Methods of administering certain VMAT2 inhibitors

文档序号：1580352 发布日期：2020-01-31 浏览：21次中文

阅读说明：本技术 施用某些vmat2抑制剂的方法 (Methods of administering certain VMAT2 inhibitors ) 是由克里斯托弗·F·奥勃良黑格·P·博齐根于 2017-10-10 设计创作，主要内容包括：提供了向有需要的患者施用选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的方法,其中所述患者还正在被施用细胞色素P450 2D6(CYP2D6)强抑制剂。(Methods of administering a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or pharmaceutically acceptable salts and/or isotopic variants thereof, to a patient in need thereof are provided, wherein said patient is also being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).)

1. A method of administering a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof, wherein said patient is also being administered a strong inhibitor of cytochrome P4502D6(CYP2D6), said method comprising:

administering a therapeutically effective amount of the VMAT2 inhibitor to the patient.

2. The method of claim 1, further comprising monitoring the patient for one or more exposure-related adverse reactions.

3. The method of claim 1 or 2, further comprising reducing the amount of the VMAT2 inhibitor based on the patient's ability to tolerate or more exposure-related adverse effects.

4. A method of administering to a patient in need thereof a vesicular monoamine transporter 2(VMAT2) inhibitor selected from the group consisting of valiphenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising:

administering to the patient a therapeutically effective amount of the VMAT2 inhibitor,

it was subsequently determined that the patient will begin treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6), and

continuing to administer a therapeutically effective amount of the VMAT2 inhibitor to the patient.

5. A method of administering to a patient in need thereof a vesicular monoamine transporter 2(VMAT2) inhibitor selected from the group consisting of valiphenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising:

administering to the patient a therapeutically effective amount of the VMAT2 inhibitor,

it was subsequently determined that the patient will begin treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6), and

administering to the patient a reduced amount of the VMAT2 inhibitor.

6. The method of claim 4 or 5, further comprising monitoring the patient for adverse effects associated with the exposure.

7. The method of of any one of claims 4-6, further comprising reducing the amount of the VMAT2 inhibitor based on the patient's ability to tolerate exposure-related adverse effects.

8. The method of of any one of claims 1-7, further comprising informing the patient or a health care provider that administration of the VMAT2 inhibitor to a patient who is also being administered a strong CYP2D6 inhibitor results in an increased exposure to (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol.

9. The method of of any one of claims 1-8, further comprising informing the patient or a health care worker that administration of the VMAT2 inhibitor to a patient who is also being administered a strong inhibitor of CYP2D6 is likely to result in an increased risk of exposure-related adverse reactions.

10. The method of of any one of claims 1-9, further comprising informing the patient or a health care worker that co-administration of the VMAT2 inhibitor and a strong CYP2D6 inhibitor is likely to prolong QT interval in the patient.

11. The method of of any one of claims 2,3, or 6-10, wherein the one or more exposure-related adverse effects are selected from lethargy, anticholinergic effects, balance impairment or fall, headache, akathisia, vomiting, nausea, joint pain, QT prolongation, elevated blood glucose, elevated body weight, respiratory infections, salivation, movement disorders, extra-pyramidal symptoms (akathisia), anxiety, insomnia, elevated prolactin, elevated alkaline phosphatase, and elevated bilirubin.

12. The method of claim 11, wherein the one or more exposure-related adverse effects are selected from lethargy, anticholinergic effects, balance impairment or fall, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation.

13. The method of claim 12, wherein the one or more exposure-related adverse effects are selected from lethargy and QT prolongation.

14. The method of any of claims 1-13, wherein the therapeutically effective amount is less than the amount administered to a patient not being administered a strong inhibitor of CYP2D 6.

15. The method of any of claims 1-13, wherein the therapeutically effective amount is the same amount as that administered to a patient not being administered a strong inhibitor of CYP2D 6.

16. The method of of any one of claims 1-15, wherein the strong CYP2D6 inhibitor is selected from the group consisting of bupropion, fluoxetine, metoclopramide, paroxetine, terbinafine, duloxetine, sertraline, and quinidine.

