Hydrogel-driven layered drug dosage form

• US 6,899,896 B2
• Filed: 12/20/2000
• Issued: 05/31/2005
• Est. Priority Date: 12/23/1999
• Status: Expired due to Fees

• Current Assignee: Bend Research Inc. (Lonza Group AG)
• Original Assignee: Pfizer Inc.
• Inventors: Roy, Michael C., Appel, Leah A., Supplee, Danni, Friesen, Dwayne T., Curatolo, William J., Beyerinck, Ronald A., Chidlaw, Mark B., Thombre, Avinash G., Waterman, Kenneth C., Fergione, Michael B.
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/745,096
• Publication Number:
  US 20010044474A1
• Time in Patent Office: 1,623 Days
• Field of Search: 424/464, 424/465, 424/480, 424/475, 424/474, 424/473, 424/468, 424/470, 424/482, 424/472
• US Class Current: 424/473
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A controlled release dosage form for sertraline has a core comprising a sertraline-containing composition and a water-swellable composition wherein the water-swellable composition is in a separate region within the core. A coating around the core is water-permeable, water-insoluble, and has at least one delivery port therethrough. In one embodiment, the dosage form releases sertraline to the use environment at an average rate of 6 to 10 wt % per hour from the second to the twenth hour after introduction to a use environment and less than about 25 wt % for the first two hours and at least 70 wt % by the twelfth hour, where the percentages correspond to the mass of drug released from the tablet divided by the total mass of drug originally present in the tablet. In another embodiment, the dosage form releases less than about 25 wt % of sertraline to the use environment by the second hour after introduction of the dosage form to the use environment, and delivers at least 25 wt % from the eighth to the twenty-fourth hour.

Claims

1. A dosage form for the controlled release of sertraline, comprising:

(a) a core comprising a sertraline-containing composition and a water-swellable composition wherein said water-swellable composition is in a separate region within said core;

(b) said sertraline-containing composition comprising sertraline and polyethylene oxide wherein sertraline makes up at least about 20 wt % of said sertraline-containing composition; and

(c) a coating around said core that is water-permeable, water-insoluble and has at least one delivery port therethrough;

wherein sertraline is in the form of a pharmaceutically acceptable salt thereof and, following introduction of said dosage form to an environment of use, said dosage form releases sertraline to said environment of use at an average rate of from about 6 to 10 wt % per hour from the second to the twelfth hour and releases less than about 25 wt % for the first two hours and releases at least 70 wt % by the twelfth hour.

6. A method for treating a depressive or anorectic disorder, comprising administering to a mammal in need of such treatment a therapeutically effective amount of sertraline in a dosage form as defined in claim 1.

15. The dosage form of claim 1, 3, 4, or 5 wherein said sertraline-containing composition further comprises a fluidizing agent selected from the group consisting of a non-reducing sugar, a salt and an organic acid and wherein said fluidizing agent has an aqueous solubility of at least 30 mg/ml.

16. The dosage form of any one of claims 1-5 wherein sertraline is present in an amount of at least 40 mgA.

17. The dosage form of any one of claims 1-5 wherein sertraline is present in an amount of at least 60 mgA.

19. The dosage form of claim 1 wherein said polyethylene oxide in said sertraline-containing composition has a molecular weight of at least about 100,000 and less than about 400,000.

21. The dosage form of claim 1, 2, 3, 4, or 5 wherein said pharmaceutically acceptable sertraline-salt has a weight average particle size of less than about 10 μ

m.

22. The dosage form of claim 1 wherein at least a portion of said sertraline-containing composition is granulated.

23. The dosage form of claim 22 wherein said sertraline-containing composition has an average granule size immediately following the granulation process of less than about 350 μ

m and said polyethylene oxide has an average molecular weight of less than 250,000.

24. The dosage form of claim 22 wherein said sertraline-containing composition, immediately following granulation, has a weight average granule size greater than about 400 μ

m and said polyethylene oxide has a molecular weight of at least about 300,000.

25. The dosage form of claim 22 wherein at least a portion of said sertraline-containing composition is wet-granulated.

26. The dosage form of claim 25 wherein wet granulation takes place with a mixture of a lower alcohol and water.

27. The dosage form of claim 26 wherein said wet granulation is conducted via a high-shear granulation process.

28. The dosage form of claim 26 wherein said lower alcohol is isopropanol.

29. The dosage form of claim 28 wherein the water content of said mixture of isopropanol and water is from 1 wt % to 30 wt %.

