CN1823749A

CN1823749A - Sertraline salts and sustained-release dosage forms of sertraline

Info

Publication number: CN1823749A
Application number: CN 200610068115
Authority: CN
Inventors: 玛丽·T·阿姆恩德; 威廉·J·柯拉托洛; 海勒·L·弗里德曼; 拉维·M·尚克; 斯科特·M·赫比格; 德韦恩·T·弗赖森; 詹姆斯·B·韦斯特
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1997-07-01
Filing date: 1998-06-15
Publication date: 2006-08-30
Also published as: AP2003002905A0; ZA985707B; AP2002002662A0; CN1907268A

Abstract

Sustained release dosage forms of sertraline which release sertraline at a rate between 1 mgA/hr and 40 mgA/hr. The dosage forms may exhibit an initial delay period during which sertraline is released at a rate less than 1 mgA/hr. The present invention is further directed to an acetate salt, an L-lactate salt and an L-aspartate salt of sertraline, pharmaceutical compositions thereof and methods of using that salt for treating various conditions and disorders. The present invention is also directed to processes for preparing sertraline acetate, sertraline L-lactate and sertraline L-aspartate.

Description

The slow release formulation of sertraline salts and Sertraline

The application be that June 15, application number in 1998 are 98806696.3 the applying date, exercise question divides an application for the application of " slow release formulation of sertraline salts and Sertraline ".

Invention field

The present invention relates to some salt of Sertraline, slow release formulation with Sertraline of improved side effect profile, and the method for treatment psychosis or other disease, this method comprises the mammal of this treatment of needs, comprises the Sertraline of this slow release formulation of human patients administration.

Background of invention

Sertraline (Sertraline) is selective serotonin cell reabsorption inhibitor (SSRI), and it especially is used as antidepressant and anoretic, and is used for the treatment of obsession, premenstrual dysphoric disease, post-traumatic stress disorder, chemicals dependence syndrome, disease, Panic disorder and premature ejaculation that anxiety is relevant.See U.S.4,536,518, disclosed International Application No. WO 92/18005, U.S.5,130,338, U.S.4,971,998, disclosed International Application No. WO 92/00103, U.S.5,061,728, U.S.4,940,731 and U.S.4,962,128, its each all be incorporated herein by reference.Sertraline is also referred to as (1S-is suitable)-4-(3, the 4-Dichlorobenzene base)-1,2,3, and 4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines, empirical formula are C ₁₂H ₁₇NCl ₂, and have structural formula:

Sertraline is the designated depression that is used for the treatment of under the most common situation, and dosage range is 50-200mg/ days usually.The half-life of Sertraline is 23 hours, and is administered once every day.

Usually, patient's initial dose is 50mg Sertraline/sky.The patient who 50mg dosage is not had response is given higher dosage.Usually, avoid surpassing the initial dose of 50mg as far as possible because it has been generally acknowledged that and under higher dosage,, tremble such as dizzy, perspire and the side effect meeting of gastrointestinal upset more serious.

If the needs that are effective can reach higher dosage by the slowly titration from low dosage.The improved Sertraline dosage form that shows lower side effect incidence rate and/or seriousness is favourable, and this is because (1) can improve patient's comfort level, and (2) dosage that can be higher than 50mg begins and need not dose titration.Begin the administration meeting successively by realizing the at first useful of antidepressant effect at higher initial dose than rising of weak point.Therefore, this Sertraline (as 200mg or higher) that allows oral high dose and improved Sertraline dosage form that side effect reduces relatively can allow the wideer treatment of Sertraline treatment to use, and the remarkable improvement that dosage compliance and convenience aspect correspondingly are provided.Similarly, reduce the incidence rate of the side effect under the low dosage and/or the improved dosage form of seriousness remarkable value is arranged too.

EP-A-259113 discloses the controlled-release device of medicine, and wherein Sertraline is shown in embodiment 4.

EP-A-429189 discloses the method with the relevant disease of Sertraline treatment anxiety, wherein can use the Sertraline acid-addition salts.

General introduction of the present invention

The invention provides the oral sustained release dosage form of Sertraline, the Sertraline tablet of the rapid release of the agglomerate dosage suitable with respect at present commercially available administration, it can reduce gastrointestinal tract and/or other side effect such as dizzy, incidence rate of trembling and perspiring and seriousness.This dosage form is by realizing that discharging Sertraline with enough slow speed works to alleviate side effect.

Those discharge 70% the dosage form that surpasses its Sertraline that contains in one hour or less time be not " slow release ", and do not constitute one aspect of the present invention.Therefore, this feature has been got rid of from the present invention and has been contained 40mg Sertraline or immediate release dosage form still less.This dosage form discharges Sertraline specially with the speed when being lower than 40mgA/, but because of it does not carry out in the slow release mode, so be excluded.

One aspect of the present invention provides the slow release formulation that is suitable for the mammal administration, comprises Sertraline, or its pharmaceutical salts, and pharmaceutical carrier.This dosage form is to be no more than 0.8mgA/ hour/kg, the speed that preferably is no more than 0.7mg/ hour/kg is discharged into Sertraline in the environment for use, condition be discharge in this dosage form (1) first hour after entering the Sertraline that is no more than with which 70% in said environment for use, and (2) discharge Sertraline with the speed of 0.02mgA/ hour/kg at least.Above-mentioned Sertraline is preferably with the Sertraline free alkali, the sertraline salts hydrochlorate, and the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.Above-mentioned mammal is the people preferably.Above-mentioned dosage form preferably exists with the matrix tablet form that is kept perfectly basically in the slow release process; Preferably exist with disintegrate matrix tablet form; Preferably exist with the matrix tablet form of part by the polymer coating that hinders Sertraline release; Preferably exist with the osmotic tablet form; Preferably have capsule with the diffusion base of film coating with the hydrogel tablet form of film coating, tablet or many granules form exist, and above-mentioned dosage form is preferably many granules.Wherein above-mentioned Sertraline is preferably with 400mgA, and more preferably with 200mgA, comparative optimization is with 100mgA, and more preferably the amount with 50mgA exists.This respect of the present invention has been described dosage form, and does not take any concrete mammiferous size into account.

Another aspect of the present invention provides the slow release formulation that is suitable for the mammal oral administration, comprise Sertraline, or its pharmaceutical salts, and pharmaceutical carrier, it is discharged into environment for use with the speed that is no more than 40mgA/ hour with Sertraline, condition be discharge in this dosage form (1) first hour after entering the Sertraline that is no more than with which 70% in said environment for use, and (2) discharge Sertraline with 1mgA/ hour at least speed.Above-mentioned Sertraline is preferably with the Sertraline free alkali, the sertraline salts hydrochlorate, and the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.Above-mentioned mammal is the people preferably.Above-mentioned dosage form preferably exists with the matrix tablet form that is kept perfectly basically in the slow release process; Preferably exist with disintegrate matrix tablet form; Preferably exist with the matrix tablet form of part by the polymer coating that hinders Sertraline release; Preferably exist with the osmotic tablet form; Preferably the hydrogel tablet form with the film coating exists; Preferably with the capsule of the diffusion base of film coating, tablet or many granules form exist, and above-mentioned dosage form is preferably many granules.Of the present invention this described the dosage form that is suitable for adult's administration of mammal such as mean stature on the one hand.Therefore, dosage form according to the present invention discharges Sertraline with 1-40mgA/ hour speed.Specific rate of release scope comprises 2-40mgA/hr, 3-40mgA/ hour, and 1-30mgA/ hour, 2-30mgA/ hour, and 3-30mgA/ hour speed.The scope of preferred 1-30mgA/ hour and 2-30mgA/ hour.The scope of 1-25mgA/ hour and 2-25mgA/ hour more preferably.

The invention still further relates to following these aspects:

1. be suitable for slow release formulation, comprise Sertraline the mammal oral administration, or its pharmaceutical salts and pharmaceutical carrier, it is discharged into Sertraline in the environment for use with the speed that is no more than 0.8mgA/ hour/kg,

Condition is will be no more than 70% of with which Sertraline in this dosage form (1) first hour after entering this environment for use to be discharged in the said environment for use, and (2) discharge Sertraline with the speed of 0.02mgA/ hour/kg at least.

2. 1 dosage form, wherein this Sertraline is with the Sertraline free alkali, the sertraline salts hydrochlorate, the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.

3. 1 dosage form, wherein this mammal is the people.

4. the dosage form of item 1 exists with the matrix tablet form that is kept perfectly basically in the slow release process.

5. the dosage form of item 1 exists with disintegrate matrix tablet form.

6. the dosage form of item 1 exists with the matrix tablet form of part by the polymer coating that hinders Sertraline release.

7. the dosage form of item 1 exists with the osmotic tablet form.

8. 1 dosage form exists with the hydrogel tablet form of film coating.

9. 1 dosage form, it is many granules.

10. 1 dosage form, with the capsule of the diffusion base of film coating, tablet or many granules form exist.

11. be suitable for slow release formulation to the mammal administration, comprise Sertraline, or its pharmaceutical salts, and pharmaceutical carrier,

It is discharged into Sertraline in the environment for use with the speed that is no more than 40mgA/ hour,

Condition is will be no more than 70% of with which Sertraline in this dosage form (1) first hour after entering this environment for use to be discharged in the said environment for use, and (2) discharge Sertraline with 1mgA/ hour at least speed.

12. 11 dosage form, wherein this Sertraline is with the Sertraline free alkali, the sertraline salts hydrochlorate, and the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.

13. the dosage form of item 11, wherein this mammal is the people.

14. the dosage form of item 11 exists with the matrix tablet form that is kept perfectly basically in the slow release process.

15. the dosage form of item 11 exists with disintegrate matrix tablet form.

16. the dosage form of item 11 exists with the matrix tablet form of part by the polymer coating that hinders Sertraline release.

17. the dosage form of item 11 exists with the osmotic tablet form.

18. 11 dosage form exists with the hydrogel tablet form of film coating.

19. the dosage form of item 11, it is many granules.

20. 11 dosage form, with the capsule of the diffusion base of film coating, tablet or many granules form exist.

21. be suitable for slow release formulation to the mammal oral administration, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier, in NaCl, be 0.075M when containing 900ml, in the USP-2 instrument of the acetate buffer of pH4.0 when 37 ℃ of down following mensuration dissolutions, this dosage form discharges Sertraline external with the speed that is lower than 40mgA/ hour

When (1) being the slow releasing capsule of slow releasing tablet or non-disintegrate as if said dosage form, this USP-2 instrument is equipped with the splash bar that stirs with 50rpm; Perhaps

When (2) being many granules as if said dosage form, this USP-2 instrument is furnished with the splash bar that stirs with 100rpm;

Discharge in first hour that condition is this dosage form (a) after the test beginning and be no more than 70% contained Sertraline and (b) discharge Sertraline with 1mgA/ hour at least speed.

22. 21 dosage form, wherein this Sertraline is with the Sertraline free alkali, sertraline salts hydrochlorate, Sertraline aspartate, Sertraline acetate or Sertraline lactate.

23. the dosage form of item 21, wherein this mammal is the people.

24. the dosage form of item 21 exists with the matrix tablet form that is kept perfectly basically in the slow release process.

25. the dosage form of item 21 exists with disintegrate matrix tablet form.

26. the dosage form of item 21 exists with the matrix tablet form of part by the polymer coating that hinders Sertraline release.

27. the dosage form of item 21 exists with the osmotic tablet form.

28. 21 dosage form exists with the hydrogel tablet form of film coating.

29. the dosage form of item 21, it is many granules.

30. 21 dosage form, with the capsule of the diffusion base of film coating, tablet or many granules form exist.

31. be suitable for the time delay of mammal oral administration is added the dosage form of slow release, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier,

This dosage form discharges Sertraline to this in mammiferous GI road in initial delay phase of 3 hours nearly with the speed that is lower than 1mgA/ hour being swallowed the back by mammal,

And discharge Sertraline with 1mgA/ hour to 40mgA/ hour speed thereafter, be no more than 70% wherein contained Sertraline as long as discharge in this dosage form first hour after said period of delay.

32. the dosage form of item 31 wherein should nearly 2 hours period of delay.

33. the dosage form of item 31 should the rate of release after period of delay be 1mgA/ hour to 30mgA/ hour wherein.

34. 31 dosage form, wherein this Sertraline is with the Sertraline free alkali, the sertraline salts hydrochlorate, and the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.

35. the dosage form of item 31, wherein this mammal is the people.

36. be suitable for the slow release formulation to the mammal administration, it has nearly 3 hours the initial delay phase, comprises Sertraline or its pharmaceutical salts and pharmaceutical carrier, in NaCl, be 0.075M when containing 900ml, when under 37 ℃, measuring dissolution in the USP-2 instrument of the acetate buffer of pH4.0, this dosage form

In corresponding to the period of described initial delay phase, discharge Sertraline with the speed that is lower than 1mgA/ hour,

37. the dosage form of item 36 wherein should nearly 2 hours period of delay.

38. the dosage form of item 36 should the rate of release after period of delay be 1mgA/ hour to 30mgA/ hour wherein.

39. 36 dosage form, wherein this Sertraline is with the Sertraline free alkali, the sertraline salts hydrochlorate, and the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.

40. the dosage form of item 36, wherein this mammal is the people.

41. the dosage form of item 36 exists with tablet form.

42. the dosage form of item 36, it is many granules.

43. be suitable for the time delay of mammal oral administration is added the dosage form of slow release, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier,

This dosage form discharges Sertraline to this in mammiferous stomach with the speed that is lower than 1mgA/ hour being swallowed the back by mammal,

And its speed with 1mgA/ hour to 40mgA/ hour is carried out slow release behind mammiferous small intestinal by this, is no more than 70% wherein contained Sertraline as long as discharge in this dosage form first hour behind mammiferous small intestinal by this.

44. the dosage form of item 43, wherein the initial of slow release is that pH-causes.

45. the dosage form of item 44 comprises preventing under the pH that is used in stomach that Sertraline from discharging, but the slow release formulation of polymer coating that can be saturating under the pH of small intestinal to Sertraline.

46. the dosage form of item 44, wherein this slow release formulation is many granules.

47. the dosage form of item 44, wherein this slow release formulation is a tablet.

48. the dosage form of item 43, it is enzyme-initiation.

49. the dosage form of item 48, comprise slow release formulation with film coating with hydrophobic liquid of in its hole, carrying, this hydrophobic liquid basically can not be saturating to water and Sertraline, but can change by enzymatic degradation, make that when in the environment of this dosage form immigration small intestinal lumen, this film becomes basically can be saturating to water and Sertraline.

50. the dosage form of item 48, wherein this slow release formulation is many granules.

51. the dosage form of item 48, wherein this slow release formulation is a skeleton.

52. 43 dosage form, wherein this Sertraline is with the Sertraline free alkali, the sertraline salts hydrochlorate, and the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.

53. the dosage form of item 43, wherein this mammal is the people.

54. be suitable for the dosage form that the pH-to the slow release of mammal oral administration causes, this dosage form has an initial period of delay before slow release begins, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier, when testing in vitro in the USP-2 instrument,

This dosage form discharges Sertraline in 0.1N HCl with the speed that is lower than 1mgA/ hour,

After this, Sertraline is discharged in the phosphate buffer of the pH6.8 that contains 1% Spheron MD 30/70 with 1mg/A hour to 40mgA/ hour speed, if in this dosage form first hour after this delays release be no more than wherein contained Sertraline remainder 70%.

55. the dosage form of item 54 comprises the slow release formulation with the coating bag quilt that contains polymer, this polymer prevents that Sertraline from discharging in described HCl with the speed above 1mg/A hour, but can thoroughly and allow its slow release to Sertraline in said phosphate buffer.

56. the dosage form of item 55, wherein this slow release formulation is many granules.

57. the dosage form of item 55, wherein this slow release formulation is a tablet.

58. 54 dosage form, wherein this Sertraline is with the Sertraline free alkali, the sertraline salts hydrochlorate, and the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.

59. the dosage form of item 54, wherein this mammal is the people.

60. be suitable for the dosage form to the enzyme-initiation of the slow release of mammal oral administration, this dosage form has an initial period of delay before slow release begins, it comprises Sertraline, or its pharmaceutical salts and pharmaceutical carrier, when testing in vitro in the USP instrument,

In 1 hour time, this dosage form discharges Sertraline in 0.1NHCl with the speed that is lower than 1mgA/ hour,

After this, speed with 1mg/A hour to 40mgA/ hour in the presence of the enzyme of the beginning that is suitable for causing this slow release is discharged into Sertraline in the phosphate buffer of the pH6.8 that contains 1% Spheron MD 30/70, if in this dosage form first hour after this delays release be no more than contained Sertraline remainder 70%.

61. the dosage form of item 60, comprise slow release formulation with film coating with hydrophobic liquid of in its hole, carrying, this hydrophobic liquid basically can not be saturating to water and Sertraline in described acid, but can change in described buffer by enzymatic degradation in the presence of described enzyme, making that this film becomes basically can be saturating to water and Sertraline.

62. the dosage form of item 60, wherein this slow release formulation is many granules.

63. the dosage form of item 60, wherein this slow release formulation is a tablet.

64. 60 dosage form, wherein this Sertraline is with the Sertraline free alkali, sertraline salts hydrochlorate, Sertraline aspartate, Sertraline acetate or Sertraline lactate.

65. the dosage form of item 60, wherein this mammal is the people.

66. be suitable for slow release formulation to the Sertraline of mammal oral administration, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier, to this mammal oral administration the time, the Sertraline plasma concentration (C of the maximum that it obtains _Max) be lower than at the Sertraline of equivalent measured C during with the agglomerate oral administration that discharges immediately _Max80%, discharge 70% of the Sertraline that is no more than with which in first hour that condition is this dosage form (1) after pharynx is gone into, and (2) discharge Sertraline with 1mgA/ hour at least speed.

67. the dosage form of item 66, it provides not as C _MaxTotal blood medicine of such proportional reduction exposes.

68. 66 dosage form, wherein this Sertraline is with the Sertraline free alkali, the sertraline salts hydrochlorate, and the Sertraline aspartate, the Lactated form of Sertraline acetate or Sertraline exists.

69. the dosage form of item 66, wherein this mammal is the people.

70. the dosage form of item 66, its form with tablet exists.

71. the dosage form of item 66, it is many granules.

72. 66 dosage form, delay of three hours adds slow release formulation in order to show nearly before slow release begins for it, and this dosage form discharges Sertraline in this period of delay with the speed that is lower than 1mgA/ hour.

73. the dosage form of item 72, wherein this delay is timeliness.

74. the dosage form of item 72, wherein this delay is spatial.

75. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline of item 1 the sustained-release oral dosage forms of effective dose.

76. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline of item 11 the sustained-release oral dosage forms of effective dose.

77. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline of item 21 the sustained-release oral dosage forms of effective dose.

78. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline that item 31 the delay of effective dose adds sustained-release oral dosage forms.

79. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline that item 36 the delay of effective dose adds sustained-release oral dosage forms.

80. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline that item 43 the delay of effective dose adds sustained-release oral dosage forms.

81. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline that item 54 the delay of effective dose adds sustained-release oral dosage forms.

82. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline that item 60 the delay of effective dose adds sustained-release oral dosage forms.

83. the treatment psychosis, premature ejaculation, the chemicals dependence syndrome, the method for premenstrual dysphoric disease and obesity comprises the mammal to this treatment of needs, comprises that human patients treats the Sertraline that item 66 the delay of effective dose adds sustained-release oral dosage forms.

84. Sertraline acetate.

85. have the Sertraline acetate of X-ray crystal structure shown in Figure 1.

86. Sertraline acetate 1/4 hydrate.

87. pharmaceutical composition comprises Sertraline acetate and a pharmaceutical carrier or a diluent of 84.

88. pharmaceutical composition comprises Sertraline acetate and a pharmaceutical carrier or a diluent of 85.

89. pharmaceutical composition comprises Sertraline acetate 1/4 hydrate and a pharmaceutical carrier or a diluent of 86.

90. Sertraline L-lactate.

91. have the Sertraline L-lactate of the item 90 of X-ray crystal structure shown in Figure 3.

92. pharmaceutical composition comprises Sertraline L-lactate and a pharmaceutical carrier or a diluent of 90.

93. pharmaceutical composition comprises Sertraline L-lactate and a pharmaceutical carrier or a diluent of 91.

94. Sertraline L-aspartate.

95. pharmaceutical composition comprises Sertraline L-aspartate and a pharmaceutical carrier or a diluent of 11.

96. treatment suffers from apositia, obsession, onychophagy, premenstrual syndrome, the schizoid type psychosis, inflammation, the method for the patient's of one or more of ergogenic disease of immune system and chemicals dependence syndrome disease, comprise the Sertraline acetate that this patient is given effective dose, Sertraline L-lactate or Sertraline L-aspartate.

97. the method for item 96, wherein administration Sertraline acetate.

98. the method for item 96, wherein administration Sertraline L-lactate.

99. treatment suffers from the method for depression patient's depression, comprises the Sertraline acetate that this patient is given effective dose, Sertraline L-lactate or Sertraline L-aspartate.

100. the method for item 99, wherein administration Sertraline acetate.

101. the method for item 99, wherein administration Sertraline L-lactate.

102. treatment suffers from the patient's of the relevant disease of anxiety method, comprises the Sertraline acetate that this patient is given effective dose, Sertraline L-lactate or Sertraline L-aspartate.

103. the method for item 102, wherein the disease that anxiety is relevant is an obsession.

104. the method for item 103, wherein administration Sertraline acetate.

105. the method for item 103, wherein administration Sertraline L-lactate.

106. prepare the method for Sertraline acetate, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and in the presence of appropriate organic solvent with Sertraline free alkali and acetic acidreaction.

107. 106 method, wherein this sertraline salts is a sertraline salts hydrochlorate and solvent is a hexane.

108. prepare the method for Sertraline acetate, comprise that Sertraline free alkali and acetic acid react in the presence of appropriate organic solvent.

109. the Lactated method of preparation Sertraline L-, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and in the presence of appropriate organic solvent, Sertraline free alkali and L-lactic acid is reacted.

110. 109 method, wherein this sertraline salts is a sertraline salts hydrochlorate and solvent is an ethyl acetate.

111. 109 method, wherein this sertraline salts is a Sertraline mandelate and solvent is an ethyl acetate.

112. the Lactated method of preparation Sertraline L-comprises Sertraline free alkali and L-lactic acid is reacted in the presence of appropriate organic solvent.

113. prepare the method for Sertraline L-aspartate, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and Sertraline free alkali and aspartic acid are reacted in the presence of appropriate organic solvent.

114. 113 method, wherein this sertraline salts is a sertraline salts hydrochlorate and solvent is water saturated ethyl acetate.

115. prepare the method for Sertraline L-aspartate, comprise Sertraline free alkali and L-aspartic acid are reacted in the presence of appropriate organic solvent.

The dosage form of " release " Sertraline that relates to means (1) to be discharged into Sertraline in mammiferous gastrointestinal (GI) road after swallowing, or (2) are discharged in the testing in vitro medium Sertraline to analyze with following in vitro tests.Therefore, " environment for use " that relates to can be gastrointestinal fluid or in vitro tests medium in the body.

Be lower than 25,30 or 40mgA/ hour Sertraline rate of release also within the scope of the invention, and even can produce better side effect profile, especially body weight is lower than the patient of 50kg, as the child.Therefore, 7mgA/ hour Sertraline speed after swallowing has been represented release characteristics within the scope of the invention and even may more be effective in the improvement side effect.Certainly, this speed must be high enough to provide therapeutic effect, that is, the Sertraline of treatment q.s should discharge in this dosage form before this dosage form is with defecate.Considerably, dosage form of the present invention should discharge Sertraline with 1mgA/ hour at least speed.

Used unit " kg " refers to the kilogram of the mammiferous body weight of being treated in " mgA/ hour/kg ".

The mouth of known non-disintegrate (as tablet and many granules) dosage form to the time of passing through of anus be about 24 hours.Dosage form of the present invention discharged at least 60% of its contained Sertraline in 24 hours, and preferably at least 70%.Not as from last GI road, i.e. small intestinal is shown in embodiment 3 from the absorption efficiency of the following Sertraline in gastrointestinal (GI) road, particularly colon.Correspondingly, it is favourable in the treatment discharging less Sertraline and discharge more Sertraline in last GI road in the infra GI road.Therefore, controlled release Sertraline dosage form of the present invention preferably at 18 hours, most preferably discharged at least 60%, its contained Sertraline of preferred at least 70% in 16 hours in 24 hours.

Though, above-mentioned dosage form generally discharged its contained Sertraline of at least 70% in 24 hours, dosage form of the present invention can fully discharge its all basically contained Sertralines before 24 hours, as long as it discharges Sertraline otherwise with the speed that is no more than 40mgA/ hour or 0.8mgA/kg/ hour.

Term " is swallowed " and is synonymous to " swallowing " here in fact.

The present invention is particularly useful for the Sertraline a large amount of relatively to patient's administration.The amount of contained Sertraline preferably is at least 10mgA in this dosage form, and may be up to 500mgA or higher.In this dosage form contained amount more preferably 25mgA to 400mgA.This dosage form can be unitary or portioning, and (as capsule or the tablet that constitutes this dosage form together) constitute as being made of two or three unit, and it at the same time or approximately take in simultaneously.

The Sertraline that uses in dosage form of the present invention can be the form of its pharmaceutical salts, and also can be anhydrous and hydrated form.Can use all this forms within the scope of the invention.Preferably, used Sertraline is a free alkali, hydrogen chlorate, aspartate, acetate or lactate.With coherent, relating to " Sertraline " that be expressed as therapeutic dose or rate of release in claims is active Sertraline for convenience, and this paper is abbreviated as " mgA ", that is, molecular weight is 306.2 non-salt, nonhydratable free alkali.The amount of representing with mgA can convert the suitable weight of the form of required any salt easily to.

The agent punishment that constitutes theme of the present invention is above-mentioned slow release formulation.This dosage form can be tablet, capsule, many granules, the many granules in tablet or the capsule, or unit pouch agent (being sometimes referred to as " wafer " in the art).Also comprise combination dosage forms, contain the one or more slow releasing tablets that are included in capsule shells such as the gelatine capsule shell as those.

Term " tablet " comprises compressed tablets, coated tablet, and matrix tablet, osmotic tablet, and other form known in the art, and as it is hereinafter open and said more fully.

Term " capsule " comprise show required slow release behavior swallowing the capsule that back capsule body disintegrate discharges the granule inclusions, and in it rests on the process in GI road, keep the complete capsule of capsule body basically.

Further, the invention provides the method for treatment psychosis and other disease, comprise, comprise human patients the mammal of this treatment of needs, the Sertraline of the sustained-release oral dosage forms of drug treatment effective dose, it discharges Sertraline with above-mentioned rate of release.This type of disease comprises those of available Sertraline treatment known in the art, comprises above-mentioned those.

Further, the invention provides the slow release formulation that is suitable for the mammal administration, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier, this dosage form is external, discharge Sertraline with the speed that is lower than 40mgA/ hour, when containing the acetate buffer that comprises 900ml, pH4.0 (0.075M, in NaCl) the USP-2 instrument of tested media in when measuring dissolution down for 37 ℃, as follows:

The example that falls into the dosage form of above-mentioned classification (1) comprises:

A. slow release is store the diffusion tablet of storehouse tablet such as coating, the swollen hydrogel tablet of osmotic tablet and film coating;

B. matrix tablet, comprise disintegrate with non-disintegrate; And

C. the capsule of non-disintegrate; This capsule shell material should be non-gelatin copolymer such as ethyl cellulose or cellulose acetate.

The example that falls into the dosage form of above-mentioned classification (2) comprises dosage unit pouch (this area is also referred to as " wafer ") and is used for the powder that the oral cavity suspends.Ideally, each granule in many granules constitutes the self-contained unit of slow release.This granule can be made into bigger unit, as by being pressed into the bigger patch unit of being more convenient for swallowing.Yet the rapid disintegrate when swallowing of this bigger unit produces many granules.

Term " many granules " refers to that wherein each granule is designed to prepare many granules of controlled release Sertraline.Ideally, each granule in many granules constitutes the self-contained unit of slow release.This granule can be made into bigger unit.Each granule of these many granules comprises Sertraline and according to one or more excipient of the processing and the needs of performance.Each particulate size is generally between about 50 μ m and about 3mm.The main many granules that are made of near the granule the lower limit of this magnitude range are sometimes referred to as powder in this article.Many granules that near the upper limit of main magnitude range thus granule constitutes are sometimes referred to as pellet in this article.Perhaps, size also is available in this extraneous pellet.

Any dosage form in above-mentioned (1) or (2) all can add in the gelatine capsule.If this dosage form is in gelatine capsule or otherwise with gelatin bag quilt, then this dosage form according to concrete dosage form under the appropriate condition as (1) or (2) described in USP-2 stir in the instrument and detecting, but need to add trypsin in this acetate buffer to concentration 0.1mg/ml.Usually, the amount of the dosage form of being surveyed or size should contain or be equivalent to 200mgA Sertraline or still less.If this dosage form contains above 200mgA, then the amount of acetate buffer tested media should increase in proportion.

Above-mentioned used test solution is acetic acid/acetate buffer, pH4.0, and this buffer is the 0.075M in NaCl, and is intended to simulate gastro-intestinal Fluid.This test fluid is made acetic acid/acetate buffer by adding potassium hydroxide (being generally the aqueous solution of 0.5M) with this solution then and is made until reaching pH4.0 by the 0.13M solution of preparation acetic acid in water.Then, the NaCl that adds capacity is formed in 0.075M among the NaCl with this solution.In whole dissolution test, keep the temperature of test solution at 37 ℃.

In-vitro release rate multiply by 0.8 by the dosage of this merging, this number is measured divided by the time of measuring under the situation about being released at existing 80% merging dosage with stripping again, and further discussion is hereinafter arranged.If the Sertraline of this merging of 80% is not to discharge in 24 hours, then the mgA Sertraline that should discharge at 24 hours should be divided by 24 hours to obtain rate of release.And burst size is no more than 40mgA in any one hour.Thereby, of the present inventionly defined slow release formulation by the external test that in the known instrument of standard, carries out easily in this respect.As described above, discharging in arbitrary hour of this mensuration should no more than 40mgA.The known USP-2 instrument of being furnished with splash bar is that the crowd knows and is described in American Pharmacopeia XXIII version (USP), dissolution determination, the 711st chapter, instrument 2.

By being placed on the dissolution determination that carries out unit dosage form in the USP-2 instrument (containing the test solution that 900ml has just described) that splash bar is housed, the temperature of measuring solution is 37 ℃, and splash bar stirs speed and is 50rpm.If this dosage form is a capsule, then in test solution, augment to the trypsin that contains 0.1mg/ml, detect in the same manner.Duplicate samples such as filtering (general 2 or 10ml) in that each time point is got this dissolution medium is called " sample point (Pull Points) " herein.Not crucial especially etc. the precise time point that duplicate samples is taken out, though for convenience can be with the sample point standardization.Filter these duplicate samples and measure Sertraline content with HPLC detection or other suitable detection method.These data are mapped to the time on the X-axle as the mgA Sertraline (active Sertraline) (or percent of the Sertraline alkali that discharges) of the release on the Y-axis.Indicate the time discharged 80% Sertraline dosage.

In order to ensure the result accurately, should carry out a plurality of one, as three, or more preferably six independent dissolutions detect and measure speed and it is average.

As above-mentioned, discharge the required time divided by 80% and from the dissolution test, calculate in-vitro release rate by the amount (multiply by 0.8 by the dosage that will merge measures) that will be equivalent to 80% Sertraline that discharges.For example, if measure 100mgA sertraline oral dosage form with this mode, and the Sertraline of this merging of 80% discharged in 8 hours, and then this rate of release is (100mg * 0.8)/8 hours, or 10mgA/ hour.Thereby this dosage form within the scope of the invention.As another example, if external test 50mgA sertraline oral dosage form, and the Sertraline of this merging of 80% (as Sertraline alkali) discharged in 0.4 hour, and then this rate of release is (50mg * 0.8)/0.4 hour, or 100mgA/ hour, and this dosage form is not within the scope of the invention.

Although the method for the medicine in-vitro release rate (as first order rate constant, zero level speed constant, initial rate etc.) of many description dosage forms is arranged, above-mentioned method provides a clear and definite test that is independent of the mechanism that Sertraline discharges from dosage form.

It should be noted that immediately the Sertraline dosage form that discharges is with known and can be from (ZOLOFT ^, the registered trade mark of Pfizer) bought with the tablet of 50mgA and 100mgA specification.When with above-mentioned dissolution in vitro test evaluation 50mgA ZOLOFT tablet, began back 0.7 hour at this dissolution test, on average there is 80% contained Sertraline to be released (promptly being dissolved in the test fluid).Therefore, calculate this 50mgA tablet that discharges immediately by said method and discharge Sertraline with 57mgA/ hour speed.When utilizing above-mentioned dissolution test evaluation two 100mgA ZOLOFT tablet (accumulated dose 200mgA), discharge in 80% contained Sertraline 1.2 hours after initial test.Therefore, calculating each 100mg tablet by said method, to discharge Sertraline with 67mg/ hour speed then be 134mg/ hour for the rate of release of the dosage of 200mg.Thereby, exemplifying as the front in vitro tests, this dosage form is not within the scope of the invention.

Further, the invention provides the slow release formulation that is suitable for the Sertraline of mammal oral administration, the Sertraline plasma concentration (C of the maximum that it obtains _Max) be lower than the Sertraline of equivalent with discharge immediately with piece (as the tablet that discharges immediately) oral administration the time measured C _Max80%.Of the present inventionly defined slow release formulation of the present invention by the suitable in vivo test of carrying out in the purpose mammal species in this respect.For example, for whether the sertraline oral dosage form of measuring slow release has improved side effect to the people, the dosage form of this Sertraline test is given the people of one group of 12 or more people's half quantity, and after the suitable elimination phase (as a week), give identical experimenter with identical specification and discharge the agglomerate dosage form immediately.Second half people elder generation administration of this group discharges the agglomerate agent immediately, gives Sertraline (slow release) test dosage forms subsequently again, and as the function mensuration blood plasma Sertraline level of time.When every group of treatment, measured each individual C _MaxAfter, determine average C _MaxIf the C of the test dosage forms of the Sertraline of slow release _MaxBe lower than the C of this agglomerate dosage form _Max80%, then the dosage form of this test will compare to the agglomerate dosage form provides side effect to improve and within the scope of the invention.In this embodiment, dosage form can be slow release, has or do not have the initial delay phase, as following.It should be noted that " discharging immediately " refers to that this agglomerate is not processed to comprise the drug-supplying system that is used for slow disintegrate or dissolves this dosage form.

(comprise the C that has just described by relevant testing in vitro as herein described or relevant body build-in test as herein described _Max) dosage form within the scope of the invention, by all about the dosage form of this type of test also within the scope of the invention.

As above-mentioned, slow release Sertraline dosage form is with respect to the C of the immediate release dosage form of the Sertraline that contains equivalent _MaxThe C that reduces is provided _MaxThat is the C that shows of slow release formulation, _MaxBe less than or equal to the C that suitable immediate release dosage form provides _Max80%.Preferred dosage form also provides not as slow release C with respect to suitable immediate release dosage form _MaxAs the total blood medicine of proportional reduction expose." total blood medicine exposes " is determined as AUC, and blood drug level (Y-axis) is to the area under a curve of time (X-axis) mapping gained.AUC generally is a meansigma methods, and the meansigma methods of all experimenters in for example above-mentioned exchange research.The mensuration of AUC is known method, and for example is described in Peter Welling (ACS Monograph 185, American Chemical Society, Washington D.C.; 1986) " pharmacokinetics; Method and number reason " in.For example, suppose the C that slow release 100mgA Sertraline dosage form A shows _MaxBe the C that 100mgA promptly releases the Sertraline dosage form _Max65%.In preferred embodiments, slow release formulation A also can show 65% the AUC of the AUC that is higher than the agglomerate dosage form.