17. The method of claim 16, wherein the strong CYP2D6 inhibitor is selected from fluoxetine, paroxetine, and quinidine.

18. The method of of any one of claims 1-17, wherein the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder.

19. The method of claim 18, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment of obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthocytosis.

20. The method of claim 19, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder.

21. The method of claim 20, wherein the hyperkinetic movement disorder is tardive movement disorder.

22. The method of claim 20, wherein the hyperkinetic movement disorder is tourette's syndrome.

23. The method of claim 20, wherein the hyperkinetic movement disorder is huntington's disease.

24. The method of claim 20, wherein the hyperkinetic movement disorder is tics.

25. The method of claim 20, wherein the hyperkinetic movement disorder is chorea associated with huntington's disease.

26. The method of claim 20, wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, huntington's disease, myoclonus, restless leg syndrome, or tremor.

27. The method of of any one of claims 1-26, wherein the VMAT2 inhibitor is administered orally.

28. The method of any of claims 1-27, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule.

29. The method of of any one of claims 1-28, wherein the VMAT2 inhibitor is administered with or without food.

30. The method of of any one of claims 1-29, wherein the VMAT2 inhibitor is valiphenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof.

31. The method of claim 30, wherein the VMAT2 inhibitor is valiphenazine or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the VMAT2 inhibitor is valiphenazine tosylate.

33. The method of claim 32, wherein the VMAT2 inhibitor is a xylene sulfonate salt of valiphenazine.

34. The method of claim 30, wherein the VMAT2 inhibitor is an isotopic variant being (2R,3R,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-bis (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-yl L-valine esters or pharmaceutically acceptable salts thereof.

35. The method of any of claims 1-34, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 20mg to about 160mg of valiphenazine free base.

36. The method of claim 35, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 20mg of valine free base.

37. The method of claim 35, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 40mg of valine free base.

38. The method of claim 35, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 60mg of valine free base.

39. The method of claim 35, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 80mg of valbenazine free base.

40. The method of claim 35, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 120mg of valine free base.

41. The method of any of claims 1-34, wherein the VMAT2 inhibitor is administered at an amount of for a period of time of and then the amount is increased to a second amount.

42. The method of claim 41, wherein the th time period is weeks.

43. A method according to claim 41 or 42 wherein the th amount is equivalent to about 40mg of valiphenazine free base.

44. The method of any of claims 41-43, wherein the second amount is equivalent to about 80mg of valbenazine free base.

45. The method of any of claims 1-34, wherein a maximum plasma concentration (Cmax) of (+) - α -DHTBZ of about 15ng to about 60ng per mL of plasma is achieved for a time period sufficient to last 8 hours_max) And a minimum plasma concentration (C) of at least 15ng (+) - α -DHTBZ per mL of plasma_min) In an amount sufficient to administer the VMAT2 inhibitor.

46. As claimed in claimThe method of any of items 1 to 34, wherein the maximum plasma concentration (C) of about 15ng to about 60ng of (+) - α -DHTBZ per mL of plasma is achieved for a period of time sufficient to last 12 hours_max) And said C_maxApproximately at least about 33% -50% of the minimum plasma concentration (C)_min) In an amount sufficient to administer the VMAT2 inhibitor.

47. The method of of any one of claims 1-34, wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve (i) a therapeutic concentration range of about 15ng to about 60ng (+) - α -DHTBZ per mL of plasma and (ii) a threshold concentration of at least 15ng (+) - α -DHTBZ per mL of plasma for a period of about 8 hours to about 24 hours.

48. The method of any of claims 1-34, wherein the therapeutically effective amount of the VMAT2 inhibitor is 10% -90% less than the amount that would be administered to a patient not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

49. The method of any of claims 1-34, wherein the therapeutically effective amount of the VMAT2 inhibitor is 20% -80% less than the amount that would be administered to a patient not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

50. The method of any of claims 1-34, wherein the therapeutically effective amount of the VMAT2 inhibitor is 30% -70% less than the amount that would be administered to a patient not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

51. The method of any of claims 1-34, wherein the therapeutically effective amount of the VMAT2 inhibitor is 40% -60% less than the amount that would be administered to a patient not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

52. The method of any of claims 1-34, wherein the therapeutically effective amount of the VMAT2 inhibitor is about 50% less than the amount that would be administered to a patient not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

53. The method of of any one of claims 1-29, wherein the VMAT2 inhibitor is (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a pharmaceutically acceptable salt and/or isotopic variant thereof.

