Method of making self-supporting therapeutic active-containing film

• US 7,824,588 B2
• Filed: 04/14/2008
• Issued: 11/02/2010
• Est. Priority Date: 10/12/2001
• Status: Expired due to Fees

• Current Assignee: Monosol Rx LLC (Kuraray Company Limited)
• Original Assignee: Monosol Rx LLC (Kuraray Company Limited)
• Inventors: Yang, Robert K., Fuisz, Joseph M., Fuisz, Richard C., Myers, Garry L.
• Primary Examiner(s): Lee; Edmund H.
• Application Number:
  US12/102,071
• Publication Number:
  US 20080260805A1
• Time in Patent Office: 932 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 method of making a self-supporting therapeutic active-containing film comprising:

(a) Mixing at least one edible polymer component, a therapeutic active composition, and at least one polar solvent to form a matrix;

(b) Forming a wet film from said matrix;

(c) Removing said polar solvent from said matrix with heat and/or radiation energy by exposing said matrix to a temperature greater than the degradation temperature of said therapeutic active composition;

wherein the temperature of the matrix is 100°

C. or less during said step of removing said polar solvent from said matrix.

2. The method of claim 1, wherein said step of removing said polar solvent from said matrix occurs in about 10 minutes or less.

3. The method of claim 1, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

4. The method of claim 1, wherein said polar solvent comprises a mixture of polar solvents.

5. The method of claim 1, further comprising the step of deaerating said matrix.

6. The method of claim 1, wherein said edible polymer is water soluble.

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

8. The method of claim 1, wherein said active composition comprises insulin.

9. The method of claim 1, wherein said active composition comprises an enzyme.

10. The method of claim 1, wherein said active composition comprises a protein.

11. The method of claim 1, wherein said active composition comprises a hormone.

12. The method of claim 1, wherein said active composition comprises a cytokine.

13. The method of claim 1, wherein said active composition comprises immunoglobin.

14. The method of claim 1, wherein said active composition comprises a polysaccharide.

15. The method of claim 1, wherein said active composition comprises a peptide.

16. The method of claim 1, wherein said active composition comprises a glycoprotein.

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

(a) Forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) Directing said premix and said at least one therapeutic active to at least one mixer; and

(c) Mixing said premix and therapeutic active to form said matrix.

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

19. The method of claim 1, wherein said therapeutic active composition is in a controlled release form.

20. The method of claim 1, wherein said method prevents substantial aggregation of said active composition.

21. The method of claim 1, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through the buccal cavity of said individual.

22. The method of claim 1, wherein said self-supporting therapeutic active-containing film has a substantially uniform thickness.

23. The method of claim 1, wherein said self-supporting therapeutic active-containing film has a substantially uniform mass to volume ratio of components.

24. The method of claim 1, wherein any air flow present during said rapidly drying step does not overcome the inherent viscosity of said wet film.

75. The method of claim 1, wherein after said step of removing said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

78. The method of claim 1, wherein after said step of removing said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

81. The method of claim 1, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through a mucosal surface of said individual.

84. The method of claim 1, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through sublingual application.

87. The method of claim 1, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual by administration within the body of the individual during surgery.

90. The method of claim 87, wherein said self-supporting therapeutic active-containing film releases said active composition over an extended period of time.

93. The method of claim 1, further comprising 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%.

96. The method of claim 1, wherein said step of forming a wet film from said matrix comprises casting said matrix.

99. The method of claim 1, wherein said step of forming a wet film from said matrix comprises extruding said matrix.

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

105. The method of claim 1, wherein said therapeutic active composition includes a contraceptive.

106. The method of claim 17, wherein said therapeutic active composition includes a contraceptive.

111. The method of claim 1, wherein said polar solvent is removed from said matrix with heat.

112. The method of claim 111, wherein said heat comprises hot air currents.

113. The method of claim 111, wherein said step of removing said polar solvent occurs in about 10 minutes or less.

114. The method of claim 111, wherein after said step of removing said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

115. The method of claim 111, wherein after said step of removing said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

116. The method of claim 111, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

117. The method of claim 111, comprising 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%.

118. The method of claim 111, wherein said polar solvent comprises a mixture of polar solvents.

119. The method of claim 111, wherein said matrix comprises an emulsion, a colloid or a suspension.

120. The method of claim 111, wherein said matrix is formed via a process comprising the steps of:

(a) forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) directing said premix and said at least one therapeutic active to at least one mixer; and

(c) mixing said premix and therapeutic active to form said matrix.