Further, the invention provides the Sertraline slow release formulation, when this dosage form enters its environment for use, as after swallowing, show the initial delay that Sertraline discharges, subsequently as above-mentioned Sertraline slow release.In period of delay, essentially no Sertraline discharges, and is lower than 1mgA/ hour minimum rate of release although " essentially no Sertraline " comprises.This type of dosage form is sometimes referred to as " time-delay adds slow release " dosage form in this article.Some side effect that the inventor has proved Sertraline is promptly felt sick, regurgitation and diarrhoea are parts or mainly by Sertraline and upper gastrointestinal, mainly the direct contact of stomach mediates, but not absorbs the back by exposing Sertraline in blood flow and system's mediation.It is preceding to carry out people's clinical research (as described in embodiment 6 hereinafter) the inventor, the part mediation characteristic of unknown these three Sertraline side effect.Therefore, show the dosage form that room and time postpones after favourable Sertraline dosage form of the present invention is included in and swallows.Show slow release Sertraline dosage form that the space postpones comprise the time of being independent of to those of its position sensing in the GI road, and have the mechanism that Sertraline discharges under one's belt that mainly or thoroughly prevents, and after this dosage form has entered duodenum, begin slow release.Be restricted as the slow release of Sertraline Once you begin, the slow release Sertraline dosage form of the speed of this slow release and degree such as above-mentioned relevant " non-delay ".The slow release formulation that space of the present invention postpones in about 30 minutes, preferably began the slow release Sertraline in about 15 minutes after passing stomach to enter duodenum.

Time delay slow release Sertraline dosage form of the present invention is after swallowing, and shows those of time delay before beginning slow release Sertraline.In the present invention, time delay refer to the space site of this dosage form in the GI road irrelevant swallow after delay.The slow release Sertraline dosage form of time delay showed after swallowing nearly 3 hours, and preferred 2 hours, most preferably 1.5 hours delay.This space postpones to make upper gastrointestinal, particularly stomach to minimize with contacting of Sertraline after oral swallowing, thereby improves the local side effect that mediates.After the delay, this dosage form then discharges Sertraline in the above-mentioned mode that speed and degree were limited about " non-delay " slow release Sertraline dosage form.

Notice that " slow release formulation " that relates in claims is meant the dosage form with the initial delay phase of realizing therein.The dosage form with the period of delay of realizing therein that relates in claims is special finger, for example " slow release formulation " with initial delay phase, time or space " delay adds the dosage form of slow release ", or similar language is such as " said dosage form with initial delay phase ".

Note, have the nature lag period, be no more than 15 minutes after swallowing usually, this dosage form is by moistening during this period, aquation, or otherwise by body fluid (GI) thus influence makes it begin dissolving and discharges Sertraline.Moistening about ten minutes typical hysteresis or induction period takes place and is included in the period of delay of being processed into this dosage form in this, thus also can think this period of delay be about 15 minutes up to 3 hours, preferred about 15 minutes to 2 hours.If this reduction or lag period are no more than 15 minutes, do not think to postpone to add slow release.It would be better to say that it only is a slow release.

Therefore, the invention provides the dosage form that is suitable for the mammal time of administration is postponed to add slow release, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier, this dosage form is swallowed the back at nearly 3 hours mammal, preferred nearly 2 hours, more preferably nearly 1.5 hours initial delay phase discharges Sertraline to this mammiferous GI road with the speed that is lower than 1mgA/ hour, and discharge Sertraline with 1mgA/ hour to 40mgA/ hour speed thereafter, be no more than 70% wherein contained Sertraline as long as discharge in this dosage form first hour after said period of delay.

This dosage form also can be the space that is suitable for the mammal oral administration and postpones to add slow release formulation, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier, this dosage form discharges Sertraline to this in mammiferous stomach with the speed that is lower than 1mgA/ hour being swallowed the back by this mammal, and after entering this mammiferous duodenum, discharge Sertraline with 1mgA/ hour to 40mgA/ hour speed, as long as entering in this mammiferous Retroduodenal first hour, this dosage form discharges and is no more than 70% wherein contained Sertraline.

Following in vitro tests can be used for measuring concrete dosage form and whether falls into the present invention, depends on whether the initial of this slow release composition is that time or space postpone.

If this dosage form is when being time delay, this in vitro tests can be fully according to aforesaid wherein the carrying out of the slow release formulation of joining day delay not.This dosage form nearly corresponding to discharging Sertraline with the speed that is lower than 1mgA/ hour in three hours of the length of this period of delay or the less time, subsequently, with 1mgA/ hour to 40mgA/ hour speed slow release Sertraline.Condition, tester can be the alternate manner identical with pure Sertraline slow release formulation with tested media.As for other dosage form, the dosage form with time delay postpones to discharge in back first hour 70% of the remainder that is no more than contained Sertraline at this.

If being the space of band pH-releaser, this dosage form postpones, the invention provides and be suitable for the dosage form that the pH-to the slow release of mammal oral administration causes, this dosage form has an initial period of delay before slow release begins, comprise Sertraline or its pharmaceutical salts and pharmaceutical carrier, when testing in vitro in the USP-2 instrument, this dosage form discharges Sertraline in 0.1N HCl with the speed that is lower than 1mgA/ hour at least one hour time, after this, Sertraline is discharged in the phosphate buffer (pH6.8) that contains 1% Spheron MD 30/70 with 1mg/A hour to 40mgA/ hour speed, if in this dosage form first hour after this delays release be no more than contained Sertraline remainder 70%.

If being the space of band enzyme-releaser, this dosage form postpones, the invention provides the dosage form that is suitable for the enzyme-initiation of the slow release of mammal oral administration, this dosage form has an initial period of delay before slow release begins, it comprises Sertraline, or its pharmaceutical salts and pharmaceutical carrier, when testing in vitro in the USP instrument, this dosage form discharges Sertraline in 0.1N HCl with the speed that is lower than 1mgA/ hour at least one hour time, after this, speed with 1mg/A hour to 40mgA/ hour in the presence of the enzyme of the beginning that is suitable for causing this slow release is discharged into Sertraline in the phosphate buffer (pH6.8) that contains 1% Spheron MD 30/70, if in this dosage form first hour after this delays release be no more than contained Sertraline remainder 70%.

In these in vitro testses, the amount of calculating the average Sertraline that per hour discharges is 1mgA/ hour,

The time of being counted is initial one hour or the longer time corresponding to this detection of this period of delay.

The objective of the invention is to reduce the incidence rate and the seriousness of the inductive side effect of Sertraline.This is important when the higher high dose of the incidence rate of side effect especially, as 100mg or higher.This purpose especially by this gastrointestinal tract of control and systemic circulation in the patient of at least a portion Sertraline administration to the exposure speed and the degree of Sertraline, thereby reduce total incidence rate of the inductive side effect of Sertraline and seriousness and realize.

Notice various slow release formulations be known and be applied to routinely this area with provide short half life chemical compound reduction administration frequency and reduce the fluctuation of blood drug level, sometimes owing to having avoided in the whole day multiple blood drug level peak and paddy to give improved safety/effectiveness.Because Sertraline is eliminated from human body and is characterised in that about 23 hours long half life, yet surprisingly slow release formulation will provide any benefit.

The present invention further provides new useful Sertraline acetate, hereinafter referred to as " Sertraline acetate " contains the Pharmaceutical composition of Sertraline acetate, uses and prepare the method for Sertraline acetate.

The present invention further provides new useful Sertraline L-lactate, hereinafter referred to as " Sertraline L-lactate " contains the Lactated Pharmaceutical composition of Sertraline L-, uses and prepares the Lactated method of Sertraline L-.

The present invention further provides new useful Sertraline L-aspartate, hereinafter referred to as " Sertraline L-aspartate " contains the Pharmaceutical composition of Sertraline L-aspartate, uses and prepare the method for Sertraline L-aspartate.

The acetate of Sertraline of the present invention be highly-water-soluble and be particularly useful for controlled release, as the slow release of Sertraline, encapsulated solution or delayed release dosage forms.And the Sertraline acetate has a useful mechanical performance and is chemistry and physical stability.These features allow to handle Sertraline easily and be created in the stable tablet of materialization in storage and the use in the dosage form process for preparation.

The L-lactate of Sertraline of the present invention be highly-water-soluble and be particularly useful for controlled release, as the slow release of Sertraline, encapsulated solution or delayed release dosage forms.And Sertraline L-lactate has a useful mechanical performance and is chemistry and physical stability.These features allow in the dosage form process for preparation, to handle Sertraline easily and be created in store and use in the stable tablet of materialization.

The aspartate of Sertraline of the present invention be highly-water-soluble and be particularly suited for being used for controlled release, as the slow release of Sertraline, encapsulated solution or delayed release dosage forms.

Therefore, the invention particularly relates to the Sertraline acetate.

The present invention be more particularly directed to have the Sertraline acetate of the atomic coordinates shown in X-ray crystal structure shown in Figure 1 and the table 40-2.

The invention further relates to Sertraline acetate 1/4 hydrate.

The invention still further relates to the method for the apositia for the treatment of the patient who suffers from apositia or anorexia, comprise the Sertraline acetate that this patient is given effective dose.

The invention still further relates to treatment and suffer from following arbitrary compulsive patient's obsession such as trichologia, pathological gambling, kleptomania and pyro method comprise the Sertraline acetate that this patient is given effective dose.

The invention still further relates to the method for the onychophagy for the treatment of the patient who suffers from onychophagy, comprise the Sertraline acetate that this patient is given effective dose.

The invention still further relates to the method (hereinafter referred to as " fidgety disease premenstruum ") of the premenstrual syndrome for the treatment of the patient who suffers from premenstrual syndrome, comprise the Sertraline acetate that this patient is given effective dose.

The invention still further relates to treatment and suffer from the schizoid type psychosis or such as anxiety neurosis, exciting disease, catatonia, undue aggressive behavior, the method for the lonely or autistic disease of patient of emotion of society comprises the Sertraline acetate that this patient is given effective dose.

The invention still further relates to treatment and suffer from inflammation such as the psoriasis or the arthritic method of inflammatory patients, comprise the Sertraline acetate that this patient is given effective dose.

The invention still further relates to treatment and suffer from the method for the disease of patient of the ergogenic disease of the immune system of being characterised in that such as rheumatoid arthritis and lupus erythematosus, comprise the Sertraline acetate that this patient is given effective dose.

The invention still further relates to treatment and suffer from the method for depression patient's depression, comprise the Sertraline acetate that this patient is given effective dose.

The invention still further relates to treatment and suffer from one or more anxieties relevant disease such as Panic disorder, general anxiety disease, agoraphobia, simple phobias, social phobia, constrain disease after the wound, the method for the disease of patient of obsession and avoidance moral character disease comprises the Sertraline acetate that this patient is given effective dose.

The present invention relates to treat the method for the relevant disease of above-mentioned anxiety, wherein the disease that this anxiety is relevant is an obsession.

The invention still further relates to the method for therapeutical chemistry product dependence syndrome disease of patient, comprise the Sertraline acetate that this patient is given effective dose.

The invention further relates to the pharmaceutical composition that comprises Sertraline acetate and pharmaceutical carrier or diluent.

The invention further relates to and comprise pharmaceutical composition with X-ray crystal structure shown in Figure 1 and pharmaceutical carrier or diluent.

Ring of the present invention relates to the method for preparing the Sertraline acetate, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and in the presence of appropriate organic solvent with Sertraline free alkali and acetic acidreaction.

Purpose of the present invention especially is the described method of epimere, and wherein this sertraline salts is the sertraline salts hydrochlorate.

Purpose of the present invention especially is the described method of epimere, and wherein this solvent is a hexane.

Further aim of the present invention is to prepare the method for Sertraline acetate, comprises that Sertraline free alkali and acetic acid react in the presence of appropriate organic solvent.

The present invention also aims to prepare the method for Sertraline acetate, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and in the presence of appropriate organic solvent with Sertraline free alkali and acetic acidreaction, and from this solvent, separate this Sertraline acetate.

Purpose of the present invention also is Sertraline L-lactate.

Purpose of the present invention is particularly in the Sertraline L-lactate with the atomic coordinates shown in X-ray crystal structure shown in Figure 3 and the table 48-2.

Still another object of the invention is to treat the method for the patient's who suffers from apositia apositia, comprises the Sertraline L-lactate that this patient is given effective dose.

Still another object of the invention is to treat obsession such as the trichologia of suffering from following arbitrary compulsive patient, pathological gambling, and kleptomania and pyro method comprise the Sertraline L-lactate that this patient is given effective dose.

Still another object of the invention is to treat the method for the patient's who suffers from premenstrual syndrome premenstrual syndrome, comprises the Sertraline L-lactate that this patient is given effective dose.

Still another object of the invention is to treat the method for the patient's who suffers from onychophagy onychophagy, comprises the Sertraline L-lactate that this patient is given effective dose.

Still another object of the invention is that treatment suffers from the schizoid type psychosis or such as anxiety neurosis, exciting disease, catatonia, undue aggressive behavior, the method of the lonely or autistic disease of patient of emotion of society comprises the Sertraline L-lactate that this patient is given effective dose.

Purpose of the present invention especially is to treat the method for the relevant disease of the anxiety described in the epimere, and wherein the disease that this anxiety is relevant is an obsession.

The present invention also aims to therapeutical chemistry product dependence syndrome patient's method, comprise the Sertraline L-lactate that this patient is given effective dose.

Further purpose of the present invention is to comprise the pharmaceutical composition of Sertraline L-lactate and pharmaceutical carrier or diluent.

Further purpose of the present invention is to comprise the Sertraline L-lactate with X-ray crystal structure shown in Figure 3 and the pharmaceutical composition of pharmaceutical carrier or diluent.

The present invention also aims to prepare the Lactated method of Sertraline L-, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and Sertraline free alkali and L-lactic acid are reacted in the presence of appropriate organic solvent.

Purpose of the present invention especially is the described method of epimere, and wherein this solvent is an ethyl acetate.

Further aim of the present invention is to prepare the Lactated method of Sertraline L-, comprise that the Sertraline mandelate forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and Sertraline free alkali and L-lactic acid are reacted.

Further aim of the present invention is to prepare the Lactated method of Sertraline L-, comprises Sertraline free alkali and L-lactic acid are reacted in the presence of appropriate organic solvent.

The present invention also aims to prepare the Lactated method of Sertraline L-, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and Sertraline free alkali and acetic acid are reacted in the presence of appropriate organic solvent, and from this solvent, separate this Sertraline L-lactate.

Purpose of the present invention also is Sertraline L-aspartate.

Still another object of the invention is to treat the method for the patient's who suffers from apositia apositia, comprises the Sertraline L-aspartate that this patient is given effective dose.

Still another object of the invention is to treat obsession such as the trichologia of suffering from following arbitrary compulsive patient, pathological gambling, and kleptomania and pyro method comprise the Sertraline L-aspartate that this patient is given effective dose.

Still another object of the invention is to treat the method for the patient's who suffers from onychophagy onychophagy, comprises the Sertraline L-aspartate that this patient is given effective dose.

Still another object of the invention is to treat the method for the patient's who suffers from premenstrual syndrome premenstrual syndrome, comprises the Sertraline L-aspartate that this patient is given effective dose.

Still another object of the invention is that treatment suffers from the schizoid type psychosis or such as anxiety neurosis, exciting disease, catatonia, undue aggressive behavior, the method of the lonely or autistic disease of patient of emotion of society comprises the Sertraline L-aspartate that this patient is given effective dose.

Still another object of the invention is to treat inflammation such as psoriasis or the arthritic method of suffering from inflammatory patients, comprises the Sertraline L-aspartate that this patient is given effective dose.

Still another object of the invention is to treat the method for the disease of patient of suffering from the ergogenic disease of the immune system of being characterised in that such as rheumatoid arthritis and lupus erythematosus, comprises the Sertraline L-aspartate that this patient is given effective dose.

Still another object of the invention is to treat the method for the depression of suffering from the depression patient, comprises the Sertraline L-aspartate that this patient is given effective dose.

Still another object of the invention is to treat suffers from one or more anxieties relevant disease such as Panic disorder, general anxiety disease, agoraphobia, simple phobias, social phobia, constrain disease after the wound, the method for the disease of patient of obsession and avoidance moral character disease comprises the Sertraline L-aspartate that this patient is given effective dose.

The present invention also aims to therapeutical chemistry product dependence syndrome patient's method, comprise the Sertraline L-aspartate that this patient is given effective dose.

The present invention also aims to prepare the method for Sertraline L-aspartate, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, the Sertraline free alkali is dispensed into this organic solvent and Sertraline free alkali and aspartic acid are reacted in the presence of appropriate organic solvent.

Further aim of the present invention is to prepare the method for Sertraline L-aspartate, comprises that Sertraline free alkali and aspartic acid react in the presence of appropriate organic solvent.

The present invention also aims to prepare the method for Sertraline L-aspartate, comprise that sertraline salts forms the Sertraline free alkali with alkali reaction in the presence of appropriate organic solvent, this Sertraline free alkali is dispensed into this organic solvent also this Sertraline free alkali and aspartic acid is reacted in the presence of appropriate organic solvent, and from this solvent, separate this Sertraline L-aspartate.

Brief description

Fig. 1 is the X-ray crystal structure (atomic coordinates) of Sertraline acetate that is derived from the X-ray crystal pattern of monocrystalline.

Fig. 2 is the crystalline characteristic x-ray diffraction pattern (longitudinal axis: intensity (CPS) for expression Sertraline acetate; Transverse axis: 2 θ (degree)).

Fig. 3 is the Lactated X-ray crystal structure of Sertraline L-(atomic coordinates) that is derived from monocrystalline X-ray crystal pattern.

Fig. 4 is the crystalline characteristic x-ray diffraction pattern (longitudinal axis: intensity (CPS) for expression Sertraline L-lactate; Transverse axis: 2 θ (degree)).

Fig. 5 is for showing that Sertraline L-aspartate is the crystalline characteristic x-ray diffraction pattern (longitudinal axis: intensity (CPS); Transverse axis: 2 θ (degree)).

Fig. 6 is PK/PD figure, the relation between the range estimation analog score of blood plasma Sertraline concentration and average report certainly in the given nauseating test among the expression embodiment.

Detailed Description Of The Invention

Slowly-releasing

Slow release formulation of the present invention can be realized widely. The unrestriced purpose in order to discuss, many embodiments hereinafter can be according to design and operating principle classification.

The first kind slow release formulation of hereinafter describing is shell system, includes but not limited to 1) non-eroding matrix, tablet, many granules, and hydrogel based system; 2) the hydrophilic erosion can be disperseed or the resolvability shell system, tablet and many granules; With 3) coated shell system. Equations of The Second Kind is comprised of storage storehouse system, and its medicine discharges by film to be regulated, such as capsule, and the tablet of dressing or many granules. The 3rd class is made of the infiltration based system, such as 1) bilayer tablet of dressing; 2) the homogeneous phase tablet core of dressing; 3) many granules of dressing; With) the infiltration capsule. The 4th class is made of swellable system, wherein by swelling and will extrude this nuclear composition by dressing or shell on every side and the passage in the skin and discharge medicine.

The first kind comprises shell system, wherein Sertraline dissolving, embedding or be dispersed in for the skeleton that postpones Sertraline and be released into another material of aqueous environments (being the chamber liquid in GI road). When Sertraline dissolving, embedding or when being scattered in this type of skeleton, the release of this medicine mainly occurs in the surface of this skeleton. Therefore, maybe when the apparatus surface dissolving of incorporating this skeleton into or corrosion and when exposing this medicine, this medicine discharges from this apparatus surface after medicine enters periphery body fluid by this matrix diffusion. In some embodiments, two kinds of mechanism are carried out simultaneously. This shell system can be large, i.e. tablet size (about 1cm), or little (＜0.3cm). This system can be unit, can be by aforesaid portioning, it is by being consisted of and realized by several subunits of basically simultaneously administration (as consisting of several of single dose), it can be comprised of the several tabloids in a capsule maybe can comprise many particles, hereinafter referred to as many granules. Many granules can have many formulation usages. For example, many granules can be used as bead or the powder of filled capsules shell, can be pressed into tablet, or himself are used for mixing to increase palatability with food (such as ice cream), or as the wafer that can be scattered in liquid such as fruit juice or the water.

The multiplicity that affects the variable that Sertraline discharges from frame device allows at different materials, the enough flexibilities in the design of the device of size and release time. The example of the modification of the Sertraline release characteristic in the specific embodiments of the embodiment in scope of the present invention is as hereinafter describing in detail.

Provide the non-erosion property matrix tablet of releasing slow Sertraline can use Sertraline free alkali and various sertraline salts such as sertraline salts hydrochlorate, the Sertraline lactate, Sertraline acetate and Sertraline aspartate and water insolubility material such as wax, cellulose, or other water insolubility polymer is made. Host material for the preparation of these formulations comprises microcrystalline cellulose such as the Avicel (registration mark of FMC Corp., Philadephia, PA), comprise each grade microcrystalline cellulose, wherein added the adhesive such as hydroxypropyl methylcellulose, wax such as paraffin, modified vegetable oil, Brazil wax, rilanit special, beeswax, and analog, with polymer such as cellulose, cellulose esters, fiber ether, poly-(vinyl chloride), poly-(vinyl acetate), the copolymer of ethyl acetate and ethene, polystyrene and analog. Can choose the adhesive of allocating the water dissolvable in the skeleton into wantonly or discharge dressing agent and comprise water dissolvable polymer such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, gather (N-ethene-2-Pyrrolidone) (PVP), poly-(oxirane) (PEO) gathers (vinyl alcohol) (PVA), xanthans, carrageenan, and other natural and synthetic material. In addition, comprise water-soluble material such as sugar or salt as the material that discharges dressing agent. Preferred water-soluble material comprises lactose, sucrose, glucose and mannitol and HPC, HPMC and PVP. In addition, solubilizing acid excipient such as malic acid, citric acid, arabo-ascorbic acid, ascorbic acid, adipic acid, glutamic acid, maleic acid, aconitic acid and aspartic acid and solubilising excipient such as partial glyceride, glyceride, glyceride ester derivatives, macrogol ester, the polypropylene glycol ester, polyol ester, APEO, sorbitan ester, the polyoxyethylene sorbitan ester, sugar ester, phosphatide, Pluronic F108, can join in the matrix tablet to improve the rate of release of Sertraline with polyethylene glycol, increase the total amount of the Sertraline that discharges, and effectively increase the absorption of Sertraline and bioavilability subsequently, especially comfortable 6 hours or the longer interior skeleton preparation that discharges Sertraline of time.

Except the composition of this shell system, the large I of this shell system affects the speed that Sertraline discharges, and therefore, generally has the composition that is different from such as the little shell system of many granules to obtain similar release characteristic such as the large shell system of tablet. This shell system on the impact of Sertraline release dynamics according in proportion behavior known in the diffusion research. In order to illustrate, following table has shown required Sertraline by the diffusion coefficient of skeleton, to realize the characteristic time that discharged in 10 hours by the different big or small shell system that spreads base machine-processed (and non-corrosive or machine-processed in conjunction with corrosion).

Radius (cm) diffusion coefficient (cm²/s)

(0.0025 50 μ m diameter) 1.7 * 10^-10

(0.1 2mm diameter) 3 * 10^-7

(0.5 1cm diameter) 7 * 10^-6

Upper table has exemplified can be along with the variation of the required size of this device for required diffusion coefficient of the target characteristic time of realizing discharging and the variation of the order of magnitude is arranged. The framework material that the Sertraline diffusion coefficient can be provided in the lower bound of diffusion coefficient scope is the polymer such as cellulose ethanoate. On the contrary, be the material that forms the polymer of hydrogel during such as hydration at the material of the upper limit of this scope. The diffusion rate of any concrete device can correspondingly be adjusted by the structure of selected material and this skeleton.

For the purpose that further exemplifies, for obtaining the non-skeleton that loses of slowly-releasing in the particle of diameter 50 μ m, can be similarly need to such as framework material or the similar material of the polymer of cellulose ethanoate, be tending towards compensating short-range slowly framework material of diffusion of small particle diameter feature. On the contrary, for obtaining the slowly-releasing in large (such as 1cm) device, then need similarly more similar liquids (such as hydrogel hereinafter) or have larger porous material. As for medium sized device, such as diameter 1mm, the framework material of available mid-level characteristics.

Notice that also the effective diffusion cofficient of Sertraline in skeleton can be by adding the known plasticizer in this area, porous or hole induce additive and are increased to required value. Also the material of available slow aquation is effectively to reduce the diffusion rate of Sertraline, particularly after just administration. Except changing effective diffusion cofficient, also can be by adding more soluble salt type (with respect to free alkali) such as the Sertraline acetate, Sertraline lactate or Sertraline aspartate or solubilising Sertraline change rate of release with minimizing gelatification, the especially excipient when chlorion exists such as acid and/or surfactant compounds.

The non-erosion property shell system of another kind of slowly-releasing comprises the Sertraline that is dispersed in the hydrogel skeleton. This embodiment is different from hereinafter the hydrophily matrix tablet of discussing, and hydrogel in this embodiment is not the compressed tablets of the solvable granular materials that maybe can lose but block polymer network. As well known in the art, hydrogel is the water-swellable network polymer. Hydrogel can be made into many geometries, such as capsule, and sheet and many particles. The standard technique of the crosslinkable polymer that as an example, tablet can be by containing 10-80% prepares. In case the formation tablet, this polymer can be crosslinked by the UV radiation of chemical cross-linking agent such as glutaraldehyde or formation hydrogel. Hydrogel is the preferred material of frame device, because it can absorb or make the water that contains large volume part, thereby can spread the medicine of solvation in skeleton. The diffusion coefficient of hydrogel Chinese traditional medicine is high characteristically, and as for high water-swellable gel, this gel Chinese traditional medicine diffusion coefficient can be tending towards the value in the pure water. This high diffusion coefficient allows the practical rate of release from relatively large device (namely need not form particulate). Be produced although the hydrogel device can fill the state of part aquation, use the Sertraline load, store, disperse and administration, preferably it is stored with dry state, disperses and administration. Except stable and convenient, the good Sertraline release dynamics that the dry state administration of hydrogel device can provide because the transportation of the second situation (be swelling hydrogel and by by the combination of the drug diffusion of the hydrogel of swelling). The preferred material that forms hydrogel comprises hydrophilic ethene and acrylate copolymer, polysaccharide such as calcium alginate, and poly-(oxirane). Particularly preferably be poly-(HEMA), poly-(acrylic acid), poly-(methacrylic acid), poly-(NVP), poly-(vinyl alcohol) and mutual copolymer thereof, and with hydrophobic monomer such as methyl methacrylate, the copolymer of vinyl acetate etc. The hydrophilic polyurethane that also preferably contains large poly-(oxirane) block. Other preferred material comprises the hydrogel of the interpenetrating networks that contain polymer, and it can form by addition polymerization or polycondensation, and its component can contain just like the hydrophilic and hydrophobic monomer of just having enumerated.

Non-erosion property matrix tablet can prepare by the common flaking method of pharmaceuticals industry. The embodiment of preferred non-erosion property matrix tablet comprises the 10-80% Sertraline, the soluble framework material of 5-50% such as cellulose, cellulose ethanoate, or ethyl cellulose, and the plasticizer of optional 5-85%, pore former or solubilising excipient, and the film-making lubricant of optional about 0.25-2%, such as dolomol, sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid, PEG-8 000, the mixture of talcum or dolomol and lauryl sodium sulfate. These materials can mix granulation and compressing tablet with the common various device of pharmaceuticals industry.

The non-many particles of skeleton that lose comprise many particles that contain Sertraline, and each particle comprises that Sertraline and one or more are selected to form and can limit the excipient of skeleton that Sertraline is dissolved into the speed of aqueous medium. The framework material that is used for this embodiment generally is water-insoluble material such as wax, cellulose or other insoluble polymer. If need, this framework material is optionally used water-soluble material (as adhesive or permeability dressing agent) preparation. Framework material for the preparation of these formulations comprises microcrystalline cellulose such as the Avicel (registration mark of FMC Corp., Philadephia, PA), comprise each grade microcrystalline cellulose, wherein added the adhesive such as hydroxypropyl methylcellulose, wax such as paraffin, modified vegetable oil, Brazil wax, rilanit special, beeswax, and analog, and synthetic polymer gathers (vinyl acetate) such as poly-(vinyl chloride), the copolymer of vinyl acetate and ethene, polystyrene and analog. The release dressing agent that can choose the water dissolvable of allocating in the skeleton wantonly comprises water dissolvable polymer such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, gather (NVP) (PVP), poly-(oxirane) (PEO) gathers (vinyl alcohol) (PVA), xanthans, carrageenan, and other natural and synthetic material. In addition, comprise water-soluble material such as sugar or salt as the material that discharges dressing agent. Preferred water-soluble material comprises lactose, sucrose, glucose and mannitol and HPC, HPMC and PVP. In addition, in the many granules of any joined skeleton in the already mentioned solubilizing acid in front or the surfactant-based excipient to improve the rate of release of Sertraline, increase the total amount of the Sertraline that discharges, and effectively increase the absorption of Sertraline and bioavilability subsequently, especially discharge the skeleton preparation of Sertraline in comfortable 6 hours or longer time.

The granose method of preferred preparation skeleton is to extrude/the spheronizing method. Method becomes piece with Sertraline with the adhesive hygrometric state for this reason, extrudes by perforate dish or mould, and places on the dish of rotation. Ideally, this extrudate is cleaved into fragment, change at capstan spherical, near-spherical or pole. The preferred method and composition of this method relates to water will comprise that the microcrystalline cellulose of about 20-75% becomes piece with the mixture wet method of the Sertraline of corresponding about 80-25%.

The granose method of preferred preparation skeleton is the rotation granulation. Method for this reason places Sertraline and excipient such as microcrystalline cellulose the rotor drum of fluid bed processor. This medicine of fluidisation and excipient spray simultaneously in conjunction with this medicine and become particle or how granular solution with excipient. The solution that sprays into fluid bed can be the aqueous solution or suspension such as polyvinylpyrrolidone or the hydroxypropyl methylcellulose of water or adhesive. The preferred composition of this method can comprise the 10-80% Sertraline, 10-60% microcrystalline cellulose, and 0-25% adhesive.

The method that further preferably prepares the many granules of skeleton comprises coated Sertraline, if matrix type excipient and the release modification that needs or solubilising excipient are examined such as the sugar kind that is called non-pareils to kind of nuclear. The known many methods of available pharmaceuticals industry are carried out this and are coated with, and are coated such as the spraying in the coated device of fluid bed, spray-drying, and granulation such as fluid bed or rotation granulation. Can be from water-based, be coated with in organic or melting solution or the suspended emulsion.

Further the granose method of preferred preparation skeleton is the preparation of Wax particles. In this method, with Sertraline and the liquid wax stirring formation homogeneous mixture of aequum, cooling was also then extruded to net and was formed particle. Preferred framework material is the wax material. Particularly preferably be castor oil and Brazil wax and the stearyl alcohol of hydrogenation.

Further the granose method of preferred preparation skeleton comprises with an organic solvent mixing with auxiliary Sertraline and framework material. This technology can be used when the need utilization has unaccommodated dystectic framework material, if use this material with molten state this moment, will cause the degraded of this medicine or framework material, or cause unacceptable melting viscosity, thereby hinder mixing of Sertraline and framework material. Sertraline and framework material can be stuck with paste to form in conjunction with the solvent of moderate, and press net to form particle, then therefrom desolventizing. Perhaps, Sertraline and framework material can be in conjunction with the solvent of q.s with this framework materials of thorough dissolving, and solution (containing the solid-state drug particle) the spray form of gained is become the particle formulation. This technological selection uses when this framework material is the synthetic polymer of HMW such as cellulose ether or ester. The solvent that typically is used for this method comprises acetone, ethanol, isopropyl alcohol, ethyl acetate and two or more mixture wherein.

The granose further method of preparation skeleton comprises the aqueous solution or the suspension that uses Sertraline and form framework material. The sprayable drying of this solution or suspension or spray or drip quench bath or by the light chamber to start the crosslinked of framework material and to solidify droplet. In this method, skeleton can be prepared by latex (as with plasticizer such as oleic acid or the ethyl cellulose that disperses with volatile water-soluble mixed solvent such as acetone or alcohol) by spray drying technology. Skeleton also can prepare by cross-linked, water-soluble polymer or glue by this method. For example, sodium alginate can contain in the solution of soluble calcium salt and crosslinked by spirt, and polyvinyl alcohol then can be by spraying in the solution that contains glutaraldehyde and crosslinked, and two and three-acrylate can be by the UV radiation and crosslinked.

In case form, the many particles of Sertraline skeleton can with can press excipient such as lactose, microcrystalline cellulose, the mixing such as Dicalcium Phosphate are suppressed this mixture and are become tablet. Disintegrant such as primojel or crosslinked PVP also can use valuably. Tablet disintegration when placing aqueous medium (such as the GI road) that this legal system is standby, thus many grain skeletons exposed, therefrom discharge Sertraline. The many particles of Sertraline skeleton also can be packed into capsule such as hard gelatin capsule.

The further embodiment of shell system has the hydrophily matrix tablet, and it finally dissolves or be dispersed in and contains the hydrophilic polymer that Sertraline and being enough to provides the amount that the control Sertraline with degree discharges. Sertraline can be by this skeleton diffusion, the combination of corrosion or dissolving or these mechanism and from this skeleton, discharging. The hydrophilic polymer that is used to form the hydrophily skeleton comprises HPMC, HPC, hydroxyethylcellulose (HEC), PEO, PVA, xanthans, carbomer, carrageenan and animal glue. Preferred material is HPMC. Also can use other similar hydrophilic polymer. In the use, this hydrophilic material is by water-soluble swollen and finally dissolve or be dispersed in water. The speed that discharges Sertraline from the agent of hydrophily skeleton can be controlled by amount and the molecular weight of the hydrophilic polymer that uses. Usually, use relatively large hydrophilic polymer can reduce rate of release, as the polymer that uses higher molecular weight. Use the polymer rising rate of release of lower molecular weight. This rate of release also can be by using water-soluble additives such as sugar, salt or soluble polymer and control. The example of these additives is sugared such as lactose, sucrose or mannitol, salt such as NaCl, KCl, NaHCO₃With water-soluble polymer such as PVP, low-molecular-weight HPC or HMPC or methylcellulose. Usually, increase the mark of the soluble material in the said preparation, then increase rate of release.

In addition, the sour excipient of any aforesaid solubilising can add in the matrix tablet to improve the rate of release of Sertraline, increase the total amount of the Sertraline that discharges, and effectively increase absorption and subsequently the bioavilability of Sertraline, especially within 6 hours or longer time, discharging the skeleton preparation of Sertraline. The hydrophily matrix tablet generally comprises the Sertraline of about 10-90% weight and the polymer of about 80-10% weight.

Preferred hydrophily matrix tablet comprises the Sertraline of about 30-80% weight, about 5%-35% HPMC, about 35% lactose of 0%-, the about 15%PVP of 0%-, about 20% microcrystalline cellulose of 0%-, and the dolomol of about 0.25-about 2%.

The mixture of polymer and/or glue also can be used for preparing the hydrophily shell system. For example, the homopolymerization polysaccharide gum such as the galactomannans (such as locust bean gum or guar gum) that mix with assorted poly-polysaccharide gum (such as the xanthans or derivatives thereof) can provide synergy, in use this synergy provides faster formation and harder skeleton to be used for release bioactive agent (such as US patent 5,455,046 and 5, disclosed in 512,297). Randomly, can add crosslinking agent such as calcium salt to improve skeleton property.

Final dissolving or the hydrophily skeleton preparation that disperses also can many particle form preparations. The many particles of hydrophily skeleton can be by the previously described relevant non-granose technology preparation of skeleton of losing. Preferred method for making is, by spraying coating method with Sertraline, the hydrophily framework material, if and need, discharge the dressing agent coating and arrive the upper or many particles of formation that pass through to granulate of sugar kind nuclear (such as non-pareils), as at Sertraline, if hydrophily framework material and needing, the rotation that discharges in the dressing agent is granulated.

Such shell system shows the non-constant release of medicine from skeleton usually. This possibility of result is derived from the flooding mechanism that medicine discharges, and to the adjusting of the geometry of this formulation and/or dressing or this formulation of part dressing can be used for advantageously making this medicine rate of release such as following as more constant.

In further embodiment, with the coated Sertraline matrix tablet of impervious dressing, and provide the hole that therefrom content of tablet is exposed to water-based GI road (such as circle hole and vertical openings). These embodiments are can magazine 77 (1988) 322-324 described at materia medica based on the U.S.4792448 of the Ranade that is incorporated herein by reference and Hansson etc. The size that this opening is general be so that the area of the lower floor's sertraline compositions that exposes account for this device surface area less than about 40%, preferably be lower than about 15%.

In another embodiment, with impermeable material in the part on its surface such as one or two tablet surface, or the coated Sertraline matrix tablet of the radial surface of tablet.

In another embodiment, produce the medicament transport opening with the coated Sertraline matrix tablet of impermeable material with through this dressing boring. This dressing can be only passed in this hole, or extends to the passage that enters this tablet.

In another embodiment, produce the medicament transport passage with the coated Sertraline matrix tablet of impermeable material and by the passage that passes whole tablet brill.

In another embodiment, with the coated Sertraline matrix tablet of impermeable material, by from impermeable dressing, removing one or more bands or downcutting one or more slits by passing this dressing, preferably produce one or more medicament transport passages in radial surface or the bonding land of this sheet.