54. The method of claim 53, wherein the VMAT2 inhibitor is (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

55. The method of claim 53, wherein the VMAT2 inhibitor is an isotopic variant that is (+) - α -3-isobutyl-9, 10-bis (methoxy-d)₃) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ]]Isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

56. A composition for treating a patient in need of a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, and administered a strong inhibitor of cytochrome P4502D6(CYP2D6), comprising a therapeutically effective amount of said VMAT2 inhibitor.

57. The composition of claim 56, wherein the patient is monitored for or more exposure-related adverse reactions.

58. The composition of claim 56 or 57, wherein after administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor, a composition comprising a reduced amount of the VMAT2 inhibitor is administered based on the patient's ability to tolerate or more exposure-related adverse reactions.

59. A composition for treating a patient in need of an inhibitor of vesicular monoamine transporter 2(VMAT2) selected from the group consisting of valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising said VMAT2 inhibitor,

characterized in that a composition comprising a therapeutically effective amount of the VMAT2 inhibitor is administered to a patient who is subsequently determined to commence treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6) after administration of a composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

60. A composition for treating a patient in need of an inhibitor of vesicular monoamine transporter 2(VMAT2) selected from the group consisting of valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising said VMAT2 inhibitor,

characterized in that a composition comprising a reduced amount of the VMAT2 inhibitor is administered to a patient who is subsequently determined to begin treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6) after administration of a composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

61. The composition of claim 59 or 60, wherein the patient is monitored for or more exposure-related adverse reactions.

62. The composition of any of claims 59-61, characterized in that, following administration of a composition comprising the therapeutically effective amount of the VMAT2 inhibitor of claim 4 or a composition comprising the reduced amount of the VMAT2 inhibitor of claim 5, a composition comprising a reduced amount of the VMAT2 inhibitor is administered based on the patient's ability to tolerate or more exposure-related adverse effects.

63. The composition of any of claims 56-62, wherein the patient or healthcare worker is informed that administration of the composition to a patient who is also being administered a strong inhibitor of CYP2D6 results in an increased exposure to (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol.

64. The composition of any of claims 56-63, wherein the patient or healthcare worker is informed that administration of the composition to a patient who is also being administered a strong inhibitor of CYP2D6 may result in an increased risk of or more exposure-related adverse reactions.

65. The composition of any of claims 56-64, wherein said patient or healthcare worker is informed that co-administration of said composition with a CYP2D6 inhibitor may prolong QT interval in said patient.

66. The composition of any one of of claims 56-65, wherein the one or more exposure-related adverse effects are selected from lethargy, anticholinergic effects, balance impairment or fall, headache, akathisia, vomiting, nausea, joint pain, QT prolongation, elevated blood glucose, elevated body weight, respiratory infections, salivation, movement disorders, extra-pyramidal symptoms (akathisia), anxiety, insomnia, elevated prolactin, elevated alkaline phosphatase, and elevated bilirubin.

67. The composition of claim 66, wherein the or more exposure-related adverse effects are selected from lethargy, anticholinergic effects, balance impairment or falls, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation.

68. The composition of claim 67, wherein the one or more exposure-related adverse effects are selected from lethargy and QT prolongation.

69. The composition of any of claims 56-68, wherein the therapeutically effective amount is less than the amount administered to a patient not being administered a strong inhibitor of CYP2D 6.

70. The composition of any of claims 56-68, wherein the therapeutically effective amount is the same amount as that administered to a patient not being administered a strong inhibitor of CYP2D 6.

71. The composition of any of claims 56-70, wherein the CYP2D6 strong inhibitor is selected from bupropion, fluoxetine, metoclopramide, paroxetine, terbinafine, duloxetine, sertraline, and quinidine.

72. The composition of claim 71, wherein said strong CYP2D6 inhibitor is selected from fluoxetine, paroxetine, and quinidine.

73. The composition of any of claims 56-72, wherein the composition is for use in treating a neurological or psychiatric disease or disorder.