30. The dosage form of claim 22 wherein said sertraline-containing composition is further wet-milled, oven-dried and dry-milled.

40. The dosage form of any one of claims 1-5 wherein said core comprises an antioxidant.

41. The dosage form of claim 40 wherein said antioxidant is selected from the group consisting of BHA, BHT, vitamin E and ascorbyl palmitate.

42. The dosage form of any one of claims 1-5 wherein said setraline-containing composition comprises an antioxidant.

43. The dosage form of claim 42 wherein said antioxidant is selected from the group consisting of BHT, BHA, vitamin E, and ascorbyl palmitate.

44. The dosage form of any one of claims 1-5 wherein said water-swellable composition comprises an antioxidant.

45. The dosage form of claim 44 wherein said antioxidant is selected from the group consisting of BHT, BHA, vitamin E, and ascorbyl palmitate.

46. The dosage form of any one of claims 1-5 wherein said pharmaceutically acceptable salt form of sertraline is highly soluble.

47. The dosage form of claim 46 wherein said highly soluble salt form is selected from the group consisting of sertraline lactate, sertraline acetate, sertraline aspartate.

48. The dosage form of any one of claims 1-5 wherein said core includes a solubilizer.

49. The dosage form of claim 48 wherein said solubilizer is an organic acid.

50. The dosage form of claim 49 wherein said organic acid is selected from the group consisting of adipic acid, citric acid, fumaric acid, malic acid, succinic acid, and tartaric acid.

51. The dosage form of claim 50 wherein the organic acid is selected from the group consisting of tartaric acid, succinic acid, and fumaric acid.

52. The dosage form of claim 51 wherein said organic acid is tartaric acid and is present in an amount equal to at least 3 wt % of said core.

53. The dosage form of claim 51 wherein said organic acid is fumaric acid and is present in an amount equal to at least 3 wt % of said core.

54. The dosage form of claim 48 wherein at least 20 wt % of said solubilizer is delivered to said use environment between 8 and 24 hours after introduction of said dosage form to said use environment.

55. The dosage form of any one of claims 1-5 wherein said sertraline-containing composition includes a solubilizer.

56. The dosage form of claim 55 wherein said solubilizer is an organic acid.

57. The dosage form of claim 56 wherein said organic acid is selected from the group consisting of adipic acid, citric acid, fumaric acid, malic acid, succinic acid, and tartaric acid.

58. The dosage form of claim 57 wherein the organic acid is selected from tartaric acid and fumaric acid.

59. The dosage form of claim 58 wherein said organic acid is tartaric acid and is present in an amount equal to at least 3 wt % of said sertraline-containing composition.

60. The dosage form of claim 58 wherein said organic acid is fumaric acid and is present in an amount equal to at least 3 wt % of said core.

61. The dosage form of claim 55 wherein at least 20 wt % of said solubilizer is delivered to said use environment between 8 and 24 hours after introduction of said dosage form to said use environment.

62. The dosage form of any of claims 1-5 wherein said water-swellable composition includes a solubilizer.

63. The dosage form of claim 62 wherein said solubilizer is an organic acid.

64. The dosage form of claim 63 wherein said organic acid is selected from the group consisting of citric acid, malic acid, and tartaric acid.

65. The dosage form of claim 64 wherein said organic acid is citric acid and is present in an amount equal to at least 3 wt % of said water-swellable composition.

66. The dosage form of claim 62 wherein at least 20 wt % of said solubilizer is delivered to said use environment between 8 and 24 hours after introduction of said dosage form to said use environment.

67. The dosage form of any one of claims 1-5 wherein sertraline is present substantially as a single polymorph.

68. The dosage form of any one of claims 1-5 wherein said water-swellable composition comprises a water-swellable polymer selected from the group consisting of polyethylene oxide, sodium starch glycolate, and sodium cross-carmellose.

69. The dosage form of any one of claims 1-5 wherein said water-swellable composition includes a colorant that contains substantially no iron (III).

70. The dosage form of any one of claims 1, 2, 3, or 5 wherein said water-swellable composition includes an osmagent.

71. The dosage form of claim 70 wherein said osmagent is selected from the group consisting of sodium chloride, sodium lactate, sodium acetate, adipic acid, citric acid, lactic acid, fumaric acid, malic acid, succinic acid, tartaric acid, xylitol, mannitol, maltitol, and sorbitol.