In another embodiment, the Sertraline matrix tablet is made taper also with the complete dressing of impermeability material. Produce the medicament transport passage by the top of downcutting this cone.

In another embodiment, the Sertraline matrix tablet is made hemisphere also with the complete dressing of impermeability material. Produce the medicament transport passage by the centre-drilling hole on this hemispheroidal plane.

In another embodiment, the Sertraline matrix tablet is made semicylinder also with the complete dressing of impermeability material. Passing thoroughly along the semicolumn axon of the center line on the plane of this semicylinder, dressing downcuts the passage that a slit (or removing a band) produces medicament transport.

Persons skilled in the art will recognize that the modification to the geometry of above-mentioned embodiment can be by considerably producing more than a method. For example, can realize by other operation as the technology by the required part dressing of direct generation the cutting or boring of passage of preparation medicament transport.

" impermeability material " thus refer to have enough thickness and to the impenetrability of Sertraline within the time period (being several hours to about one day) that predetermined medicine discharges so that most of Sertraline passes through this passage the material of " impermeability material " release. This dressing can be by selecting to have to the coating material of enough low diffusion coefficients of Sertraline and being coated onto enough thick obtaining. The material that forms the impermeability dressing of these embodiments comprises that wherein the diffusion coefficient of Sertraline is lower than about 10^-7cm ²Any material of/s. Noticing that aforementioned diffusion coefficient can be amplified to is enough to allow Sertraline discharge from frame device, as above-mentioned. Yet as for the device of the type of the opening that is provided with macroscopic view of discussing now or passage, the material with this diffusion coefficient can effectively can not be saturating to Sertraline with respect to the Sertraline transportation of passing this passage. Preferred coating material comprises film forming polymer and wax. Particularly preferably be thermoplastic polymer, such as poly-(ethylene-co-vinyl acetate), poly-(vinyl chloride), ethyl cellulose and cellulose acetate ester. These materials present required low Sertraline permeability when being painted with the coating of the thickness that surpasses about 100 μ m.

Equations of The Second Kind Sertraline slow release formulation of the present invention comprises that film is regulated or storage storehouse system such as film-dressing-diffusion-Ji capsule, tablet, or many granules. Capsule, tablet and many granules can all be storage storehouse system, such as the diffusion-Ji's of film-dressing. In this type of, the storage storehouse of Sertraline is surrounded by the speed limit film. Sertraline is crossed over film by the known mass transportation mechanism in this area, includes but not limited to dissolve in film, spreads or pass through subsequently the diffusion in the hole of the liquid filling in film by wearing film. These single storage storehouse system formulations can be large as containing the tablet in single large storage storehouse, or many granules are as containing the capsule of a plurality of storages storehouse particle, and each is coated with film respectively. This dressing can be non-porous, but to Sertraline can be saturating (for example Sertraline can directly spread by film), or it can be porous.

Can use sustained release coating known in the art to prepare this film, polymer coating especially, such as cellulose esters or ether, acrylate copolymer, or the mixture of polymer. Preferred material comprises ethyl cellulose, cellulose acetate ester and cellulose acetate-butyrate ester. This polymer can be used as solution or aqueous liquid dispersion or the latex in the organic solvent. This dressing operation can such as the fluidized bed coating device, be carried out in the standard device of Wurster dressing device or revolving bed dressing device.

If need, the permeability of this dressing can be regulated by mixing two or more materials. The porous method that is particularly useful of nursing one's health this dressing comprises that the water-soluble material of the segmentation that adds scheduled volume such as sugar or salt or water-soluble polymer are to solution or the dispersion (such as water-based latex) of stand-by film forming polymer. When this formulation was ingested the aqueous medium in GI road, these water-solubility membrane additives spilt this film, stayed to be convenient to the hole that medicine discharges. This film dressing also can be modified by adding plasticizer, as known in the art.

Thereby the useful especially variation that is used for the method for film dressing comprises this dressing polymer of dissolving in the mixture of selected solvent so that when dressing is dry, in used coating solution inversion of phases occurs, and causes having the film of loose structure. Many embodiment of the coat system of this type see the European patent specification 0357369B1 that is disclosed in March 7 nineteen ninety that is incorporated herein by reference.

The form of this film is particular importance not, has permeability characteristics cited herein as long as satisfy. Yet concrete film design has the restriction of film form in order to reach required saturating property. This film can be unbodied or crystalline state. It can have the form of any type that is produced by any concrete method, and can be, for example, interfacial polymerization film (comprising the thin speed limit top layer on the porous holder), porous hydrophilic film, porous hydrophobic membrane, aquagel membrane, ionic membrane, and other this class film that is characterized as the saturating property of the control of Sertraline designs.

Useful storage storehouse system implementation plan is to have the capsule that contains the speed limit membrane material, comprises the shell of aforesaid membrane material, and fills the Sertraline pharmaceutical composition. The concrete advantage of this form is that this capsule can be independent of the pharmaceutical composition preparation, therefore, and can be with medicine there being the process conditions of adverse effect prepare capsule. Preferred embodiment is the capsule with the made shell of the made porous of heat forming technology or transmissibility polymer. Particularly preferred embodiment is the capsule shells that is the asymmetric membrane form; The film that namely has thin density region and its most of thickness to be consisted of by the saturating property of height porous material in one side. The preferred method for preparing the asymmetric membrane capsule comprises the exchange of solvent inversion of phases, and the polymer solution that wherein wraps on the capsule finishing die is induced and is separated by exchange this solvent with miscible non-solvent. The example that is used for asymmetric membrane of the present invention is disclosed in aforesaid EP specification 0357369B1.

Tablet also can be storage storehouse system. The sheet that contains Sertraline is endorsed by the various standard techniques in the pharmaceuticals industry and is prepared. These endorse the dressing with aforesaid speed limit dressing, and the Sertraline in its permission storage storehouse (sheet nuclear) passes dressing with required speed and spreads.

Embodiment of another storage storehouse system comprises many granules, wherein each particle with the polymer coating that designs to obtain the slowly-releasing of Sertraline. The particle of each many granule contains Sertraline and one or more preparation and the required excipient of performance. The size of aforesaid each particle is generally between about 50 μ m and 3mm, although the also available bead that surpasses this scope. Generally, this bead comprises Sertraline and one or more adhesives. Owing to usually need to produce little and easy-to-swallow formulation, the pellet that contains with respect to the more manifold Sertraline of excipient is preferred. Adhesive for the preparation of these beads comprises that microcrystalline cellulose is (such as Avicel^, FMC Corp.), HPC, the material that HPMC is relevant with it or combination. Usually, be used for the adhesive of granulation and film-making, such as starch, pregelatinised starch, and PVP also can be used for forming many particles.

The many granules of technology preparation storage storehouse system's Sertraline that available this area is known include but not limited to, extrude and the spheronizing method wet granulation, fluidized bed granulation and revolving bed granulation technique. In addition, also can by utilize medicine coating technique such as powder dressing with sertraline compositions (medicine adds excipient) be building up to kind nuclear (such as the non-pareil kind) or by will the Sertraline solution in the suitable binder solution or dispersion liquid be sprayed onto kind of a nuclear (at fluid bed such as Wurster dressing device or rotate in the working apparatus) and prepare this bead. Suitable composition and the example of method are the spraying Sertraline/dispersion liquid of hydroxy propyl cellulose promotor composition in water. Valuably, Sertraline can surpass its in water solubility limit and in the waterborne compositions of packing into.

The method of the many granular core of preferred preparation of this embodiment is that aforementioned relevant skeleton is granose extrudes/the spheronizing method. The preferred technique of this method and composition comprise that the mixture wet method of the Sertraline of microcrystalline cellulose that water will about 5-75% and corresponding about 95-25% becomes piece. Especially preferred is with the microcrystalline cellulose of about 5-30 % and the Sertraline of corresponding about 95-70%.

The method of many granular core of preferred this embodiment of preparation is the rotation granulation, as described in the many particles of the relevant skeleton of preamble.

The granose method of preferred this embodiment of preparation is the method with Sertraline and optional other excipient pelleted seed nuclear, granose such as the relevant skeleton of preamble as described in.

The sustained release coating that available this area is known, especially polymer coating prepare this film, as described in the system of the relevant storage of preamble storehouse. Suitable and preferred polymer coating material, equipment and coating method also comprise aforesaid those.

The rate of release of Sertraline from many granules of dressing also can be passed through such as the composition of pastille nuclear and the content of adhesive, the thickness of dressing and saturating property, and granose surface area is to the recently control of volume. Those skilled in the art should know that the thickness that increases dressing can reduce rate of release, can increase rate of release and increase the saturating property of dressing or granose surface area to the ratio of volume. If need the saturating property that to regulate this dressing by mixing two or more materials. Useful dressing series comprises the mixture of the polymer of the insoluble and water soluble of water, respectively for example ethyl cellulose and hydroxypropyl methylcellulose. Useful especially modification to this dressing is water-soluble material such as sugar and the salt that adds segmentation. When placing aqueous medium, these water-solubility membrane additives spill this film, stay to be convenient to the hole that medicine discharges. The film dressing also can be modified by adding the known plasticizer in this area. Thereby a useful especially film dressing modification is utilized selected solvent mixture so that when dressing is dry, in used coating solution inversion of phases occurs, and causes having the film of loose structure.

Preferred embodiment is with comprising one or more following materials of about 50-95% Sertraline and 5-50%: microcrystalline cellulose, PVP, many particles of HPC and HPMC. Each nuclear perhaps contains PEG with the dry aqueous liquid dispersion that forms the ethyl cellulose of continuous film, and sorbierite or glycerine are coated as the cellulose acetate membrane of release regulator.

The 3rd class Sertraline slow release formulation comprises infiltration releasing device or " osmotic pumps " that this area is known. Osmotic pumps comprises the nuclear that contains the infiltration compositions useful that is surrounded with pellicle. Term among the present invention " semi-transparent " refers to that water can see through this film, but solute soluble in water sees through film with the speed more much lower than water. In the use, when placing aqueous environment, this device is owing to the osmotically active of nucleus absorbs water. Because the semi permeability around film, the content (comprising medicine and any excipient) of device can not see through the non-porous district of this film and leave this device by the osmotic pressure driving by opening or passage, this opening or passage are to be formed in advance in the formulation, perhaps, because the breaking of weak spot of under the impact of osmotic pressure, mixing in advance in the dressing and forming at GI road situ, perhaps by dissolving with to remove the water-soluble hole of mixing in the dressing former and form at GI road situ. Permeate effective composition and comprise the water-soluble substances that produces colloid osmotic pressure, and water-swellable polymer. Medicine itself (if highly-water-soluble) can be the infiltration active ingredient of this mixture. Sertraline acetate and lactate have respectively 65 and the solubility of 125mg/ml, and 2-4 atmospheric osmotic pressure can be provided, and are enough to produce some osmotic drive power. Because Sertraline is alkali, its solubility is generally higher when acid pH. Therefore, the infiltration validity of Sertraline can be assisted because there being acidic buffer in the preparation. Pharmaceutical composition can be by movably distribution or piston separate from infiltration active ingredient.

The material that is used to form pellicle comprises polyamide, polyester, and cellulose derivative. Preferably cellulose ether and ester. Particularly preferably be cellulose acetate, cellulose acetate-butyrate, and ethyl cellulose. Useful especially material is included in the preparation process or the material of the one or more exit passageways of spontaneous formation when placing environment for use. These preferred materials comprise porous polymer, its hole by as preparation process hereinafter in phase transformation or the water soluble ingredient that is present in the film by dissolving form.

One class has the material of special purposes in being formed for permeating the pellicle of releasing device be porous hydrophobic polymer or the saturating film of steam, see the pending trial U.S. application serial no 08/096,144 of the common transfer of the submission in 22 days July in 1993 that is incorporated herein by reference. These materials are water permeabilities of height, but are highly impervious to water-soluble solute. The saturating property of the height water of these materials is owing to there are many microcosmic holes (i.e. the hole more much bigger than molecule size). Although porous, these materials are impervious because of not moistening this hole of aqueous water and to the molecule in the aqueous solution. The water of gas phase easily passes the film that these materials are made. This film is also referred to as the thoroughly film of steam.

The preferred embodiment of this type of infiltration releasing device is made of the double-layer tablet of dressing. The dressing of this sheet comprises water penetration but wherein contains basically the thoroughly film of Sertraline and excipient. This dressing contains and contains one or more exit passageways that the Sertraline layer links and be used for release of pharmaceutical compositions. Sheet nuclear is made of two-layer: one deck contains sertraline compositions (comprising optional bleeding agent and hydrophilic water insoluble polymer may) and another layer is made of the water swellable gel, contains or do not contain other bleeding agent. This type of releasing device is schematically illustrated among the embodiment 20.

When placing aqueous medium, the suction of tablet permeable membrane causes that sertraline compositions forms dispersible waterborne compositions and causes hydrogel layer to expand and the promotion sertraline compositions, impels sertraline compositions to emit exit passageway. This sertraline compositions swellable and the complementary Sertraline that impels is emitted exit passageway. Sertraline also can be from this type of dissolving or is dispersed in the delivery system the composition that flows out exit passageway and discharges.

The rate of release of Sertraline can by as saturating property and the thickness of dressing, contain the osmotic pressure of Sertraline layer, the water activity of hydrogel layer and the surface area of this device and control. Person of skill in the art will appreciate that the thickness that increases dressing can reduce rate of release, and the water of the saturating property of rising dressing or hydrogel is active or the osmotic pressure that contains the Sertraline layer maybe the surface area of this device can improve rate of release.

Be used to form the exemplary materials of sertraline compositions, except Sertraline itself, comprise HPMC, PEO and PVP and other pharmaceutical carrier. In addition, can add bleeding agent such as sugar or salt, particularly sucrose, mannitol or NaCl. The material that is used to form hydrogel layer comprises sodium carboxymethylcellulose, poly-(oxirane), poly-(acrylic acid), (polyacrylic acid) sodium and other HMW water wetted material. In addition, can add bleeding agent such as sugar or salt. Especially advantageously poly-(oxirane) of the about 5000000-7500000 of molecular weight.

The material that is used to form this dressing is cellulose esters, cellulose ether, and cellulose esters-ether. Preferably cellulose acetate and ethyl cellulose and randomly with as the infiltration ornamental equivalent PEG.

Exit passageway must be positioned at the next door of the tablet that contains sertraline compositions. This exit passageway more than one can be arranged. This exit passageway can be mechanically or laser drill, or produce at tablet with special tool(s) in the compressing tablet process and be difficult to dressing district or alternate manner and produce exit passageway. But Sertraline from the rate of release optimization of this device with provide reach optimum therapeuticing effect mammal is discharged the method for Sertraline.

Osmosis system also can be prepared by the homogeneous phase nuclear that the pellicle dressing centers on. Shown in embodiment 16,17 and 18, Sertraline can be introduced in the sheet nuclear of other excipient of also containing the osmotic drive power that provides enough and optional solubilising excipient such as acid or surfactant type compound. The pellicle dressing can be by conventional coating tablets technology as carrying out with disc type dressing device (pan coater). Then, can in dressing, hole and formation medicine release channel in this dressing by laser or other mechanical means. Perhaps, this passage can be by splitting a part of dressing or as above-mentionedly produce the zone be difficult to dressing at sheet and form.

The embodiment of Sertraline sustained release osmotic dosage form in accord of the present invention comprises the infiltrative tablet that contains Sertraline, and it is coated with by asymmetric membrane, and wherein this asymmetric membrane is overseas except low closely knit porous region, has one or more thin compact zones. This type film is similar to for those of reverse osmosis industry, the general higher water permeation flux that obtains than with closely knit film of allowing. When being applied to pharmaceutical dosage form such as tablet, asymmetric membrane allows the medicament slow release of high drug flux and good control. This asymmetric membrane comprises the semipermeable polymers material, i.e. water penetration and to salt and organic solute such as the not saturating material of medicine (such as Sertraline).

The material that is used to form pellicle comprises polyamide, polyester and cellulose derivative. Preferably cellulose ether and ester. Particularly preferably be cellulose acetate, cellulose acetate-butyrate, and ethyl cellulose. Useful especially material is included in the preparation process or the material of the one or more exit passageways of spontaneous formation when placing environment for use. These preferred materials comprise porous polymer, and this hole is by forming such as phase transformation in the preparation process hereinafter or by the water soluble ingredient that exists in the dissolving film.

Asymmetric membrane forms by phase inversion method. This dressing polymer such as ethyl cellulose or cellulose acetate are dissolved in the solvent system of mixing of the mixture of the solvent (such as acetone) that contains ethyl cellulose or cellulose acetate and non-solvent (such as water). Select the composition of solvent of this mixing so that solvent (such as acetone) is more volatile than non-solvent (such as water). When tablet immerses this solution, shifts out and during dry this tablet, the solvent composition of this solvent mixture is faster than the volatilization of non-solvent composition. The variation of this solvent composition produces phase transformation in the dry run, causes polymer to be deposited on this tablet as the porosu solid with thin closely knit outside area. This outside area has a plurality of holes that discharge by its generation medicine.

In the preferred embodiment of the coated tablet of asymmetric film, this polymer/solvent/non-solvent mixture is sprayed on the tablet bed (on the tablet coating device as in the Freund HCT-60 tablet coating device). In this method, with thick this tablet of porous region dressing, and with outermost thin compact zone.

In environment for use such as GI road, water sees through the semi permeability asymmetric membrane and sucks this sheet nuclear. Because the soluble material in the sheet nuclear dissolves, and has set up the osmotic pressure gradient of cross-film. When the hydraulic pressure in the film of coated nuclear surpassed the pressure of environment for use (such as the GI chamber), the solution that contains Sertraline " was taken out " by the hole that forms in the pellicle and is gone out this formulation. The constant permeable pressure head of cross-film causes stable good control ground to discharge Sertraline in environment for use. The Sertraline that a part is dissolved in this tablet is also discharged by diffusion. The several exemplary preparation of this type device is shown in embodiment 16,17, in 18 and 19.

In the coated Sertraline tablet embodiment of this asymmetric film, sertraline salts is because its water solubility and preferred. Especially preferred salt hydrochlorate, aspartate, acetate and lactate. Wherein, most preferably acetate and lactate. Further preferably contain one or more solubilising excipient, ascorbic acid, arabo-ascorbic acid, citric acid, glutamic acid, aspartic acid, partial glyceride, glyceride, glyceride ester derivatives, macrogol ester, the polypropylene glycol ester, polyol ester, APEO, sorbitan ester, polyoxyethylene sorbitan ester, sugar ester, phosphatide, Pluronic F108, and polyethylene glycol. Solubilising excipient ascorbic acid most preferably, aspartic acid, Capmul MCM C8, glycerin monostearate, glyceryl monolaurate and C₈-C ₁₀Partial glyceride.

Osmotic tablets also prepares with the bleeding agent of the second semi-transparent dressing encirclement and/or the core sheet of solubilising excipient with medicated layer available containing at first again. This core sheet that contains bleeding agent and/or solubilising excipient can be standby by the known standard preparation legal system of pharmaceuticals industry. Medicated layer can be applied to around this nuclear by spraying-coating method, wherein drug solution or pulp bales is examined to sheet. This medicine and excipient also can be by utilizing the sheet press to form as 19 described circumnuclear the second medicated layer preparation " layering " type configurations of embodiment are laminated to around sheet examines. Can powder coating (solvent-free) be administered to around the sheet nuclear with this compression coating method. Then, the many methods known by this area are applied to semi-transparent dressing on the layering nuclear, as the aforementioned spray coating or immersion coating method.

Another embodiment of slowly-releasing Sertraline osmotic dosage form of the present invention is made of the many particles of the Sertraline that is coated with asymmetric membrane. The many particles that contain Sertraline are by for example extruding/spheronizing method or fluidized bed prilling method, or as aforementioned mixture with Sertraline and water-soluble polymer be coated with the non-pareil kind and prepare. Then, with the coated many particles of Sertraline that contain of the solution spray of polymer in the mixture of solvent and non-solvent as the aforementioned to form many particles of asymmetric membrane dressing. This spray coating operation is preferably carried out in fluidized bed coating device such as Glatt GPCG-5 fluidized bed coating device. The polymer that is used to form the semi permeability asymmetric membrane is as described in the above-mentioned relevant asymmetric membrane coating tablet and select. Similarly, the excipient of the similar many granular core of described selection of relevant asymmetric membrane coating tablet as mentioned.

With permeating capsule with above-mentioned relevant osmotic tablets and the same or similar composition preparation of many Particle Phases. Capsule shells or its part can be semi permeability and are prepared by above-mentioned material. Then, this capsule can be packed into by Sertraline, and the excipient of penetrating power is provided, and powder or the liquid of optional solubilising excipient composition. Also can prepare this capsule core makes it have bilayer or the multilayer composition that is similar to above-mentioned double-layer tablet.

The 4th class Sertraline slow release formulation of the present invention comprises the U.S. series number 07/296 of the common transfer that is described in the common pending trial that is incorporated herein by reference, swellable sheet and many granules of the dressing of 464 (on January 12nd, 1989 submitted to, published July 7 nineteen ninety to be EP 378404A2). The swellable sheet of dressing comprises and contains Sertraline and swollen material, is preferably the sheet nuclear of hydrophilic polymer, is coated with the film that contains hole or hole, and in the water-based environment for use, this hydrophilic polymer can be by extruding or emit Sertraline in this hole or the hole. Perhaps, it is former that this film can contain low-molecular weight water-soluble hole polymerization or that be dissolved in the water-based environment for use, as long as can extrude hydrophilic polymer and Sertraline by the hole. The former example in hole is water-soluble polymer such as hydroxypropyl methylcellulose, and low molecular weight compound such as glycerine, sucrose, glucose and NaCl. In addition, can be by in dressing, forming the hole with laser or other mechanical means in dressing boring. In the 4th class Sertraline slow release formulation, membrane material can comprise any film forming polymer, comprises water penetration or fluid-tight polymer, if be deposited on film on the sheet nuclear be porous or contain the former or macroscopic pores in water-soluble hole and be used for water and enter and the Sertraline slowly-releasing. The available Sertraline that is coated with porous or contains the former film in hole/swollen material nuclear prepares many particles (or bead) similarly. The embodiment of this 4th class Sertraline slow release formulation can be multilayer, as described in EP 378404A2.

Also can prepare the wherein quick initial release of sub-fraction dosage, subsequently the slow release formulation of the residual most of dosage of slowly-releasing. The Sertraline release characteristics that merges in this situation is in the scope of slow release formulation of the present invention, being Sertraline discharges with the speed that is lower than 40mgA/ hour, be no more than 70% contained Sertraline as long as in first hour that swallows or test after initial, discharge, and (2) discharge Sertraline with 1mgA/ hour at least speed.

When preparation during Sertraline, use highly dissoluble salt, otherwise increase the formulation of Sertraline solubility, or both merge to be referred to as " high-dissolvability type " be useful. Hereinafter will from the viewpoint discussion of preparation use high-dissolvability type Sertraline reason and due to advantage. Perhaps because used salt type or because used concrete excipient in this formulation, the high-dissolvability type should realize at least Sertraline solubility of 10mgA/ml.

Help the sertraline salts of solubilising Sertraline or can be of value to the slow release formulation of nearly all type with the excipient of Sertraline coupling. The Sertraline of solubilising can increase by the concentration gradient based on the system that spreads of increase such as skeleton formulation and storage storehouse formulation the release from this formulation. The Sertraline of dissolving also increases the release of osmotic dosage form, because more soluble Sertraline can increase the osmotic pressure in the nuclear and increase Sertraline concentration in the fluid of extracting or extrude this formulation out. In addition, the Sertraline of solubilising can absorb from GI by ancillary drug and be conducive to slow release formulation. For example, the medicine of higher concentration can increase absorption owing to stride the higher concentration gradient of rectal wall in colon.

Dissolving is even more important to slowly-releasing Sertraline formulation, because Sertraline is tending towards forming gel in many aqueous solution, is included in the solution such as the intestinal fluid of chloride ion-containing. The Sertraline gel can form by only chlorion being introduced in Sertraline acetate or the Sertraline lactate. Gel also can form by introduce sour combination such as tartaric acid or acid and surfactant such as butanedioic acid and lauryl sodium sulfate in Sertraline solution similarly. Yet other acid and/or surfactant compounds can provide solubilization, minimize gel-forming and be provided at the aqueous solution that contains chlorion such as intestinal fluid in discharge the preparation basis of Sertraline.

The gelling of Sertraline is amazing, and prevents that the ability of some additive of this gelling from being to make us surprised and unpredictable.

The gelling of Sertraline can be especially at the non-shell system that loses in slow release formulation, storage storehouse system, and destroyed in the osmosis system. In each of the slow release formulation of these types, the release of medicine depends on the distance that medicine passes in the device (skeleton or coatings) and is transported in the environmental liquids. This medicament transport can occur by diffusion or to stream mechanism. In these two kinds of mechanism, the formation of gel can transportation reduce several orders of magnitude or more, and can cause in many cases showing the device that incomplete medicine discharges (as be less than total medicine in the preparation 70%).

Therefore, it is favourable using the method for Sertraline in the solubilising slow release formulation. A kind of method of solubilising Sertraline is that preparation has the sertraline salts than highly dissoluble, such as the Sertraline lactate, and Sertraline acetate, and Sertraline aspartate. Preferred salt in water, show above Sertraline HCl salt more than 3 times solubility, and the latter's solubility is about 3mgA/ml.

The method of another kind of solubilising Sertraline is to use this paper to be referred to as the reagent of " solubilizer ", and its actual functional capability is the Sertraline solubility in the identical environment for use when not having solubilizer and increase and preferably keep the solubility of Sertraline (or its salt) in environment for use.

The useful many solubilizer of this paper can be divided into seven large classes:

1. organic acid and acylate;

2. partial glyceride namely is lower than the glycerol derivatives of complete esterification, comprises monoglyceride and double glyceride.

3. glyceride;

4. glyceride ester derivatives;

5. macrogol ester;

6. polypropylene glycol ester;

7. polyol ester;

8. APEO;

9. Isosorbide Dinitrate; With

10. Sorbitan ethoxylate

11. carbonate.

The amount of the solubilizer that should use is based on concrete solubilizer.

If usefulness is organic acid solubilizer, preferred solubilising dosage is calculated as the amount that coefficient multiply by used Sertraline, wherein coefficient is organic acid solubility to the ratio of sertraline salts solubility: the amount of (organic acid or salt solubility/Sertraline or its salt solubility) * Sertraline, wherein said solubility represents with mg/ml. Above-mentioned expression formula is about, and some adjustment are conducive to optimization. Generally, above-mentioned expression formula can provide the amount of final consumption ± 25%, although the solubilizer of introducing higher amount is also without any special other advantage. In addition, can add acylate to regulate organic acid pH and/or its solubility, the effectively solubilization of this reagent of optimization.

As for the solubilizer of other listed type, usually, the amount of used solubilizer be the wherein 1-150% of used Sertraline weight, preferably 1-100%, more preferably 3-75% in the formulation. The available amount that surpasses 150% solubilizer is although it is believed that any special benefit can be provided as a rule.

Be used for organic acid example of the present invention and comprise malic acid, citric acid, arabo-ascorbic acid, adipic acid, glutamic acid, aspartic acid, maleic acid, aconitic acid and ascorbic acid. Preferred acid is citric acid, arabo-ascorbic acid, ascorbic acid, glutamic acid and aspartic acid. The mixture of acylate such as alkaline-earth metal (magnesium, calcium) salt and alkali metal salt (lithium, potassium, sodium) salt and organic acid and salt thereof also is effective. Calcium salt such as calcium carbonate, calcium acetate, Calcium Ascorbate, calcium citrate, calcium gluconate monohydrate, calcium lactobionate, Calcium gluceptate, calcium levulinate, calcium pantothenate, calcium propionate, calcium dihydrogen phosphate (calcium phosphate dibasic) and calcium saccharate are preferred acylates.

The case summary of the compound in above-mentioned other type is in table 1.

Table 1 solubilizer

Type	Example, chemical name	Example, trade name (source)
Type	Example, chemical name	Example, trade name (source)	Partial glyceride	Capmul MCM C8	Monocaprylin ^(Sigma)，Capmul ^ MCM(Abitec)，Imwitor ^308(Huls)
	C ₈-C ₁₀Partial glyceride	Capmul ^MCM(Abitec)，Imwitor ^742(Huls)， Imwitor ^988(Huls)	Partial glyceride	Capmul MCM C8
	C ₈-C ₁₀Partial glyceride			Glyceryl monooleate	Myverol ^18-99(Eastman)，Calgene ^ GMO(Calgene)，Capmul ^GMO(Abitec)
	Masine 35-1	Myverol ^18-92(Eastman)		Glyceryl monooleate
	Masine 35-1	Myverol ^18-92(Eastman)		Glycerin monostearate	Imwitor ^191(Huls)Calgene ^GSO(Calgene)
	Glyceryl monolaurate	Imwitor ^312(Huls)Calgene ^GLO(Calgene)		Glycerin monostearate	Imwitor ^191(Huls)Calgene ^GSO(Calgene)
	Glyceryl monolaurate	Imwitor ^312(Huls)Calgene ^GLO(Calgene)		GLYCERYL DILAURATE	Capmul ^GDL(Abitec)
				GLYCERYL DILAURATE	Capmul ^GDL(Abitec)
			Glyceride	Glyceryl triacetate	Triacetin(Sigma)
			Glyceride	Glyceryl triacetate	Triacetin(Sigma)
			Glyceride ester derivatives	The glyceride that PEG-derives	Cremophor ^RH40，Cremophor ^RH60(BASF)， Acconon ^CA5，CA-9，CA-15，W230，TGH(Abitec)
	The glyceride of poly-glycol	Gelucire ^44/14，42/12，50/13，53/10，35/10，48/09， 46/07，62/05，50/02；Labrasol ^(Gattefosse)； Capmul ^3GO；3GS，6G2O，6G2S，10G4O， 10G10O(Abitec)	Glyceride ester derivatives	The glyceride that PEG-derives
	The glyceride of poly-glycol
Macrogol ester	PEG 200 monolaurates, PEG 400 monolaurates, PEG 600 monolaurates,	Calgene ^20-L，Calgene ^40-L， Calgene ^60-L
Macrogol ester		Calgene ^20-L，Calgene ^40-L， Calgene ^60-L		PEG 200 monostearates, PEG 400 monostearates, PEG 600 monostearates	Calgene ^20-S，Calgene ^40-S， Calgene ^60-S
	PEG 200 dilaurates, PEG 400 dilaurates,	Calgene ^22-L，Calgene ^42-L Calgene ^62-L			Calgene ^20-S，Calgene ^40-S， Calgene ^60-S

PEG 600 dilaurates
PEG 600 dilaurates		The polypropylene glycol ester	Two sad propylene glycol esters	Captex ^200(Abitec)
		The polypropylene glycol ester	Two sad propylene glycol esters	Captex ^200(Abitec)
		Polyol ester	The mono laurate binaryglycol ester	Calgene ^DGL
The mono laurate propylene glycol ester	Calgene ^PGML	Polyol ester	The mono laurate binaryglycol ester	Calgene ^DGL
The mono laurate propylene glycol ester	Calgene ^PGML		Ascorbyl palmitate	Ascorbyl Palmitate(Sigma)
			Ascorbyl palmitate	Ascorbyl Palmitate(Sigma)
		APEO	The PEG lauryl ether	Nonionic L-4(Calgene)
The PEG stearyl ether	Nonionic S-20(Calgene)，Myrj45，52，53， 59(Sigma)	APEO	The PEG lauryl ether	Nonionic L-4(Calgene)
The PEG stearyl ether	Nonionic S-20(Calgene)，Myrj45，52，53， 59(Sigma)	Isosorbide Dinitrate	The mono laurate Isosorbide Dinitrate	Calgene ^SML，Span ^20(Sigma)
Single oleic acid Isosorbide Dinitrate	Calgene ^SMO，Span ^80(Sigma)	Isosorbide Dinitrate	The mono laurate Isosorbide Dinitrate	Calgene ^SML，Span ^20(Sigma)
Single oleic acid Isosorbide Dinitrate	Calgene ^SMO，Span ^80(Sigma)	Sorbitan ethoxylate	The POE-20 Arlacel-20	Calgene ^PSML-20，Span ^20(Sigma)， Tween ^20(Sigma)，Capmul ^POE-L(Abitec)
The POE-20 monoleate	Tween ^80，PSMO-20	Sorbitan ethoxylate	The POE-20 Arlacel-20
The POE-20 monoleate	Tween ^80，PSMO-20	Sucrose ester	Sucrose monolaurate	Ryoto LW-1540(Chem Service)
		Sucrose ester	Sucrose monolaurate	Ryoto LW-1540(Chem Service)
		Phosphatide	Lecithin	Lecithin(Sigma)
Mixed phosphatide	Emphos D 70-30C(Witco)	Phosphatide	Lecithin	Lecithin(Sigma)
Mixed phosphatide	Emphos D 70-30C(Witco)	Block copolymer	Pluronic F108	Pluronic ^F-68，F127，L-62(BASF)
		Block copolymer	Pluronic F108	Pluronic ^F-68，F127，L-62(BASF)
		Polyethylene glycol	PEG 3350	Various sources

In addition, other compound as solubilizer is ethyl propionate in the present invention, methylparoban, propylparaben, propyl propionate, niacinamide, Ethyl vanillin, p-aminobenzoic acid, fourth hydroxyanisol, imidurea, and glycerine. Notice also that preferred composition includes or without the organic acid of corresponding acylate and list above one or more or table 1 in the mixture of non-organic solubilized agent. Also it should be noted that usually and find: for the most effective, the solubility of this solubilizer in the moisture environment for use of chloride ion-containing is at least 1mg/ml, and is preferably greater than 5mg/ml.

Preferred solubilizer group except aforesaid preferred organic acid, comprises in the table 2 those.

The preferred solubilizer of table 2

Type	Example, chemical name	Example, trade name (source)
Type	Example, chemical name	Example, trade name (source)	Partial glyceride	Capmul MCM C8	Monocaprylin(sigma)，Capmul ^ MCM(Abitec)，Imwitor ^308(Huls)
	C ₈-C ₁₀Partial glyceride	Capmul ^MCM(Abitec)，Imwitor ^742(Hu ls)，Imwitor ^988(Huls)	Partial glyceride	Capmul MCM C8
	C ₈-C ₁₀Partial glyceride			Glyceryl monooleate	Imwitor ^191(Huls)Calgene ^ GSO(Calgene)
	Masine 35-1	Imwitor ^312(Huls)Calgene ^ GLO(Calgene)		Glyceryl monooleate	Imwitor ^191(Huls)Calgene ^ GSO(Calgene)
	Masine 35-1	Imwitor ^312(Huls)Calgene ^ GLO(Calgene)
Glyceride	Glyceryl triacetate	Triacetin(Sigma)
Glyceride	Glyceryl triacetate	Triacetin(Sigma)
Isosorbide Dinitrate	The mono laurate Isosorbide Dinitrate	Calgene ^SML，Span ^20(Sigma)
Isosorbide Dinitrate	The mono laurate Isosorbide Dinitrate	Calgene ^SML，Span ^20(Sigma)		Single oleic acid Isosorbide Dinitrate	Calgene ^SMO，Span ^80(Sigma)
				Single oleic acid Isosorbide Dinitrate	Calgene ^SMO，Span ^80(Sigma)
			Phosphatide	Lecithin	Lecithin(Sigma)
	Mixed phosphatide	Emphos D70-30C(Witco)	Phosphatide	Lecithin	Lecithin(Sigma)
	Mixed phosphatide	Emphos D70-30C(Witco)
Block copolymer	Pluronic F108	Pluronic ^F-68，F127，L-62(BASF)
Block copolymer	Pluronic F108	Pluronic ^F-68，F127，L-62(BASF)
Polyethylene glycol	PEG 3350	Various sources

Annotate: above-mentioned merchandise resources is as follows:

Abitec Corp.Janesville，WI

BASF，Parsippany，NJ

Calgene Chemical Inc.Skokie，IL

Chem Servce，Inc.，West Chester，PA

Huls America，Piscataway，NJ

Sigma，St.Louis，MO

Witco，Houston，TX。

Preferred solubilizer combination comprises: (1) organic acid adds identical or different organic acid salt, (2) organic acid add nonionic solubilizer as list at table 1 those in any, and (3) organic acid adds identical or different organic acid salt and adds nonionic solubilizer.

Particularly preferred single solubilizer comprises aspartic acid, Capmul MCM C8, mono laurate monoglyceride, calcium acetate, ascorbic acid, citric acid, glutamic acid and calcium carbonate. Most preferably aspartic acid, Capmul MCM C8 and calcium acetate.