74. The composition of claim 73, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment of obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthocytosis.

75. The composition of claim 74, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder.

76. The composition of claim 75, wherein the hyperkinetic movement disorder is tardive movement disorder.

77. The composition of claim 75, wherein the hyperkinetic movement disorder is Tourette's syndrome.

78. The composition of claim 75, wherein the hyperkinetic movement disorder is Huntington's disease.

79. The composition of claim 75, wherein the hyperkinetic movement disorder is tics.

80. The composition of claim 75, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

81. The composition of claim 75, wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremor.

82. The composition of any one of claims 56 to 81, , wherein the composition is administered orally.

83. The composition of , wherein the composition is administered in the form of a tablet or capsule.

84. The composition of any of claims 56-83, wherein said composition is administered with or without food.

85. The composition of any of claims 56-84, wherein the VMAT2 inhibitor is valiphenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof.

86. The composition of claim 85, wherein the VMAT2 inhibitor is valiphenazine or a pharmaceutically acceptable salt thereof.

87. The composition of claim 86, wherein the VMAT2 inhibitor is valiphenazine tosylate.

88. The composition of claim 87 wherein the VMAT2 inhibitor is a xylene sulfonate salt of valbenazine.

89. The composition of , wherein the composition is administered in an amount equivalent to about 20mg to about 120mg of valbenazine free base of the VMAT2 inhibitor.

90. The composition of claim 89, wherein said composition is administered in an amount equivalent to about 40mg of valbenazine free base of said VMAT2 inhibitor.

91. The composition of claim 89, wherein said composition is administered in an amount equivalent to about 80mg of the valiphenazine free base of the VMAT2 inhibitor.

92. The composition of claim 89, wherein said composition is administered in an amount equivalent to about 120mg of valbenazine free base of said VMAT2 inhibitor.

93. The composition of of any one of claims 56-88, wherein the composition is administered at the th amount of the VMAT2 inhibitor for a time period and then the amount is increased to a second amount.

94. The composition of claim 93, wherein the time period is weeks.

95. A composition according to claim 93 or 94 wherein said th amount is equivalent to about 40mg of valbenazine free base.

96. The composition of any of claims 93-95, wherein the second amount is equivalent to about 80mg of valbenazine free base.

97. The composition of any of claims 56-88, wherein a maximum plasma concentration (Cmax) of (+) - α -DHTBZ of about 15ng to about 60ng per mL of plasma is achieved for a time period sufficient to last 8 hours_max) And a minimum plasma concentration (C) of at least 15ng (+) - α -DHTBZ per mL of plasma_min) In an amount to administer the composition.

98. The composition of any of claims 56-88, wherein a maximum plasma concentration (Cmax) of (+) - α -DHTBZ of about 15ng to about 60ng per mL of plasma is achieved for a period of time sufficient to last 12 hours_max) And said C_maxApproximately at least about 33% -50% of the minimum plasma concentration (C)_min) In an amount to administer the composition.

99. The composition of any of claims 56 to 88, wherein composition is administered in an amount sufficient to achieve (i) a therapeutic concentration range of about 15ng to about 60ng (+) - α -DHTBZ per mL of plasma and (ii) a threshold concentration of at least 15ng (+) - α -DHTBZ per mL of plasma for a period of time extending from about 8 hours to about 24 hours.

100. The composition of any of claims 56-88, wherein the amount of the VMAT2 inhibitor is 10% -90% less than the amount that would be administered to a patient that is not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

101. The composition of any of claims 56-88, wherein the amount of the VMAT2 inhibitor is 20% -80% less than the amount that would be administered to a patient that is not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

102. The composition of any of claims 56-88, wherein the amount of the VMAT2 inhibitor is 30% -70% less than the amount that would be administered to a patient that is not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

103. The composition of any of claims 56-88, wherein the amount of the VMAT2 inhibitor is 40% -60% less than the amount that would be administered to a patient that is not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

104. The composition of any of claims 56-88, wherein the amount of the VMAT2 inhibitor is 50% less than the amount that would be administered to a patient that is not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

105. The composition of claim 85, wherein the VMAT2 inhibitor is an isotopic variant being (2R,3R,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-bis (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-yl L-valine esters or pharmaceutically acceptable salts thereof.

