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1. WO1999001121 - SELS DE SERTRALINE ET FORMES POSOLOGIQUES DE SERTRALINE, A LIBERATION PROLONGEE

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CLAIMS
1. A sustained-release dosage form suitable for oral administration to a mammal, comprising sertraline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
which dosage form releases sertraline into a use environment at a rate not exceeding 0.8 mgA/hr/kg,
provided said dosage form (1) releases not more than 70% of the
sertraline contained therein within the first hour following entry into said use environment and (2) releases sertraline at a rate of at least 0.02 mgA/hr/kg.
2. A dosage form as defined in claim 1, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.
3. A dosage form as defined in claim 1, wherein said mammal is a human.
4. A dosage form as defined in claim 1, in the form of a matrix tablet which remains substantially intact during the period of sustained release.
5. A dosage form as defined in claim 1, in the form of a disintegrating matrix tablet.
6. A dosage form as defined in claim 1, in the form of a matrix tablet partially coated with a polymer which impedes the release of sertraline.
7. A dosage form as defined in claim 1, in the form of an osmotic tablet.

8. A dosage form as defined in claim 1, in the form of a membrane-coated hydrogel tablet.
9. A dosage form as defined in claim 1, which is multiparticulate.
10. A dosage form as defined in claim 1 , in the form of a membrane-coated diffusion-based, capsule, tablet or murtiparticuiate.
11. A sustained-release dosage form suitable for administration to a mammal, comprising sertraline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
which dosage form releases sertraline into a use environment at a rate not exceeding 40 mgA/hr, provided said dosage form (1) releases not more than 70% of the
sertraline contained therein within the first hour following entry into said use environment and (2) releases sertraline at a rate of at least 1 mgA/hr.
12. A dosage form as defined in claim 11 wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.
13. A dosage form as defined in claim 11, wherein said mammal is a human.
14. A dosage form as defined in claim 11, in the form of a matrix tablet which remains substantially intact during the period of sustained release.
15. A dosage form as defined in claim 11, in the form of a disintegrating matrix tablet.
16. A dosage form as defined in claim 11 , in the form of a matrix tablet partially coated with a polymer which impedes the release of sertraline.
17. A dosage form as defined in claim 11, in the form of an osmotic tablet.

18. A dosage form as defined in claim 11 , in the form of a membrane-coated hydrogel tablet.
19. A dosage form as defined in claim 11, which is multiparticulate.
20. A dosage form as defined in claim 11, in the form of a membrane-coated fiffusion-based tablet or multiparticulate.
21. A sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form releases sertraline at a rate less than 40 mgA/hr in vitro when dissolution tested in a USP-2 apparatus containing 900 ml of acetate buffer, pH 4.0, which is 0.075 M in NaCl, as follows:
(1) if said dosage form is a sustained release tablet or a non-disintegrating sustained release capsule, said USP-2 apparatus is equipped with a paddle stirring at 50 rpm;
(2) if said dosage form is a multiparticulate, said USP-2 apparatus is equipped with a paddle stirring at 100 rpm;
provided said dosage form (a) releases not more than 70% of the sertraline contained therein within the first hour following initiation of testing and (b) releases sertraline at a rate of at least 1 mgA/hr.

22. A dosage form as defined in claim 21, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.
23. A dosage form as defined in claim 21, wherein said mammal is a human.
24. A dosage form as defined in claim 21 , in the form of a matrix tablet which remains substantially intact during the period of sustained release.
25. A dosage form as defined in claim 21, in the form of a disintegrating matrix tablet.
26. A dosage form as defined in claim 21, in the form of a matrix tablet partially coated with a polymer which impedes the release of sertraline.
27. A dosage form as defined in claim 21, in the form of an osmotic tablet.

28. A dosage form as defined in claim 21, in the form of a membrane-coated hydrogel tablet.
29. A dosage form as defined in claim 21, which is multiparticulate.
30. A dosage form as defined in claim 21, in the form of a membrane-coated diffusion-based tablet or multiparticulate.
31. A temporally delayed plus sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
which dosage form, following ingestion by said mammal, releases sertraline into said mammal's GI tract at a rate less than 1 mgA/hr for an initial delay period of up to 3 hours,
and which thereafter releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr, provided said dosage form releases not more than 70 % of the sertraline contained therein within the first hour after said delay period.
32. A dosage form as defined in claim 31, wherein said delay period is up to two hours.
33. A dosage form as defined in claim 31, wherein the rate of release following said delay period is from 1 mgA/hr to 30 mgA/hr.
34. A dosage form as defined in claim 31, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.