The combination of the surfactant compounds of further preferably preferred acid and preferred solubilising. Carry out among the filler test of the candidate's that the sertraline salts of test and low solubility such as sertraline salts hydrochlorate share solubilizer such as the embodiment.

The embodiment of preferred slow release formulation is the osmosis system that comprises a nuclear, this nuclear contains Sertraline lactate or Sertraline acetate or Sertraline aspartate, acid is such as ascorbic acid, arabo-ascorbic acid, citric acid, glutamic acid or aspartic acid, and the soluble sugar as bleeding agent when needed, adhesive material such as microcrystalline cellulose, the hydrophilic polymer of swellable, and lubricant such as dolomol. Preferred embodiment comprises Sertraline lactate or Sertraline acetate.

The embodiment of another preferred slow release formulation is the osmosis system that comprises a nuclear, this nuclear contains Sertraline lactate or Sertraline acetate, acid is such as ascorbic acid, arabo-ascorbic acid, citric acid, glutamic acid or aspartic acid, surfactant-based material such as partial glyceride, glyceride, Isosorbide Dinitrate, phosphatide, Pluronic F108, and polyethylene glycol, if and need, increase the soluble sugar of osmotic pressure in the nuclear, the hydrophilic polymer of swellable, adhesive material such as microcrystalline cellulose and lubricant such as dolomol.

The embodiment of another preferred slow release formulation is the osmosis system that comprises a nuclear, this nuclear contains Sertraline lactate or Sertraline acetate, surfactant-based material such as partial glyceride, glyceride, Isosorbide Dinitrate, phosphatide, Pluronic F108, and polyethylene glycol, increase the soluble sugar of osmotic pressure in the nuclear, if and need the hydrophilic polymer of swellable, adhesive material such as microcrystalline cellulose and lubricant such as dolomol.

The embodiment of preferred slow release formulation is arbitrary in osmosis system such as aforementioned three osmosis systems, and further uses the asymmetric membrane dressing by the phase inversion method preparation to be coated with. For being used for these film systems, particularly preferably be the Sertraline lactate, the same with partial glyceride with aspartic acid as ascorbic acid.

Postpone to add slowly-releasing

Since another object of the present invention be reduce upper GI road to the high concentration Sertraline be exposed to alleviate some side effect (as feeling sick diarrhoea and gastric disorder causing nausea), the slowly-releasing that the formulation of another type is included in Sertraline begins those formulations that front introducing postpones. This formulation can be described to that the space postpones to add slowly-releasing Sertraline formulation or time delay adds slowly-releasing Sertraline formulation, as above-mentioned. In principle, comprise that any delayed release device of above-mentioned many embodiments can be coated with outside (normally all covering) dressing, it begins prerequisite for delayed release (namely being lower than 1mgA/ hour) at slowly-releasing. The type that provides time or space to postpone is provided this dressing.

The first embodiment can exemplify and be a kind of tablet, comprise contain Sertraline namely release nuclear, its dressing is useful on the first dressing of the polymeric material that the type of slowly-releasing Sertraline from this nuclear is provided and is used in case swallow the second dressing of type that formulation namely provides the delayed release of medicine. In case this tablet leaves stomach or after predetermined time this second dressing break and become transmissibility. First (interior) dressing be coated in and be enclosed in this tablet around. Second (appearance or outer) dressing is coated in and is enclosed in around the first dressing.

This tablet can also can contain the Sertraline for the treatment of effective dose with the known technology preparation in this area and add with the required excipient of this technology formation tablet. The second dressing is to postpone dressing, or time delay or space delay.

The first dressing can be sustained release coating known in the art, and especially polymer coating is with the film for preparing as aforementioned storage storehouse system uses. Suitable and preferred polymer coating material, equipment, and coating method also comprise aforesaid those.

Material for the preparation of second on the tablet (delay) dressing comprises the polymer that this area is known, the enteric coating of the delayed release that causes such as the pH of medicine. This dressing can not be saturating to Sertraline under the pH of stomach, but in the small intestine environment by dissolving, disintegration or otherwise break and become transmissibility, thus Sertraline can freely pass through this dressing. Relatively insoluble and can not be saturating under the pH under one's belt, but more solvable and pH sensitive polymer can be saturating comprises polyacrylamide under the pH of small intestine and colon, the acid phthalic acid ester of phthalic acid derivatives such as hydrocarbon, acetic acid phthalic acid starch ester, the Cellacefate ester, other phthalic acid cellulose esters, the cellulose ether phthalic acid ester, HPMCP, phthalic acid cellulose ester, phthalic acid HPMC ester, O-phthalic acid methyl cellulose ester, the phthalic acid polyvinyl acetate, the hydrogen phthalate polyvinyl acetate, cellulose acetate phthalate sodium, acid phthalic acid starch ester, styrene-maleic acid dibutyl phthalate copolymer, the Cellulose acetotrimellitate ester, styrene-maleic acid phthalic acid polyvinyl acetate copolymer, styrene and maleic acid, polyacrylic acid derivative such as acrylic acid and acrylate copolymer, polymethylacrylic acid and its ester, the polyacrylic acid methacrylic acid copolymer, shellac, and the copolymer of vinylacetate and crotonic acid.

Preferred pH sensitive polymer comprises shellac, and phthalic acid derivatives especially is the Cellacefate ester, phthalic acid polyvinyl acetate, and Hydroxypropyl Methylcellulose Phathalate ester; The Cellulose acetotrimellitate ester; Polyacrylic acid derivative especially comprises the copolymer of acrylic acid and at least one acrylate, is mixed with the poly-polymethacrylic acid methyl ester of the copolymer of acrylic acid and its ester, and the copolymer of vinylacetate and crotonic acid.

Especially preferred pH sensitive polymer group comprises the Cellacefate ester, the phthalic acid polyvinyl acetate, the Hydroxypropyl Methylcellulose Phathalate ester, the Cellulose acetotrimellitate ester, the anionic acrylic copolymer of methacrylic acid and methyl methacrylate, and the copolymer that contains acrylic acid and at least a acrylate.

Adjust the thickness of delayed release coating to provide required lag characteristic. Usually, thicker dressing is more corrosion-resistant, thus and the delay of more being grown. The thickness range of preferred dressing is from about 20 μ m to about 1mm.

When swallowing, the tablet of dual dressing is by stomach, and wherein the second dressing prevents the release (namely keeping rate of release to be lower than 1mg/ hour) of Sertraline there under the dominant acid condition. If this sheet passes stomach (wherein can mediate some side effect) and enters small intestine (pH wherein is higher), this second dressing corrodes according to the physicochemical property of selected materials or dissolves. When the corrosion of the second dressing or dissolving, the first dressing prevents from discharging immediately or fast of Sertraline and regulates this discharging to prevent high concentration, thereby side effect is minimized.

Second embodiment that delay adds slowly-releasing Sertraline formulation comprises many granules, wherein as each particle such as the aforementioned tablet by dual dressing, at first produce the polymer of slowly-releasing Sertraline with design, then with the polymer that designs the beginning of the delayed release in GI road environment when swallowing this formulation. Bead contains Sertraline and can contain one or more processing and required excipient of performance. The many granules that preferably contain most of Sertraline with respect to adhesive. These many granules can be composition also can be by the technology preparation (comprise and extruding and the spheronizing method, wet granulation process, fluidized bed granulation method, and revolving bed granulation, kind structure etc.) of any aforesaid many granules for the preparation of storing the storehouse system.

This sustained release coating can be used by known in the art. Suitable and preferred polymer coating material, equipment, and coating method also comprise aforesaid those.

The method of the rate of release of Sertraline from many granules (i.e. many granules before it accepts delayed release coating) of this sustained release coating and this dressing of modification is controlled by the factor as the many granules of aforesaid storage storehouse system's Sertraline also.

The second film of many granules of dual dressing or dressing are the delayed release coatings that is applied to as above-mentioned tablet on the first sustained release coating, and can be formed by identical material. But, preferably after having dissolved or corroded, delayed release coating carries out slowly-releasing or the controlled release of Sertraline, therefore, the advantage of this embodiment can realize by the appropriate combination of delayed release feature and sustained releasing character, and independent delayed release part can or can not need standard compliant USP enteric standard. The thickness of the dressing of adjustment delayed release is to provide required lag characteristic. Usually, dressing is more thick more corrosion-resistant, thus and the delay of more being grown.

The 3rd embodiment that postpones to add slowly-releasing Sertraline formulation comprises can lose or the non-Sertraline skeleton nuclear that loses, be generally tablet or many granules, as aforementioned, it is surrounded by the beginning that postpones the Sertraline slowly-releasing and directly ends coating tablet and pass stomach to the dressing in duodenum or farther place. The polymer that is used for delayed release coating is the polymer of pH sensitivity, as the storage storehouse tablet and many granules of aforementioned dressing.

The delay that pH causes adds slowly-releasing Sertraline formulation and also can pass through with moisture insolubility film forming polymer, preferred semi-transparent polymer such as cellulose acetate or ethyl cellulose, and the monofilm of the mixture that is selected from the above-mentioned polymer of enumerating of pH sensitivity comes dressing matrix tablet or many granules or osmotic tablets nuclear or many granular core and forms. Preferred and the particularly preferred pH sensitive polymer of this embodiment be above-mentioned those preferably with particularly preferred pH sensitive polymer. The preferred coating membrane of this embodiment comprises the polymer of 10-70%pH sensitivity. Usually, thicker coating membrane can provide longer delay. Usually, the polymer content of lower pH sensitivity can provide longer delay in the coating membrane. This delay can be further by introducing water-soluble polymer such as HPMC more or less, and low molecular weight compound such as glycerine, sucrose, glucose, sodium chloride, citric acid, and fumaric acid and controlling. This time delay can be by selecting water miscible former raising of fenestra with lower solubility or slower aquation. For example, with respect to fumaric acid, citric acid causes the delay of lacking owing to citric acid than highly dissoluble as the former meeting in film dressing hole.

The 4th embodiment comprises osmotic dosage form, as described in the relevant part of " slowly-releasing " in front, but is processed into the period of delay that has more than 15 minutes. This infiltration embodiment comprises double-layer tablet, it comprises that (1) contains Sertraline and bleeding agent layer, bleeding agent wherein is lactose, sucrose, organic acid or alkali, salt or analog, (2) contain the polymer of swelling such as the second layer of PEO, and (3) surround the polymer coating of this whole double-layer tablet, and this dressing comprises preferred semipermeable polymers such as cellulose acetate, with the one or more Sertraline outlet openings that contain the Sertraline side that are positioned at this sheet. Can will should be processed into osmotic dosage form by increasing this film thickness or reducing its porous period of delay suitably. This delay can have the therapeutic advantage to interact such as the metabolism that reduces side effect and minimizing and concomitant medication.

The osmotic dosage form that delay of the present invention adds slow release formulation comprises that containing Sertraline examines tablet and many granules, is surrounded by the semi permeability asymmetric membrane. This nuclear tablet contains Sertraline, permeates effective solute and optional acid Sertraline solubilizer, the inhibitor of surfactant-based Sertraline gel-forming, swollen polymer, the polymer of change viscosity, and other drug excipient commonly used that needs. Medicine itself (if highly-water-soluble) can be the infiltration active ingredient of this mixture. Preferred sertraline salts. Especially preferred salt hydrochlorate, aspartate, acetate and lactate. Wherein, most preferably acetate and lactate. Sertraline acetate and lactate have respectively 65 and the solubility of 125mg/ml, and 2-4 atmospheric osmotic pressure can be provided, and are enough to produce some osmotic drive power.

The material that is used to form pellicle comprises polyamide, polyester, and cellulose derivative. Preferably cellulose ether and ester. Particularly preferably be cellulose acetate, cellulose acetate-butyrate, and ethyl cellulose. Useful especially material is included in the preparation process or the material of the one or more exit passageways of spontaneous formation when placing environment for use. Prepare the porous dressing with these preferred materials, its hole forms by the phase transformation in the preparation process or by the water soluble ingredient that exists in the dissolving film. The preparation of phase transformation asymmetric semipermeable membrane has above been described.

In the preferred embodiment of the coated tablet of asymmetric film, this polymer/solvent/non-solvent mixture is sprayed on the tablet bed (on the tablet coating device as in the Freund HCT-60 tablet coating device). In this method, with thick this sheet of porous region dressing, and with outermost thin compact zone. For formation causes the compact zone that postpones, under causing for the preparation of the condition without the phase transformation condition of the asymmetric membrane coating tablet of period of delay, spray spray liquid far different.

In environment for use such as GI road, water sees through the semi permeability asymmetric membrane and sucks this sheet nuclear. Because the soluble material in the sheet nuclear dissolves, and has set up the osmotic pressure gradient of cross-film. When the hydraulic pressure in the film of coated nuclear surpassed the pressure of environment for use (such as the GI chamber), the solution that contains Sertraline went out this formulation by the hole " pump " that forms in the pellicle.

Preferably, be included in this tablet or many granules nuclear in be one or more Sertraline solubilising excipient, comprise ascorbic acid, arabo-ascorbic acid, citric acid, glutamic acid, aspartic acid, partial glyceride, glyceride, glyceride ester derivatives, macrogol ester, the polypropylene glycol ester, polyol ester, APEO, Isosorbide Dinitrate, polyoxyethylene sorbitan ester, sugar ester, phosphatide, Pluronic F108, and polyethylene glycol. Solubilising excipient ascorbic acid most preferably, aspartic acid, Capmul MCM C8, glycerin monostearate, glyceryl monolaurate and C₈-C ₁₀Partial glyceride.

Can be processed into by the composition of selecting asymmetric membrane this period of delay nearly 3 hours or more, as passing through selective membrane polymer (such as cellulose acetate or ethyl cellulose) to the ratio of plasticizer (such as PEG-3350 or other water-soluble plasticizer). Increase film thickness or membrane polymer and plasticiser ratio is caused time delay of more growing. This delay can be further by introducing water-soluble polymer such as HPMC more or less, and low molecular weight compound such as glycerine, sucrose, glucose, sodium chloride, citric acid and fumaric acid and control. This time delay can be by selecting to have former raising of water-soluble fenestra of lower solubility or slower aquation. For example, with respect to fumaric acid, citric acid is led short delay owing to citric acid than highly dissoluble as the former meeting in film dressing hole. Can increase to depart from a little desirable phase transformation condition time delay by the non-solvent of introducing low ratio in this coating solution. Time delay can be by introducing the infiltration excipient of larger proportion, or have the excipient of higher osmotic pressure, or solubilizer is in this caryogamy side and reduce. The osmotic tablet that has exemplified asymmetric membrane dressing of the present invention among the embodiment 17 and 18 adds slowly-releasing Sertraline formulation.

The embodiment that the 5th delay adds slow release formulation comprises the U.S. series number 07/296 of the common transfer that is described in the common pending trial that is incorporated herein by reference, swellable hydrogel tablet and many granules of the dressing of 464 (on January 12nd, 1989 submitted to, published July 7 nineteen ninety to be EP 378404A2). The swellable tablet of dressing comprises and contains Sertraline and swollen material, is preferably the sheet nuclear of hydrophilic polymer, is coated with the film that contains hole or hole, and in the water-based environment for use, Sertraline can be extruded and emit to this hydrophilic polymer from this hole or hole. Perhaps, it is former that this film can contain the water-soluble hole that is dissolved in water-based environment for use polymerization or low-molecular-weight, as long as can extrude hydrophilic polymer and Sertraline by the hole. The former example in hole is water-soluble polymer such as hydroxypropyl methylcellulose, and low molecular weight compound such as glycerine, sucrose, glucose and NaCl, citric acid and fumaric acid. In addition, can be by in dressing, forming the hole with laser or other mechanical means in dressing boring. Add in the embodiment of slowly-releasing Sertraline formulation the 5th delay, membrane material can comprise any film forming polymer, comprise water penetration or can not the water penetration polymer, if be deposited in film on the sheet nuclear be porous or to contain water-soluble hole former or have for water and enter the macroscopic pores that discharges with Sertraline.

For hydrogel tablet and many granules of the swelling of dressing, the preferred swollen polymer of this nuclear comprises PEO and the carboxymethyl cellulose of molecular weight from 3000 to 500,000. Preferred dressing polymer comprises cellulose acetate and ethyl cellulose and hydrophobic polymer such as EVA (ethane-acetic acid ethyenyl ester).

For swelling hydrogel tablet and many granules of dressing, can be processed into by the composition of selecting asymmetric membrane this period of delay nearly 3 hours or more, namely by the selective membrane ratio former to the hole. Increase film thickness or membrane polymer and the former ratio in hole is caused time delay of more growing. This time delay can be by selecting to have former raising of water-soluble fenestra of lower solubility or slower aquation. For example, with respect to fumaric acid, citric acid causes the delay of lacking owing to citric acid than highly dissoluble as the former meeting in film dressing hole. Can reduce time delay by introducing larger proportion low-molecular-weight (as being lower than 20,000 dalton) swollen polymer in this nuclear preparation.

The 6th embodiment is the enzyme initiating system, the liquid film dressing of the support that causes such as the described type enzyme of International Application Serial No. PCT/US93/07463 (on June 9th, 1994 published with WO 94/12159, was incorporated herein by reference). This dressing is microporous hydrophobic membrane, has the hydrophobic liquid that transmits in the hole of this film. This film surrounds and helps diffusion skeleton nuclear or the osmotically active nuclear that the control Sertraline discharges after this formulation is discharged stomach. This hydrophobic liquid all basically can not be saturating to aqueous environments and following slow release formulation. Thereby changing, the hydrophobic liquid physical efficiency make it can be saturating to aqueous environments. After mammal swallows formulation, postpone Sertraline and be released into gastronintestinal system until this formulation is discharged from stomach and enters duodenum. The hydrophobic liquid of transmission changes, thus its be at small intestinal lumen but not in the stomach hydrophobic liquid in postponing the dressing hole of enzyme-catalyzed change break so that film become can be saturating to water and Sertraline. Exemplary hydrophobic liquid is triglycerides, fatty acid anhydride, cholesterol fatty acid ester, hydrophobic amino-acid ester and analog. Preferred triglycerides comprises the oleic acid triglycerides, Trivent OCG, laurate triglycerides, olive oil, palm oil, coconut oil, sesame seed oil, corn oil, peanut oil, soybean wet goods. Preferred fatty acid anhydride comprises caprylic anhydride, lauric anhydride, tetradecanoic acid etc. The mixture of available hydrophobic liquid. Exemplary microporous hydrophobic holder phase shift films or coating material comprise cellulose esters, Merlon, polyalkenes, polystyrene, polyvinyl ester, polysiloxanes, polyacrylate and polyester. Preferably can not be saturating to Sertraline with the dewatering microporous film of the hydrophobic liquid that transmits, until gastrointestinal enzyme variation of catalysis in hydrophobic oil, as following.

In environment for use, be in the small intestinal lumen, lipase or the esterase aforesaid hydrophobic oil of degrading forms the surfactant product in the hole of the microporous barrier of this embodiment, thereby produce the water-based passage, and the Sertraline in the device nuclear can be discharged by this passage the hydrophobic support film of micropore. In case this phase shift films becomes porous, the release of Sertraline can limit by the slowly-releasing that installs below or porous and the thickness of porous hydrophobic dressing are controlled.

Cause in the liquid phase shift films of supporting at above-mentioned enzyme, hydrophobic oil can be used as Small Intestine Protease such as trypsase, the substrate of carboxypeptidase and chymotrypsin. Exemplary oil is the hydrophobic ester of amino acid derivativges.

Postpone to add in the further embodiment of slowly-releasing Sertraline formulation in the space, use and contain at small intestinal lumen but not Sertraline tablet, capsule, pellet or the powder agent of the coated slowly-releasing of the dressing of the composition of the mould short degraded of the enzyme in the gastral cavity. Dressing is included under the body temperature wax or the triglycerides for solid-state natural or synthetic source. In preferred embodiments, what comprise 2-20% is the material of liquid under body temperature, and it is by intestinal enzymes (such as trypsase, chymotrypsin, elastoser, lipase) degraded. Those of above-mentioned relevant " the liquid film device of the support that enzyme causes " (" enzyme triggered supported liquid membrane devices ") on the active liquid of suitable enzymatic. Preferred wax dressing is with the Sertraline tablet of dressing not, capsule, and the 3-20% of pellet or powder agent weight uses.

In the 7th embodiment, but the Sertraline formulation that preparation time postpones, the Sertraline tablet of slowly-releasing, pellet, or granule, and further dressing has water-soluble and/or the water-destructible property retardation layer. In preferred embodiments, Sertraline matrix tablet or the bead of the disintegration of pot life retardation layer dressing or non-disintegration. The preferred dressing that postpones comprises HPC, HPMC, PEO and PVP. For tablet, this dressing can be such as the HCT-30 available from Freund company, HCT-60, or carry out in the tablet coating device of HCT-130 dressing device. With the HPMC aqueous solution or other this tablet of suitable polymer coating until the final weight of the 5-50% of the weight of final coating tablet. Heavier coat weight, the delay before causing Sertraline to be released into environment for use such as GI chamber beginning is longer. Also can include but not limited to ethyl cellulose (EC) by introducing a small amount of weak water-soluble polymer to moderate this time delay, and cellulose acetate (CA) and acetylbutyrylcellulose are in coated formula and increase. For example, coated formula can be by 95: 5HPMC/EC to 50: 50HPMC/EC, or 95: 5HPMC/CA to 50: 50HPMC/CA consists of. In the situation of the polymer coating system of this mixing, need to regulate solvent composition with the mixture of dissolved water dissolubility and weak water-soluble polymer. For example, can use as required acetone and water, or the mixture of second alcohol and water. Bead and particle can be used similarly dressing of fluidized bed coating device such as Glatt GPCG-5 dressing device. For pellet, dressing comprise dressing not the bead nuclear weight about 10% to 100%. For the Sertraline powder agent, dressing accounts for not about 15%-200% of the bead nuclear weight of dressing.

Salt

The present invention relates to the Sertraline acetate, it can follow these steps to preparation.

The free alkali of Sertraline is dissolved in suitable organic solvent such as ethyl acetate; Unsaturated hydrocarbons such as hexane or pentane; Aromatic hydrocarbon is such as benzene or toluene; Or ring or acyclic ether such as dioxane, oxolane, the combination of diethyl ether or methoxy methyl ether or its combination or any those solvents and water. Suitable organic solvent is any such solvent, and wherein the free alkali of Sertraline freely dissolves, and the acetate of Sertraline is especially insoluble and be convenient to form required crystal formation. Preferred hexane because the ability of its dissolving Sertraline, can not dissolve the ability of Sertraline acetate and the quality of the crystal that obtains with its granulation the time. The temperature of solution maintains room temperature or rises to the boiling point of solvent for use. Preferably be warming up to the boiling point a little less than solvent for use, generally between 30 ℃ to 60 ℃. If use hexane, preferably be warming up to about 40 ℃. Then, add excessive acetic acid in reactant mixture. Usually, the Sertraline of preferred every equivalent adds the acetic acid of 1 to 2 equivalent. Typically, the acetic acid that adds 1.1 equivalents. When reaction was finished, the Sertraline acetate precipitated usually. Once in a while, for obtaining better Sertraline acetate yield, cool off this reactant mixture, usually to about room temperature or about 0 ℃. After this salt precipitation, it is normally favourable to continue stirring or granulation precipitation. During granulation, usually preferably in room temperature or a little more than room temperature and be no more than 35 ℃ and carry out. The formed crystal of isolated by filtration. The acetate crystal of Sertraline is with hexane washing and dry under the temperature that raises and decompression, and 30-60 ℃ usually, 24-48 hour or be enough to basically remove time of all trace hexanes and any unreacted acetic acid.

Perhaps, the Sertraline acetate can directly by the salt of Sertraline, such as sertraline salts hydrochlorate or mandelate preparation, need not the Sertraline of separated free bases type. Typically, the sertraline salts hydrochlorate is used for this preparation. During with this step, this sertraline salts is pulp and dropping or minute small quantities of aqueous base that adds dilution in water. The pH of this solution of monitoring is to prevent from adding excessive alkali in adding the alkali process. Typically, pH maintains about 6.5-9.5. Preferably, pH maintains 8.5. The suitable aqueous base that can be used for this reaction comprises NaOH, Na₂CO ₃，NaHCO ₃，K ₂CO ₃And KHCO₃ Preferably, use NaOH. The free alkali of the Sertraline that so forms is dispensed into immiscible organic solvent such as hexane, ethyl acetate, benzene, toluene or ether such as diethyl ether, dioxane or methoxy methyl ether. Generally, preferred hexane. Separate the unmixing organic phase and wash organic phase with water to remove chlorion from aqueous phase. Then, process as in the previous paragraph the organic phase of the Sertraline that contains the free alkali type to obtain the Sertraline acetate.

The present invention relates to Sertraline Pfansteihl salt, it can follow these steps to preparation.

The free alkali of Sertraline is dissolved in suitable organic solvent such as ethyl acetate; Unsaturated hydrocarbons such as hexane or pentane; Aromatic hydrocarbon is such as benzene or toluene; Or ring or acyclic ether such as dioxane, oxolane, the combination of diethyl ether or methoxy methyl ether or its combination or any those solvents and water. Suitable organic solvent is any such solvent, and wherein the free alkali of Sertraline freely dissolves, and the Pfansteihl salt of Sertraline is especially insoluble and be convenient to form required crystal formation. Ethyl acetate is because the ability of its dissolving Sertraline can not be dissolved Sertraline Pfansteihl salt and the quality of the crystal that obtains with its granulating the time. The temperature of solution maintains room temperature or rises to the boiling point of solvent for use. Preferably be warming up to the boiling point a little less than solvent for use, generally between 30 ℃ to 60 ℃. If use ethyl acetate, preferably be warming up to about 40 ℃. Then, add excessive Pfansteihl in reactant mixture. Usually, the Sertraline of preferred every equivalent adds the Pfansteihl of 1 to 2 equivalent. Typically, the Pfansteihl that adds 1.1 equivalents. When reaction was finished, Sertraline Pfansteihl salt was settled out usually. Once in a while, for obtaining better Sertraline Pfansteihl salt yield, cool off this reactant mixture, usually to about room temperature or about 0 ℃. After this salt precipitation, it is normally favourable to continue stirring or granulation precipitation. During granulation, usually preferably in room temperature or a little more than room temperature and be no more than 35 ℃ and carry out. Filter and collect formed crystal. The Pfansteihl salt crystal of Sertraline is with ethyl acetate or hexane washing and dry under the temperature that raises and decompression, and 30-60 ℃ usually, 24-48 hour or be enough to basically remove time of all trace solvent and any unreacted L-lactic acid.

Perhaps, Sertraline Pfansteihl salt can directly by the salt of Sertraline, such as sertraline salts hydrochlorate or mandelate preparation, need not the Sertraline of separated free bases type. Typically, the sertraline salts hydrochlorate is used for this preparation. During with this step, this sertraline salts is pulp and dropping or minute small quantities of aqueous base that adds dilution in water. The pH of this solution of monitoring is to prevent from adding excessive alkali in adding the alkali process. Typically, pH maintains about 6.5-9.5. Preferably, pH maintains 8.5. The suitable aqueous base that can be used for this reaction comprises NaOH, Na₂CO ₃，NaHCO ₃，K ₂CO ₃And KHCO₃ Preferably, use NaOH. The free alkali of the Sertraline that so forms is dispensed into immiscible organic solvent such as hexane, ethyl acetate, benzene, toluene or ether such as diethyl ether, dioxane or methoxy methyl ether. Generally, ethyl acetate. From aqueous phase separation unmixing organic phase and wash organic phase with water to remove chlorion. Then, process as in the previous paragraph the organic phase that contains free alkali type Sertraline and obtain Sertraline Pfansteihl salt.

Sertraline Pfansteihl salt also can directly be prepared by the Sertraline mandelate. During with this step, by U.S. patent No.4, the pulp in the mixture of water and suitable organic solvent of the Sertraline mandelate of 536,518 described methods preparation. The suitable organic solvent of this reaction usefulness comprises ethyl acetate; Unsaturated hydrocarbons such as hexane or pentane; Aromatic hydrocarbon is such as benzene or toluene; Or ring or acyclic ether such as dioxane, oxolane, diethyl ether or methoxy methyl ether. By this slurry being chilled to below the room temperature such as 0 ℃-20 ℃. Typically, reaction mixture is to about 15 ℃. Free the subtracting by adding suitable alkali of Sertraline produces. This reaction comprises NaOH with suitable alkali, Na₂CO ₃，NaHCO ₃，K ₂CO ₃And KHCO₃ Preferably, use NaOH. Add capacity alkali and be converted into the Sertraline free alkali to this reactant mixture fully to guarantee the Sertraline mandelate. Typically, when water layer pH was about 9.6, this transformation was thoroughly. The organic layer that contains the Sertraline free alkali partly separates from water-based, and usually with other this water-based part of organic solvent extraction partly. Merge and concentrated organic layer. Once in a while, need to filter to clarify this solution. Directly add Pfansteihl and in this solution, also usually stir the longer time of this reactant mixture with the formed Sertraline L-of granulation lactate. Usually, this stirs and continued preferably about 16-24 hour 8-48 hour. Then, such as above-mentioned separation and purifying Sertraline Pfansteihl salt.

The present invention relates to the Sertraline L-Aspartic acid salt of crystallization, it can follow these steps to preparation.

The free alkali of Sertraline is dissolved in suitable organic solvent such as ethyl acetate; Unsaturated hydrocarbons such as hexane or pentane; Aromatic hydrocarbon is such as benzene or toluene; Or ring or acyclic ether such as dioxane, oxolane, the combination of diethyl ether or methoxy methyl ether or its combination or any those solvents and water. Suitable organic solvent is any such solvent, and wherein the free alkali of Sertraline freely dissolves, and the L-Aspartic acid salt of Sertraline is especially insoluble and be convenient to form required crystal formation. Preferred combination the ethyl acetate of a small amount of water because the ability of its dissolving Sertraline and L-Aspartic acid, the crystal mass that can not dissolve Sertraline L-Aspartic acid salt and with its granulating the time, obtain. The solution that preferably contains the ethyl acetate of 2 to 3% water. Especially preferably the solution that contains the ethyl acetate of 3% water. The temperature of solution maintained room temperature or rise to the boiling point of solvent for use. Preferably the temperature with solution maintains room temperature. Then, add excessive aspartic acid in reactant mixture. Usually, the Sertraline of preferred every equivalent adds the aspartic acid of 1 to 2 equivalent. Typically, the aspartic acid that adds 1.1 equivalents. When reaction was finished, Sertraline L-Aspartic acid salt was settled out usually. Once in a while, for obtaining better Sertraline L-Aspartic acid salt yield, cool off this reactant mixture, usually to about room temperature or about 0 ℃. After this salt precipitation, it is normally favourable to continue stirring or granulation precipitation. During granulation, usually preferably in room temperature or a little more than room temperature and be no more than 35 ℃ and carry out. Filter and collect formed crystal. The L-Aspartic acid salt crystal of Sertraline washs with water saturated ethyl acetate and is dry under the temperature that raises and decompression, usually 30-60 ℃, 24-48 hour or be enough to basically remove time of all trace ethyl acetate, water and any unreacted aspartic acid.

Perhaps, Sertraline L-Aspartic acid salt can directly by the salt of Sertraline, such as sertraline salts hydrochlorate or mandelate preparation, need not the Sertraline of separated free bases type. Typically, the sertraline salts hydrochlorate is used for this preparation. During with this step, this sertraline salts hydrochlorate is pulp and dropping or minute small quantities of aqueous base that adds dilution in water. The pH of this solution of monitoring is to prevent from adding excessive alkali in adding the alkali process. Typically, pH maintains about 6.5-9.5. Preferably, pH maintains 8.5. The suitable aqueous base that can be used for this reaction comprises NaOH, Na₂CO ₃，NaHCO ₃，K ₂CO ₃And KHCO₃ Preferably, use rare NaOH. The free alkali of the Sertraline that so forms is dispensed into immiscible organic solvent such as hexane, ethyl acetate, benzene, toluene or ether such as diethyl ether, dioxane or methoxy methyl ether. Generally, the aqueous hydrochloric acid ethyl ester of preferred 2-3%. Separate the unmixing organic phase and wash organic phase with water to remove chlorion from aqueous phase. Then, process as in the previous paragraph the organic phase that contains free alkali type Sertraline and obtain Sertraline L-Aspartic acid salt.

Such as U.S. Patent No. 4,536,518 is described or by use alkali such as NaOH, Na₂CO ₃， NaHCO ₃，K ₂CO ₃Or KHCO₃In and the aqueous solution of sertraline salts such as sertraline salts hydrochlorate or Sertraline mandelate and prepare the free alkali of Sertraline. The free alkali of Sertraline can be used for solution or isolates as crystalline solid.

By U.S.4,536,518 described methods prepare sertraline salts hydrochlorate and Sertraline mandelate.

Measure Sertraline acetate, the hygroscopicity of Sertraline Pfansteihl salt and Sertraline aspartate with humidity micro poiso such as VTI wetting balance instrument (VTI humidity micro poiso, MB 300G and MB 300W, VTI company, Hialeah, Florida, the U.S.). With the Sertraline acetate, Sertraline Pfansteihl salt and Sertraline aspartate are exposed in the atmosphere that humidity range is 10%-90%. In whole hygroscopicity mensuration process, holding temperature is at 25 ℃. Measure hygroscopicity and the absorption isotherm of these three kinds of salt in the atmosphere with VTI wetting balance instrument. These three kinds of salt are non-hygroscopic in the humidity range of studying.

By testing its compression stress, solid fraction, dynamic impression, the elastic modelling quantity of reduction, Quasi-static Indentation, elastic modelling quantity, the mechanical performance of modulus of shearing and stretching strength determination Sertraline acetate and Sertraline Pfansteihl salt. Table 1 has been listed the test result of Sertraline acetate mechanical performance.

Table 1: the mechanical performance of Sertraline acetate

Performance	Test	The Sertraline acetate
Performance	Test	The Sertraline acetate	Compression pressure, MPa	The compacting preparation	36.7(2.5)
Solid fraction	The compacting preparation	0.831	Compression pressure, MPa	The compacting preparation	36.7(2.5)
Solid fraction	The compacting preparation	0.831	Dynamic identation hardness, MPa	Dynamic impression	60.0(0.4)
The elastic modelling quantity that reduces, GPa	Dynamic impression	5.1(0.5)	Dynamic identation hardness, MPa	Dynamic impression	60.0(0.4)
The elastic modelling quantity that reduces, GPa	Dynamic impression	5.1(0.5)	Quasi-static Indentation hardness, MPa	Quasi-static Indentation	25.1(1.3)
Elastic modelling quantity, GPa	Quasi-static Indentation	2.2(0.2)	Quasi-static Indentation hardness, MPa	Quasi-static Indentation	25.1(1.3)
Elastic modelling quantity, GPa	Quasi-static Indentation	2.2(0.2)	Modulus of shearing, MPa	Quasi-static Indentation	99.9(19.1)
Hot strength, MPa	Tension failure	0.52(0.03)	Modulus of shearing, MPa	Quasi-static Indentation	99.9(19.1)

Table 1a has listed the measuring mechanical property result of Sertraline Pfansteihl salt.