106. The composition of any of claims 1-84, wherein the VMAT2 inhibitor is (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a pharmaceutically acceptable salt and/or isotopic variant thereof.

107. The composition of claim 106, wherein the VMAT2 inhibitor is (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

108. The composition of claim 106, wherein the VMAT2 inhibitor is an isotopic variant being (+) - α -3-isobutyl-9, 10-bis (methoxy-d)₃) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ]]Isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

Brief description of the invention

A method of administering a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof, wherein said patient is also being administered a strong inhibitor of cytochrome P4502D6(CYP2D6), said method comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor.

Also provided is a method of administering to a patient in need thereof an inhibitor of vesicular monoamine transporter 2(VMAT2) selected from the group consisting of valiphenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or pharmaceutically acceptable salts and/or isotopic variants thereof, comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor, subsequently determining that said patient will begin treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6), and continuing to administer to said patient a therapeutically effective amount of said VMAT2 inhibitor.

Also provided is a method of administering to a patient in need thereof an inhibitor of vesicular monoamine transporter 2(VMAT2) selected from the group consisting of valiphenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or pharmaceutically acceptable salts and/or isotopic variants thereof, comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor, and subsequently determining that said patient will begin treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6), and administering to said patient a reduced amount of said VMAT2 inhibitor.

These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in its entirety.

Drawings

Figure 1A mean (± SD) dose adjusted valiphenazine concentrations were similar with (3.375 ± 2.037ng/mL/mg) or without (3.683 ± 2.360ng/mL/mg) a concomitant CYP2D6 inhibitor (P ═ 0.249).

Figure 1b. mean dose normalized to [ + ] - α -HTBZ concentrations were also similar with (0.534 ± 0.321ng/mL/mg) or without (0.513 ± 0.326ng/mL/mg) concomitant CYP2D6 inhibitor (P ═ 0.571).

Detailed Description

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are to be interpreted in an open, inclusive sense, i.e. as "including but not limited to". In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to " embodiments" or " embodiments" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least embodiments the appearances of the phrases "in embodiments" or "in embodiments" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

In addition, as used in this specification and the appended claims, the singular forms "/ (a)", "/ (an)" and "the" include plural references unless the context clearly dictates otherwise.

As used herein, "valiphenazine" may be referred to as (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl (S) -2-amino-3-methyl-butanoate; or as (2R,3R,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-dimethoxy-3- (2-methylpropyl) -2H-benzo [ a ] quinolizin-2-yl L-valine ester or as NBI-98854.

As used herein, "(+) - α -HTBZ" means a compound that is an active metabolite of valphenazine having the structure:

(+) - α -HTBZ can be called (2R,3R,11bR) or called (+) - α -DHTBZ or called (+) - α -HTBZ or called R, R, R-DHTBZ or called (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or called (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or called NBI-98782.

As used herein, "NBI-136110" refers to a compound that is a metabolite of valphenazine having the structure:

as used herein, "isotopic variation" means a compound containing an unnatural proportion of an isotope at or more atoms that make up such a compound¹H) Deuterium (1)²H) Tritium (a)³H) Carbon-11 (C)¹¹C) Carbon-12 (C)¹²C) Carbon-13 (C)¹³C) Carbon-14 (C)¹⁴C) Nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F) Fluorine-18 (¹⁸F) Phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S), chloro-35 (³⁵Cl), chloro-36 (³⁶Cl), chloro-37 (³⁷Cl), bromo-79 (⁷⁹Br), bromo-81 (⁸¹Br), iodine-123 (¹²³I) Iodine-125 (¹²⁵I) Iodine-127 (¹²⁷I) Iodine-129 (¹²⁹I) And iodine-131 (¹³¹I) In certain embodiments, an "isotopic variant" of a compound contains an unnatural proportion of or more isotopes, including but not limited to hydrogen (i.e., hydrogen)¹H) Deuterium (1)²H) Carbon-12 (C)¹²C) Carbon-13 (C)¹³C) Nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O) and oxygen-18 (¹⁸In certain embodiments, an "isotopic variant" of a compound contains a non-natural proportion of or more isotopes, including but not limited to tritium (tritium)³H) Carbon-11 (C)¹¹C) Carbon-14 (C)¹⁴C) Nitrogen-13 (¹³N), oxygen-14 (¹⁴O) and oxygen-15 (¹⁵O). It should be understood that,in the compounds as provided herein, any hydrogen may be, as an example, where feasible according to the judgment of a person skilled in the art, any hydrogen may be²H, or by way of example, any carbon may be¹³C, or as an example, any of the nitrogens may be¹⁵N, and as an example, any oxygen may be¹⁸And O. In certain embodiments, an "isotopic variation" of a compound contains a non-natural proportion of deuterium.