72. The dosage form of any one of claims 1-3 or 5 wherein said water-swellable composition contains substantially no osmotically effective agent.

73. The dosage form of claim 68 wherein said polyethylene oxide in said water-swellable composition has a molecular weight of between 3,000,000 and 8,000,000.

74. The dosage form of any one of claims 1-5 wherein the water-swellable polymer in the water-swellable composition is only PEO and the mass of said sertraline-containing composition divided by the mass of said water-swellable composition is at least 1.5.

75. The dosage form of any one of claims 1-5 wherein the water-swellable polymer in the water-swellable composition comprises sodium starch glycolate or sodium cross-carmellose and the mass of said sertraline-containing composition divided by the mass of said water-swellable composition is at least 3.0.

76. The dosage form of any one of claims 1-5 wherein said dosage form is a tablet with a hardness H in Kp given by the expression:

(35D²)−

1≦

H≦

(35D²)+6

where D is the diameter in inches of the tooling used to compress said core.

77. The dosage form of any of claims 1-4 wherein said coating comprises a hydrophilic cellulosic polymer.

78. The dosage form of claim 77 wherein said hydrophilic cellulosic polymer is selected from the group consisting of cellulose acetate, and mixtures of cellulose acetate and a second polymer.

80. The dosage form of claim 77 wherein said hydrophilic cellulosic polymer is a plasticized or unplasticized version of a cellulose ester, cellulose ether or cellulose ester-ether.

82. The dosage form of claim 80 wherein said cellulose ester, cellulose ether or cellulose ester-ether is selected from the group consisting of cellulose acetate, cellulose acetate butyrate and ethyl cellulose.

83. The dosage form of claim 82 wherein said hydrophilic cellulosic polymer has a degree of substitution equivalent to 25 to 42 wt % acetyl groups.

84. The dosage form of claim 83 wherein said hydrophilic cellulosic polymer has a degree of substitution equivalent to 39 to 41 wt % acetyl groups.

85. The dosage form of claim 82 wherein said cellulose acetate has a molecular weight of at least 45,000.

86. The dosage form of any one of claims 1-5 wherein said coating is formed from a solution having a weight ratio of cellulose acetate to polyethylene glycol of from 9:

1 to 6.5;

3.5.

87. The dosage form of any one of claims 1-5 wherein said coating is formed from a solution having a water concentration of greater than 4 wt %.

88. The dosage form of claim 86 wherein said coating is formed from a solution having a water concentration of greater than 4 wt %.

89. The dosage form of any one of claims 1-5 wherein said coating is formed from a solution having a water concentration of greater than 15 wt %.

90. The dosage form of claim 86 wherein said coating is formed from a solution having a water concentration of greater than 15 wt %.

91. The dosage form of any one of claims 1-5 wherein said coating in the dry state is porous with a density of less than 0.9 times that of the nonporous coating material.

92. The dosage form of claim 91 wherein said coating in the dry state has a density of less than 0.75 times that of the nonporous coating material.

93. The dosage form of claim 91 wherein said coating comprises a polymeric asymmetric membrane comprising a thick, porous region and a dense thin region.

94. The dosage form of any one of claims 1-5 wherein said coating has a water flux (40/75) of at least 1.0×

10<sup>−

3</sup> gm-hr/cm².

95. The dosage form of any one of claims 1-5 wherein said coating has a mass of from 3 to 30 wt % of said core.

96. The dosage form of claim 95 wherein said coating has a mass of from 8 to 25 wt % of said core.

97. The dosage form of any one of claims 1-5 wherein said dosage form has at least one delivery port in communication with said sertraline-containing composition and at least one other delivery port in communication with said water-swellable composition, and said water-swellable composition contains substantially no colorant.

98. The dosage form of any one of claims 1-5 wherein at least 5 wt % of sertraline is released into said use environment within 1 hour of said dosage form being introduced into said use environment.

100. The dosage form of any one of claims 1-2 wherein at least 80 wt % of sertraline is released into said use environment within 12 hours after introduction of said dosage form into said use environment.

101. The dosage form of claim 100 wherein at least 90 wt % of sertraline is released into said use environment within 12 hours after introduction of said dosage form into said use environment.

102. The dosage form of any one of claims 1-5 wherein said dosage form delivers at least 95 wt % of sertraline into said use environment within 24 hours after introduction of said dosage form into said use environment.