Table 1a: the mechanical performance of Sertraline Pfansteihl salt

Performance	Test	The Sertraline acetate
Performance	Test	The Sertraline acetate	Compression pressure, MPa	The compacting preparation	52.8(0.7)
Solid fraction	The compacting preparation	0.862	Compression pressure, MPa	The compacting preparation	52.8(0.7)
Solid fraction	The compacting preparation	0.862	Dynamic identation hardness, MPa	Dynamic impression	81.6(1.6)
The elastic modelling quantity that reduces, GPa	Dynamic impression	7.4(0.6)	Dynamic identation hardness, MPa	Dynamic impression	81.6(1.6)
The elastic modelling quantity that reduces, GPa	Dynamic impression	7.4(0.6)	Quasi-static Indentation hardness, MPa	Quasi-static Indentation	31.1(1.4)
Elastic modelling quantity, GPa	Quasi-static Indentation	2.0(0.2)	Quasi-static Indentation hardness, MPa	Quasi-static Indentation	31.1(1.4)
Elastic modelling quantity, GPa	Quasi-static Indentation	2.0(0.2)	Modulus of shearing, MPa	Quasi-static Indentation	113.9(4.6)
Hot strength, MPa	Tension failure	0.56(0.02)	Modulus of shearing, MPa	Quasi-static Indentation	113.9(4.6)

Mechanical performance such as the hot strength of medicine compact (medicine, excipient and medicine and excipient), elastic modelling quantity and hardness can not be passed through the used standard method evaluation of metallurgy, because medical solid can not be compressed into fully uniform fine and close part. Generally, four class mechanical performances below conventional evaluation the: elasticity, viscoplasticity, plasticity and fracture. Four classes all help three events of compacting process, i.e. compression suspends and decompression. The mechanical performance evaluation of drug powder is difficult, distributes because affect key parameter such as the particle diameter of mechanical performance measurement, and crystal habit, superficial makings, degree of crystallinity and crystallography symmetry are quite large in these changes in material. Yet compressing tablet performance index (hereinafter referred to as " ITP ") is used for compressing tablet performance (Hiestand, E.N.Smith, D.P.Powder Tech., 38:145-159,1984 of prediction medicine compact; Hiestand, E.N., Smith, D.P.Adv, Ceram., 9:47-57,1984). These indexes are derived from the key of the automatic reaction of estimating this compact and measure (not measuring) in compacting process. By measuring and calculating these mechanical performances, it will be understood by those skilled in the art that the fundamental characteristics of drug powder. This understanding can make those skilled in the art determine whether can prepare Tabules. ITP mechanical performance such as hot strength, the measurements and calculations of the hardness of the compacts of impression modulus and compression are finished (J.Pharm.Sci, 60:758-763,1971 by the method for Hiestand; J.Pharm.Sci., 63:605-612,1974; J.Pharm.Sci., 74:768-770,1985; Pharmaceutial Technology, 8:54-66,1989; Int.J.Pharm., 67:217-229,1991; Int.J.Pharm., 67:231-246,1991).

Mechanical measurement can be finished routinely with the square compacts of pure medicine (Sertraline acetate and Sertraline Pfansteihl salt). Measure in triplicate, and prepare compacts by single shaft to compression and the decompression of three axles.

The material behavior that affects the uncompacted most critical of powder is its ductility, elasticity and hot strength. Ductility is impacted by pendulum and is measured, and is the dynamic indentation test of measuring this compacts hardness. The hardness of this compound and its ductility are inversely proportional to. Because plastic deformation increases combination between particle, high ductility or soft are optimal. Typically, the dynamic identation hardness value that is lower than 100MPa is high; The value of 100-200MPa scope is critical and be low greater than the value of 200MPa.

The amount that the elastic modelling quantity of this compacts (also claiming Young's modulus) is replied by the impression of measuring after (accurate elasticity) identation hardness test that prolongs is measured. Need in decompression process, have the material of low elasticity reaction, hint that this material is to show low elastic modulus. The elasticity number that surpasses 8GPa is high, and the elasticity number of 1-8GPa is medium and value that be lower than 1GPa is low.

The transverse compression of hot strength by compacts is until cause tension failure to be measured. Need to have high hot strength. The hot strength that surpasses 2MPa is high, is medium and value that be lower than 0.8MPa is low between the value of 0.8-2.0MPa.

Hiestand ITP is that following feature consists of: embrittlement index (this paper is called BFI), best bonding index (this paper is called bBI), the poorest bonding index (this paper is called wBI) and strain exponent (this paper is called SI).

BFI is the tendency of measuring from compacts fracture or segmentation under the stress in the crackle that exists in the compacts and hole. Those skilled in the art can be illustrated in processing (i.e. fracture) such as the tendency in the fracture of tablet from the tablet press machine ejection process or in film dressing process or segmentation with BFI. The embrittlement exponential quantity is 0 to be outstanding, is good between the value of 0.01-0.09 scope, is critical and value 0.2-1.0 is poor between the value of 0.1-0.19 scope.

Bonding index is to estimate compact to keep the bonding ability of intergranular in the elastic recovery process. Hiestand has been classified as the process of plastic deformation the main mechanism of the bonding formation of tablet when drug powder is accepted stress under the load. The evaluation of plastic deformation is used for calculating bonding index. Because decompression is the key step in the film-making process, it is important estimating bonding index. The bonding ability that stands the strain relief in the compression process between the particle that the evaluations of the poorest bonding index (wBI) and best bonding index (bBI) form in compression process. Under the condition of high speed film-making, wBI is better than bBI availability. It is outstanding being greater than or equal to 2 bonding exponential quantity, and is good between the value of 0.8-1.9, is critical between the value of 0.3-0.7, is poor and be lower than 0.3 value.

Stress exponent is the measuring of elastic recovery of compacts. It can be described as the not degree of the elastic recovery of load stage of measuring. Can estimate elastic modelling quantity with the elastic recovery from Indentation Process.

Sample by the performance test of standard method processing machinery. For producing reliable data, this sample must not have mechanical defect, such as micro-crack. Therefore, use the tablet press machine of U.S. Patent No. 4,880,373 described preparation specializations. This tablet press machine single shaft press-powder end (namely unidirectional), the then three axles powder (that is, three-dimensional) that slowly reduces pressure. Compress this sample to the compacts of predetermined extent, be called with reference to state. This allows this mechanical properties data to be equivalent to be pressed into same other material with reference to state. It is 0.85 that the compacting step of standard is pressed onto solid fraction with powder. Solid fraction, or relative density are that the apparent density of this compacts is divided by true (definitely) density of this compacts. The apparent density of this compacts is by measuring its volume and recording divided by quality. This measures normally cm³/ g. Measure the real density of this powder by the helium hydrometry. Usually, for obtaining required solid fraction, must carry out careful weighing powder sample tentative compacting and measure the solid fraction of gained compacts. Carry out the adjustment of solid fraction by the increase and decrease powder weight.

Be with three axles decompression sheet press (such as U.S. Patent No. 4,880,373 described preparations) as the square compacts of specimen, use the square upper and lower punching of square combination die and 1.9cm and make. Prelubricated mould and lower punching be contained on the tablet press machine and this mould in insert the powder of pre-weighing. Strike off the top that powder surface also places upper punching the mould powder with spatula. For guaranteeing the accurate of height, usually this process of computer control. The hydraulic jack of mould is stretched fully, the two halves of punch die are forced together tightly. Then, the punching oil cylinder is stretched fully this powder of uniaxial compression. In case oil cylinder stretches fully, at five minutes suspending period of this state maintenance. In this time-out process, punching and punch die loosen owing to the stress in the sample loosens to be forced in to a certain degree. When the EOT end of timeout, computer is removed the power between the metal-metal on punching and the punch die hydraulic jack, then, begins three axles decompression 15 minutes. In this process, punching and punch die power slowly withdraw simultaneously, keep pressure with 1 pair 1 ratio, until reach the available minimum force of hydraulic system. Then, recover final compacts and repeat this process. In lower punching, be equipped with the spring pressurization bolt, with hole, the same manner preparing centre compacts. Usually, mesopore passes 75 % of this compacts. Use is equipped with the little puncher that has a brill of same diameter with the punching bolt and is finished this hole. All samples relaxed 18-24 hour before test.

This compacts that loosens is as the test specimen of mechanical measurement. Following table has been summed up measuring technology, the crucial measurement, and the performance of measuring in the test.

Technology and the mensuration of table 2 test mechanical performance

Technology	The crucial measurement	The performance of measuring	The performance of deriving
Technology	The crucial measurement	The performance of measuring	The performance of deriving	Identation hardness	1 starting altitude, hi 2 rebound height, hr 3 strings footpath, a	Dynamic stiffness, H ₀	1 elastic modelling quantity that reduces, E ' 2 viscoplasticity are normal, VE 3 the poorest bonding indexes, BI_wThe bonding index of 4 crisp/viscoplasticity, bBI_v
Identation hardness	1 loosens power, F 2 strings footpath, a	1 quasistatic hardness, H ₁₀2 modulus of shearing, G	1 best bonding index, BI _b2 viscoplasticity constants, VE 3 elastic modelling quantity, E	Identation hardness		Dynamic stiffness, H ₀
Identation hardness	1 loosens power, F 2 strings footpath, a	1 quasistatic hardness, H ₁₀2 modulus of shearing, G		Fracture
	1 power, F 2 compacts thickness, T	1 hot strength, σ T	1 the poorest bonding index, BI _w2 best bonding indexes, BI _b3 embrittlement indexes, the bonding index of BFI 4 crisp/viscoplasticity, bBI_v	Fracture
	1 power, F 2 compacts thickness, T	1 hot strength, σ T		Fracture	1 power, F 2 compacts thickness, T	The hot strength of 1 fracture, σ T ₀	1 embrittlement index, BFI
Flow of powder	1. shear strength	The effective angle of 1 interior friction,	1 homogeneous flows and counts UFN	Fracture	1 power, F 2 compacts thickness, T	The hot strength of 1 fracture, σ T ₀	1 embrittlement index, BFI

Dynamic identation hardness H_o, by US Patent No, 4,885, the 933 described H that measure compacts with the pendulum Apparatus for Impacting at low-temp_o This compacts is loaded on air pressure drives in the folder, and under compacts, be lined with solid. The initial angle balance that the spherical pendulum of known quality and diameter is being scheduled to before release. Discharge this pendulum towards compacts, impact this compacts and resilience. Measuring this pendulum passes the time required between two photoelectric tubes of preset distance and automatically calculates pendulum rebound height hr. These measurements and calculations are carried out easily by computer. From its folder, shift out compacts with impression, and install to (Surfanalyzer 5000, Federal Products, Inc., Providence, Rhode Isand) on the surface topography instrument. Carefully load onto the probe of this instrument, then, scan the impression surface by crossing. Carry out three parallel scanning at each impression. Pass for the first time the impression center, for the second time with equidistant the carrying out in arbitrary limit of scanning in the first time for the third time. Keep the characteristic of whole three scannings and directly and by equation (1) calculate H by the loop curve match with the string of measuring impression₀，

H ₀＝((4mgrh _r)/πa ⁴)*((h _i/h _r)-0.375) (1)，

Wherein m and r are quality and the radiuses of indentor, and g is gravity constant, and a is the string radius of impression and hi and hr are the initial sum rebound height of indentor.

Quasi-static Indentation hardness, H₁₀, by U.S. Patent No. 4,957,003 described by the electronic spherical indentor of slow promotion to the compacts surface to the distance of being scheduled to and remain on that position to regular time with mensuration H₁₀ This is called suspending period. Usually keep this indentor at the about 5-20 in that position minute, and preferred 10 minutes. At the end of suspending period, the power on the meter record indentor. Remove this compacts, such as scanning as the test of above-mentioned pendulum and analyze its impression, and H₁₀Calculate by formula (2),

H ₁₀＝F _r/(πa ²) (2)，

Wherein Fr be behind the time out on the indentor loosen power and a is the string radius of impression. It is fixing in place with this compacts to drive folder by air pressure. The indentor diameter is same as pendulum diameter (2.54cm). The depth of penetration of Quasi-static Indentation device is so that the string radius of this impression is matched with the string radius that produces in shock-testing.

The hot strength of rule compacts, σ T measures by this compacts of transverse compression between the static pressing plate of preset width and electronic pressing plate to fracture. Power on the continuous monitoring pressing plate and after test in computer screen display force-time curve. Be tested and appraised the breakaway poing of the violent decline that common performance exerts oneself and analyze this feature. Fracture when event flag also is used for helping the evaluation sample visible crack to occur. Then, by formula (3) tensile strength calculated.

σ _T＝F _break/(W _p ^*T)*PTF (3)

Wherein Wp is platen width, and T is compacts width and PTF is vertical tensile force, when plate is wide be compacts width 40% the time, it is 0.16. Thereby the compression speed in this experiment is by constant and regulate pressing plate speed and make time constant fall into 10-20 to monitor between second computing time. Have suitable time constant, avoided the material viscoelasticity effect. Time constant is defined as F on the force-time curve_SplitAnd F_SplitTime between/e (second), wherein F_SplitPower when being the compacts fracture, and F_Split/ e is index, F_SplitAnd F_SplitTime difference between/e is defined as " time constant ". The normalization of time constant is introduced and is calculated with the impact on its fracture of the viscoplasticity of eliminating material.

(compromised) hot strength of fracture, σ T₀, be that identical instrument and electronic speed arranges mensuration in the centre bore compacts is tested with the hot strength of rule. Pressing following formula (3) calculates.

Powder mass flow under the powder room temperature in non-compacting balance the simple template shear box of common 50% rear usefulness was assessed at the powder of non-compacting to reach given relative humidity (RH) at least 18 hours. Shear box is pressed Hiestand and Wilcox, J.Pham.Sci., 1969,58,1403-10; Hiestand etc., J.Pharm.Sci., 1973,62,1513-1517; With Hiestand and Wells, Proceedings International Powder and Bulk Solids Handling and Processing Conference, Rosemnont, IL, the described preparation of May10-12 (1977). Form the powder annular bed of the thick and 63.5-82.5mm diameter of 4-6mm on the coarse sandpaper surface with template. Remove template and will adhere to manometric slide plate by towing cable and place on this powder. Place a weight and begin starter at this slide plate, the slide plate that promotes load passes powder. By pressure gauge METHOD FOR CONTINUOUS DETERMINATION thrust. This power rapidly increases to maximum until the mode that this slide plate begins to shear moves past this powder, observes the reduction of power this moment. Then, the reverse motor direction until towing cable fluff. Then, draw again this motor to maximum, force, and reverse motor direction again. Repeat this process several times until the power of reproduction maximum. Then, operate this powder bed to original shape. The slide plate of bearing identical weight is put back on the powder top. Repeat said process until obtain stable force. Change this powder bed of shape and at this slide plate with different weight whole process repeated. The effective angle of interior friction is calculated as steady shear stress to the arc tangent (arctg) of the slope of a curve of consolidation stress. This parameter is used for calculating the uniform flux number, UFN, and shown in (4),

UFN＝0.667*(42-δ) (4)，

Wherein δ is the effective angle of interior friction.

The Sertraline acetate is without any the defective that hinders the bonding formation of particle and maintenance in compression and decompression process. Particularly, find that the Sertraline acetate has the ductility and relative low elastic modelling quantity of height. In a word, the Sertraline acetate have remarkable mechanical performance and particle bond ability and from but the outstanding candidate of film-making.

The value of Lactated intrinsic mechanical performance shows that it does not hinder in compression and decompression process that particle bond forms and the shortcoming of maintenance. The hot strength of finding Sertraline Pfansteihl salt is high. And its compression pressure is greater than hardness. It is the remarkable candidate of film-making that the value of its compressing tablet index is pointed out it. In a word, Sertraline Pfansteihl salt has remarkable mechanical performance, particle bond ability and compressing tablet exponential quantity. Therefore, Sertraline Pfansteihl salt is the remarkable candidate of film-making.

Measure Sertraline acetate, the degree of crystallinity of Sertraline Pfansteihl salt and Sertraline L-Aspartic acid salt by polarization microscope and powder x-ray diffraction. At room temperature use x-ray diffractometer (Diffraktometer 5000, Siemens Analytical X-ray System, Inc., 6300 Enterprise, Lane, Madison, WI 53719-1173) to measure powder x-ray diffraction figure. Sample places the aluminum carriage and usually with the angle of diffraction 2 θ, is increased to 35 ° from 5 °, and the gate time in 0.02 ° of per step and a second scans. With two kinds of instruments: differential scanning calorimetry device (DSC 4, Perkin Elmer, USA) and thermogravimeter (SSC 5200, Seiko, Japan) are measured hot property, fusing point, the loss in weight in melting heat and the heating process.

Be to measure the Sertraline acetate, the dissolubility of Sertraline Pfansteihl salt and Sertraline L-Aspartic acid salt adds an equal portions Sertraline acetate, in the water gaging of Sertraline Pfansteihl salt or the Sertraline L-Aspartic acid salt mensuration in the cap nut bottle. For accelerating the acquisition of balance, the saturated solution of preparation under the temperature of room temperature can be higher than. Bottle is placed on the circulator that immerses 40 ℃ of water-baths. Under this temperature, add the capacity sertraline salts until in this bottle, there is excessive solid. Keep this bottle 40 ℃ 6 hours, this moment be cooled to 15 ℃, 2 hours. Then, regulate bottle temperature to 25 ℃ and maintain this temperature until 2 days. When equilibration time finishes, filter this solution, measure the pH of filtrate and analyze an equal portions filtrate to measure the concentration of Sertraline in the solution with reversed-phase HPLC. With Waters Symmetry C-18,250 * 4.6mm post, 1.0mL/ minute mobile phase eluant solution carry out HPLC and analyze. This post is available from Waters company, 34 Mapple Street, Milford, MA01757. By mixing the 270ml oxolane, 230ml methyl alcohol and 400ml buffer solution prepare mobile phase solution. This buffer solution prepares in 1 premium on currency by adding 1.7ml phosphoric acid and 3.5ml triethylamine. Excessive solid in the receiving flask, dry and with microscope and its degree of crystallinity of heat analysis and research. Acetate water solubility of the present invention is 84mg/ml. The water solubility of Sertraline Pfansteihl salt of the present invention is 125mg/ml. The water solubility of Sertraline L-Aspartic acid salt of the present invention is 28.6mgA/mL. Highly water-soluble allows to discharge in the short period of time more Sertraline material, and it is particularly useful in the acute indication (acute indications). In addition, high-dissolvability is favourable in the infiltration oral controlled release formulation that discharges Sertraline solution with control mode.

The Sertraline acetate, Sertraline Pfansteihl salt, the chemical stability of Sertraline L-Aspartic acid salt has been carried out the sample of acceleration for stabilization sexual assault with reverse hplc mensuration (condition is the same) and has been measured. In the acceleration for stabilization sexual assault, Sertraline acetate sample has carried out the various combinations in the humidity and temperature condition of different time length. The combination of following humidity and temperature condition is particularly useful for estimating the chemical stability of Sertraline and various salt thereof. In these researchs, quantitative Sertraline acetate active and the impurity and the catabolite that exist. Usually, if the amount of the new impurity that detects is lower than 0.1% of used medication amount, think that then medicine is stable. Measured the Sertraline acetate, Sertraline Pfansteihl salt, Sertraline L-Aspartic acid salt is at solid-state and Stability in solution.

The acceleration for stabilization property testing is by the Sertraline acetate, and Sertraline Pfansteihl salt or Sertraline L-Aspartic acid salt carry out under the standard test condition of the humidity and temperature of ICH (the uniformity international conference of the specification requirement of human drug legislation) guide definition. Usually, the Sertraline acetate, Sertraline Pfansteihl salt, the sample of Sertraline L-Aspartic acid salt is in 40 ℃ ± 2 ℃/75%RH ± 5% time 24 weeks of evaluation. In addition, sample places following condition: 50 ℃ ± 2 ℃ C/20%RH, 24 weeks; 70 ℃ ± 2 ℃/RH＜10%, 3 week. Also by being placed on the 0.01N hydrochloric acid solution, in 6 weeks, in 50 ℃ and the 0.01N NaOH solution, in 6 weeks, estimate Sertraline acetates, Sertraline Pfansteihl salt, the stability of Sertraline L-Aspartic acid salt for 50 ℃. Use the reverse hplc assay of the same condition to carry out purity and the degraded of all samples of stability test. When at the Sertraline acetate, Sertraline Pfansteihl salt when carrying out above-mentioned experiment on the Sertraline L-Aspartic acid salt, does not find that content surpasses 0.01% new catabolite of parent compound. The Sertraline acetate, Sertraline Pfansteihl salt, each purity of Sertraline L-Aspartic acid salt sample is greater than 99%.

In the disease that requires in the open and appended claims at treatment this paper, can be with the Sertraline acetate, Sertraline Pfansteihl salt, Sertraline L-Aspartic acid salt are made into for example U.S. Patent No. 4,536,518 disclosed immediate release dosage forms. Perhaps, can be with the Sertraline acetate, Sertraline Pfansteihl salt, Sertraline L-Aspartic acid salt is made into controlled release form, such as slow release formulation, encapsulated solution dosage or delayed release dosage forms. This slow release formulation, the preparation of encapsulated solution dosage and delayed release dosage forms and occupation mode are disclosed in the U. S. application of common pending trial of common transfer that title is respectively " the encapsulated solution dosage of Sertraline " and " delayed release dosage forms of Sertraline " (Pfizer's file number is respectively PC9838JTJ and PC9824JTJ, and each is to specify the PCT application of the U.S. and be incorporated herein by reference).

Usually, the Sertraline acetate, generally with the dosed administration of about 0.2mgA/kg body weight/day to about 10mgA/kg body weight/day, pipe will change according to patient's to be controlled disease and selected concrete method of administration to the greatest extent for Sertraline Pfansteihl salt, Sertraline L-Aspartic acid salt. Typically, preferred dosage range is the about 15mgA-200mgA Sertraline of the average adult patient acetate that body weight is about 70kg, Sertraline Pfansteihl salt, Sertraline L-Aspartic acid salt/sky. Yet preferred dosage will depend on the Sertraline acetate of administration, Sertraline Pfansteihl salt, apparent other factors of the dosage of Sertraline L-Aspartic acid salt and those skilled in the art such as physician.

Abbreviation used herein " Mpa " refers to MPa and " Gpa " refers to gpa.

Term used herein " osmotic tablet " refers to the controlled-release solid formulation by the osmotic pressure driving.

With consistent, therapeutic dose and rate of release relate in claims " Sertraline " refers to active Sertraline, is abbreviated as " mgA " for conveniently, and namely molecular weight is the non-salt of 306.2g/mol, nonhydratable free alkali. Can convert the mgA amount to suitable weight that molecular weight is the Sertraline acetate of 366.3g/mol easily. The molecular weight of 1/4 hydrate forms of Sertraline acetate is 370.8g/mol. The Lactated molecular weight of Sertraline L-is 396.3g/mol. The molecular weight of Sertraline L-Aspartic acid salt is 439.3g/mol.

The present invention will illustrate by following non-restrictive example.Usually, embodiment proves the incidence rate of the gastrointestinal side-effect of sertraline oral and IV administration, the alleviation of these side effect of controlled release form, the preparation of the Sertraline slow release formulation in the scope of the invention, salt, its preparation method etc.

In following examples, used following definition and test:

1. " Q " is used in reference to the amount of the Sertraline of described mgA or percent (%) expression.Q is relevant to time or " sample point " that the solution that takes out predetermined part is used to detect Sertraline, as target take-off time or sample point down with a hour expression.Therefore, 15% " Q ₁" refer to that 15% Sertraline dissolved in 1 hour.

2. except as otherwise noted, the amount of percent (%) expression refers to the percent based on the weight of gross weight.

3. " t _80%" refer to the time that 80% Sertraline discharges from this dosage form (hour).

4. rate of release defines with following formula:

Rate of release=0.8* (dosage)/t _80%Or if in 24 hours, do not discharge the Q of 80% Sertraline ₂₄/ 24

5. " Surelease ^" be Colorcon Inc., West Point, PA are the aqueous of ethyl cellulose, the registered trade mark of complete plastifying polymeric dispersions.

6. " Opadry ^" be Colorcon Inc., West Point, the registered trade mark with the plastifying cellulose ether of a class (comprising hydroxypropyl emthylcellulose, hydroxypropyl cellulose and methylcellulose) that is used for providing at the powder type that water is rebuild is provided PA.

7. " mgA " is the abbreviation of " the milligram number of active Sertraline ".For example, " 200mgA " refers to 200 milligrams active Sertraline.

8. " the many granules of X mgA " (wherein X is a quantity) refers to contain the granose amount of X mgA.For example, " the many granules of 100mgA " refer to contain the weight of many granules of the active Sertraline of 100mgA.

9. dissolution in vitro test: following testing in vitro is used to screen the body endoadaptation of slow release embodiment of the present invention.If concrete dosage form satisfies external or body internal standard disclosed herein, then it is within the scope of the invention.

The slow release formulation of Sertraline is at American Pharmacopeia XXIII (USP), dissolution determination, and the 711st chapter is tested in the instrument 2 disclosed standard USP rotating rod instruments.Rod (becomes many granules if this dosage form is many granules or rapid disintegrate with the 50rpm rotation; then be 100rpm), this stripping (0.13M acetic acid) in as the acetate buffer of the 900mL that contains 0.075M NaCl that regulates pH to 4.0 with KOH of tested media is carried out under 37 ℃.The container that covers stripping is with vaporization prevention.If use gelatine capsule, then need add the trypsin of 0.1mg/ml in buffer.The specified time after test beginning (being about to this dosage form inserts in instrument), from tested media, take out and filteringly wait increment (general 2 or 10ml) and analyze Sertraline by reverse hplc or other suitable quantitative analysis methods.The stripping result be reported as dissolved mgA Sertraline to time or dissolved active Sertraline to the time.The slow release formulation that satisfies following standard is within the scope of the invention: in the zero-time of 80% drug release, (1) Sertraline rate of release is above-mentioned between 1mgA/ hour-40mgA/ hour; (2) the Sertraline rate of release was no more than 40mgA/ hour in arbitrary hour; (3) discharge the Sertraline be less than 70% introducing in first hour in environment for use.

For postponing is the embodiment that the delay of timeliness adds slow release, is undertaken by the experiment of the embodiment of above-mentioned pure slow release fully.This dosage form discharges Sertraline with the speed that is lower than 1mgA/ hour in corresponding to nearly 3 hours or the less time of period of delay, subsequently, discharge Sertraline with the speed between 1mgA/ hour-40mgA/ hour.

The test easily that adds the embodiment of slow release for space of the present invention delay is that the dissolution in vitro test is divided into two-part improvement project, it is described in nineteen ninety-five American Pharmacopeia (USP 23), joint (724), trifle " postpones to discharge (enteric coating) article-general drug release standard ", it is introduced 2 hours test Sertralines and discharges in mimic gastric juice (" acid test "), subsequently the drug release in the intestinal juice of test simulation (" middle property testing ").For do not contain many granules or rapidly disintegrate become granose tablet and capsule, oar stirs with 50rpm.Become granose dosage form for many granules or rapid disintegrate, oar stirs with 100rpm.If use gelatine capsule, then need add the trypsin of 0.1mg/ml in buffer.Two stages of regulating this testing in vitro postpone to add the embodiment of slow release with the space of the present invention that is used to estimate present description.

The embodiment that postpones to add slow release for the space of pH initiation, testing in vitro carries out as described in USP " enteric experiment ", require " acidity " stage (among 0.1N HCls) of dosage form of the present invention (a) in test, discharge Sertraline at least 1 hour with the speed that is no more than 1mgA/ hour, (b) " neutrality " stage of test, the Sertraline rate of release is between 1mgA/ hour-40mgA/ hour, as long as discharge 70% addition of the Sertraline of no more than introducing in first hour of " neutrality " stage of test.If need, " acidity " stage of test part can surpass 1 hour, promptly in addition stricter condition under and this embodiment also within the scope of the invention.Being calculated as follows of Sertraline rate of release in " neutrality " stage of test.80% the dosage that writes down interpolation after postponing in 1 hour is discharged into the time in neutrality (pH6.8) medium, carry out division then, wherein molecule is 80% of this dosage of representing of mgA, and the denominator time that to be 80% the dosage that adds be discharged in neutrality (pH6.8) medium deducts 1 hour (or At All Other Times, if acidic phase was above 1 hour)." acidity " the stage part of test was carried out 1 hour in the 0.1N of 750ml HCl.After 1 hour, add the 250ml tertiary sodium phosphate that contains the 10gm Spheron MD 30/70 and in acid medium, (contain this dosage form), and regulate pH to pH6.8 with 2M HCl or 2M NaOH.The dissolubility of Sertraline in phosphate buffer (pH6.8) is low.Therefore, add in neutral (pH6.8) phosphate medium of Spheron MD 30/70 (1%w/v) with the dissolubility that increases Sertraline so that dissolved " leak condition " (" sink conditions ") to be provided.

The space of causing for the described enzyme of the disclosure postpones to add the embodiment of slow release, and the release of Sertraline is by pancreatic lipase in the small intestinal, esterase, or the existing of protease " initiation ".The delay that causes for lipase adds the external assessment of slow release formulation, with the 5mg/ml porcine pancreatic lipase (Sigma Chem., St.Louis, MO) add the dissolution test second in the dissolve medium of sexual stage.For the delayed release dosage forms of esterase or protease initiation, suitable esterase or protease (as viokase, trypsin, Chymotrypsin, elastoser) are added into the second stage of testing in vitro.Therefore, test is carried out in the identical mode of space delayed dosage forms that causes with pH, but in the sexual stage be suitable for causing enzyme that slow release begins in the presence of carry out.If Spheron MD 30/70 is lipase, esterase or protease degeneration, then the 1st of " neutrality " stage the hour in the existence of enzyme with do not have to carry out under the situation of Spheron MD 30/70.After 1 hour of " neutrality " stage, add the 10g Spheron MD 30/70.

Embodiment 1

This embodiment proves that the slow release formulation (dosage of 200mg divides 16 12.5mg dosage, zero time and the per hour administration in 15 hours) of Sertraline has caused the side effect seriousness that reduces with respect to 200mg agglomerate single dose.

In double blinding, at random, in the parallel group of research of placebo, the healthy male experimenter is divided into three groups.Group A, " agglomerate administration group " divides two 100mg Sertraline immediate-release tablet formulations (ZOLOFT ^R) agent of the single 200mg Sertraline of acceptance.With 50ml water with this tablet administration.Agglomerate administration group was per hour also accepted the 50ml placebo solution in 15 hours.Placebo solution contains lactose, thereby menthol and polyvinylpyrrolidone are guaranteed double blinding with the outward appearance and the mouthfeel of simulation Sertraline solution.Group B, " gradation administration group " accepts identical accumulated dose, in 15 hours with the solution of speed administration 12.5mg Sertraline in 50ml water of 12.5mg potion per hour.B group is also accepted two tablets of placebo when first time administration.The C group, " placebo group " accepts comfort sheet and comfort solution at suitable corresponding time point.All administrations behind overnight fasting of all experimenters.

Before administration, 0.5,1 after the administration, 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,18,20,22,24,36,48,72,96,120,144,168,192 and 240 hours blood samplings.With capillary gas chromatography blood plasma Sertraline concentration.Total general to the exposure of Sertraline be blood plasma Sertraline concentration by measuring each experimenter in every given group to the area under a curve (AUC) of time, calculate the average A UC of this group then and measure.C _MaxBe observed maximum blood plasma Sertraline concentration in the experimenter.T _MaxBe to reach C _MaxTime.The drug plasma dynamics data of this embodiment sees among the table 1-1.

Before administration and the each blood-sample withdrawal, each experimenter fills out an application form, it is made of a series of " visual simulation scales " (" Visual Analogue Scales "), wherein requires each experimenter to classify with 0-10 on the seriousness of some possible side effect.The experimenter is apprised of " 0 " and means no effect, and " 10 " refer to the worst may acting on.

Have 45 experimenters and finished this research, A, B, the C group respectively has 15 people.Eight kinds of side effect for estimating at 30 time points have obtained totally 10,800 visual simulation scale evaluations of estimate.

It is similar that total general Sertraline that table 1-1 proof is reflected in two administration groups of A among the AUC and B group exposes.For gradation administration group, such as material, C _MaxBe lower and T _MaxBe long, the single agglomerate agent because administration was carried out in 15 hours.Three experimenters of 200mg agglomerate administration group were vomiting in 4.15,11.2 and 7.6 hours.Because occurring in whole three experimenters' basic blood drug level, vomiting reaches T back and two _MaxAfter, these experimenters' date processing is not different with other experimenter's date processing.The vomiting incident does not take place in the experimenter of 15 hours gradation dosage regimens.Therefore, 15 hours gradation dosage regimens show the incidence of vomiting with respect to the reduction of agglomerate dosage regimen.

The following side effect visual simulation scale data analysis that carries out.To concrete experimenter's concrete side effect (as stomachache), the visual analogue scale score addition after the administration in 24 hours gets " cumulative score ".All members' " score adds up " addition is organized in one treatment, divided by the quantity of experimenter in this group score that on average added up.The scale of the score that on average adds up is not corresponding to initial 0-10 scale, because it has reflected the summation of all the non-zero scores in the whole evaluation phase.Table 1-2 represents the score that on average adds up of a series of gastrointestinal side-effects: stomachache, feel sick, and just anxious, regurgitation, diarrhoea, and angina abdominis.Also estimated non-gastrointestinal side-effect: dizzy and tremble.

Table 1-2 has proved that the overall seriousness of the inductive side effect of Sertraline of 15 hours gradation drug treatments is lower.

Table 1-1

With single dose administration, or with the per hour administration in 15 hours of 16 12.5mg dosage

The Sertraline pharmacokinetics (meansigma methods) of 200mg dosage

Treatment

C _max(ng/ml)

T _max(hour)

AUC ₀-last (ng. hour/ml)

200mg single dose (A group)	74	6	1646
200mg single dose (A group)	74	6	1646	Hour 12.5mg/ totally 15 hours (B group)	32	16	1227

Table 1-2

The visual simulation score data that on average adds up of various side effect, in every group whole 15

The experimenter's is average, sees the explanation of " score on average adds up " in the description

Score on average adds up

Side effect	A organizes (agglomerate administration)	B organizes (dividing 16 administrations)	C organizes (placebo)
Side effect	A organizes (agglomerate administration)	B organizes (dividing 16 administrations)	C organizes (placebo)	Stomachache	2.7	0.1	1.7
Feel sick	17.5	2.6	1.2	Stomachache	2.7	0.1	1.7
Feel sick	17.5	2.6	1.2	Just anxious	3.1	0.5	0.6
Regurgitation	4.0	0.3	0.3	Just anxious	3.1	0.5	0.6
Regurgitation	4.0	0.3	0.3	Angina abdominis	3.1	0.1	0.9
Diarrhoea	3.9	0.2	0.2	Angina abdominis	3.1	0.1	0.9
Diarrhoea	3.9	0.2	0.2	Dizzy	13.8	0.5	6.8
Tremble	7.9	1.7	0.5	Dizzy	13.8	0.5	6.8

Embodiment 1 proves that further (1) side effect can be released into gastrointestinal speed by the control Sertraline and alleviate, (2) cause the gastrointestinal tract of gradation administration and systemic side effects to compare to that the agglomerate administration is reduced to or contain the also useful side effect feature of slow release formulation that is less than the 200mg Sertraline near level (table 1-2) and (3) of placebo with the release of the speed of 200mg/15hr=13.3mg/hr.In the process of the first half that the 200mg/15hr gradation administration of carrying out present embodiment is studied, in 7 hours, discharge eight 12.5mg dosage, observed side effect intensity is low (accumulated dose 100mg).Similarly, in preceding 1/4th stages that gradation administration in 200mg/15 hour of present embodiment is studied, discharged the dosage of four 12.5mg in 3 hours, observed side effect intensity is low (accumulated dose 50mg).

On the other hand, side effect (especially general mediation mediate but not Sertraline directly contacts with gastrointestinal tremble with dizzy) can improve by the maximum Sertraline concentration of controlling in the systemic circulation after oral.At this embodiment, 16 * 12.5mg gradation administration provides C _MaxBe 32ng/ml, side effect seriousness is extremely low.On the other hand, the administration of 200mg agglomerate provides C _MaxBe 74ng/ml, and show pronounced side effects.

Embodiment 2

This embodiment prove Sertraline slow release formulation (dosage of 200mg divide 8 times zero the time and the per hour administration in 7 hours) caused the side effect seriousness that reduces with respect to 200mg agglomerate single dose.

In double blinding, at random, in the parallel group of research of placebo, the healthy male experimenter is divided into three groups.Group A (n=14) is with two 100mg Sertraline immediate-release tablet formulations (ZOLOFT ^R) accept 200mg Sertraline agent single dose (" agglomerate administration " group).With 50ml water with this tablet administration.Group A per hour also accepted the 50ml placebo solution in 7 hours.Placebo solution contains lactose, menthol.Group B (n=16) accepts identical accumulated dose, in 7 hours with the solution (" gradation administration group ") of speed administration 25mg Sertraline in 50ml water of a 25mg dosage per hour.B group is also accepted two tablets of placebo when first time administration.C group (n=15) is accepted comfort sheet and comfort solution at suitable corresponding time point.All administrations behind overnight fasting of all experimenters.

Before administration, 0.5,1 after the administration, 2,3,4,5,6,7,8,9,11,13,15,17,24,48,72,96,120 and 144 hours blood samplings.Also survey blood drug level, C in an identical manner _Max, T _MaxAnd AUC.The drug plasma dynamics data of this embodiment sees among the table 2-1.

Before administration and the each blood-sample withdrawal, each experimenter fills out an application form, and it is by constituting as embodiment 1 described a series of " visual simulation scale ".Have 45 experimenters and finished this research.Estimate three kinds of side effect at 30 time points, obtained totally 4,500 visual simulation scale evaluations of estimate.