35. A dosage form as defined in claim 31, wherein said mammal is a human.
36. A temporally delayed plus sustained release dosage form suitable for administration to a mammal, said dosage form having an initial temporal delay period of up to 3 hours, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when dissolution tested in vitro in a USP-2 apparatus containing 900 ml of acetate buffer, pH 4.0, which is 0.075 M in NaCl,
releases sertraline at a rate less than 1 mgA/hr for a period corresponding to said delay period and, thereafter,
releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr, provided the dosage form releases not more than 70 % of the remaining sertraline contained therein within the first hour following said delay.
37. A dosage form as defined in claim 36, wherein said delay period is up to two hours.
38. A dosage form as defined in claim 36, wherein the rate of release following said delay period is from 1 mgA/hr to 30 mgA/hr.
39. A dosage form as defined in claim 36, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.
40. A dosage form as defined in claim 36, wherein said mammal is a human.
41. A dosage form as defined in claim 36, in the form of a tablet.
42. A dosage form as defined in claim 36, which is multiparticulate.
43. A spatially delayed plus sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
which dosage form, following ingestion by said mammal, releases sertraline into said mammal's stomach at a rate less than 1 mgA/hr,
and which, after having passed into said mammal's small intestine, effects sustained release at a rate of from 1 mgA/hr to 40 mgA/hr, provided said dosage form releases not more than 70 % of the sertraline contained therein within the first hour after passing into said mammal's small intestine.
44. A dosage form as defined in claim 43, wherein the onset of sustained release is pH-triggered.
45. A dosage form as defined in claim 44, comprising a sustained release dosage form coated with a polymer that prevents release of sertraline at the pH of the stomach, but which is permeable to sertraline at the pH of the small intestine.
46. A dosage form as defined in claim 44, wherein said sustained release dosage form is multiparticulate.
47. A dosage form as defined in claim 44 wherein said sustained release dosage form is a tablet.
48. A dosage form as defined in claim 43, which is enzyme-triggered.
49. A dosage form as defined in claim 48, comprising a sustained release dosage form coated with a membrane having a hydrophobic liquid entrained within the pores thereof, said hydrophobic liquid being substantially impermeable to water and sertraline, but capable of changing, through
enzymatic degradation, so that said membrane becomes substantially
permeable to water and sertraline when said dosage form moves into the
environment of the small intestinal lumen.
50. A dosage form as defined in claim 48, wherein said sustained release dosage form is multiparticulate.
51. A dosage form as defined in claim 48, wherein said sustained release dosage form is a matrix.
52. A dosage form as defined in claim 43, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.
53. A dosage form as defined in claim 43, wherein said mammal is a human.
54. A sustained release pH-triggered dosage form suitable for oral administration to a mammal, said dosage form having an initial delay period prior to the onset of sustained release, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when tested in vitro in a USP-2 apparatus,
releases sertraline into 0.1 N HCl at a rate less than 1 mgA/hr for 1 hour and, thereafter,
releases sertraline into phosphate buffer, pH 6.8 containing 1% polysorbate

80 at a rate of from 1 mgA/hr to 40 mgA/hr, provided the dosage form releases not more than 70 % of the remaining sertraline contained therein within the first hour following said delay.
55. A dosage form as defined in claim 54, comprising a sustained release dosage form coated with a coating comprising a polymer that prevents release of sertraline in said HCl at a rate exceeding 1 mgA/hr, but which is permeable to and allows sustained release of sertraline in said phosphate buffer.
56. A dosage form as defined in claim 55, wherein said sustained release dosage form is multiparticulate.
57. A dosage form as defined in claim 55, wherein said sustained release dosage form is a tablet
58. A dosage form as defined in claim 54, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.
59. A dosage form as defined in claim 54, wherein said mammal is a human.
60. A sustained release enzyme-triggered dosage form suitable for oral administration to a mammal, said dosage form having an initial delay period prior to the onset of sustained release, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when tested in vitro in a USP apparatus
releases sertraline into 0.1 N HCl at a rate less than 1 mgA/hr for a period of 1 hour and, thereafter,
releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr into phosphate buffer, pH 6.8, containing 1% polysorbate 80 and in the presence of an enzyme suitable for triggering the onset of said sustained release, provided the dosage form releases not more than 70 % of the remaining sertraline contained therein within the first hour following said delay.

61. A dosage form as defined in claim 60, comprising a sustained release dosage form coated with a membrane having a hydrophobic liquid entrained within the pores thereof, said hydrophobic liquid being substantially impermeable to water and sertraline in said acid, but capable of changing in said buffer, through enzymatic degradation in the presence of said enzyme, so that said membrane becomes substantially permeable to water and sertraline.
62. A dosage form as defined in claim 60, wherein said sustained release dosage form is murtiparticuiate.
63. A dosage form as defined in claim 60, wherein said sustained release dosage form is a tablet.
64. A dosage form as defined in claim 60, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.
65. A dosage form as defined in claim 60, wherein said mammal is a human.
66. A sustained release dosage form suitable for oral administration to a mammal, comprising sertraline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which dosage form, when orally dosed to said mammal, results in a maximum sertraline plasma concentration, Cmax, which is less than 80% of the Cmax determined when an equal dose of sertraline is orally administered in the form of an immediate release bolus provided said sustained release dosage form (1) releases not more than 70% of the sertraline contained therein within the first hour following ingestion and (2) releases sertraline at a rate of at least 1 mgA/hr.
67. A dosage form as defined in claim 66, which provides a total blood drug exposure that is not proportionately decreased as much as Cmax.
68. A dosage form as defined in claim 66, wherein said sertraline is present as sertraline free base, sertraline hydrochloride, sertraline aspartate, sertraline acetate or sertraline lactate.
69. A dosage form as defined in claim 66, wherein said mammal is a human.
70. A dosage form as defined in claim 66, in the form of a tablet.