103. The dosage form of any one of claims 1-5 wherein said coating includes sertraline.

104. The dosage form of any one of claims 1-5 wherein said dosage form has an additional sertraline-containing coating surrounding said coating that is water-soluble or water erodible.

105. The dosage form of any one of claims 1-5 wherein at least a portion of said sertraline is released such that improved absorption of sertraline from the GI tract is observed relative to a dosage form that releases standard size sertraline hydrochloride crystals at the substantially same release profile.

106. The dosage form of any one of claims 1, 2, 4 or 5 wherein said dosage form releases sertraline to said environment of use at an average rate of from about 7 to about 12 wt % per hour from the second to the tenth hour and less than about 25 wt % for the first two hours and at least 70 wt % by the tenth hour.

107. The dosage form of any one of claims 1, 2, 4 or 5 wherein said dosage form releases sertraline to said environment of use at an average rate of from about 10 to about 16 wt % per hour from the second to the eighth hour and at least 70 wt % by the eighth hour.

2. A dosage form for the controlled release of sertraline, comprising:

(a) a core comprising a sertraline-containing composition and a water-swellable composition wherein said water-swellable composition is in a separate region within said core;

(b) said sertraline-containing composition comprising sertraline, polyethylene oxide having a molecular weight of at least 500,000, and a fluidizing agent; and

(c) a coating around said core that is water-permeable, water-insoluble and has at least one delivery port therethrough;

wherein sertraline is in the form of a pharmaceutically acceptable salt thereof and, following introduction of said dosage form to an environment of use, said dosage form releases sertraline to said environment of use at an average rate of from about 6 to 10 wt % per hour from the second to the twelfth hour and releases less than about 25 wt % for the first two hours and releases at least 70 wt % by the twelfth hour.

7. A method for treating a depressive or anorectic disorder, comprising administering to a mammal in need of such treatment a therapeutically effective amount of sertraline in a dosage form as defined in claim 2.

10. The dosage form of claim 2 wherein said fluidizing agent is selected from the group consisting of a non-reducing sugar, a salt and an organic acid and wherein said fluidizing agent has an aqueous solubility of at least 30 mg/ml.

11. The dosage form of claim 10 wherein said sugar is selected from the group consisting of xylitol, mannitol, sorbitol, and maltitol.

12. The dosage form of claim 11 wherein said sugar is xylitol.

13. The dosage form of claim 10 wherein said salt is selected from the group consisting of sodium chloride, sodium acetate and sodium lactate.

14. The dosage form of claim 10 wherein said organic acid is selected from the group consisting of adipic acid, citric acid, malic acid, succinic acid, and tartaric acid.

18. The dosage form of claim 2, 4, or 5 wherein sertraline comprises at least about 20 wt % of said sertraline-containing position.

3. A dosage form for the controlled release of sertraline, comprising:

(a) a core comprising a sertraline-containing composition and a water-swellable composition wherein said water-swellable composition is in a separate region within said core;

(b) said sertraline-containing composition comprising sertraline and a polymeric entraining agent wherein sertraline makes up at least about 20 wt % of said sertraline-containing composition; and

(c) a coating around said core that is water-permeable, water-insoluble and has at least one delivery port therethrough;

wherein sertraline is in the form of a pharmaceutically acceptable salt thereof and, following introduction of said dosage form to an environment of use, said dosage form releases sertraline to said environment of use at an amount of less than about 25 wt % by the second hour and at least about 40 wt % by the eighth hour and releases at least about 25 wt % from the eighth to the twenty-fourth hour.

8. The dosage form of any one of claims 3, 4, or 5 wherein said polymeric entraining agent is selected from the group consisting of hydroxy propyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, and polyethylene oxide.

9. The dosage form of claim 8 wherein said polymeric entraining agent is polyethylene oxide.

20. The dosage form of claim 9 wherein said polyethylene oxide in said sertraline-containing composition has a molecular weight of at least about 100,000 and less than about 400,000.

31. The dosage form of claim 9 wherein at least a portion said sertraline-containing composition is granulated.

32. The dosage form of claim 31 wherein said sertraline-containing composition has an average granule size immediately following the granulation process of less than about 350 μ

m and said polyethylene oxide has an average molecular weight of less than 250,000.

33. The dosage form of claim 31 wherein said sertraline-containing composition, immediately following granulation, has a weight average granule size greater than about 400 μ

m and said polyethylene oxide has a molecular weight of at least about 300,000.