121. The method of claim 111, wherein said matrix comprises at least one taste-masking agent.

122. The method of claim 1, wherein said polar solvent is removed from said matrix with radiation energy.

123. The method of claim 122, wherein said radiation energy comprises infrared energy, radio frequency radiation, or microwave energy.

124. The method of claim 122, wherein said step of removing said polar solvent occurs in about 10 minutes or less.

125. The method of claim 122, wherein after said step of removing said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

126. The method of claim 122, wherein after said step of removing said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

127. The method of claim 122, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

128. The method of claim 122, comprising 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%.

129. The method of claim 122, wherein said polar solvent comprises a mixture of polar solvents.

130. The method of claim 122, wherein said matrix comprises an emulsion, a colloid or a suspension.

131. The method of claim 122, wherein said matrix is formed via a process comprising the steps of:

(a) forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) directing said premix and said at least one therapeutic active to at least one mixer; and

(c) mixing said premix and therapeutic active to form said matrix.

132. The method of claim 122, wherein said matrix comprises at least one taste-masking agent.

177. The method of claim 1, wherein said matrix comprises a dispersion.

178. The method of claim 17, wherein said matrix comprises a dispersion.

183. The method of claim 1, wherein said at least one edible polymer, said therapeutic active composition, and said at least one polar solvent are each ingestible materials.

186. The method of claim 1, wherein said self-supporting therapeutic active-containing film is orally administrable.

189. The method of claim 1, wherein said therapeutically active composition is in the form of a particle.

25. A method of making a self-supporting therapeutic active-containing film comprising:

(a) Mixing at least one edible polymer component, a therapeutic active composition, and at least one polar solvent to form a matrix;

(b) Forming a wet film from said matrix;

(c) Removing said polar solvent from said matrix with heat and/or radiation energy by heating said matrix to a temperature that is less than the boiling point of said at least one polar solvent so as to form a viscoelastic film.

26. The method of claim 25, wherein said temperature of said matrix is less than about 100 °

C.

27. The method of claim 25, wherein said step of removing said polar solvent from said matrix occurs in less than about 10 minutes.

28. The method of claim 25, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

29. The method of claim 25, wherein said polar solvent comprises a mixture of polar solvents.

30. The method of claim 25, further comprising the step of deaerating said matrix.

31. The method of claim 25, wherein said edible polymer is water soluble.

32. The method of claim 25, wherein said matrix comprises an emulsion, a colloid or a suspension.

33. The method of claim 25, wherein said active composition comprises insulin.

34. The method of claim 25, wherein said active composition comprises an enzyme.

35. The method of claim 25, wherein said active composition comprises a protein.

36. The method of claim 25, wherein said active composition comprises a hormone.

37. The method of claim 25, wherein said active composition comprises a cytokine.

38. The method of claim 25, wherein said active composition comprises immunoglobin.

39. The method of claim 25, wherein said active composition comprises a polysaccharide.

40. The method of claim 25, wherein said active composition comprises a peptide.

41. The method of claim 25, wherein said active composition comprises a glycoprotein.

42. The method of claim 25, wherein said matrix is formed via a process comprising the steps of:

(a) Forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) Directing said premix and said at least one therapeutic active to at least one mixer; and

(c) Mixing said premix and therapeutic active to form said matrix.

43. The method of claim 25, wherein said matrix comprises at least one taste-masking agent.

44. The method of claim 25, wherein said therapeutic active composition is in a controlled release form.

45. The method of claim 25, wherein said method prevents substantial aggregation of said active composition.

46. The method of claim 25, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through the buccal cavity of said individual.

47. The method of claim 25, wherein said self-supporting therapeutic active-containing film has a substantially uniform thickness.

48. The method of claim 25, wherein said self-supporting therapeutic active-containing film has a substantially uniform mass to volume ratio of components.

49. The method of claim 25, wherein any air flow present during said step of removing said polar solvent from said matrix does not overcome the inherent viscosity of said wet film.

76. The method of claim 25, wherein after said step of removing said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

79. The method of claim 25, wherein after said step of removing said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

82. The method of claim 25, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through a mucosal surface of said individual.

85. The method of claim 25, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through sublingual application.

88. The method of claim 25, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual by administration within the body of the individual during surgery.

91. The method of claim 88, wherein said self-supporting therapeutic active-containing film releases said active composition over an extended period of time.