With respect to the compounds provided herein, when a particular atom position is indicated as having deuterium or "D", it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium by about 0.015%. The positions indicated as having deuterium typically have in particular embodiments a minimum isotopic enrichment factor of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each indicated deuterium position. Isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

As used herein, a substance is a "substrate" for enzymatic activity when it can be chemically converted by the action of an enzyme on the substance. The substrate may be activated or inactivated by an enzyme.

"enzymatic activity" broadly refers to the specific activity of an enzyme (i.e., the rate of enzyme conversion of a substrate per mg or mole of enzyme) as well as the metabolic effects of such conversion.

When the specific activity of an enzyme or the metabolic effects of the specific activity of an enzyme can be reduced by the presence of a substance, the substance is an "inhibitor" of the enzyme activity, regardless of the precise mechanism of such reduction. For example, the agent may be an inhibitor of enzyme activity by competitive, noncompetitive, allosteric, or other type of enzyme inhibition, by reducing the expression of an enzyme, or other direct or indirect mechanism. Co-administration of a given drug with an inhibitor can reduce the rate of metabolism of the drug through the listed metabolic pathways.

When the specific activity of an enzyme or the metabolic action of the specific activity of an enzyme can be increased by the presence of a substance, the substance is an "inducer" of the enzyme activity, regardless of the precise mechanism of such increase. For example, the agent may be an inducer of enzymatic activity by increasing the rate of reaction, by increasing expression of the enzyme, by allosteric activation, or other direct or indirect mechanism. Co-administration of a given drug with an enzyme inducer may increase the rate of excretion of the drug that is metabolized by the indicated pathway.

Any of these effects on enzyme activity can occur at a given concentration of active agent in a single sample, donor, or patient, regardless of clinical significance.

As used herein, a "strong inhibitor of CYP2D 6" is a compound that increases the area under the concentration time curve (AUC) of a sensitive index substrate for the CYP2D6 pathway by >5 fold. Exponential substrates predictably show increased exposure due to inhibition or induction of a given metabolic pathway and are commonly used in prospective clinical drug-drug interaction studies. A sensitive index substrate is one that exhibits an AUC increase of >5 fold using a strong index inhibitor of a given metabolic pathway in clinical drug-drug interaction studies. Examples of sensitive index substrates for the CYP2D6 pathway are fluoxetine and paroxetine. See, e.g., https:// www.fda.gov/drugs/subversion pro processes/subversions/drug interaction at 093664. htm: tables for substrates, inhibitors and inducers and http:// www.ildcare.eu/downloads/artseninfo/drugs _ metabolic _ by _ cyp450s. pdf.

As used herein, "hyperkinetic disorder" or "hyperkinetic movement disorder" or "hyperkinesia" refers to a condition or disease characterized by excessive, abnormal, involuntary movement. These neurological conditions include tremor, dystonia, myoclonus, athetosis, huntington's disease, tardive dyskinesia, tourette's syndrome, dystonia, hemitoseisis, chorea, senile chorea or tics.

As used herein, "tardive syndrome" includes, but is not limited to, tardive dyskinesia, tardive dystonia, delayed akathisia, delayed tics, myoclonus, tremor, and emergency withdrawal syndrome. Tardive dyskinesia is characterized by rapid, repetitive, stereotypical, involuntary movements of the face, limbs, or trunk.

As used herein, "about" means ± 20% of the stated value, and more specifically includes ± 10%, ± 5%, ± 2% and ± 1% of the stated value.

As used herein, "AUC" refers to the area under the curve or integral of the plasma concentration of an active pharmaceutical ingredient or metabolite over time after an administration event.