34. The dosage form of claim 31 wherein at least a portion of said sertraline-containing composition is wet-granulated.

35. The dosage form of claim 34 wherein wet granulation takes place with a mixture of a lower alcohol and water.

36. The dosage form of claim 35 wherein said wet granulation is conducted via a high-shear granulation process.

37. The dosage form of claim 35 wherein said lower alcohol is isopropanol.

38. The dosage form of claim 37 wherein the water content of said mixture of isopropanol and water is from 1 wt % to 30 wt %.

39. The dosage form of claim 31 wherein said sertraline-containing composition is further wet-milled, oven-dried and dry-milled.

108. A method for treating a depressive or anorectic disorder, comprising administering to a mammal in need of such treatment a therapeutically effective amount of sertraline in a dosage form as defined in claim 3.

144. A method as claimed in claim 6, 7, 108, 109, 110, or 112, wherein said mammal is a human.

4. A dosage form for the controlled release of sertraline, comprising:

(a) a core comprising a sertraline-containing composition and a water-swellable composition wherein said water-swellable composition is in a separate region within said core and contains substantially no osmotically effective agent;

(b) said sertraline-containing composition comprising sertraline and a polymeric entraining agent; and

(c) a coating around said core that is water-permeable, water-insoluble and has at least one delivery port therethrough;

wherein sertraline is in the form of a pharmaceutically acceptable salt thereof and, following introduction of said dosage form to an environment of use, said dosage form releases sertraline to said environment of use at an average rate of from about 6 to 10 wt % per hour from the second to the twelfth hour and releases less than about 25 wt % for the first two hours and releases at least 70 wt % by the twelfth hour.

99. The dosage form of claim 4 wherein said dosage form delivers less than 10 wt % of sertraline within 2 hours after introduction of said dosage form to said use environment.

109. A method for treating a depressive or anorectic disorder, comprising administering to a mammal in need of such treatment a therapeutically effective amount of sertraline in a dosage form as defined in claim 4.

5. A dosage form for the controlled release of sertraline, comprising:

(a) a core comprising a sertraline-containing composition and a water-swellable composition wherein said water-swellable composition is in a separate region within said core;

(b) said sertraline-containing composition comprising sertraline and a polymeric entraining agent; and

(c) a hydrophilic cellulosic polymeric coating around said core that is porous, water-insoluble, and has at least one delivery port therethrough;

wherein sertraline is in the form of a pharmaceutically acceptable salt thereof and, following introduction of said dosage form to an environment of use, said dosage form releases sertraline to said environment of use at an average rate of from about 6 to 10 wt % per hour from the second to the twelfth hour and releases less than about 25 wt % for the first two hours and releases at least 70 wt % by the twelfth hour.

79. The dosage form of claim 5 wherein said hydrophilic cellulosic polymer is selected from the group consisting of cellulose acetate, and mixtures of cellulose acetate and a second polymer.

81. The dosage form of claim 5 wherein said hydrophilic cellulosic polymer is a plasticized or unplasticized version of a cellulose ester, cellulose ether or cellulose ester-ether.

110. A method for treating a depressive or anorectic disorder, comprising administering to a mammal in need of such treatment a therapeutically effective amount of sertraline in a dosage form as defined in claim 5.

111. A dosage form for the controlled release of sertraline, comprising:

(a) a core comprising a sertraline-containing composition and a water-swellable composition wherein each is in a separate region within said core;

(b) said sertraline-containing composition comprising sertraline, an entraining agent, and a concentration-enhancing polymer; and

(c) a coating around said core that is water-permeable, water-insoluble and has at least one delivery port therethrough;

wherein said dosage form provides a maximum concentration of sertraline in a use environment that is at least 1.25-fold higher than the equilibrium concentration of sertraline in said use environment provided by a control dosage form, and a concentration of sertraline in said use environment that exceeds said equilibrium concentration for a longer time than a concentration provided by said control dosage form exceeds said equilibrium concentration, wherein said control dosage form is free from said concentration-enhancing polymer and comprises an equivalent quantity of sertraline.

112. A method for treating a depressive or anorectic disorder, comprising administering to a mammal in need of such treatment a therapeutically effective amount of sertraline in a dosage form as defined in claim 111.

113. The dosage form of claim 111 wherein said sertraline-containing composition further comprises a solubilizer.

114. The dosage form of claim 111 wherein said sertraline is present as a highly-soluble salt form.

115. The dosage form of claim 111 wherein said concentration-enhancing polymer is selected from the group consisting of

(a) ionizable cellulosic polymers;

(b) non-ionizable cellulosic polymers; and

(c) vinyl polymers and copolymers having substituents selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido.