It is similar that total general Sertraline that table 2-1 proof is reflected in two administration groups of A among the AUC and B group exposes.For gradation administration group, such as material, C _MaxBe lower and T _MaxBe long, the single agglomerate dosage form because administration was carried out in 7 hours.Four experimenters of 200mg agglomerate administration group vomitted 2.6,2.8 in 2.8 and 3.8 hours.These four experimenters' pharmacokinetic data is not included in table 2-1 average.An experimenter of 7 hours gradation dosage regimens was vomiting in 12.6 hours.Because this occurs in this individual T _MaxBack 3.5 hours, its data are not included in the average analysis of gradation administration group.Observe 4 times in agglomerate administration group and gradation administration group respectively and 1 vomiting incident shows, gradation administration in 7 hours shows lower incidence of vomiting, and the Sertraline dosage of the treatment shown in the pharmacokinetics AUC is provided simultaneously.

As described in embodiment 1, carry out the analysis of side effect visual simulation calibration data.Table 2-2 has proved that the overall seriousness of the inductive side effect of Sertraline of 8 hours gradation drug treatments is lower.

Therefore, side effect can be released into gastrointestinal speed and alleviates by the control Sertraline.Thereby embodiment 2 proofs discharge the reduction (table 2-2) that causes side effect seriousness with the speed of 200mg/7hr=28.6mg/hr (or slower).

Embodiment 2 also proves and contains the also useful side effect feature of slow release formulation that is less than the 200mg Sertraline.In the process of carrying out the present embodiment first half, in 3 hours, discharge four 25mg dosage, observed side effect intensity is low (accumulated dose 100mg).

As embodiment 1, side effect (especially trembling with dizzy) can improve by the maximum Sertraline concentration in the systemic circulation behind the control oral administration.In this embodiment, 8 * 25mg gradation administration provides C _MaxBe 46ng/ml, and the administration of 200mg agglomerate provides C _MaxBe 75ng/ml.This 8 * 25mg gradation dosage regimen shows the side effect seriousness lower than agglomerate dosage regimen.

Table 2-1

With single dose administration, or with the per hour administration in 8 hours of 7 25mg dosage

The Sertraline pharmacokinetics (meansigma methods) of 200mg dosage

Treatment	C _max(ng/ml)	T _max(hr)	AUC _{O-is last}(ng.hr/ml)
Treatment	C _max(ng/ml)	T _max(hr)	AUC _{O-is last}(ng.hr/ml)	The 200mg single dose	75	5.4	1744
25mg/hr totally 7 hours	46	10.4	1439	The 200mg single dose	75	5.4	1744

Table 2-2

Score on average adds up

Side effect	A organizes (agglomerate administration)	B organizes (dividing 8 administrations)	C organizes (placebo)
Side effect	A organizes (agglomerate administration)	B organizes (dividing 8 administrations)	C organizes (placebo)	Regurgitation	3.9	0.1	0.1
Dizzy	10.4	4.8	2.1	Regurgitation	3.9	0.1	0.1
Dizzy	10.4	4.8	2.1	Tremble	8.9	2.7	0.3

Embodiment 3

This embodiment proof is when Sertraline directly delivers medicine to the gastrointestinal various piece, and its absorption is different.The dosage form that discharges most of Sertraline before arriving horizontal stroke or descending colon provides higher general Sertraline than the dosage form that discharges the Sertraline of significant quantity in horizontal stroke or descending colon and exposes.

Each scheme administration 200mg Sertraline or placebo that intersects with four kinds of different modes of two groups of six volunteers (A and B group).Administration is by (1) oral tablet, or (2) inject stomach by nasointestinal tube with solution, duodenum, or the ileocecum district of small intestinal, or (3) inject transverse colon by the anus intubate.

Under four kinds of different situations, the A winding is subjected to (1) sertraline oral promptly to release sheet to add the placebo solution of injecting stomach, or (2) oral placebo sheet adds the Sertraline solution that injects stomach, or (3) oral placebo sheet adds the Sertraline that returns blind joint place that injects small intestinal, and (4) oral placebo sheet adds the placebo solution of returning blind joint place of injecting small intestinal.Under four kinds of different situations, the B winding is subjected to (1) sertraline oral promptly to release sheet to add the placebo solution of injecting duodenum, or (2) oral placebo sheet adds the Sertraline solution that injects duodenum, or (3) oral placebo sheet adds the Sertraline that injects transverse colon, and (4) oral placebo sheet adds the placebo solution of injecting transverse colon.

The sertraline oral preparation divides the administration of two 100mg sheets.With the speed administration of 20ml/min as the injectant of 2mg/ml solution 5 minutes.

Before the administration, after the administration 0.5,1,1.5,2,4,6,8,10,12,16,24,36,48,72,96,120,144,192 and 240 hours blood-sample withdrawals.Also press embodiment 1 and measure Sertraline blood drug level, C _Max, T _MaxAnd AUC.The drug plasma dynamics data of this embodiment is shown among the table 3-1.

Table 3-1 provides the measured average C of various dosage regimens _Max, T _MaxAnd AUC.The AUC (total general exposes) that injection harmonization of the stomach duodenum district provides is to record 79% and 110% of AUC after the oral tablet administration.Therefore, the absorption (except farther zone, because the material of administration far moved along with the time) from these zones of gastrointestinal is similar to the absorption from oral tablet.Inject AUC that the ileocecal region of small intestinal produces and be record behind the oral tablet 62%.Therefore, this ileocecal region (except farther zone) has the ability of limited absorption Sertraline.Inject AUC that transverse colon causes and be oral tablet measured 16%.Therefore, horizontal (with farther falling) colon has the ability of more limited absorption Sertraline.

Table 3-1

Be discharged into the pharmacokinetics of the 200mg Sertraline of gastrointestinal various piece

The A group
The A group				Route of administration	C _Maximum(ng/ml)	T _Maximum(hour)	AUC _{0-is last}(ng hour/ml)
Oral tablet	39.9	7.0	1174.5	Route of administration	C _Maximum(ng/ml)	T _Maximum(hour)	AUC _{0-is last}(ng hour/ml)
Oral tablet	39.9	7.0	1174.5	Stomach injects	35.6	7.0	923.1
Return blind injection	27.3	5.0	727.1	Stomach injects	35.6	7.0	923.1
Return blind injection	27.3	5.0	727.1	The B group
Route of administration	C _Maximum(ng/ml)	T _Maximum(hour)	AUC _{0-is last}(ng hour/ml)	The B group
Route of administration	C _Maximum(ng/ml)	T _Maximum(hour)	AUC _{0-is last}(ng hour/ml)	Oral tablet	44.7	6.7	1153.4
Duodenum injects	48.8	3.7	1270.3	Oral tablet	44.7	6.7	1153.4
Duodenum injects	48.8	3.7	1270.3	Colon injects	10.9	4.4	179.4

Embodiment 4

This embodiment illustrates preparation slow release Sertraline hydrophilic matrix tablet, and it is to form based on it, and the different speed of size and shape discharges Sertraline.The method comprises the table 4-1 of (1) mixing except magnesium stearate, the whole components shown in 4-2 and the 4-3; (2) screening and this identical component of remix; (3) add and mix magnesium stearate; And with final mixture tabletting.

Size is 200-350g batch in, with Turbula vibroscope system (Basal, Switzerland) the sertraline salts hydrochlorate was mixed 15 minutes with other all composition except magnesium stearate in suitable cylinder.Then, with this mixture by 20 mesh sieves and jolting 15 minutes again.Then, added magnesium stearate and this mixture of jolting 2 minutes.Tablet machine (Manesty F-Press with routine, Manesty Machines, Liverpool, England) whole mixture is pressed into tablet, instrument punching with 1/4 inch * 3/4 inch tunicle of embodiment 4A-4M, 13/32 inch standard round concave surface (SRC) punching of embodiment 4N and 4O, the instrument punching of 1/4 inch * 1/2 inch tunicle of embodiment 4P-4X, perhaps the instrument punching of 1/4 of embodiment 4Y-4AD inch * 9/16 inch tunicle.The compositions of the mixture preparation by direct each component of compression is summarized in table 4-1 (embodiment 4A-4O) with 200mgA Sertraline/sheet respectively, be shown in table 4-2 (embodiment 4P-4X) with 100mgA Sertraline/sheet, be shown in table 4-3 (embodiment 4Y-4AD) with 50mgA Sertraline/sheet.

Table 4-1

The slow release hydrophilic matrix tablet compositions of on F-Press, directly suppressing with the dosage of 200mg/ sheet

Embodiment	Sertraline chemical compound % ^*	HPMC K100LV ¹ ％	HPMC K4M ² ％	Lactose %	DCP ³ ％	MgSt ⁴ ％	Sheet heavy (mg)
Embodiment	Sertraline chemical compound % ^*	HPMC K100LV ¹ ％	HPMC K4M ² ％	Lactose %	DCP ³ ％	MgSt ⁴ ％	Sheet heavy (mg)	4A	29.8	24.9	5.0	-	39.3	1.0	750
4B	29.8	34.9	5.0	-	29.3	1.0	750	4A	29.8	24.9	5.0	-	39.3	1.0	750
4B	29.8	34.9	5.0	-	29.3	1.0	750	4C	29.8	41.6	8.2	-	19.4	1.0	750
4D	39.8	24.9	5.0	-	29.3	1.0	562	4C	29.8	41.6	8.2	-	19.4	1.0	750
4D	39.8	24.9	5.0	-	29.3	1.0	562	4E	29.8	24.9	5.0	39.3	-	1.0	750
4F	29.8	34.9	5.0	29.3	-	1.0	750	4E	29.8	24.9	5.0	39.3	-	1.0	750
4F	29.8	34.9	5.0	29.3	-	1.0	750	4G	29.8	41.6	8.2	19.4	-	1.0	750
4H	39.8	24.9	5.0	29.3	-	1.0	562	4G	29.8	41.6	8.2	19.4	-	1.0	750
4H	39.8	24.9	5.0	29.3	-	1.0	562	4I	30.0	20.0	10.0	38.0	-	2.0	750
4J	30.0	15.0	15.0	38.0	-	2.0	750	4I	30.0	20.0	10.0	38.0	-	2.0	750
4J	30.0	15.0	15.0	38.0	-	2.0	750	4K	30.0	50.0	10.0	8.0	-	2.0	750
4L	30.0	33.3	16.7	18.0	-	2.0	750	4K	30.0	50.0	10.0	8.0	-	2.0	750

4M	30.0	25.0	25.0	18.0	-	2.0	750
4M	30.0	25.0	25.0	18.0	-	2.0	750	4N	39.8	24.9	5.0	-	29.3	1.0	562
4O	39.8	24.9	5.0	29.3	-	1.0	562	4N	39.8	24.9	5.0	-	29.3	1.0	562

¹HPMC refers to hydroxypropyl emthylcellulose, and Methocel K100LV (Dow Chemical, Midland, MI)

²HPMC refers to hydroxypropyl emthylcellulose, and Methocel K4M (Dow Chemical, Midland, MI)

³DCP refers to the calcium phosphate dihydrate of binary, and Emcompress (Edward Mendell Co., Surrey, UK)

⁴MgSt refers to magnesium stearate

^*Sertraline chemical compound % reflection reaches the amount of the bent salt of the required house of 200mgA.

Table 4-2

The slow release hydrophilic matrix tablet compositions of on F-Press, directly suppressing with the dosage of 100mg/ sheet

Embodiment	Sertraline chemical compound % ^*	HPMC K100LV ¹ ％	HPMC K4M ² ％	Lactose %	MgSt ³ ％	Sheet heavy (mg)
Embodiment	Sertraline chemical compound % ^*	HPMC K100LV ¹ ％	HPMC K4M ² ％	Lactose %	MgSt ³ ％	Sheet heavy (mg)	4P	30.0	20.0	10.0	38.0	2.0	375
4Q	15.0	24.4	12.2	46.4	2.0	750	4P	30.0	20.0	10.0	38.0	2.0	375
4Q	15.0	24.4	12.2	46.4	2.0	750	4R	30.0	15.0	15.0	38.0	2.0	375
4S	15.0	18.3	18.3	46.4	2.0	750	4R	30.0	15.0	15.0	38.0	2.0	375
4S	15.0	18.3	18.3	46.4	2.0	750	4T	30.0	33.3	16.7	18.0	2.0	375
4U	15.0	40.6	20.4	22.0	2.0	750	4T	30.0	33.3	16.7	18.0	2.0	375
4U	15.0	40.6	20.4	22.0	2.0	750	4V	30.0	26.6	13.4	28.0	2.0	375
4W	15.0	32.5	16.3	34.2	2.0	750	4V	30.0	26.6	13.4	28.0	2.0	375
4W	15.0	32.5	16.3	34.2	2.0	750	4X	15.0	30.5	6.1	46.4	2.0	750

³MgSt refers to magnesium stearate

Table 4-3

The slow release hydrophilic matrix tablet compositions of on F-Press, directly suppressing with the dosage of 50mg/ sheet

Embodiment

Sertraline

HPMC

Lactose

MgSt ³

Sheet is heavy

	Chemical compound % ^*	K100LV ¹ ％	K4M ² ％	％	％	(mg)
	Chemical compound % ^*	K100LV ¹ ％	K4M ² ％	％	％	(mg)	4Y	30.0	20.0	10.0	38.0	2.0	187.5
4Z	15.0	24.4	12.2	46.4	2.0	375	4Y	30.0	20.0	10.0	38.0	2.0	187.5
4Z	15.0	24.4	12.2	46.4	2.0	375	4AA	15.0	18.3	18.3	46.4	2.0	375
4AB	15.0	40.6	20.4	22.0	2.0	375	4AA	15.0	18.3	18.3	46.4	2.0	375
4AB	15.0	40.6	20.4	22.0	2.0	375	4AC	15.0	32.5	16.3	34.2	2.0	375
4AD	15.0	30.5	6.1	46.4	2.0	375	4AC	15.0	32.5	16.3	34.2	2.0	375

³MgSt refers to magnesium stearate

Embodiment 5

The sustained-release matrix tablets of the selection of the embodiment 4 shown in the table 5-1 discharges with external slow release dissolution testing procedure test, its Sertraline of representing with the percent of accumulated dose with mensuration with the quantitative Sertraline of reversed-phase HPLC analysis, as following.

The slow release formulation of Sertraline is at American Pharmacopeia XXIII (USP), dissolution determination, and the 711st chapter is tested in the instrument 2 disclosed standard USP rotation oar instrument.Oar carries out under 37 ℃ in (0.13M acetic acid) in as the acetate buffer of the 900mL that contains 0.075M NaCl that transfers pH to 4.0 with KOH of tested media with 50rpm rotation and stripping.The container that covers stripping is with vaporization prevention.The specified time after test beginning (being about to this dosage form inserts in instrument), from tested media, take out and filteringly wait increment (general 2 or 10ml) and by the following analysis Sertraline of reverse hplc.

Quantitative by the following Sertraline that carries out of reversed-phase HPLC.The fixed volume of 20 μ l is injected analytical column (150mm length * 3.9mm diameter Nova-Pac C-18 post).Permanent composition flow of solvent is 40/15/45 aqueous acetic acid salt buffer, methanol and acetonitrile composition by percent by volume.The aqueous acetic acid salt buffer is prepared as follows: (1) adds the 2.86ml glacial acetic acid 1000ml conical flask that has magnetic stirring bar that places ice bath; (2) stir down with in the 3.48ml triethylamine adding flask; (3) and with flask be added to scale and good the mixing.The methanol (15%v/v) and the HPLC level acetonitrile (45%v/v) that add the HPLC level in hydrotropism's acetate buffer (40%).After mixing fully, vacuum filtration mobile phase also outgases with 0.45 μ m PTFE filter membrane (Lid-X 305, disposable solid-liquid separator).Flow rate of mobile phase is 1.8ml/min, detects Sertraline with UV under 254nm.

Be reported as dissolved Sertraline percent the dissolution of time be the results are shown in table 5-1 (n=3 sheet).Embodiment 4P, 4Q, 4V, 4X, 4Z, 4AB, 4AC and 4AD satisfy the dissolution standard and are slow release embodiments of the present invention.Do not have test chart 4-1, other prescription of 4-2 and 4-3, but it also is a slow release embodiment of the present invention.

Table 5-1

Table 4-1, the external Sertraline slow release of the hydrophilic matrix tablet compositions shown in 4-2 and the 4-3

Embodiment	Q ₁(％)	Q ₄(％)	Q ₈(％)	Q ₁₂(％)	Q ₁₆(％)	Q ₂₄(％)
Embodiment	Q ₁(％)	Q ₄(％)	Q ₈(％)	Q ₁₂(％)	Q ₁₆(％)	Q ₂₄(％)	4P	13.2	26.6	41.4	56.1	70.0	89.7
4Q	9.6	20.4	32.4	47.8	60.2	75.2	4P	13.2	26.6	41.4	56.1	70.0	89.7
4Q	9.6	20.4	32.4	47.8	60.2	75.2	4V	6.3	20.9	40.2	54.0	65.1	82.1
4X	8.9	24.8	44.1	61.3	73.7	92.2	4V	6.3	20.9	40.2	54.0	65.1	82.1
4X	8.9	24.8	44.1	61.3	73.7	92.2	4Z	11.3	25.8	43.0	59.0	73.3	88.4
4AB	5.0	16.4	28.7	40.4	51.9	70.7	4Z	11.3	25.8	43.0	59.0	73.3	88.4
4AB	5.0	16.4	28.7	40.4	51.9	70.7	4AC	5.7	19.6	37.3	54.9	70.4	92.2
4AD	9.6	28.5	52.0	72.4	86.2	96.8	4AC	5.7	19.6	37.3	54.9	70.4	92.2

Q=represents the report value of drug release percent of 3 meansigma methods.

Embodiment 6

This embodiment proves that some Sertraline side effect (as feeling sick regurgitation and diarrhoea) partly or is mainly mediated with upper gastrointestinal directly the contact by oral Sertraline, but not mediates by absorbing the Sertraline that exists in the systemic circulation of back.The Sertraline that shows the delayed release dosage forms (promptly postponing to add slow release formulation) before the slow release by oral administration is avoided the Sertraline side effect that therefore stomach can further improve local mediation.

Bigger double blinding in a group at random, in the parallel group of research of placebo, is divided into two groups (research I) with healthy male subjects.Two 100mg Sertralines of A component sheet (the commercially available 100mg tablet of Zoloft) is accepted single 200mg Sertraline dosage (" agglomerate administration group ").With 50 these sheets of ml water administration.The B winding is subjected to two tablets of placebo.All experimenters administration after the fasting surfeit.

Before administration, 0.5,1 after the administration, 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,18,20,22,24,36,48,72,96,120,144,168,192 and 240 hours blood samplings.With capillary gas chromatography blood plasma Sertraline concentration.Total general is to the area under a curve (AUC) of the exposure of the Sertraline blood plasma Sertraline concentration by each experimenter in measuring every given group to the time, calculates the average A UC of this group then and measures.C _MaxBe observed maximum blood plasma Sertraline concentration in the experimenter.

T _MaxBe to reach C _MaxTime.Behind the administration 200mg Sertraline, average C _MaxBe 74ng/ml, average T _MaxBe 6 hours, and average A UC is 1646ng-hr/ml (15 experimenters' is average).

Carry out similar second research (research II).Behind the administration 200mg Sertraline, average C _MaxBe 75ng/ml, average T _MaxBe 5.4hr, average A UC is 1744ng-hr/ml (11 experimenters' is average).Four experimenters of 200mg dosage group vomitted 2.6,2.8 in 2.8 and 3.8 hours.These four experimenters' data are not included in the pharmacokinetics meansigma methods.

Before administration and the each blood-sample withdrawal, each experimenter fills out an application form, and it is made of a series of " visual simulation scales ", wherein requires each experimenter to comment grade according to 0-10 on the seriousness of some possible side effect.The experimenter is apprised of " 0 " and means no effect and " 10 " refer to the worst may acting on.The indication experimenter is between the side effect of 0 to 10 moderate.

Have 30 experimenters and finished research I, A, the B group respectively has 15 people.Each side effect for estimating at 30 time points has obtained totally 900 visual simulation scale evaluations of estimate.Totally 29 experimenters have finished that research II:A group has 14 people and the B group has 15 people.Every kind of side effect for estimating at 30 time points has obtained 870 visual simulation scale evaluations of estimate.

Fig. 6 represents to study the relation between the visual simulation score of feeling sick of blood plasma Sertraline concentration among the I and average report certainly.Following this figure that obtains being called pharmacokinetics-medicine efficacy relation figure (" PK/PD figure ").To 15 experimenters in the A group, at each blood-sample withdrawal time point with blood plasma Sertraline concentration on average with the average Sertraline concentration of the A group that obtains each time point.Similarly, to 15 experimenters of A group, it is average at each time point the visual simulation of feeling sick to be got score value.The average nauseating score (Y-axis) of each time point is mapped to the Sertraline plasma concentration (X-axis) of corresponding time point.Arrow proof PK/PD relation on the figure developed along with the time.The PK/PD figure of Fig. 6 shows " clockwise hysteresis " of 200mg agglomerate dosage.Therefore, along with time lapse, the score of feeling sick and blood plasma Sertraline concentration all increase up to nauseating score and are being lower than C _MaxBlood plasma house blood woods concentration the time reach maximum.When reaching C _MaxDuring (～70ng/ml), nauseating score drops to lower value.Along with subsequently blood plasma Sertraline concentration reduces, think that nauseating score value is lower than the identical measured score of blood plasma Sertraline concentration of time point formerly.This " clockwise hysteresis " (or " Proteresis ") meets such explanation, be Sertraline inductive feel sick significantly at contacting by Sertraline and GI road direct mediate but not mediate by the Sertraline that exists in the general blood fully because on average nauseating score is not to be relevant to blood plasma Sertraline concentration monotonously.Early stage time point (0-3hr) after oral, the Sertraline of oral administration mainly contacts with stomach.Because feeling sick not is directly to be relevant to blood plasma Sertraline concentration monotonously, and obviously mainly local mediation by contacting with gastrointestinal, in the gastrointestinal tract of bottom such as duodenum or jejunum, discharge Sertraline and can cause reducing, thereby and reduce and feel sick with the time of contact of upper gastrointestinal wall.

Among the research I, diarrhoea also shows clockwise hysteresis in its side effect score in to blood plasma Sertraline concentration curve.Obtained maximum diarrhoea score in 3 hours after administration, this is out and away early than the average blood plasma T that observes among these experimenters _Max6 hours.Therefore, the release of delay sertraline oral can cause less diarrhoea up to passing stomach.

As above-mentioned, in research 2, four experimenters show regurgitation.The individual PK/PD figure of these experimenters' side effect regurgitation shows clockwise hysteresis.Therefore, postpone the release of sertraline oral up to reducing regurgitation by stomach.

Embodiment 7

This embodiment illustrates preparation slow release Sertraline of the present invention granose method, and it comprises with microcrystalline Cellulose as nodulizer, and water is as granulating agent, prepares the many granular core of Sertraline of coating not up to reaching mean diameter＞1mm by the rotating granulation method.

With the fluid bed processor that has the rotor insert (Glatt GPCG-1, Glatt Air Techniques, Ramsey, NJ) the many granules of preparation Sertraline.300g Sertraline medicine and 300g microcrystalline Cellulose are housed as nodulizer in the rotating cylinder.Then, tangentially spray water in the revolving bed of medicine and microcrystalline Cellulose up to reaching cohesion terminal point (by the mean diameter definition).After finishing granulation, dry many granules are lower than 2% (measuring by loss on drying or LOD) up to its water content in rotary fluidized bed.These granose compositions and main technologic parameters are listed among the table 7-1.

Table 7-1

Used many granulometric composition of slow release Sertraline and main technologic parameters in the rotating granulation processing

Embodiment number	Sertraline ^*(gram)	Avicel (gram)	Water (gram)	Spinner velocity (rpm)	Spray velocity (g/min)	Terminal point LOD (%H ₂O)	Mean diameter (μ m)
Embodiment number	Sertraline ^*(gram)	Avicel (gram)	Water (gram)	Spinner velocity (rpm)	Spray velocity (g/min)	Terminal point LOD (%H ₂O)	Mean diameter (μ m)	7A	300	300	1100	640	15-20	49	1200

^*The Sertraline amount of hydrochloride form

Embodiment 8

This embodiment illustrates the method for the many granules of preparation slow release Sertraline of the present invention, and it discharges with different rates, and this depends on the thickness of sustained release coating.This method comprises that (1) makes the not Sertraline many granular core of coating as granulation agent and water or binder solution by the rotation granulation with having or not having microcrystalline Cellulose; (2) on nuclear, apply the speed limit coating.This embodiment has further estimated the release characteristic of the many granules of slow release.

Add multiplexer (Glatt GPCG-1, Glatt Air Techniques, Ramsey, NJ) the many granules of preparation Sertraline with the fluid bed that the rotor insert is housed.300-500 gram Sertraline medicine and 0-500 gram microcrystalline Cellulose are housed as nodulizer in this rotating cylinder.Tangentially spray into water, plastifying hydroxypropyl emthylcellulose (Opadry ^TM) or polyvinylpyrrolidone (Povidone C15) binder solution (10% solid concentration) in the revolving bed up to reaching cohesion terminal point (by the mean diameter definition).In the preparation process of these preparations, the target mean diameter is between 100-1400 μ m.After finishing granulation, dry final many granules are less than 2% (loss on drying, LOD measures) up to its water content in rotary fluidized bed.Water is specified among the table 8-1 of embodiment 8A-8F as the summary of the composition of many granules of granulating agent preparation.Utilization is made up of as the many granular core in the said preparation preparation process of granulating agent the binder solution of aqueous Opadry or Povidone solution composition, and preparation parameter is shown among the table 8-2 of embodiment 8G-8S with the summary of the final mean diameter that is produced.

Table 8-1

The many granular core of Sertraline used in the rotation pelletization of water as granulating agent are formed and preparation parameter

Embodiment number	Sertraline (gram)	Avicel (gram)	Water (gram)	Spinner velocity (rpm)	Spray velocity (g/min)	Terminal point LOD (b) (%H ₂O)	Mean diameter (μ m)
Embodiment number	Sertraline (gram)	Avicel (gram)	Water (gram)	Spinner velocity (rpm)	Spray velocity (g/min)	Terminal point LOD (b) (%H ₂O)	Mean diameter (μ m)	8A	300	300	1340	640	13	39	320
8B	300	300	1340	640	12	41	470	8A	300	300	1340	640	13	39	320
8B	300	300	1340	640	12	41	470	8C	500	500	2950	640-585	13-15	42	465
8D	335	165	630	630	14	36	510	8C	500	500	2950	640-585	13-15	42	465
8D	335	165	630	630	14	36	510	8E	300 ^(a)	300	700	630	13	37	370
8f	300	300	1060	630	12	45	600	8E	300 ^(a)	300	700	630	13	37	370

(a) spray the sertraline salts hydrochlorate＜10 μ m that mill

(b) LOD-loss on drying.

Table 8-2

With used in the rotating granulation process of binder solution as granulating agent

The many granular core of Sertraline form and preparation parameter

Embodiment number	Sertraline (gram)	Avicel (gram)	Binding agent (10%)	Spinner velocity (rpm)	Spray velocity (g/min)	Outlet temperature (℃)	Air velocity (Pa)	Mean diameter (μ m)
Embodiment number	Sertraline (gram)	Avicel (gram)	Binding agent (10%)	Spinner velocity (rpm)	Spray velocity (g/min)	Outlet temperature (℃)	Air velocity (Pa)	Mean diameter (μ m)	8G	500	0	OC	640	5-15	33	10-14	530
8H	500	0	OC	640	5	34	10	130	8G	500	0	OC	640	5-15	33	10-14	530
8H	500	0	OC	640	5	34	10	130	8I	500	0	OC	640	5	32	10	205
8J	500	0	OC	640	10	27	12	270	8I	500	0	OC	640	5	32	10	205

8K	400	100	OC	640	15	30	13	320
8K	400	100	OC	640	15	30	13	320	8L	375	125	OC	800	26	31	20	680
8M	375	125	OC	810	21	37	10	340	8L	375	125	OC	800	26	31	20	680
8M	375	125	OC	810	21	37	10	340	8N	375	125	PVP	800	25	33	8	Do not survey
8O	375	125	OC	855	24	36	8	1400	8N	375	125	PVP	800	25	33	8	Do not survey
8O	375	125	OC	855	24	36	8	1400	8P	375	125	OC	855	25	37	8	390
8Q	375	125	OC	855	24	36	10	510	8P	375	125	OC	855	25	37	8	390
8Q	375	125	OC	855	24	36	10	510	8R	375	125	OC	855	24	37	12	360
8S	375	125	OC	855	24	36	11	430	8R	375	125	OC	855	24	37	12	360

OC refers to Opadry ^TMClear, plastifying hydroxypropyl emthylcellulose

PVP refers to Povidone C15, plastifying polyvinylpyrrolidone.

Then, rotating fluidized bed (Glatt GPCG-1, Glatt Air Techniques, Ramsey, NJ) in the speed limit coating spray bag by many granular core of Sertraline granule (implementing 8D) up to reaching required terminal point (coating weighs %).Among this embodiment, the speed limit coating is by being diluted to 25% solid plastifying ethyl cellulose (Surelease ^TM) suspension and hydroxypropyl emthylcellulose (Opadry ^TM, Colorcon Inc.) forms, and weight ratio is 85%Surelease ^TMTo 15%Opadry ^TMWith this coating be applied to by on the made many granular core granule of present embodiment to coating content between 5wt% to 25wt%.

Embodiment 9

This embodiment illustrates the non-erosion property matrix tablet of preparation slow release Sertraline.The method comprises the whole components of (1) mixing except magnesium stearate; (2) screening and this identical component of remix; (3) add and mix magnesium stearate; And (4) are with final mixture tabletting.This embodiment has further estimated the Sertraline release in vitro feature of this matrix tablet with the described testing in vitro of this description.

Size is 100g batch in, with Turbula vibroscope system (Basal, Switzerland) Sertraline was mixed 10 minutes with other all composition except magnesium stearate in suitable cylinder.Then, this mixture was passed through 40 mesh sieves and remix 5 minutes.Then, add magnesium stearate and mixing 5 minutes.Use Manesty F-Press, (Manesty Machines, Liverpool England), are pressed into tablet with whole mixture, use the top to the diameter ratio at the end be 1: 3 and high be 2: 5 taper tablet machining tool punching to the base ratio.Directly the made compositions summary with 127mgA Sertraline/sheet of this formula mixture of compression is shown among the table 9-1.

Table 9-1

On F-Press, be the 127mgA/ sheet by the made dosage of direct compression

The non-erosion property matrix tablet of slow release compositions

% Sertraline chemical compound ^*	％Ethocel ¹	The % lactose	％MgSt	Sheet heavy (mg)
% Sertraline chemical compound ^*	％Ethocel ¹	The % lactose	％MgSt	Sheet heavy (mg)	33.7	40.0	24.3	2.0	420

1Ethocel ^TM，Ethylcellulose NF Standard Premium，viscosity 10，Dow Chemical

^*The Sertraline chemical compound amount of hydrochloride form

The final non-matrix tablet that loses of slow release of testing in vitro step test with embodiment 5 described slow release formulations.The results are shown among the table 9-2 (n=1 sheet).This is non-to lose that matrix tablet satisfies the dissolution standard and is slow release embodiment of the present invention.

Table 9-2

Non-erosion property matrix tablet compositions among the table 9-1 is containing 0.075M NaCl, pH4.0

900ml 0.13M acetate buffer in external Sertraline under 37 ℃

Slow release (slurry is fast to be set among the USP instrument #2 of 50rpm being furnished with)

Q ₁(％)	Q ₄(％)	Q ₈(％)	Q ₁₂(％)	Q ₁₆(％)	Q ₂₄(％)	Rate of release ^↑(mgA/ hour)
Q ₁(％)	Q ₄(％)	Q ₈(％)	Q ₁₂(％)	Q ₁₆(％)	Q ₂₄(％)	Rate of release ^↑(mgA/ hour)	6.2	13.9	23.1	28.5	33.8	41.2	2.2

The drug report value % that Q=discharges represents a slice

^↑Refer to that the Sertraline rate of release is calculated based on 24 hours time points because 80% release did not occur in testing period of 24 hours.

Embodiment 10

This embodiment proves that organic acid has the ability of the dissolubility of rising sertraline salts hydrochlorate.This acid is by soluble in water with candidate's acid, stirs excessive sertraline salts hydrochlorate at least 8 hours then in this acid solution and screens.Then, the concentration by Sertraline in the HPLC assay determination supernatant.This result of the test is listed in the table below among the 10-1.The dissolubility of listed most of sour sertraline salts hydrochlorate that successfully raise (normal dissolubility 2.5mg/ml) in the table.

Table 10-1

Excipient	About excipient concentration (mg/ml)	Sertraline dissolubility (mg/ml)
Excipient	About excipient concentration (mg/ml)	Sertraline dissolubility (mg/ml)	D, L MALIC ACID	900	21
Citric acid	600	20	D, L MALIC ACID	900	21
Citric acid	600	20	Arabo-ascorbic acid	400	19
Adipic acid	14	12	Arabo-ascorbic acid	400	19

Maleic acid	700	6.4
Maleic acid	700	6.4	The L-aspartic acid	10	5.5
Tartaric acid	1400	5.5	The L-aspartic acid	10	5.5
Tartaric acid	1400	5.5	L-glutamic acid	12	5.4
Fumaric acid	11	3.1	L-glutamic acid	12	5.4
Fumaric acid	11	3.1	Tannic acid	2000	2.8
D, L-tyrosine	600	2.2	Tannic acid	2000	2.8

Based on this screening test, preferred acid is malic acid, citric acid, arabo-ascorbic acid, and adipic acid.Maleic acid, the L-aspartic acid, tartaric acid and L-glutamic acid also improve sertraline salts hydrochlorate dissolubility significantly.Some have this sour controlled release form in nuclear can be than there not being these sour better effects if.For discharge drug solution based on the preparation of infiltration especially like this.

Embodiment 11

This embodiment has the ability of the dissolubility of rising Sertraline acetate by being similar to the method proof organic acid that is used for hydrochlorate among the embodiment 10.Excipient, excipient concentration and Sertraline dissolubility are listed in the table below among the 11-1.Based on these results, the preferred acid that is included in the needs increase Sertraline acetate dissolubility in the dosage form is ascorbic acid, arabo-ascorbic acid, citric acid, lactic acid, aspartic acid, glutamic acid and equisetic acid.

Table 11-1

Excipient	Excipient concentration (mg/ml)	Sertraline dissolubility (mg/ml)
Excipient	Excipient concentration (mg/ml)	Sertraline dissolubility (mg/ml)	Ascorbic acid	400	＞425
Arabo-ascorbic acid	400	＞330	Ascorbic acid	400	＞425
Arabo-ascorbic acid	400	＞330	Citric acid	600	146
Lactic acid	213	＞294	Citric acid	600	146
Lactic acid	213	＞294	Aspartic acid	7	110
Glutamic acid	12	108	Aspartic acid	7	110
Glutamic acid	12	108	Equisetic acid	500	＞92
The itaconic acid	150	72	Equisetic acid	500	＞92
The itaconic acid	150	72	Succinic acid	77	28
No	-	64	Succinic acid	77	28

Embodiment 12

This embodiment has the ability of rising Sertraline lactate at the water dissolubility by being similar to method proof organic acid and three kinds of calcium salts of being used for hydrochlorate among the embodiment 10.Excipient, excipient concentration and Sertraline lactate dissolubility are listed in the table below among the 12-1 in the aqueous test solution.The dissolubility of Sertraline lactate in water is about 125mg/ml.Following data show that eight kinds of organic acid solns have Sertraline lactate, adipic acid, arabo-ascorbic acid, itaconic acid, citric acid, aspartic acid, glutamic acid, histidine and the ascorbic acid of the dissolubility that is same as approximately or is higher than 125mg/ml.Simultaneously, two kinds mixture solution also has high-dissolvability in these acid; Ascorbic acid and aspartic acid.Sertraline lactate dissolubility is at calcium salt soln, separately (calcium citrate) or be mixed with high-dissolvability is also arranged in the ascorbic acid.