94. The method of claim 25, further comprising 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%.

97. The method of claim 25, wherein said step of forming a wet film from said matrix comprises casting said matrix.

100. The method of claim 25, wherein said step of forming a wet film from said matrix comprises extruding said matrix.

103. The method of claim 25, wherein said step of forming a wet film from said matrix comprises forming said wet film in the form of a sheet.

107. The method of claim 25, wherein said therapeutic active composition includes a contraceptive.

108. The method of claim 42, wherein said therapeutic active composition includes a contraceptive.

133. The method of claim 25, wherein said polar solvent is removed from said matrix with heat.

134. The method of claim 133, wherein said heat comprises hot air currents.

135. The method of claim 133, wherein said step of removing said polar solvent occurs in about 10 minutes or less.

136. The method of claim 133, wherein after said step of removing said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

137. The method of claim 133, wherein after said step of removing said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

138. The method of claim 133, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

139. The method of claim 133, comprising 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%.

140. The method of claim 133, wherein said polar solvent comprises a mixture of polar solvents.

141. The method of claim 133, wherein said matrix comprises an emulsion, a colloid or a suspension.

142. The method of claim 133, wherein said matrix is formed via a process comprising the steps of:

(a) forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) directing said premix and said at least one therapeutic active to at least one mixer; and

(c) mixing said premix and therapeutic active to form said matrix.

143. The method of claim 133, wherein said matrix comprises al least one taste-masking agent.

144. The method of claim 25, wherein said polar solvent is removed from said matrix with radiation energy.

145. The method of claim 144, wherein said radiation energy comprises infrared energy, radio frequency radiation, or microwave energy.

146. The method of claim 144, wherein said step of removing said polar solvent occurs in about 10 minutes or less.

147. The method of claim 144, wherein after said step of removing said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

148. The method of claim 144, wherein after said step of removing said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

149. The method of claim 144, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

150. The method of claim 144, comprising 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%.

151. The method of claim 144, wherein said polar solvent comprises a mixture of polar solvents.

152. The method of claim 144, wherein said matrix comprises an emulsion, a colloid or a suspension.

153. The method of claim 144, wherein said matrix is formed via a process comprising the steps of:

(a) forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) directing said premix and said at least one therapeutic active to at least one mixer; and

(c) mixing said premix and therapeutic active to form said matrix.

154. The method of claim 144, wherein said matrix comprises at least one taste-masking agent.

179. The method of claim 25, wherein said matrix comprises a dispersion.

180. The method of claim 42, wherein said matrix comprises a dispersion.

184. The method of claim 25, wherein said at least one edible polymer, said therapeutic active composition, and said at least one polar solvent are each ingestible materials.

187. The method of claim 25, wherein said self-supporting therapeutic active-containing film is orally administrable.

190. The method of claim 25, wherein said therapeutically active composition is in the form of a particle.

50. A method of making a self-supporting therapeutic active-containing film comprising:

(a) Mixing at least one edible polymer component, a therapeutic active composition, and at least one polar solvent to form a matrix;

(b) Forming a wet film from said matrix;

(c) Using heat and/or radiation energy to remove said polar solvent from said matrix to form a visco-elastic state without forming bubbles.

51. The method of claim 50, wherein said matrix is heated to a temperature of less than about 100 °

C.

52. The method of claim 50, wherein said step of using heat and/or radiation energy to remove said polar solvent from said matrix occurs in less than about 10 minutes.

53. The method of claim 50, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

54. The method of claim 50, wherein said polar solvent comprises a mixture of polar solvents.

55. The method of claim 50, further comprising the step of deaerating said matrix.

56. The method of claim 50, wherein said edible polymer is water soluble.

57. The method of claim 50, wherein said matrix comprises an emulsion, a colloid or a suspension.

58. The method of claim 50, wherein said active composition comprises insulin.

59. The method of claim 50, wherein said active composition comprises an enzyme.

60. The method of claim 50, wherein said active composition comprises a protein.

61. The method of claim 50, wherein said active composition comprises a hormone.

62. The method of claim 50, wherein said active composition comprises a cytokine.

63. The method of claim 50, wherein said active composition comprises immunoglobin.

64. The method of claim 50, wherein said active composition comprises a polysaccharide.

65. The method of claim 50, wherein said active composition comprises a peptide.

66. The method of claim 50, wherein said active composition comprises a glycoprotein.

67. The method of claim 50, wherein said matrix is formed via a process comprising the steps of:

(a) Forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) Directing said premix and said at least one therapeutic active to at least one mixer; and

(c) Mixing said premix and therapeutic active to form said matrix.