116. The dosage form of claim 113 or 114 wherein said concentration-enhancing polymer is selected from the group consisting of

(a) ionizable cellulosic polymers;

(b) non-ionizable cellulosic polymers; and

(c) vinyl polymers and copolymers having substituents selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido.

117. The dosage form of claim 116 wherein said concentration-enhancing polymer is a cellulosic polymer selected from the group consisting of cellulosic esters, cellulosic ethers, and cellulosic esters/ethers.

118. The dosage form of claim 116 wherein said concentration-enhancing polymer is selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of polyvinyl pyrrolidone and polyvinyl acetate and aqueous-soluble cellulosic polymers.

119. The dosage form of claim 113 wherein said solubilizer is an organic acid.

120. The dosage form of claim 119 wherein said organic acid is selected from the group consisting of adipic acid, citric acid, fumaric acid, malic acid, succinic acid, and tartaric acid.

121. The dosage form of claim 114 wherein said highly soluble salt form is selected from the group consisting of sertraline lactate, sertraline acetate, and sertraline aspartate.

122. The dosage form of claim 111 wherein said core comprises anantioxidant.

123. The dosage form of claim 111 wherein said sertraline-containing composition comprises an antioxidant.

124. The dosage form of claim 111 wherein said water-swellable composition comprises an antioxidant.

125. The dosage form of claim 111 wherein said water-swellable composition comprises a solubilizer.

126. The dosage form of claim 111 wherein said water-swellable composition comprises a water-swellable polymer selected from the group consisting of polyethylene oxide, sodium starch glycolate, and sodium croscarmellose.

127. The dosage form of claim 111 wherein said water-swellable composition comprises a colorant that contains substantially no iron (111).

128. The dosage form of claim 111 wherein the water-swellable polymer in the water-swellable composition is only PEO and the mass of said sertraline-containing composition divided by the mass of said water-swellable composition is at least 1.5.

129. The dosage form of claim 111 wherein the water-swellable polymer in the water-swellable composition comprises sodium starch glycolate or sodium croscarmellose and the mass of said sertraline-containing composition divided by the mass of said water-swellable composition is at least 3.0.

130. The dosage form of claim 112 wherein said dosage form is a tablet with a hardness H in Kp given by the expression:

(35D²)−

1≦

H≦

(35D²)+6

where D is the diameter in inches of the tooling used to compress said core.

131. The dosage form of claim 111 wherein said coating comprises a hydrophilic cellulosic polymer.

132. The dosage form of claim 111 wherein said coating is formed from a solution having a weight ratio of cellulose acetate to polyethylene glycol of from 9:

1 to 6.5;

3.5.

133. The dosage form of claim 111 wherein said coating is formed from a solution having a water concentration of greater than 4 wt %.

134. The dosage form of claim 111 wherein said coating is formed from a solution having a water concentration of greater than 15 wt %.

135. The dosage form of claim 111 wherein said coating in the dry state is porous with a density of less than 0.9 times that of the nonporous coating material.

136. The dosage form of claim 111 wherein said coating has a water flux (40/75) of at least 1.0×

10<sup>−

3</sup> gm-hr/cm².

137. The dosage form of claim 111 wherein said coating has a mass of from 3 to 30 wt % of said core.

138. The dosage form of claim 111 wherein said dosage form has at least one delivery port in communication with said sertraline-containing composition and at least one other delivery port in communication with said water-swellable composition, and said water-swellable composition contains substantially no colorant.

139. The dosage form of claim 111 wherein at least 5 wt % of sertraline is released into said use environment within 1 hour of said dosage form being introduced into said use environment.

140. The dosage form of claim 111 wherein at least 80 wt % of sertraline is released into said use environment within 12 hours after introduction of said dosage form into said use environment.

141. The dosage form of claim 111 wherein said dosage form delivers at least 95 wt % of sertraline into said use environment within 24 hours after introduction of said dosage form into said use environment.

142. The dosage form of claim 111 wherein said dosage form has an additional sertraline-containing coating surrounding said coating that is water-soluble or water erodible.

143. The dosage form of claim 111 wherein at least a portion of said sertraline is released such that improved absorption of sertraline from the GI tract is observed relative to a dosage form that releases standard size sertraline hydrochloride crystals at the substantially same release profile.