71. A dosage form as defined in claim 66, which is murtiparticuiate.
72. A dosage form as defined in claim 66, which is a delayed plus sustained release form exhibiting a delay period of up to three hours prior to the onset of sustained release, said dosage form releasing sertraline at a rate of not more than 1 mgA/hr during said delay period.
73. A dosage form as defined in claim 72, wherein said delay is temporal.

74. A dosage form as defined in claim 72, wherein said delay is spatial.

75. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a sustained-release oral dosage form as defined in claim 1.
76. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a sustained-release oral dosage form as defined in claim 11.
77. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a sustained-release oral dosage form as defined in claim 21.
78. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a delayed plus sustained-release oral dosage form as defined in claim 31.
79. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a delayed plus sustained-release oral dosage form as defined in claim 36.

80. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a delayed plus sustained-release oral dosage form as defined in claim 43.
81. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a delayed plus sustained-release oral dosage form as defined in claim 54.
82. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a delayed plus sustained-release oral dosage form as defined in claim 60.
83. A method for treating a psychiatric illness, premature ejaculation, chemical dependency, premenstrual dysphoric disorder, or obesity, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a delayed plus sustained-release oral dosage form as defined in claim 66.
84. Sertraline acetate.
85. Sertraline acetate of claim 84 having the X-ray crystal structure of Figure 1.
86. Sertraline acetate· 1/4 hydrate.
87. A pharmaceutical composition comprising sertraline acetate of claim

84 and a pharmaceutically acceptable carrier or diluent.
88. A pharmaceutical composition comprising sertraline acetate of claim

85 and a pharmaceutically acceptable carrier or diluent.
89. A pharmaceutical composition comprising sertraline acetate · 1/4 hydrate of claim 86 and a pharmaceutically acceptable carrier or diluent.
90. Sertraline L-lactate.

91. Sertraline L-lactate of claim 90 having the X-ray crystal structure of Figure 3.
92. A pharmaceutical composition comprising sertraline L-lactate of claim

90 and a pharmaceutically acceptable carrier or diluent.
93. A pharmaceutical composition comprising sertraline L-lactate of claim

91 and a pharmaceutically acceptable carrier or diluent.
94. Sertraline L-aspartate.
95. A pharmaceutical composition comprising sertraline L-aspartate of claim 11 and a pharmaceutically acceptable carrier or diluent.
96. A method for treating a disease or condition selected from anorexia, impulse disorders, onychophagia, premenstrual syndrome, psychotic disorders of the schizophrenictype, inflammatory disorders, hyperactive immune system disorders, and chemical dependency in a subject suffering from one or more of said diseases or conditions comprising administering to said subject an effective amount of sertraline acetate, sertraline L-lactate or sertraline L-aspartate.
97. A method of claim 96 wherein sertraline acetate is administered.
98. A method of claim 96 wherein sertraline L-lactate is administered.
99. A method for treating mental depression in a mentally-depressed subject comprising administering to said subject an effective amount of sertraline acetate, sertraline L-lactate or sertraline L-aspartate.
100. A method of claim 99 wherein sertraline acetate is administered.
101. A method of claim 99 wherein sertraline L-lactate is administered.
102. A method for treating an anxiety-related disorder in a subject suffering therefrom comprising administering to said subject an effective amount of sertraline acetate, sertraline L-lactate or sertraline L-aspartate.
103. A method of claim 102 wherein said anxiety-related disorder is obsessive-compulsive disorder.
104. A method of claim 103 wherein sertraline acetate is administered.
105. A method of claim 103 wherein sertraline L-lactate is administered.
106. A process for preparing sertraline acetate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline free base into an organic solvent and reacting said sertraline free base with acetic acid in the presence of a suitable organic solvent.

107. A process of claim 106 wherein said salt of sertraline is sertraline hydrochloride and said solvent is hexane.
108. A process for preparing sertraline acetate comprising reacting sertraline free base with acetic acid in the presence of a suitable organic solvent.
109. A process for preparing sertraline L-lactate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline free base into an organic solvent and reacting said sertraline free base with L-lactic acid in the presence of a suitable organic solvent.
110. A process of claim 109 wherein said salt of sertraline is sertraline hydrochloride and said solvent is ethyl acetate.
111. A process of claim 109 wherein said salt of sertraline is sertraline mandelate and said solvent is ethyl acetate.
112. A process for preparing sertraline L-lactate comprising reacting sertraline free base with L-lactic acid in the presence of a suitable organic solvent.
113. A process for preparing sertraline L-aspartate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partrtioning said sertraline free base into an organic solvent and reacting said sertraline free base with aspartic acid in the presence of a suitable organic solvent
114. A process of claim 113 wherein said salt of sertraline is sertraline hydrochloride and said solvent is ethyl acetate saturated with water.
115. A process for preparing sertraline L-aspartate comprising reacting sertraline free base with L-aspartic acid in the presence of a suitable organic solvent.