As used herein, "AUC_0-t"is the integration under the plasma concentration curve from time 0 (dose) to time" t ".

As used herein, "AUC_0-∞"is the AUC from time 0 (dosing) to time infinity. Unless stated otherwise, AUC means AUC_0-∞. Often, the drug is packaged in a salt form, such as valphenazine xylene sulfonate, and the dosage form specification refers to the mass of this salt form or the equivalent mass of the corresponding free base (valphenazine).

As used herein, C_maxIs a pharmacokinetic parameter which refers to the maximum plasma concentration observed after delivery of the active pharmaceutical ingredient. C_maxTime t at maximum plasma concentration_maxThen (c) is performed.

As used herein, "co-administration" and variations thereof mean that at least two drugs are administered to a patient sequentially, simultaneously, or thus in close temporal proximity to each other (e.g., over the same day or a period of weeks or 30 days, or sufficiently close that each of the at least two drugs can be detected simultaneously in the plasma).

As used herein, "adjusting administration," "varying administration," "adjusting dose," or "varying dose" are all equivalent and mean gradually decreasing, or increasing the dose of a substance, ceasing administration of a substance to a patient, or replacing the substance with a different active agent.

As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into a patient by art-recognized introduction means.

As used herein, the term "disorder" or "disorder" as used herein is intended to be generally synonymous and used interchangeably with the terms "disease", "syndrome" and "condition" (as in medical conditions), as all reflect abnormal conditions that impair normal function of the human or animal body or parts thereof, often manifested by distinguishing signs and symptoms.

As used herein, "dose" means a measured amount of active agent that a patient takes times, in certain embodiments, where the active agent is not valine free base, then that amount is the molar equivalent of the corresponding amount of valine free base.

As used herein, "dosing regimen" means the dose of active agent first administered to a patient and the interval (time or symptom) between any subsequent doses of the active agent administered to the patient, such as about 20mg to about 160mg per day times, e.g., times per day about 20mg, about 40mg, about 60mg, about 80mg, about 100mg, about 120mg, or about 160 mg.

As used herein, an "effective amount" and a "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount that, when administered to a subject or patient (e.g., a human subject or patient), is non-toxic and effective for producing some desired therapeutic effect. The precise therapeutically effective amount for a subject can depend, for example, on the physical constitution and health of the subject, the nature and extent of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinical practitioner.

As used herein, "communicate" means to refer to or provide published information, e.g., to provide a user with an active agent having published information; or verbally, e.g., by communication at a seminar, meeting, or other educational presentation, by conversation between a medication sales representative and a healthcare worker, or by conversation between a healthcare worker and a patient; or to present the desired information to the user for understanding purposes.

As used herein, "indicia" means all labels or other written, printed, graphical, electronic, verbal, or instructional communication means pertaining to a pharmaceutical product or dosage form or accompanying such pharmaceutical product or dosage form.

As used herein, "health care worker" means a worker in the health care arts who may need or utilize information about an active agent (including its dosage form), including information about safety, efficacy, administration, or pharmacokinetics. Examples of healthcare workers include physicians, pharmacists, physician assistants, nurses, support personnel, care givers (which may include family members or guardians), emergency medical workers, and veterinarians.

As used herein, "guidelines" means FDA-approved patient labels for drug products that comply with the regulations set forth in 21CFR 208 and other applicable regulations, including information on how safe a patient uses a drug product.A guideline is scientifically accurate and is based on and does not conflict with the approved professional labels for drugs under 21CFR 201.57, but the language need not be the same as the portion of its corresponding approved label.A guideline is generally applicable to drugs with special risk management information.

As used herein, "patient" or "individual" or "subject" means a mammal, including a human, in need of treatment, and generally refers to the recipient of the treatment.

As used herein, "patient package insert" means information about how safe a patient uses a drug, which is part of an FDA approved label, which is an extension of a professional label for that drug that may be issued to a patient at the time of dispensing, which provides consumer-oriented information about the product in non-professional language, e.g., which may describe benefits, risks, how to identify risks, dosages, or administrations.

