising the steps of:

(a) Forming a master batch premix comprising said polymer and said solvent;

(b) Directing said premix and said anti-emetic compound to at least one mixer; and

(c) Mixing said premix and anti-emetic compound to form said matrix.

65. The process of claim 1, wherein said process prevents substantial aggregation of said active comprising at least one anti-emetic compound.

66. The process of claim 1, wherein any air flow present during said step of drying does not overcome the inherent viscosity of said film.

67. The process of claim 1, wherein said hot air currents are provided by radiation energy.

68. The process of claim 67, wherein said radiation energy comprises infrared energy, radio frequency radiation, or microwave energy.

69. The process of claim 1, wherein said step of forming a film from said matrix comprises casting said matrix.

70. The process of claim 1, wherein said step of forming a film from said matrix comprises extruding said matrix.

71. The process of claim 1, wherein said step of forming a film from said matrix comprises forming a wet film in the form of a sheet.

72. The process of claim 1, wherein said active comprising at least one anti-emetic compound comprises at least one anti-nauseant.

73. The process of claim 1, wherein said anti-emetic compound comprises granisetron.

2. A process for forming an ingestible film having a substantially uniform distribution of components comprising an active comprising at least one anti-emetic compound, comprising the steps of:

(a) combining a polymer component, a solvent, and at least one anti-emetic compound to form a matrix with a substantially uniform distribution of said components;

(b) forming a film from said matrix;

(c) providing a conveyor surface having top and bottom sides;

(d) feeding said film onto said top side of said surface; and

(e) drying said film within about 10 minutes or fewer using hot air currents to at least said bottom side of said conveyor surface to lock in said substantially uniform distribution of components without degradation of said anti-emetic compound, said air currents having a temperature of at least 60°

C.

4. The process of claim 2, wherein said drying step maintains a non-self-aggregating uniform heterogeneity of said components throughout said film.

5. The process of claim 2, wherein said film is self-supporting.

6. The process of claim 2, wherein a specific amount of said anti-emetic compound is obtained from said film by cutting said film to a predetermined size.

7. The process of claim 2, wherein a specific amount of said anti-emetic compound is obtained from said film by cutting said film to a predetermined weight.

8. The process of claim 2, wherein said drying of said film reduces the weight percent of said solvent to about 10% or less.

9. The process of claim 2, wherein said drying of said film reduces the weight percent of said solvent to about 6% or less.

10. The process of claim 2, wherein said solvent comprises a polar solvent.

11. The process of claim 10, wherein said solvent comprises a mixture of polar solvents.

12. The process of claim 2, wherein said polymer is water soluble.

13. The process of claim 2, wherein said polymer is an edible polymer.

14. The process of claim 2, wherein said polymer component, said active comprising at least one anti-emetic compound, and said solvent are each ingestible materials.

15. The process of claim 2, wherein said active comprising at least one anti-emetic compound is in the form of a particle.

16. The process of claim 2, wherein said matrix comprises an emulsion, a colloid or a suspension.

17. The process of claim 2, wherein said matrix comprises a dispersion.

18. The process of claim 2, wherein said matrix comprises at least one taste-masking agent.

19. The process of claim 2, wherein said active comprising at least one anti-emetic compound is in a controlled release form.

20. The process of claim 2, wherein said ingestible film releases said active comprising at least one anti-emetic compound over an extended period of time.

21. The process of claim 2, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through the buccal cavity of said individual.

22. The process of claim 2, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through a mucosal surface of said individual.

23. The process of claim 2, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through sublingual application.

24. The process of claim 2, wherein said ingestible film is orally administrable.

25. The process of claim 2, wherein said ingestible film has a substantially uniform thickness.

26. The process of claim 2, wherein the ingestible film has a variation of active content of less than 10% per film unit.

27. The process of claim 2, further comprising the step of forming a plurality of individual dosage units of substantially the same size, wherein the active content of individual dosage units has a variance of no more than 10%.

28. The process of claim 2, further comprising the step of deaerating said matrix.

29. The process of claim 2, wherein said matrix is formed via a process comprising the steps of:

(a) Forming a master batch premix comprising said polymer and said solvent;

(b) Directing said premix and said anti-emetic compound to at least one mixer; and

(c) Mixing said premix and anti-emetic compound to form said matrix.

30. The process of claim 2, wherein said process prevents substantial aggregation of said active comprising at least one anti-emetic compound.

31. The process of claim 2, wherein any air flow present during said step of drying does not overcome the inherent viscosity of said film.

32. The process of claim 2, wherein said hot air currents are provided by radiation energy.

33. The process of claim 2, wherein said radiation energy comprises infrared energy, radio frequency radiation, or microwave energy.