68. The method of claim 50, wherein said matrix comprises at least one taste-masking agent.

69. The method of claim 50, wherein said therapeutic active composition is in a controlled release form.

70. The method of claim 50, wherein said method prevents substantial aggregation of said active composition.

71. The method of claim 50, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through the buccal cavity of said individual.

72. The method of claim 50, wherein said self-supporting therapeutic active-containing film has a substantially uniform thickness.

73. The method of claim 50, wherein said self-supporting therapeutic active-containing film has a substantially uniform mass to volume ratio of components.

74. The method of claim 50, wherein any air flow present during said method does not overcome the inherent viscosity of said wet film.

77. The method of claim 50, wherein after said step of using heat and/or radiation energy to remove said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

80. The method of claim 50, wherein after said step of using heat and/or radiation energy to remove said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

83. The method of claim 50, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through a mucosal surface of said individual.

86. The method of claim 50, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual through sublingual application.

89. The method of claim 50, wherein said self-supporting therapeutic active-containing film is capable of providing administration of said active composition to an individual by administration within the body of the individual during surgery.

92. The method of claim 89, wherein said self-supporting therapeutic active-containing film releases said active composition over an extended period of time.

95. The method of claim 50, further comprising 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 method of claim 50, wherein said step of forming a wet film from said matrix comprises casting said matrix.

101. The method of claim 50, wherein said step of forming a wet film from said matrix comprises extruding said matrix.

104. The method of claim 50, wherein said step of forming a wet film from said matrix comprises forming said wet film in the form of a sheet.

109. The method of claim 50, wherein said therapeutic active composition includes a contraceptive.

110. The method of claim 67, wherein said therapeutic active composition includes a contraceptive.

155. The method of claim 50, wherein said polar solvent is removed from said matrix with heat.

156. The method of claim 155, wherein said heat comprises hot air currents.

157. The method of claim 155, wherein said step of removing said polar solvent from said matrix occurs in about 10 minutes or less.

158. The method of claim 155, wherein after said step of removing said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

159. The method of claim 155, wherein after said step of removing said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

160. The method of claim 155, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

161. The method of claim 155, comprising 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%.

162. The method of claim 155, wherein said polar solvent comprises a mixture of polar solvents.

163. The method of claim 155, wherein said matrix comprises an emulsion, a colloid or a suspension.

164. The method of claim 155, wherein said matrix is formed via a process comprising the steps of:

(a) forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) directing said premix and said at least one therapeutic active to at least one mixer; and

(c) mixing said premix and therapeutic active to form said matrix.

165. The method of claim 155, wherein said matrix comprises at least one taste-masking agent.

166. The method of claim 50, wherein said polar solvent is removed from said matrix with radiation energy.

167. The method of claim 166, wherein said radiation energy comprises infrared energy, radio frequency radiation, or microwave energy.

168. The method of claim 166, wherein said step of removing said polar solvent from said matrix occurs in about 10 minutes or less.

169. The method of claim 166, wherein after said step of removing said polar solvent from said matrix, the matrix comprises 10% or less polar solvent.

170. The method of claim 166, wherein after said step of removing said polar solvent from said matrix, the matrix comprises less than 6% polar solvent.

171. The method of claim 166, wherein the self-supporting therapeutic active-containing film has a variation of active content of less than 10% per film unit.

172. The method of claim 166, comprising 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%.

173. The method of claim 166, wherein said polar solvent comprises a mixture of polar solvents.

174. The method of claim 166, wherein said matrix comprises an emulsion, a colloid or a suspension.

175. The method of claim 166, wherein said matrix is formed via a process comprising the steps of:

(a) forming a master batch premix comprising said at least one polymer and said at least one polar solvent;

(b) directing said premix and said at least one therapeutic active to at least one mixer; and

(c) mixing said premix and therapeutic active to form said matrix.

176. The method of claim 166, wherein said matrix comprises at least one taste-masking agent.

181. The method of claim 50, wherein said matrix comprises a dispersion.

182. The method of claim 67, wherein said matrix comprises a dispersion.

185. The method of claim 50, wherein said at least one edible polymer, said therapeutic active composition, and said at least one polar solvent are each ingestible materials.

188. The method of claim 50, wherein said self-supporting therapeutic active-containing film is orally administrable.

191. The method of claim 50, wherein said therapeutically active composition is in the form of a particle.