Table 12-1

Excipient	Excipient concentration (mg/ml)	Sertraline lactate dissolubility (mg/ml)
Excipient	Excipient concentration (mg/ml)	Sertraline lactate dissolubility (mg/ml)	Adipic acid	14	360
Arabo-ascorbic acid	400	＞217	Adipic acid	14	360
Arabo-ascorbic acid	400	＞217	The itaconic acid	150	＞202
Citric acid	600	162	The itaconic acid	150	＞202
Citric acid	600	162	Aspartic acid	7	＞155
Glutamic acid	12	＞125	Aspartic acid	7	＞155
Glutamic acid	12	＞125	Histidine	42	＞116
Ascorbic acid/aspartic acid	400/7	116	Histidine	42	＞116
Ascorbic acid/aspartic acid	400/7	116	Aspartic acid	400	102
Glycine	250	66	Aspartic acid	400	102
Glycine	250	66	Equisetic acid	200	＜59
Tartaric acid	1400	12	Equisetic acid	200	＜59
Tartaric acid	1400	12	Fumaric acid	11	＜9
Sorbic acid	3	＜9	Fumaric acid	11	＜9
Sorbic acid	3	＜9	Calcium lactate/ascorbic acid	50/400	160
Calcium citrate	10	165	Calcium lactate/ascorbic acid	50/400	160
Calcium citrate	10	165	Calcium carbonate/ascorbic acid	50/400	176
Do not have	-	125	Calcium carbonate/ascorbic acid	50/400	176

Embodiment 13

The Sertraline villaumite and all Sertraline lactates and Sertraline acetate be preferable over Sertraline than low solubility prompting nuclear preparation and remain in the solution what high chloride ion concentration existed, promptly it does not precipitate or forms gel-like material when having chloride ion.Find that by following screening test when having chloride ion some organic acid and salt suppress the precipitation or the gelling of Sertraline.The Sertraline lactate is (in contrast) or be dissolved in the water with candidate's excipient separately.Then, add sodium chloride (as concentrated solution) and observed result.If this solution keeps clarification and liquid, think that then excipient is useful.The chloride ion that joins in the excipient solution that keeps settled solution is many more, and this excipient is useful more.Following table 13-1 shows the result of this screening test, shows that all test excipient all increase Sertraline concentration in the chloride solution.

Table 13-1

Excipient	Excipient concentration (mg/ml)	NaCl concentration (mM)	Final Sertraline concentration (mg/ml)	Observed result after NaCl adds
Excipient	Excipient concentration (mg/ml)	NaCl concentration (mM)	Final Sertraline concentration (mg/ml)	Observed result after NaCl adds	Do not have	-	38	22	Gel/precipitation
Ascorbic acid/aspartic acid	400/7	152	162	Solution	Do not have	-	38	22	Gel/precipitation
Ascorbic acid/aspartic acid	400/7	152	162	Solution	Aspartic acid	7 7	114 152	162 100	Solution gel
Ascorbic acid	400	100	102	Precipitation	Aspartic acid	7 7	114 152	162 100	Solution gel
Ascorbic acid	400	100	102	Precipitation	Ascorbic acid/calcium lactate	400/50	150	165	Solution
Ascorbic acid/calcium carbonate	400/50	150	170	Little turbid	Ascorbic acid/calcium lactate	400/50	150	165	Solution
Ascorbic acid/calcium carbonate	400/50	150	170	Little turbid	Citric acid/calcium lactate	600/50	150	162	Solution
Histidine	42	150	110	Microdeposit	Citric acid/calcium lactate	600/50	150	162	Solution

Embodiment 14

Screening organic compound (solubilizing agent) increases the Sertraline lactate and is containing or the ability of the dissolubility in the aqueous solution of chloride not.Add excessive Sertraline lactate in candidate's solubilizing agent and organic acid aqueous solution in most cases.Organic acid be saturated in these solution and the concentration of other solubilizing agent shown in table 14-1.Measure balance Sertraline dissolubility.Then, add NaCl in this saturated solution and measure final Sertraline concentration.The results are summarized among the table 14-1 of these screening tests.

Table 14-1

	Solubilizing agent	Solubilizing agent concentration (mg/ml)	Organic acid	Sertraline dissolubility (mg/ml)	NaCl concentration (mM)	Sertraline concentration (containing NaCl)
	Solubilizing agent	Solubilizing agent concentration (mg/ml)	Organic acid	Sertraline dissolubility (mg/ml)	NaCl concentration (mM)	Sertraline concentration (containing NaCl)	1	Do not have (contrast)	-	Do not have	125	150	5
2	Single caprylin	10	Ascorbic acid	160	150	160	1	Do not have (contrast)	-	Do not have	125	150	5
2	Single caprylin	10	Ascorbic acid	160	150	160	3	Glyceryl triacetate	100	Ascorbic acid	170	150	170
4	Glycerol monobutyralte	50	Do not have	120	150	120	3	Glyceryl triacetate	100	Ascorbic acid	170	150	170
4	Glycerol monobutyralte	50	Do not have	120	150	120	5	Diacetine	50	Ascorbic acid	120	150	120
6	Imwitor ^312	10	Ascorbic acid	120	150	120	5	Diacetine	50	Ascorbic acid	120	150	120
6	Imwitor ^312	10	Ascorbic acid	120	150	120	7	Imwitor ^375	10	Ascorbic acid	120	150	120
8	Imwitor ^742	50	Do not have	120	150	120	7	Imwitor ^375	10	Ascorbic acid	120	150	120
8	Imwitor ^742	50	Do not have	120	150	120	9	Imwitor ^988	50	Do not have	140	100	140
10	Triethyl citrate	50	Ascorbic acid	160	150	160	9	Imwitor ^988	50	Do not have	140	100	140
10	Triethyl citrate	50	Ascorbic acid	160	150	160	11	Pluronic ^L31	50	Do not have	120	100	120
12	Cremophore EL	50	Ascorbic acid	120	150	120	11	Pluronic ^L31	50	Do not have	120	100	120
12	Cremophore EL	50	Ascorbic acid	120	150	120	13	SAIB	50	Ascorbic acid	120 ^*	150	120
14	The octyl group sodium lactate	50	Ascorbic acid	120	150	120	13	SAIB	50	Ascorbic acid	120 ^*	150	120
14	The octyl group sodium lactate	50	Ascorbic acid	120	150	120	15	Sucrose monolaurate	50	Do not have	150	150	150
16	The lauryl sodium lactate	50	Ascorbic acid	120	150	120	15	Sucrose monolaurate	50	Do not have	150	150	150
16	The lauryl sodium lactate	50	Ascorbic acid	120	150	120	17	Span ^80	50	Ascorbic acid	120	150	120

Embodiment 15

This embodiment illustrates that the solubilizing agent of Sertraline also can increase the dissolution rate of Sertraline.By adding solid drugs, candidate's solubilising excipient and other excipient under some situation such as organic acid and penetrating agent (as sugar) are in the 1.8ml centrifuge tube and measure to the effect of Sertraline dissolution rate for candidate's excipient.In microcentrifuge, rotate this sample cell 5 minutes with compacted powder with 14KG.The buffer that adds 150 μ l stomaches is to the powder of this compacting and stir this sample a little, then in microcentrifuge with 14KG rotation 2 minutes.Then, from centrifuge, shift out sample and allow its noiseless leaving standstill be moved out of up to solution.After the stomach buffer adds this pile of grounds, after totally ten minutes, from sample, shift out solution, and analyze to measure Sertraline concentration with HPLC.

The dissolved Sertraline concentration of measuring from supernatant is as the function calculation dissolution rate of the time in ten minutes of stripping (mg Sertraline/ml-min).The excipient mixture of these dissolution rates and mensuration is summarized among the following table 15-1.As shown, compare with independent Sertraline and compare with ascorbic acid with Sertraline, several excipient mixtures remarkable (about 3X or higher) that contain solubilizing agent increase the bent dissolution rate of house.

Table 15-1

Candidate's excipient		Organic acid	Organic acid concentration (wt%)	Penetrating agent	Penetrating agent concentration (wt%)	Other excipient	Other excipient concentration (wt%)	Sertraline salts type concentration (wt%)	Sertraline dissolution rate (mg/ml-min)
Candidate's excipient										Title	Concentration
Do not have	--									Title	Concentration	Do not have	--	Do not have		Do not have	--	Lactate 100	0.9
Do not have	--	Do not have	--	Ascorbic acid	51.0	Lactose	20	Do not have	--	Lactate 14	3.5	Do not have	--	Do not have		Do not have	--	Lactate 100	0.9
Imwitor ^312	5.0	Do not have	--	Ascorbic acid	51.0	Lactose	20	Do not have	--	Lactate 14	3.5	Ascorbic acid	49.5	Lactose	12.5	CaCO ₃	5	Lactate 14	20.9
Imwitor ^312	5.0	Lecithin	5.0	Ascorbic acid	51.0	Lactose	15	Do not have	--	Lactate 14	10	Ascorbic acid	49.5	Lactose	12.5	CaCO ₃	5	Lactate 14	20.9
PEG 3550	5.0	Lecithin	5.0	Ascorbic acid	51.0	Lactose	15	Do not have	--	Lactate 14	10	Ascorbic acid	51.0	Lactose	15	Do not have	--	Lactate 14	9.3
PEG 3550	5.0	Capmul ^MCM	5.0	Ascorbic acid	71.0	Do not have		Do not have	--	Lactate 24	14.5	Ascorbic acid	51.0	Lactose	15	Do not have	--	Lactate 14	9.3
Capmul ^MCM	4.7	Capmul ^MCM	5.0	Ascorbic acid	71.0	Do not have		Do not have	--	Lactate 24	14.5	Do not have	Do not have	Lactose	17	CaCO ₃Calcium citrate	4.7 4.7	Lactate 13.1	4.3
Capmul ^MCM	4.7	Imwitor ^191	5.0	Ascorbic acid	49.5	Lactose	12.5	CaCO ₃	1.0	Lactate 14	8.0	Do not have	Do not have	Lactose	17	CaCO ₃Calcium citrate	4.7 4.7	Lactate 13.1	4.3
Myrerol ^(18-99)	5.0	Imwitor ^191	5.0	Ascorbic acid	49.5	Lactose	12.5	CaCO ₃	1.0	Lactate 14	8.0	Ascorbic acid	49.5	Lactose	12.5	Do not have	--	Lactate 14	6.4
Myrerol ^(18-99)	5.0	Span ^60	5.0	Ascorbic acid	51.0	Lactose	15	Do not have	--	Lactate 14	9.5	Ascorbic acid	49.5	Lactose	12.5	Do not have	--	Lactate 14	6.4
Palmic acid resists bad blood base ester	6.8	Span ^60	5.0	Ascorbic acid	51.0	Lactose	15	Do not have	--	Lactate 14	9.5	Do not have	Do not have	Lactose	74.2	Do not have	--	Lactate 19	4.3
Palmic acid resists bad blood base ester	6.8	Methyl butex propylparaben propyl propionate	0.5/0.5 /1.0	Ascorbic acid	50.0	Lactose	17.5	Do not have	--	Lactate 14	11.5	Do not have	Do not have	Lactose	74.2	Do not have	--	Lactate 19	4.3
Imwitor ^312	6.8	Methyl butex propylparaben propyl propionate	0.5/0.5 /1.0	Ascorbic acid	50.0	Lactose	17.5	Do not have	--	Lactate 14	11.5	Aspartic acid	74.2	Do not have		Do not have	--	Lactate 19	5.3

Embodiment 16

This embodiment illustrates the method for preparing osmotic tablets, and this sheet comprises the sheet nuclear that contains Sertraline that is surrounded by semi permeability asymmetric membrane coating.With the pestle of 6.5 inch diameters, (AvicelPH102, FMC) hand-ground sertraline salts hydrochlorate is 10 minutes to use citric acid and microcrystalline Cellulose.Then, magnesium stearate was sneaked into as lubricant in 60 seconds with the spatula stirring.The sertraline salts hydrochlorate is 8.5: 63.8: 23.7 to microcrystalline Cellulose to the weight ratio of magnesium stearate to citric acid: 4; Gross weight is 10 grams.In the improved hydraulic jack that Pressure gauge and 3/8 inch shrinkage pool are housed (Dayton manufacturing) under 2500PSI pressure 2 seconds, mixture is pressed into the 470mg sheet.The size of gained tablet is that 3/8 inch diameter and 1/4 inch are thick.With the spray speed of LDCS-20 disc type coating device (Vector Corp.) with per minute 20 grams, it is 40cfm with throughput that inlet temperature is 40 ℃, semipermeable membrane coating (exercise question of authorizing as on June 10th, 96 is the U.S. Patent application No.397 of the application of asymmetric membrane in releasing device, and 974 is described) is administered on these sheets.Coating solution contain 10% weight cellulose acetate (Eastman Chemical, CA398-10), 2.5% Polyethylene Glycol (BASF, PEG 3350), 15% water and 72.5% acetone.Before the test at 50 ℃ of following sheets one hour of dry these coatings.After the drying, the weight of used coating material is 15.4% of gross weight.These tablets contain the Sertraline of 50mgA/ tablet amounts.

Embodiment 17

Permeate releasing piece with examining and apply the asymmetric membrane coating with embodiment 16 described preparation sheets basically to the same procedure preparation on this nuclear.The composition of this nuclear and coating solution change in embodiment 16 used those (shown in table 17-1).Embodiment 16 lists in table 17-1 so that comparison.Shown tangible nuclear is formed to change and is comprised: Sertraline dosage form, the type of solubilizing agent and amount, and the type of penetrating agent and amount.Change binding agent (Avicel) as required, the amount of lubricant (magnesium stearate) and solubilizing agent is to obtain good film-making and wet performance.These tablets contain the Sertraline of 50mgA/ tablet amounts.

Table 17-1

Embodiment number	The nuclear compositions												Infiltration coating solution
	The nuclear compositions												Infiltration coating solution					Nuclear heavy (mg)	Medicine		Acid		Solubilizing agent		Penetrating agent		Avicel wt％	MgSt. wt％	Other	Polymer type	Polymer wt%	PEG wt％	Water wt%	Coat weight (doing wt%)
			The salt type	wt％	Type	wt％	Type	wt％	Type	wt％								Nuclear heavy (mg)	Medicine		Acid		Solubilizing agent		Penetrating agent
16			The salt type	wt％	Type	wt％	Type	wt％	Type	wt％	470	Chloride	12	Do not have		Do not have		Lactose	66	20	2	Do not have	CA	10	2.5	15									15.4
16	17a	470	Lactate	14	Do not have		Do not have		Lactose	65.4	470	Chloride	12	Do not have		Do not have		Lactose	66	20	2	Do not have	CA	10	2.5	15	19.3	1.33	Do not have	EC	6	4	8	1	15.4
17b	17a	470	Lactate	14	Do not have		Do not have		Lactose	65.4	470	Acetate	14	Ascorbic acid	50	Do not have		Lactose	20	15	Do not have	Myrj	EC	6	4	10	19.3	1.33	Do not have	EC	6	4	8	1	10.1
17b	17c	470	Lactate	14	Ascorbic acid	50	Do not have		Lactose	15	470	Acetate	14	Ascorbic acid	50	Do not have		Lactose	20	15	Do not have	Myrj	EC	6	4	10	21	Do not have	Do not have	EC	6	4	10	10.1	10.1
17d	17c	470	Lactate	14	Ascorbic acid	50	Do not have		Lactose	15	470	Lactate	14	Citric acid	50	Do not have		Lactose	20	15	Do not have	Tween	EC	6	4	10	21	Do not have	Do not have	EC	6	4	10	10.1	9.9
17d	17e	470	Lactate	14	Aspartic acid	11	Do not have		Fructose	38	470	Lactate	14	Citric acid	50	Do not have		Lactose	20	15	Do not have	Tween	EC	6	4	10	29.5	2.5	Calcium acetate	CA	10	2.5	15	11	9.9
17f	17e	470	Lactate	14	Aspartic acid	11	Do not have		Fructose	38	470	Lactate	14	Do not have		Im	5	Lactose	58.4	20	2.6	Do not have	EC	6	4	10	29.5	2.5	Calcium acetate	CA	10	2.5	15	11	10
17f	17g	470	Lactate	14	Do not have		Im	5	Xylitol	53.5	470	Lactate	14	Do not have		Im	5	Lactose	58.4	20	2.6	Do not have	EC	6	4	10	25	2.5	Do not have	CA	10	2.5	15	15.5	10
17h	17g	470	Lactate	14	Do not have		Im	5	Xylitol	53.5	470	Lactate	14	Ascorbic acid	50	MC	5	Lactose	12.5	12.5	Do not have	Myrj	EC	6	4	10	25	2.5	Do not have	CA	10	2.5	15	15.5	10.5
17h	17i	470	Lactate	14	Glutamic acid	10	MC	5	Sucrose	50	470	Lactate	14	Ascorbic acid	50	MC	5	Lactose	12.5	12.5	Do not have	Myrj	EC	6	4	10	15	Do not have	Calcium lactate, Myrj	EC	6	4	10	10.5	10.5
17j	17i	470	Lactate	14	Glutamic acid	10	MC	5	Sucrose	50	470	Lactate	14	Ascorbic acid	11	MC	5	Sucrose	53	15		Myrj	EC	6	4	10	15	Do not have	Calcium lactate, Myrj	EC	6	4	10	10.5	10.1
17j	17k	470	Lactate	14	Ascorbic acid	32	Im	5	Lactose	12	470	Lactate	14	Ascorbic acid	11	MC	5	Sucrose	53	15		Myrj	EC	6	4	10	29	3	CaCO ₃	EC	7	3	6	15.1	10.1
17l	17k	470	Lactate	14	Ascorbic acid	32	Im	5	Lactose	12	470	Lactate	14	Ascorbic acid	32	Im	5	Lactose	12	29.5	2.6	CaCO ₃	EC	6	4	10	29	3	CaCO ₃	EC	7	3	6	15.1	10.1
17l	17m	470	Lactate	14	Aspartic acid	11	Im	5	Fructose	36	470	Lactate	14	Ascorbic acid	32	Im	5	Lactose	12	29.5	2.6	CaCO ₃	EC	6	4	10	27	2.5	Calcium acetate	CA	10	2.5	15	10.3	10.1
17n	17m	470	Lactate	14	Aspartic acid	11	Im	5	Fructose	36	470	Lactate	14	Glycine	25	Im	5	Fructose	28.5	25	2.5	Do not have	CA	10	2.5	15	27	2.5	Calcium acetate	CA	10	2.5	15	10.3	15.9
17n	17o	580	Lactate	11.2	Ascorbic acid	36.5	Glyceryl triacetate	4.2	Lactose	16.2	470	Lactate	14	Glycine	25	Im	5	Fructose	28.5	25	2.5	Do not have	CA	10	2.5	15	31.1	Do not have	Myrj	EC	6	4	10	10	15.9
17p	17o	580	Lactate	11.2	Ascorbic acid	36.5	Glyceryl triacetate	4.2	Lactose	16.2	470.5	Lactate	13.9	Succinic acid	37.2	PEG	15.9	Lactose	37.9	Do not have	Do not have	Klucel.SLS	EC	6	4	10	31.1	Do not have	Myrj	EC	6	4	10	10	10
17p	17q	536	Lactate	12.1	Aspartic acid	44	Capmul	4.4	Lactose	12	470.5	Lactate	13.9	Succinic acid	37.2	PEG	15.9	Lactose	37.9	Do not have	Do not have	Klucel.SLS	EC	6	4	10	22.1	1.5	CaCO ₃	EC	6	4	10	9.9	10
17r	17q	536	Lactate	12.1	Aspartic acid	44	Capmul	4.4	Lactose	12	470	Lactate	14	Ascorbic acid	37	Span 60	5	Lactose	11.4	25	2.6	CaCO3	EC	6	4	10	22.1	1.5	CaCO ₃	EC	6	4	10	9.9	9.8
17r	17s	470	Lactate	14	Ascorbic acid	37	Lecithin	5	Lactose	11.4	470	Lactate	14	Ascorbic acid	37	Span 60	5	Lactose	11.4	25	2.6	CaCO3	EC	6	4	10	25	2.6	CaCO ₃	EC	6	4	10	9.9	9.8
17t	17s	470	Lactate	14	Ascorbic acid	37	Lecithin	5	Lactose	11.4	470	Lactate	14	Ascorbic acid	32	Im	5	Lactose	12	29.5	2.7	CaCO ₃	EC	7	3	6	25	2.6	CaCO ₃	EC	6	4	10	9.9	17
17t	17u	470	Lactate	14	Ascorbic acid	32	Im	5	Lactose	12	470	Lactate	14	Ascorbic acid	32	Im	5	Lactose	12	29.5	2.7	CaCO ₃	EC	7	3	6	29.5	2.7	CaCO ₃	EC	6	4	8	15	17
17v	17u	470	Lactate	14	Ascorbic acid	32	Im	5	Lactose	12	470	Lactate	14	Aspartic acid	11	Im	5	Fructose	36	27	2.5	Calcium acetate	CA	10	2.5	15	29.5	2.7	CaCO ₃	EC	6	4	8	15	20
17v	17w	470	Lactate	14	Aspartic acid	11	Do not have		Fructose	38	470	Lactate	14	Aspartic acid	11	Im	5	Fructose	36	27	2.5	Calcium acetate	CA	10	2.5	15	29.5	2.5	Calcium acetate	CA	10	2.5	15	10	20

IM=Imwitor 312 Capmul=Capmul MCM Tween=Tween 80 CA=cellulose acetate 398-10

The single caprylin Mgst.=of MC=magnesium stearate Klucel=Klucel EF EC=Ethocel S-100

PEG=Polyethylene Glycol 3350 Myrj=Myrj 52 SLS=sodium lauryl sulphates

Embodiment 18

Except the solution that in digestion instrument, uses 750ml and mixing speed as the 100rpm, press the Sertraline rate of release of the dosage form of embodiment 5 described step measurements embodiment 16 and 17 described selections.The analysis of the Sertraline that discharges is to measure by reversed-phase high-performance liquid chromatography (RP HPLC).

Show among the 18-1 with the results are shown in of rate of release test that these steps are carried out.Listed two dosage forms, 18a and 18b (preparation 16 and 17a), the rate of release that shows be lower than rate of release that the present invention requires and as a comparison embodiment comprised.These two preparations all contain sertraline salts (hydrochlorate or lactate) and independent lactose as penetrating agent and there is not the excipient of solubilising.Listed preparation 18c among the table 18-1,18e and 18h contain the solubilising excipient and have showed the slow release of Sertraline, are embodiment of the present invention.Dosage form 18d, 18f and 18g are the embodiments that delay of the present invention adds slow release.Similarly, remaining dosage form also is the Sertraline dosage form of embodiment of the present invention among the embodiment 17 (17b-w).

Table 18-1

Sertraline discharges Test No.	The embodiment of tablet number	At the specific medicine umber (%) that time discharged
		At the specific medicine umber (%) that time discharged							0Hr	1Hr	2Hr	4Hr	8Hr	12Hr	20Hr
		18a	16	0	0	0	0	0	0Hr	1Hr	2Hr	4Hr	8Hr	12Hr	20Hr	0	0
18b	17a	18a	16	0	0	0	0	0		0	0	1	2	-	10(17hr)	0	0	12
18b	17a	18c	17e		0	6	15	35		0	0	1	2	-	10(17hr)	62	76	12	78
18d	17j	18c	17e		0	6	15	35		0	0	0	4	19	28	62	76	44	78
18d	17j	18e	17m		0	8	19	37		0	0	0	4	19	28	60	73	44	83
18f	17n	18e	17m		0	8	19	37	0	0.7	6	17	37	54	78	60	73		83
18f	17n	18g	17v	0	0.4	4	13	31	0	0.7	6	17	37	54	78	41	53
18h	17w	18g	17v	0	0.4	4	13	31		0	8	18	38	56	64	41	53	66

Embodiment 19

This embodiment proof is based on the Sertraline tablet of infiltration, and it is by being surrounded by Sertraline and excipient layer, and the kernel that contains penetrating agent and solubilising excipient that is surrounded by the semi permeability coating is again formed.The tablet of this embodiment and the difference of other embodiment are to have prepared and contain acid, the kernel of binding agent and solubilizing agent, and film-making, and place the inside of the tablet of bigger pastille.Pestle with 4.5 inch diameters grinds citric acid and microcrystalline Cellulose (Avicel, PH102, FMC) 5 minutes.Then, add polyoxyethylene 40 monostearates (Myrj52, BASF) and ground 1 minute.Citric acid is 86.1: 9.8: 4.1 to microcrystalline Cellulose to the weight ratio of Myrj, and gross weight is 4 grams.Except the sheet punching is 1/4 inch, it is described to press embodiment 16, this blended mixture is pressed into the tablet of 232mg.The sheet nuclear diameter of gained is 1/4 inch and thickness is 1/4 inch.Mixture as embodiment 17 preparation outer plates.It contains weight ratio is 14: 50: 20: 15: 1 Sertraline lactate, and succinic acid, lactose, (Tween 80, ICI) for Avicel and Sorbitan ethoxylate.Place the bottom of 3/8 inch punch die of standard by the mixture that 200mg is contained medicine, place the 232mg citrate tablet then at an upper portion thereof and the 270mg that reinjects contains the mixture of medicine and prepares final tablet thereon.Then, suppress this sheet with the condition that is same as embodiment 16.The size of the tablet of gained is 3/8 inch diameter, and 1/2 inch thick.With the method that is same as embodiment 16 the semipermeable membrane coating is administered on this sheet.Be similar to embodiment 5 described rate of release test results and show that the osmotic dosage form of this Sertraline is embodiment of the present invention.

Embodiment 20

This embodiment proves the method for the osmotic tablet that preparation is made of the double-layer tablet nuclear that is surrounded by the semi permeability coating.For formation contains the granule of medicine, mix following material and wet granulation: 50-200 gram Sertraline and pharmaceutical salts thereof in blender; 250-325 gram poly(ethylene oxide) (molecular weight is about 100,000) and 0-275 gram poly(ethylene oxide) (molecular weight is about 200,000); 10-30 gram mean molecule quantity is about 11,300 hydroxypropyl methylcellulose; And 0-10mg magnesium stearate.Second granulation of the preparation second layer comprises that it is about 5,000 that about 110-140 restrains mean molecule quantity in sheet nuclear, 000-7,500,000 poly(ethylene oxide); 5-25 gram mean molecule quantity is about 11,300 hydroxypropyl methylcellulose; 40-70 restrains sucrose; And 0-10 gram magnesium stearate.These granulations are used to prepare that ground floor contains Sertraline and the major part of the second layer is the double-layer tablet nuclear of swellable hydrophilic material.Then, these double-layer tablet are the semi-transparent coating bag quilt of about 3350 Polyethylene Glycol with the mean molecule quantity that contains 70%-98% cellulose acetate (acetyl content is 32%-39.8%) and 2-30%.The side that contains Sertraline at this tablet in coating forms at least one exit passageway.

Embodiment 21

With water penetration outer coatings preparation infiltration releasing piece, get out the passage of release aperture as the Sertraline that is dissolved in aqueous solution contained in this sheet nuclear by outer coatings.Basically press embodiment 17 identical methods and prepare, 11.0wt% aspartic acid, 47.4wt% sucrose, the sheet nuclear that 25.0wt%Avicel PH101 and 2.6wt% magnesium stearate are formed (total nuclear heavily is 470mg) by 14.0wt% Sertraline lactate.Then, with embodiment 17 described methods, be used in the acetone by 6% ethyl cellulose (Ethocel S-100, DowChemical), the 4wt% Polyethylene Glycol (PEG 3350, thus BASF) and these sheets nuclears of solution coating of forming of 8wt% water make that coat weight is every 70.4mg (the overall budget garment piece heavily is 540.4mg).For some tablets wherein, get out 3 holes that each diameter is 340 μ m (every totally 6 holes) at each face of each sheet.For second group of tablet, get out 18 holes that each diameter is 340 μ m (each tablet is 36 holes altogether) at every face of every.

The Sertraline of testing every type tablet with embodiment 5 described 0.75 liter of acetate/brine buffer solution discharges.The Sertraline percent that is discharged into receptor solution of every type tablet is shown in following table 21-1 as the function of time.Two types tablet all demonstrates similar release characteristic, and the release that shows medicine is mainly to be osmotic drive, (or discharge and mainly spread, the tablet in 36 holes should than about 6 times soon of the releases of the tablet in 6 holes).

Table 21-1

Time	The Sertraline (%) that discharges
Time	The Sertraline (%) that discharges		(hr)	6-hole tablet	36-hole tablet
0	0	0	(hr)	6-hole tablet	36-hole tablet
0	0	0	1	3	7
2	12	17	1	3	7
2	12	17	4	26	32
8	44	44	4	26	32
8	44	44	12	47	46

Embodiment 22

This embodiment has described swelling hydrogel controlled release Sertraline tablet.With the poly(ethylene oxide) (PEO-20K) of sertraline salts hydrochlorate or acetate or lactate or aspartate (50mgA Sertraline) and 20K molecular weight (350mg) and other solubilizing agent and mixed with excipients, and on Manesty Type-F3-Press with this mixture film-making.With this tablet of cellulose acetate solution spray coating in the acetone with 14% heavy final dry coationg of the sheet that obtains total coating.On the one side of this tablet of a part, pass the hole that coating gets out (by machinery, laser or alternate manner) 2mm diameter.In this tablet of another part, the whole center of passing this tablet gets out the hole of 2mm diameter.

Embodiment 23

This embodiment has described swelling hydrogel controlled release Sertraline tablet.With the poly(ethylene oxide) (PEO-20K) of sertraline salts hydrochlorate or acetate or lactate or aspartate (50mgA Sertraline) and 20K molecular weight (350mg) and other solubilizing agent and mixed with excipients, and on Manesty Type-F3-Press with this mixture film-making.With this tablet of the cellulose acetate/hydroxypropyl cellulose in 9: 1 acetone/methanol (1: 1) solution spray coating with 15% heavy final dry coationg of the sheet that obtains total coating.

Embodiment 24

This embodiment has described swelling hydrogel controlled release Sertraline tablet.With the poly(ethylene oxide) (PEO-100K) of sertraline salts hydrochlorate or acetate or lactate or aspartate (50mgA Sertraline) and 100K molecular weight (350mg) and other solubilizing agent and mixed with excipients, and on Manesty Type-F3-Press with this mixture film-making.With this tablet of cellulose acetate solution spray coating in the acetone with 14% heavy final dry coationg of the sheet that obtains total coating.On the one side of this tablet of a part, pass the hole that coating gets out (by machinery, laser or alternate manner) 2mm diameter.In this tablet of another part, the whole center of passing this tablet gets out the hole of 2mm diameter.

Embodiment 25

This embodiment has described swelling hydrogel controlled release Sertraline tablet.With the poly(ethylene oxide) (PEO-20K) of sertraline salts hydrochlorate or acetate or lactate or aspartate (50mgA Sertraline) and 20K molecular weight (350mg) and other solubilizing agent and mixed with excipients, and on Manesty Type-F3-Press with this mixture film-making.This tablet of sucrose in the acetone soln of cellulose acetate (2.5%) and PEG-600 (2.5%) (50/60 order) suspension spray coating.Cellulose acetate is 1: 1: 2 to PEG-600 to the weight ratio of sucrose in the coating.Final coating be the sheet of total coated heavy 15%.

Embodiment 26

This embodiment has described swelling hydrogel controlled release Sertraline tablet.With the poly(ethylene oxide) (PEO-20K) of sertraline salts hydrochlorate or acetate or lactate or aspartate (50mgA Sertraline) and 20K molecular weight (350mg) and other solubilizing agent and mixed with excipients, and on Manesty Type-F3-Press with this mixture film-making.9/1 this tablet of acetone/methanol solution spray coating with cellulose acetate (2.2%) and HPC (2.2%).Cellulose acetate is 1: 1 to the weight ratio of HPC in the coating, and final coating to be the sheet of total coating heavy 15%.

Embodiment 27

This embodiment has described the slow release Sertraline tablet of the coating of the perforation of passing centre bore release Sertraline.With sertraline salts hydrochlorate or acetate or lactate or aspartate (50mgA Sertraline) and lactose, magnesium stearate, and optional ethyl cellulose and other mixed with excipients, and on ManestyType-F3-Press tabletting.This sheet of methanol solution coating with ethylene vinyl acetate.After the drying, coat weight be the not tablet of coating gross weight 15%.On the one side of this tablet of a part, pass the hole that coating gets out (by machinery, laser or alternate manner) 2mm diameter.In this tablet of another part, the whole center of passing this tablet gets out the hole of 2mm diameter.The Sertraline rate of release changes along with the variation of the ethyl cellulose cellulose content of this tablet.

Embodiment 28

This embodiment has described the preparation that (enteric coating) space that pH causes postpones to add slow release Sertraline tablet.As embodiment 4,9, the hydrogel tablet of 16,17,19,20,21,22,23,24,25,26 and 27 preparation Sertraline sustained-release matrixes or infiltration or coating.

Formulation coated preparation by table 28-1.

Table 28-1

Coated preparation

Composition	Function	6WT％
Composition	Function	6WT％	Eudragit L30D-55	The polymer of enteric	16.0
Triethyl citrate	Plasticizer	1.6	Eudragit L30D-55	The polymer of enteric	16.0
Triethyl citrate	Plasticizer	1.6	Talcum	Antitack agent	4.0
Water	Solvent	78.4	Talcum	Antitack agent	4.0

With Freund HCT-30Hi-Coater with the coating solution spraying to the Sertraline slow releasing tablet.Used coating [Eudragit polymer+triethyl citrate+Talcum] is between the heavy 5-25% of the sheet of coating not.These coated tablets do not discharge Sertraline hardly or under the pH of stomach, and discharge Sertraline in mode (1mgA/hr-40mgA/hr) slowly after moving into duodenum.

Embodiment 29

This embodiment illustrates that the space that preparation pH causes postpones to add the granose method of slow release Sertraline.

Press embodiment 7 and the many granules of 8 described preparation slow release Sertralines.Add multiplexer (Glatt GPCG-1) with Wurster bottom spraying fluid bed and use the coating that postpones release.It is～5 to～50% that typical delays discharges the coating level.Delayed release coating is to contain 12.3% methacrylic acid copolymer (Eudragit ^L30D-55), 6.2% Talcum, the suspension of 1.5% triethyl citrate and 80% water.

Because dissolving in pH, this delayed release coating is higher than in 5.5 the environment, so many granules of preparation prevent the release of the coated granules nuclear of Sertraline from the stomach of low pH, and allow Sertraline from pH greater than discharging in 5.5 small intestinal and the nuclear of the coated granules the colon.

Embodiment 30

This embodiment illustrates that the space that has the pH initiation of protective layer between the delay release film of many granular core of slow release and pH initiation postpones to add the preparation method of the many granules of slow release Sertraline.This dosage form design is improved any physics or chemical incompatibility between slow release nuclear and the release membranes.This method comprises the many granular core of (1) preparation slow release Sertraline; (2) on this nuclear particle, use the protectiveness coating; And (3) use second, pH sensitivity, delayed release coating on first coating.

Press embodiment 7 and the many granular core of 8 described preparation slow release Sertralines.Add multiplexer with fluid bed, spraying contains 5% plastifying hydroxypropyl methyl fiber (Opadry on this slow release nuclear particle ^) solution of solution is up to the coating of using 10%.

Add multiplexer with the same fluid bed and use delayed release coating (typically, it is the 5-50% of the granose final weight of coating).Delayed release coating is to contain 12.3% methacrylic acid copolymer (Eudragit ^L30D-55), 6.2% Talcum, the suspension of 1.5% triethyl citrate and 80% water.

Embodiment 31

The space that the pH that this embodiment explanation has the Cellacefate coating causes postpones to add slow release Sertraline coated tablet.

As

embodiment

4,9,16,17,19,20,21,22,23,24,25,26 and 27 preparation Sertraline slow releasing tablet.Then, at HCT-60 Hi-Coater ^Spraying coating device (Freund Ind.Corp., Tokyo) in, with this slow releasing tablet of acetone soln spraying coating of Cellacefate (CAP).With 25% (weight) phthalic acid diethyl ester (DEP) plasticising CAP.Spraying q.s CAP is the final coating polymer weight of 5-50wt% to produce dry back with respect to the sheet bed weight of coating not to this tablet.

Embodiment 32

The space that the pH that this embodiment explanation has the barrier coating causes postpones the preparation of the slow release Sertraline tablet of CAP-coating.

As

embodiment

4,9,16,17,19,20,21,22,23,24,25,26 and 27 described preparation Sertraline slow releasing tablet.Use HCT-60Hi-Coater ^Spraying coating hydroxypropyl methylcellulose (HPMC; Colorcon, aqueous solution Inc).In this method, with respect to initial slow releasing tablet weight, with the agent of 5wt%HPMC barrier coating peridium patch.Then, in HCT-60Hi-Coater, further spray this sheet of coating with embodiment 31 described CAP and DEP plasticizer.Spraying capacity CAP on this sheet is heavy so that produce the final coating polymer of the dry back 5-50wt% heavy with respect to the sheet of coating not.The HPMC coating is as the barrier between slow release Sertraline sheet and the responsive CAP coating of pH.This barrier coating prevents for example too early stripping (or reduction) under one's belt the low pH environment of this CAP coating, may be owing to cause because of the local higher pH of the sheet inside due to the existence of Sertraline.