34. The process of claim 2, wherein said step of forming a film from said matrix comprises casting said matrix.

35. The process of claim 2, wherein said step of forming a film from said matrix comprises extruding said matrix.

36. The process of claim 2, wherein said step of forming a film from said matrix comprises forming a wet film in the form of a sheet.

37. The process of claim 2, wherein said active comprising at least one anti-emetic compound comprises at least one anti-nauseant.

38. The process of claim 2, wherein said anti-emetic compound comprises granisetron.

3. A process for forming an ingestible film having a substantially uniform distribution of components comprising at least one anti-emetic compound, comprising the steps of:

(a) forming a master batch premix of a polymer component and a solvent;

(b) feeding a predetermined amount of said premix to at least one mixer;

(c) adding at least one anti-emetic compound to said at least one mixer;

(d) mixing said anti-emetic compound and said predetermined amount of said premix to form a matrix having a substantially uniform distribution of components;

(e) forming a film from said matrix;

(f) providing a conveyor surface having top and bottom sides;

(g) feeding said film onto said top side of said surface; and

(h) drying said film using heat applied to at least said bottom side of said conveyor surface such that the components of said film are heated to a temperature at least 60°

C., without degradation of said anti-emetic compound,

wherein said drying step comprises rapidly forming a visco-elastic film within about the first 4.0 minutes by applying hot air currents to at least said bottom side of said surface to lock in said substantially uniform distribution of components; and

drying said visco-elastic film to form a self-supporting ingestible film having a substantially uniform distribution of components.

74. The process of claim 3, wherein said drying step maintains a non-self-aggregating uniform heterogeneity of said components throughout said film.

75. The process of claim 3, wherein said ingestible film is self-supporting.

76. The process of claim 3, wherein a specific amount of said anti-emetic compound may be obtained from said film by cutting said film to a predetermined size.

77. The process of claim 3, wherein a specific amount of said anti-emetic compound may be obtained from said film by cutting said film to a predetermined weight.

78. The process of claim 3, wherein said drying of said film reduces the weight percent of said solvent to about 10% or less.

79. The process of claim 3, wherein said drying of said film reduces the weight percent of said solvent to about 6% or less.

80. The process of claim 3, wherein said solvent comprises a polar solvent.

81. The process of claim 80, wherein said solvent comprises a mixture of polar solvents.

82. The process of claim 3, wherein said polymer is water soluble.

83. The process of claim 3, wherein said polymer is an edible polymer.

84. The process of claim 3, wherein said polymer component, said active comprising at least one anti-emetic compound, and said solvent are each ingestible materials.

85. The process of claim 3, wherein said active comprising at least one anti-emetic compound is in the form of a particle.

86. The process of claim 3, wherein said matrix comprises an emulsion, a colloid or a suspension.

87. The process of claim 3, wherein said matrix comprises a dispersion.

88. The process of claim 3, wherein said matrix comprises at least one taste-masking agent.

89. The process of claim 3, wherein said active comprising at least one anti-emetic compound is in a controlled release form.

90. The process of claim 3, wherein said ingestible film releases said active comprising at least one anti-emetic compound over an extended period of time.

91. The process of claim 3, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through the buccal cavity of said individual.

92. The process of claim 3, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through a mucosal surface of said individual.

93. The process of claim 3, wherein said ingestible film is capable of providing administration of said active comprising at least one anti-emetic compound to an individual through sublingual application.

94. The process of claim 3, wherein said ingestible film is orally administrable.

95. The process of claim 3, wherein said ingestible film has a substantially uniform thickness.

96. The process of claim 3, wherein the ingestible film has a variation of active content of less than 10% per film unit.

97. The process of claim 3, further comprising the step of forming a plurality of individual dosage units of substantially the same size, wherein the active content of individual dosage units has a variance of no more than 10%.

98. The process of claim 3, further comprising the step of deaerating said matrix.

99. The process of claim 3, wherein said process prevents substantial aggregation of said active comprising at least one anti-emetic compound.

100. The process of claim 3, wherein any air flow present during said step of drying does not overcome the inherent viscosity of said film.

101. The process of claim 3, wherein said hot air currents are provided by radiation energy.

102. The process of claim 101, wherein said radiation energy comprises infrared energy, radio frequency radiation, or microwave energy.

103. The process of claim 3, wherein said step of forming a film from said matrix comprises casting said matrix.

104. The process of claim 3, wherein said step of forming a film from said matrix comprises extruding said matrix.

105. The process of claim 3, wherein said step of forming a film from said matrix comprises forming a wet film in the form of a sheet.

106. The process of claim 3, wherein said active comprising at least one anti-emetic compound comprises at least one anti-nauseant.

107. The process of claim 3, wherein said anti-emetic compound comprises granisetron.