Embodiment 33

The space that the pH that this embodiment explanation has the barrier coating causes postpones the preparation that (the acrylic resin coating) adds slow release Sertraline tablet.

As

embodiment

4,9,16,17,20,21,22,23,24,25,26 and 27 described preparation Sertraline slow releasing tablets.Use HCT-60 Hi-Coater, with HPMC (Colorcon, the Sertraline tablet of aqueous solution spray coating slow release Inc.).In this method, 5wt% (with respect to initial weight) the barrier coating bag of using HPMC is by this sheet.

Formulation coated preparation by table 28-1.

With Freund HCT-30 Hi-Coater with the coating solution spraying to the slow release Sertraline sheet of HPMC-coating.

Used acrylic resin total polymer weight is the 5-50% of Sertraline slow releasing tablet bed.The HPMC undercoating is as the barrier between the acrylic resin coating of Sertraline and pH sensitivity.This barrier coating prevents for example too early stripping (or reduction) under under one's belt the low pH environment of acrylic resin coating, and this may be because the local higher pH of the sheet inside due to the existence of Sertraline causes.

Embodiment 34

(water is activatory) that this embodiment description time postpones adds the preparation of the Sertraline tablet of slow release.

Press embodiment 4,9,16,17,19,20,21,22,23,24,25,26 and 27 described preparation slow release Sertraline sheets.Then, such as HCT-30, HCT-60, or in the tablet coating device of HCT-130Coater (Freund Inc), with water solublity and/or water-destructible property retardation layer bag by these sheets.With this sheet of HPMC aqueous solution coating is the 5-50% of the final weight of this coated tablet up to final coat weight.Heavy more coating begins to be released into environment for use (gastrointestinal cavity) at Sertraline and produces long more delay before.This time delay can by introduce few a little less than the middle amount water-soluble polymer (including but not limited to ethyl cellulose (EC), cellulose acetate (CA), butanoic acid cellulose acetate) in coated preparation and increase.For example, this coated preparation can be by 95: 5HPMC/EC to 50: 50HPMC/EC, or 95: 5HPMC/CA to 50: 50HPMC/CA forms.Under the situation of this blended polymer coating system, may need to regulate the mixture of solvent composition with dissolving water solublity and weak water-soluble polymer.For example, can use acetone on demand, the mixture of second alcohol and water.

In environment for use, the dosage form of this embodiment shows the delay that Sertraline discharges during this coating polymer postpones to add the slow releasing tablet surface dissolution from Sertraline.After the delay, this Sertraline slow releasing tablet is with the speed release Sertraline wherein between 1mg/hr-40mg/hr.

Embodiment 35

This embodiment illustrates that preparation comprises the method for the osmotic tablets that contains Lactated nuclear of Sertraline that is surrounded by semi permeability asymmetric membrane coating.Equipment with standard in the pharmaceuticals industry prepares sheet nuclear.Mix and comprise 13.8wt% Sertraline lactate, the 11wt%L-aspartic acid, the 5wt% calcium acetate, the sheet nuclear composition of 29.5wt% microcrystalline Cellulose and 38.2wt% fructose is then by roll squeezer and grinding.Then, the material of this grinding is mixed with the 2.5wt% magnesium stearate (Kilian T-100) preparation gross weight is the final composite material of the sheet of 470mg on conventional tablet machine to be formed for.Disc type coating device (LDCS-20, Vector Corp.) with side opening is administered to semi permeability asymmetric membrane coating (as United States Patent (USP) 5,612,059 is described) on the sheet.To contain 10wt% cellulose acetate 398-10,2.5wt%PEG 3350, and the coating solution of 15wt% water and 72.5% acetone has 10wt% coating amount with the speed spraying coating of 20g/min on sheet to sheet.

Embodiment 36

This embodiment illustrates that preparation comprises the method for the osmotic tablets that contains Lactated nuclear of Sertraline that is surrounded by semi permeability asymmetric membrane coating.Equipment with standard in the pharmaceuticals industry prepares sheet nuclear.Use comprises 13.8wt% Sertraline lactate, 5% glyceryl monolaurate, and the 11wt%L-aspartic acid, the 5wt% calcium acetate, the sheet nuclear composition of 27wt% microcrystalline Cellulose and 35.7wt% fructose prepares sheet nuclear.Beginning, glyceryl monolaurate and 14wt% microcrystalline Cellulose carry out wet granulation with ethanol (95%) as the wet granulation solvent.After the dry also grinding, wet granular mixes with above-mentioned composition (microcrystalline Cellulose that comprises surplus), also grinds by roll squeezer then.Then, the material of this grinding is mixed with the 2.5wt% magnesium stearate (Kilian T-100) preparation gross weight is the final composite material of the sheet of 470mg on conventional tablet machine to be formed for.Disc type coating device (LDCS-20, Vector Corp.) with side opening is administered to semi permeability asymmetric membrane coating (as United States Patent (USP) 5,612,059 is described) on the sheet.To contain 10wt% cellulose acetate 398-10,2.5wt%PEG 3350, and the coating solution of 15wt% water and 72.5% acetone sprays coating to sheet with the speed of 20g/min.The tablet and a collection of tablet that has the 20wt% coating that prepare a collection of 10wt% of having coating.

Embodiment 37

(chemical compound of preparation AA 200.2mg) is dissolved in the ethyl acetate (200 μ l) the Sertraline acetate with Sertraline alkali in the 5ml reaction bulb.Add glacial acetic acid (41.2 μ l) in the Sertraline aqueous slkali that continues to stir.Add the ethyl acetate of other 500 μ l so that stir.Allow this reactant mixture granulating 5 hours at room temperature.Cross filter solid, with the washing of 10ml ethyl acetate and then 40 ℃ of dryings 20 hours in vacuum tank.Measuring productive rate is 16%, 126 ℃ of mp.

Embodiment 38

(chemical compound of preparation AA 200mg) is dissolved in the hexane (1.5ml) the Sertraline acetate with Sertraline alkali in the 10ml reaction bulb.Heat this solution to 40 ℃.Add glacial acetic acid (41.2 μ l) in the Sertraline aqueous slkali.Allow this reactant mixture be cooled to room temperature and also follow granulating 1 hour.Cross filter solid, and in vacuum tank 40 ℃ of dryings 72 hours.Measuring productive rate is 90%, 126 ℃ of mp.

Embodiment 39

The Sertraline acetate is with sertraline salts hydrochlorate (125g) slurrying in the mixture of water (1 liter) and hexane (2.5 liters).Adding NaOH (25% aqueous solution, 35ml).With Sertraline alkali be assigned to hexane mutually in.Separate hexane layer.With hexane (500ml) aqueous layer extracted once more.Merge hexane layer.The hexane solution to 50 of heating Sertraline alkali ℃.Add glacial acetic acid (23ml) in the Sertraline aqueous slkali.50 ℃ of following stirred reaction mixtures 30 minutes.Cooling off this reactant mixture stirs under room temperature and the room temperature and spends the night.Filter crystal and be the hexane wash five times of 250ml with cumulative volume.In vacuum tank, descended dry these solids 48 hours in 40 ℃.Productive rate is 89%, mp126 ℃.

Embodiment 40

The monocrystal x-ray analysis has been measured representational crystal and at Siemens R3RA/V diffractometer, Siemens's Analysis of X-ray system company, and 6300 Enterprise Lane, Madison collects the setting of 1 dust data on the WI 53719-1173.Atomic scattering factor is taken from the world table of X-radiocrystallography.The international table of X-radiocrystallography, IV volume, the 55th, 99 and 149 page, Birmingham Kynoch Press, 1974.The SHELXTL system has made things convenient for all crystallography to calculate (Nicolet instrument company, 5225 Verona Rd, Madison, WI 53711,1981 for G.M.Sheldrick, SHELXTL service manual).At room temperature collect all diffractometer data.Following table 40-1 has summed up relevant crystal, data collection and purification parameter.

Obtained test structure by direct method.Conventional refining this test structure.Disparity map has illustrated low amounts of water on diad.Purification shows that the population number of this water is 0.25.If may, calculate the hydrogen position.By the hydrogen on difference Fourier technological orientation methyl hydrogen and the nitrogen.The hydrogen that no-fix is waterborne.Add the hydrogen parameter in this structural agent calculating, but purify.The displacement of calculating in the purified final circulation of least square all is lower than 0.1 of its corresponding standard deviation.Final R-index is 8.97%.Final difference Fourier shows does not have the electron density of putting that lose or wrong.

The purification structure that is shown in Fig. 1 is mapped with the mapping of the SHELXTL shown in said SHELXTL service manual box.Do not set up absolute configuration.

Table 40-1

The crystal parameter of Sertraline acetate
The crystal parameter of Sertraline acetate		General formula	C ₁₇H ₁₈NCl ₂+C ₂H ₃O ₂-·0.25H ₂O(371.3)
The crystal medium	Water	General formula	C ₁₇H ₁₈NCl ₂+C ₂H ₃O ₂-·0.25H ₂O(371.3)
The crystal medium	Water	Crystal size (mm)	0.10×0.16×0.22
The aperture	A=15.629 (8) dust	Crystal size (mm)	0.10×0.16×0.22
The aperture	A=15.629 (8) dust		B=8.695 (3) dust
	C=15.048 (3) dust		B=8.695 (3) dust
	C=15.048 (3) dust		α＝90.0°
	β＝110.45(3)°		α＝90.0°

	γ＝90.0°
	γ＝90.0°		V=1916 (1) dust
Basic at interval	C2		V=1916 (1) dust
Basic at interval	C2	Molecule/every hole	4
The density of calculating, g/cm ³	1.287	Molecule/every hole	4
The density of calculating, g/cm ³	1.287	The linear absorption factor, mm ^-1	3.144

Table 40-2 atomic coordinates (* 10 ⁴) and suitable isotope shift coefficient (dust ²* 10 ³)

	x	y	z	U(eq) ^*
	x	y	z	U(eq) ^*	C(1)	8321(14)	10711(22)	-3626(12)	79(2)
C(2)	7559(13)	10583(20)	-3227(12)	66(2)	C(1)	8321(14)	10711(22)	-3626(12)	79(2)
C(2)	7559(13)	10583(20)	-3227(12)	66(2)	C(3)	7581(14)	8997	-2770(12)	83(2)
C(4)	8453(11)	8847(21)	-1902(11)	67(2)	C(3)	7581(14)	8997	-2770(12)	83(2)
C(4)	8453(11)	8847(21)	-1902(11)	67(2)	C(5)	9260(11)	9344(22)	-2182(12)	66(2)
C(6)	9268(14)	10390(22)	-2917(12)	87(2)	C(5)	9260(11)	9344(22)	-2182(12)	66(2)
C(6)	9268(14)	10390(22)	-2917(12)	87(2)	C(7)	10033(16)	10928(24)	-3028(14)	103(2)
C(8)	10898(14)	10516(24)	-2347(14)	91(2)	C(7)	10033(16)	10928(24)	-3028(14)	103(2)
C(8)	10898(14)	10516(24)	-2347(14)	91(2)	C(9)	10883(16)	9557(24)	-1637(14)	97(2)
C(10)	10115(12)	9074(21)	-1513(12)	67(2)	C(9)	10883(16)	9557(24)	-1637(14)	97(2)
C(10)	10115(12)	9074(21)	-1513(12)	67(2)	C(11)	8555(14)	7256(22)	-1473(14)	79(2)
C(12)	8418(12)	6975(22)	-625(12)	66(2)	C(11)	8555(14)	7256(22)	-1473(14)	79(2)
C(12)	8418(12)	6975(22)	-625(12)	66(2)	C(13)	8514(14)	5542(25)	-215(12)	89(2)
C(14)	8760(12)	4314(21)	-708(18)	90(2)	C(13)	8514(14)	5542(25)	-215(12)	89(2)
C(14)	8760(12)	4314(21)	-708(18)	90(2)	C(15)	8861(18)	4526(27)	-1587(15)	132(2)
C(16)	8763(14)	6002(22)	-1905(13)	88(2)	C(15)	8861(18)	4526(27)	-1587(15)	132(2)
C(16)	8763(14)	6002(22)	-1905(13)	88(2)	N(17)	8112(9)	9728(19)	-4522(10)	65(2)
C(18)	8616(14)	10130(25)	-5161(13)	98(2)	N(17)	8112(9)	9728(19)	-4522(10)	65(2)
C(18)	8616(14)	10130(25)	-5161(13)	98(2)	C1(19)	8377(5)	5313(12)	862(4)	127(2)
C1(20)	8816(6)	2473(13)	-178(6)	144(2)	C1(19)	8377(5)	5313(12)	862(4)	127(2)
C1(20)	8816(6)	2473(13)	-178(6)	144(2)	C(1A)	9993(16)	5929(28)	-3685(16)	157(3)

C(2A)	9026(12)	5594(27)	-4223(12)	83(2)
C(2A)	9026(12)	5594(27)	-4223(12)	83(2)	O(3A)	8771(11)	4331(19)	-4476(12)	119(2)
O(4A)	8464(12)	6651(19)	-4306(11)	116(2)	O(3A)	8771(11)	4331(19)	-4476(12)	119(2)
O(4A)	8464(12)	6651(19)	-4306(11)	116(2)	O(1W)	10000(37)	2700(33)	-5000(37)	132(4)

^*Suitable isotope U is defined as orthogonal U _Ij/ 3rd of a trace of tensor

Embodiment 41

Sertraline acetate osmotic tablets

This embodiment illustrates that preparation comprises the method for the osmotic tablets of the sheet nuclear that contains the Sertraline acetate that is surrounded by semi permeability asymmetric membrane coating.Equipment with standard in the pharmaceuticals industry prepares sheet nuclear.Comprise 14wt% Sertraline acetate with the pestle manual mixing, the 50wt% ascorbic acid, the 20wt% lactose, (Mgrj 52, Sigma Chemical, St.Louis, sheet nuclear composition MO) for 15wt% microcrystalline Cellulose and 1wt% Polyethylene Glycol stearic acid ether.Being used for this composite material in single station tablet machine (F-Press) preparation gross weight is the sheet of 470mg.With the disc type coating device of side opening (LDCS-20, Vector Corp., 675 44th St., Marion IA52302) is administered to semi permeability asymmetric membrane coating (as United States Patent (USP) 5,612,059 is described) on the sheet.To contain 6wt% ethyl cellulose S-100,4wt%PEG 3350, the coating solution of 10wt% water and 80% acetone with the speed of 20g/min spraying coating to the sheet up to the 10wt% coating content that obtains on the sheet.

Embodiment 42

This embodiment explanation is used to prepare and is designed for the main granose preparation method that discharges the delayed release dosage forms of Sertraline under stomach.This method comprises that (1) prepares the not many granular core of Sertraline acetate of coating; (2) on this karyosome, use the coating of protection; And (3) use the delayed release coating of second layer pH sensitivity on first coating.

Add multiplexer (Ramsey, NJ 07446 for Model GPCG-1, Glatt Air Techniques) preparation with the fluid bed that has the rotor insert and contain many granular core of medicine.If rotor drum begins to adorn with 400gA Sertraline medicine (Sertraline acetate, Sertraline lactate or Sertraline aspartate) and contains 5% poly-(ethyl acrylate, acrylic acid methyl ester .) (Eudragit ^NE-30-D), 5% plastifying hydroxypropyl emthylcellulose (Opadry ^, Colorcon, West Point, PA 19486) and the binder solution of 90% water be sprayed on the revolving bed up to the average core particle diameter that reaches about 250 μ m.

To contain 5% plastifying hydroxypropyl emthylcellulose (Opadry ^) solution spraying add on the karyosome of the not coating in the multiplexer to the identical fluid bed that has the rotor insert.Coating has strengthened the adhesion of final delay release coating to karyosome in the middle of this.

Add multiplexer with the same fluid bed and use delayed release coating (general, as to postpone release standard needs 5-50%) for satisfying.This delayed release coating is to contain 12.3% methacrylic acid copolymer (Eudragit ^L30D-55, Rohm GMBH, Darmstadt, Germany; U.S.Office; Somerset, NJ), 6.2% Talcum, the suspension of 1.5% triethyl citrate and 80% water.End product is that mean diameter is that the delay of about 300 μ m discharges many granules.

Embodiment 43

(chemical compound of preparation AA 200mg) is dissolved in the ethyl acetate (200 μ l) Sertraline L-lactate with Sertraline alkali in 10ml taper reaction bulb.(solid 68.5mg) is dissolved in separately in the ethyl acetate (100 μ l) with L-lactic acid.Under continuing to stir, add the L-lactic acid solution in the Sertraline aqueous slkali with magnetic stirring apparatus.In about 2 minutes of the back, observe precipitation in the Sertraline aqueous slkali adding the L-lactic acid solution fully.Allow this reactant mixture granulation spend the night (18 hours) at room temperature.Filtering-depositing is also used this solid of 1ml ethyl acetate rinsing.In vacuum tank, descended dry these solids 20 hours in 40 ℃.Qualitative and identify that this exsiccant solid is a Sertraline L-lactate.Measuring productive rate is 72%, mp153 ℃.

Embodiment 44

Sertraline L-lactate is in the 50ml round-bottomed flask, and (the change house thing of preparation AA 1.0g) is dissolved in the ethyl acetate (20ml) and heats this solution to 40 ℃ with Sertraline alkali.L-lactic acid (342.5mg) is dissolved in ethyl acetate (5ml) separately.A small amount of repeatedly the adding in the solution of L-lactic acid solution in the round-bottomed flask that continues to stir with magnetic stirring apparatus.After the L-lactic acid solution adds, under 40 ℃, reactant mixture was stirred 2 hours.Then, allow this reactant mixture be chilled to room temperature and filter this solid.With the 5ml ethyl acetate wash this solid and under vacuum in 40 ℃ of dryings 24 hours.Identify that this exsiccant solid is a Sertraline L-lactate.Calculating this productive rate is 86%, 153 ℃ of mp.

Embodiment 45

Sertraline L-lactate is dissolved in Sertraline alkali (10g) in the isopropyl alcohol (150ml) and heats this solution to 40 ℃ in the 500ml round-bottomed flask.L-lactic acid (3.4g) is dissolved in ethyl acetate (25ml) separately.The a small amount of solution of L-lactic acid solution in the round-bottomed flask that continues to stir with magnetic stirring apparatus that repeatedly adds.After the L-lactic acid solution adds, under 40 ℃, reactant mixture was stirred 4 hours.Then, allow this reactant mixture be chilled to room temperature and filter this solid.With this solid of 50ml hexane wash and under vacuum in 40 ℃ of dryings 48 hours.Identify that this exsiccant solid is a Sertraline L-lactate.Calculating productive rate is 94%, mp153 ℃.

Embodiment 46

Sertraline L-lactate is with Sertraline mandelate (750g) slurrying in the mixture of water (3.9 liters) and ethyl acetate (3.9 liters).Cool off this slurry to 15 ℃.(25% aqueous solution 250ml) obtains the solution of pH9.6 to add NaOH.The Sertraline free alkali is dispensed into isolating ethyl acetate layer.With 3.4 liters of other ethyl acetate extraction water layers.Ethyl acetate layer with 3.9 premium on currency washing merging.Concentrating the ethyl acetate layer that contains Sertraline alkali under vacuum also filters to clarify this solution.Add L-lactic acid (155g) in this solution.This reactant mixture of granulation is 20 hours under the room temperature.Filter this solid, with ethyl acetate (400ml, each) washing 4 times.Spend the night in 40 ℃ of these crystal of drying under the vacuum.Calculating productive rate is 84%, mp153 ℃.

Embodiment 47

Sertraline L-lactate becomes mud with sertraline salts hydrochlorate (300g) in 3: 1 mixture of water (3 liters) and ethyl acetate (1 liter).Add the pH regulator to 8.0 of about 1 liter of 1N NaOH solution with this slurry.With the Sertraline free alkali be dispensed into ethyl acetate mutually in.Thoroughly separate biphase by allowing this biphasic solution not have the standing over night of stirring.Then, the separating ethyl acetate layer and with twice of 3 liters of deionized water wash to remove chloride ion.Concentrate under the vacuum contain Sertraline alkali final ethyl acetate layer to 300ml to remove residual water.Heating contains the ethyl acetate solution to 40 ℃ of Sertraline alkali.L-lactic acid is dissolved in ethyl acetate forms 7.5M solution.Continue to stir down and repeatedly add lactic acid solution on a small quantity in Sertraline alkali liquor.Allow this mixture stir and granulating spend the night (16-20 hour).Filter this crystal and use equivalent (200ml, each) ethyl acetate washing 4 times.40 ℃ of down dry these crystal spend the night in the vacuum tank.Productive rate is 97%, mp153 ℃.

Embodiment 48

The monocrystal x-ray analysis has been measured representational crystal and collected 1 dust data on Siemens R3RA/v diffractometer (maximum sin θ/λ=0.5) has been set.Atomic scattering factor is taken from the world table of X-radiocrystallography.The international table of X-radiocrystallography, IV volume, the 55th, 99 and 149 page, Birmingham KynochPress, 1974.The SHELXTL system has made things convenient for all crystallography to calculate (see GM.Sheldrick, SHELXTL service manual, Nicolet instrument company, 5225 Verona Rd, Madison, WI 53711,1981).At room temperature collect all diffractometer data.Following table 48-1 has summed up relevant crystal, data collection and purification parameter.

Table 48-1

Sertraline L-lactate crystal parameter
Sertraline L-lactate crystal parameter		General formula	C ₁₇H ₁₈NCl ₂ ⁺C ₃H ₅O ₃ ^-(396.3)
The crystal medium	Ethyl acetate	General formula	C ₁₇H ₁₈NCl ₂ ⁺C ₃H ₅O ₃ ^-(396.3)
The crystal medium	Ethyl acetate	Crystal size (mm)	0.07×0.07×0.11
The aperture	A=8.660 (5) dust	Crystal size (mm)	0.07×0.07×0.11
The aperture	A=8.660 (5) dust		B=24.43 (1) dust
	C=9.382 (3) dust		B=24.43 (1) dust
	C=9.382 (3) dust		α＝90.0°
	β＝91.94(3)°		α＝90.0°
	β＝91.94(3)°		γ＝90.0°
	V=1984 (2) dust ³		γ＝90.0°

Basic at interval	P2 ₁
Basic at interval	P2 ₁	Molecule/every hole	4
The density of calculating, g/cm ³	1.327	Molecule/every hole	4
The density of calculating, g/cm ³	1.327	The linear absorption factor, mm ^-1	3.101

Obtained test structure by direct method.Conventional this test structure of purifying.If may, calculate the hydrogen position.By the hydrogen on difference Fourier technological orientation methyl hydrogen and nitrogen and the oxygen.The hydrogen parameter is added in this structural agent calculating, but purify.The displacement of calculating in the final circulation that method of least square is purified all is lower than 0.1 of its corresponding standard deviation.Final R-index is 5.49%.Final difference Fourier shows does not have the electron density of putting that lose or wrong.

Be shown in the SHELXTL mapping box mapping that the purification structure of Fig. 3 is used.Absolute configuration is by method (Hamilton, Acta Cryst, 1965,18,502-510 and Ibers etc., ActaCryst, 1964,17, the 781-782) mensuration of Ibers and Hamilton.X-ray absolute configuration meets L-lactate configuration.Atomic coordinates is listed among the table 48-2.

Table 48-2 atomic coordinates ( ^*10 ⁴) and suitable isotope shift coefficient (dust ²* 10 ³)

	x	y	z	U(eq) ^*
	x	y	z	U(eq) ^*	C(1)	-4173(13)	4373(5)	7866(10)	44(2)
N(1A)	-4127(10)	3773(4)	7483(9)	47(2)	C(1)	-4173(13)	4373(5)	7866(10)	44(2)
N(1A)	-4127(10)	3773(4)	7483(9)	47(2)	C(1B)	-5542(14)	3455(6)	7614(12)	69(2)
C(2)	-2556(12)	4576(6)	8220(10)	54(2)	C(1B)	-5542(14)	3455(6)	7614(12)	69(2)
C(2)	-2556(12)	4576(6)	8220(10)	54(2)	C(3)	-1658(12)	4605(5)	6877(11)	55(2)
C(4)	-2328(12)	5027(5)	5834(10)	44(2)	C(3)	-1658(12)	4605(5)	6877(11)	55(2)
C(4)	-2328(12)	5027(5)	5834(10)	44(2)	C(4A)	-4064(12)	4979(5)	5658(10)	45(2)
C(5)	-4860(13)	5273(5)	4565(11)	49(2)	C(4A)	-4064(12)	4979(5)	5658(10)	45(2)
C(5)	-4860(13)	5273(5)	4565(11)	49(2)	C(6)	-6411(15)	5250(6)	4430(12)	68(2)
C(7)	-7291(13)	4981(6)	5430(13)	68(2)	C(6)	-6411(15)	5250(6)	4430(12)	68(2)
C(7)	-7291(13)	4981(6)	5430(13)	68(2)	C(8)	-6563(13)	4705(5)	6491(12)	56(2)
C(8A)	-4955(12)	4700(5)	6662(10)	39(2)	C(8)	-6563(13)	4705(5)	6491(12)	56(2)
C(8A)	-4955(12)	4700(5)	6662(10)	39(2)	C(1′)	-1539(12)	5015(5)	4411(10)	46(2)
C(2′)	-1022(12)	5517(5)	3816(12)	52(2)	C(1′)	-1539(12)	5015(5)	4411(10)	46(2)
C(2′)	-1022(12)	5517(5)	3816(12)	52(2)	C(3′)	-308(13)	5493(5)	2508(11)	52(2)
C1(1)	243(5)	6117(2)	1757(4)	91(1)	C(3′)	-308(13)	5493(5)	2508(11)	52(2)
C1(1)	243(5)	6117(2)	1757(4)	91(1)	C(4′)	-9(13)	5024(6)	1820(11)	54(2)
C1(2)	972(4)	4996	258(3)	81(1)	C(4′)	-9(13)	5024(6)	1820(11)	54(2)

C(5′)	-486(14)	4545(5)	2414(11)	56(2)
C(5′)	-486(14)	4545(5)	2414(11)	56(2)	C(6′)	-1219(14)	4538(5)	3694(11)	52(2)
C(1X)	495(13)	7219(5)	-5303(11)	47(2)	C(6′)	-1219(14)	4538(5)	3694(11)	52(2)
C(1X)	495(13)	7219(5)	-5303(11)	47(2)	N(1XA)	648(11)	7826(4)	-4926(9)	50(2)
C(1XB)	-814(13)	8109(5)	-4598(12)	58(2)	N(1XA)	648(11)	7826(4)	-4926(9)	50(2)
C(1XB)	-814(13)	8109(5)	-4598(12)	58(2)	C(2X)	2126(14)	7016(5)	-5601(12)	67(2)
C(3X)	3130(13)	6938(6)	-4263(11)	64(2)	C(2X)	2126(14)	7016(5)	-5601(12)	67(2)
C(3X)	3130(13)	6938(6)	-4263(11)	64(2)	C(4X)	2437(13)	6525(5)	-3240(10)	53(2)
C(4XA)	702(12)	6586(5)	-3183(11)	46(2)	C(4X)	2437(13)	6525(5)	-3240(10)	53(2)
C(4XA)	702(12)	6586(5)	-3183(11)	46(2)	C(5X)	-45(14)	6304(5)	-2112(12)	55(2)
C(6X)	-1610(15)	6299(5)	-1995(13)	65(2)	C(5X)	-45(14)	6304(5)	-2112(12)	55(2)
C(6X)	-1610(15)	6299(5)	-1995(13)	65(2)	C(7X)	-2501(16)	6604(6)	-2945(14)	80(2)
C(8X)	-1807(13)	6890(5)	-4024(12)	56(2)	C(7X)	-2501(16)	6604(6)	-2945(14)	80(2)
C(8X)	-1807(13)	6890(5)	-4024(12)	56(2)	C(8XA)	-206(12)	6900(5)	-4117(10)	39(2)
C(1X′)	3233(13)	6545(5)	-1796(10)	49(2)	C(8XA)	-206(12)	6900(5)	-4117(10)	39(2)
C(1X′)	3233(13)	6545(5)	-1796(10)	49(2)	C(2X′)	3944(14)	6083(5)	-1250(11)	58(2)
C(3X′)	4642(13)	6084(5)	101(11)	52(2)	C(2X′)	3944(14)	6083(5)	-1250(11)	58(2)
C(3X′)	4642(13)	6084(5)	101(11)	52(2)	C1(3)	5554(5)	5501(2)	743(3)	85(1)
C(4X′)	4732(14)	6569(6)	875(11)	62(2)	C1(3)	5554(5)	5501(2)	743(3)	85(1)
C(4X′)	4732(14)	6569(6)	875(11)	62(2)	C1(4)	5695(4)	6600(2)	2528(3)	78(1)
C(5X′)	3978(14)	7023(5)	350(11)	62(2)	C1(4)	5695(4)	6600(2)	2528(3)	78(1)
C(5X′)	3978(14)	7023(5)	350(11)	62(2)	C(6X′)	3293(15)	7006(5)	-982(11)	63(2)
C(1Y)	1318(16)	2575(6)	9581(14)	106(2)	C(6X′)	3293(15)	7006(5)	-982(11)	63(2)
C(1Y)	1318(16)	2575(6)	9581(14)	106(2)	C(2Y)	540(13)	3113(5)	9839(11)	57(2)
O(3Y)	103(10)	3150(5)	11268(8)	87(2)	C(2Y)	540(13)	3113(5)	9839(11)	57(2)
O(3Y)	103(10)	3150(5)	11268(8)	87(2)	C(4Y)	-786(14)	3217(5)	8778(12)	49(2)
O(5Y)	-479(11)	3255(4)	7509(8)	86(2)	C(4Y)	-786(14)	3217(5)	8778(12)	49(2)
O(5Y)	-479(11)	3255(4)	7509(8)	86(2)	O(6Y)	-2081(10)	3239(4)	9294(8)	65(2)
C(1Z)	6352(15)	8746(8)	-2633(15)	110(2)	O(6Y)	-2081(10)	3239(4)	9294(8)	65(2)
C(1Z)	6352(15)	8746(8)	-2633(15)	110(2)	C(2Z)	4677(13)	8843(6)	-2407(12)	66(2)
O(3Z)	4349(11)	8757(5)	-1000(8)	101(2)	C(2Z)	4677(13)	8843(6)	-2407(12)	66(2)
O(3Z)	4349(11)	8757(5)	-1000(8)	101(2)	C(4Z)	3602(14)	8483(5)	-3343(11)	50(2)
O(5Z)	3800(10)	8497(4)	-4676(7)	66(2)	C(4Z)	3602(14)	8483(5)	-3343(11)	50(2)

O(6Z)

2594(10)

8209(4)

-2782(7)

60(2)

^*Suitable isotope U is defined as orthogonal U _Ij/ 3rd of a track of tensor (trace).

Embodiment 49

Sertraline L-lactate osmotic tablets

This embodiment illustrates that preparation comprises the method for the osmotic tablets that contains Lactated nuclear of Sertraline L-that is surrounded by semi permeability asymmetric membrane coating.Equipment with standard in the pharmaceuticals industry prepares sheet nuclear.Mix and comprise 13.8wt% Sertraline L-lactate, the 11wt%L-aspartic acid, the 5wt% calcium acetate, the sheet nuclear composition of 29.5wt% microcrystalline Cellulose and 38.2wt% fructose is then by roll squeezer and grinding.Then, the material of this grinding is mixed with the 2.5wt% magnesium stearate (Killian T-100) preparation gross weight is the final composite material of the sheet of 470mg on conventional tablet machine to be formed for.With the disc type coating device of side opening (675 44th St., Marion, IA 52302 for LDCS-20, Vector Corp.) semi permeability asymmetric membrane coating (as United States Patent (USP) 5,612,059 is described) is administered on the sheet.To contain 10wt% cellulose acetate 398-10,2.5wt%PEG 3350, and the coating solution of 15wt% water and 72.5wt% acetone has 10wt% coating content with the speed spraying coating of 20g/min on sheet to sheet.

Embodiment 50

The Lactated osmotic tablets of Sertraline L-

This embodiment illustrates that preparation comprises the method for the osmotic tablets that contains Lactated nuclear of Sertraline L-that is surrounded by semi permeability asymmetric membrane coating.Equipment with standard in the pharmaceuticals industry prepares sheet nuclear.Sheet nuclear is prepared as follows: glyceryl monolaurate (5%) carries out wet granulation with ethanol (95%) as the wet granulation solvent with the 14wt% microcrystalline Cellulose.After the dry also grinding, wet granular and 13.8wt% Sertraline L-lactate, the 11wt%L-aspartic acid, the 5wt% calcium acetate, other 13wt% microcrystalline Cellulose and 35.7wt% fructose mix.After adding whole compositions, granule is also ground by roll squeezer.Then, the material with this grinding mixes with the 2.5wt% magnesium stearate to be formed for (Kilian T-100, Kilian﹠amp on conventional tablet machine; Co., 415 Sargon Way Unit 1, Horsham, PA 19044) the preparation gross weight is the final composite material of the sheet of 470mg.With the disc type coating device (LDCS-20, Vector Corp.) of side opening semi permeability asymmetric membrane coating (special 5,612 as the U.S., 059 is described) is administered on the sheet.To contain 10wt% cellulose acetate 398-10,2.5wt%PEG 3350, and the coating solution of 15wt% water and 72.5wt% acetone sprays coating to sheet with the speed of 20g/min.The tablet and a collection of tablet that has the 20wt% coating that prepare a collection of 10wt% of having coating.

Embodiment 51

The Lactated encapsulated solution dosage of Sertraline L-is at Capmul MGM ^TMIn (Columbus, Ohio 43219 for sad mono and di-glycerides and sad, Abitec company) with the prepared at concentrations Sertraline L-lactate solution of 75mgA/ml.With packing volume encapsulated this solution in soft gelatin of 0.67ml, obtain the dosage unit of 50mgA.

Embodiment 52

(preparation AA chemical compound 200.3mg) is dissolved in ethyl acetate (800 μ l have used water saturation) to Sertraline L-aspartate Sertraline free alkali.L-aspartic acid (95.53mg) is suspended in ethyl acetate (3ml has used water saturation).Add the aspartic acid suspension in the Sertraline free base solution.Stirred this reactant mixture 24 hours.Filter this solid, with the washing of water saturated ethyl acetate and in vacuum tank 40 ℃ dry 48 hours down.Sertraline L-aspartate yield is 96.4%.mp247℃。

Preparation AA

The Sertraline free alkali is with sertraline salts hydrochlorate (2.5g) water-soluble (1 liter).The 1N NaOH that adds aequum is 8.0 up to the pH regulator with this solution in this solution.Filter the gained solid and use deionized water (50ml/ restrains solid) washing.40 ℃ were descended dry this solid 48 hours in vacuum tank.Yield is 98%, mp67 ℃.

Preparation BB

The Sertraline free alkali is with sertraline salts hydrochlorate (300g) slurrying in 3: 1 mixture of water (3 liters) and ethyl acetate (1 liter).Adding about 1 liter of 1N NaOH solution is 8.0 with the pH regulator of this slurry.With the Sertraline free alkali be dispensed into ethyl acetate mutually in.Thoroughly separate biphase by allowing this biphasic solution not have the standing over night of stirring.Then, the separating ethyl acetate layer and with twice of 3 liters of deionized water wash to remove chloride ion.Concentrate under the vacuum contain Sertraline alkali final ethyl acetate layer to 300ml to remove residual water.

Claims

1. be suitable for slow release formulation to the mammal oral administration, comprise Sertraline, or its pharmaceutical salts and pharmaceutical carrier, it is discharged into Sertraline in the environment for use with the speed that is no more than 0.8mgA/ hour/kg, this environment for use is the mammal gastrointestinal tract or is the testing in vitro medium of 0.075M for the acetate buffer of pH4.0 and in NaCl

Condition be discharge in this dosage form (1) first hour after entering this environment for use the Sertraline that is no more than with which 70% in said environment for use, and (2) discharge Sertraline with the speed of 0.02mgA/ hour/kg at least;

Wherein said dosage form is many granules.

2. be suitable for slow release formulation, comprise Sertraline the mammal administration, or its pharmaceutical salts and pharmaceutical carrier,

This dosage form is discharged into Sertraline in the environment for use with the speed that is no more than 40mgA/ hour, and this environment for use is the mammal gastrointestinal tract or is the testing in vitro medium of 0.075M for the acetate buffer of pH4.0 and in NaCl,

Condition be discharge in this dosage form (1) first hour after entering this environment for use the Sertraline that is no more than with which 70% in said environment for use, and (2) discharge Sertraline with 1mgA/ hour at least speed,

Wherein said dosage form is many granules.