As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material can be incorporated into a pharmaceutical composition for administration to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards for toxicological and manufacturing testing, or that it is contained in the inactive ingredient guidelines set forth by the U.S. food and drug administration. "pharmacologically active" (or simply "activity"), as in a "pharmacologically active" (or "active") derivative or analog, refers to a derivative or analog that has the same type of pharmacological activity as the parent compound and is approximately equivalent in degree. The term "pharmaceutically acceptable salts" includes acid addition salts formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferrous hydroxide, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

As used herein, "product" or "pharmaceutical" means a dosage form of an active agent plus published information, and optionally packaging.

As used herein, a "product insert" means a professional label (prescription information) for a drug, a patient package insert for a drug, or a medication guide for a drug.

As used herein, "professional label" or "prescription information" means an official specification of a drug approved by a regulatory agency (e.g., FDA or EMEA) governing the marketing of drugs, which includes a summary of necessary scientific information needed for safe and effective use of the drug, such as, for example, indications and usage; dosage and administration; who should take it; adverse events (side effects); instructions for use in a particular population (pregnant women, children, elderly, etc.); safety information for the patient, etc.

As used herein, "published material" means a medium that provides information, including printed, audio, video, or electronic media, such as flyers, messages, product inserts, printed labels, internet websites, internet webpages, internet popups, radio broadcasts, or television broadcasts, compact discs, DVDs, audio recordings, or other recorded or electronic media.

As used herein, "risk" means the probability or chance that an adverse reaction, injury, or other undesirable outcome is caused by a medical treatment, "acceptable risk" means the measure of the risk of injury, or disease caused by a medical treatment that an individual or population will tolerate "acceptable" will depend on the perceived advantages of the individual or population as a return for assuming risk, whether they accept any scientific and other recommendations provided with respect to the extent of risk, and numerous other factors (political and social).

As used herein, "safety" means the incidence or severity of adverse events associated with administration of an active agent, including adverse effects associated with patient-related factors (e.g., age, sex, race, ethnicity, disease of interest, renal or hepatic dysfunction, comorbidities, genetic characteristics such as metabolic state, or environment) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medication).

As used herein, "t" is_max"is a pharmacokinetic parameter which indicates the time to maximum plasma concentration after delivery of the active pharmaceutical ingredient.

As used herein, "t" is_1/2"or" plasma half-life "or" elimination half-life "and the like are pharmacokinetic parameters that indicate the apparent plasma terminal half-life, i.e., the time for the plasma concentration to decrease by half after drug absorption and distribution is complete.

As used herein, "treating" or "treatment" refers to a therapeutic application that slows or halts the progression of a disorder, a prophylactic application that prevents the development of a disorder, and/or reverses a disorder. Reversing the condition is different from therapeutic applications that slow or arrest the progression of the condition in that, using a reversal method, not only is the progression of the condition completely arrested, but the cellular behaviour shifts to some extent to the normal state observed in the absence of the condition.

As used herein, "VMAT 2" refers to human vesicular monoamine transporter isoform 2, an integral membrane protein that functions to transport monoamines, particularly neurotransmitters such as dopamine, norepinephrine, serotonin and histamine, from the cytosol of the cell into synaptic vesicles.

As used herein, the term "VMAT 2 inhibitor", "inhibition of VMAT 2", or "inhibition of VMAT 2" refers to the ability of a compound disclosed herein to alter the function of VMAT 2. A VMAT2 inhibitor may block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2, or by forming a non-covalently bound complex. Such inhibition may be exhibited only in specific cell types, or may be incidental to a particular biological event. The terms "VMAT 2 inhibitor", "inhibiting VMAT 2", or "inhibition of VMAT 2" also mean altering the function of VMAT2 by reducing the probability of complex formation between VMAT2 and a natural substrate.

There is provided a method of administering an inhibitor of the vesicular monoamine transporter 2(VMAT2) selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof, wherein said patient is also being administered a strong inhibitor of the cytochrome P4502D6(CYP2D6), said method comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor.

In certain embodiments, the method further comprises determining whether the patient is also being administered a strong inhibitor of CYP2D 6.

In certain embodiments, the method further comprises monitoring the patient for or more exposure-related adverse events.

In certain embodiments, the method further comprises reducing the amount of the VMAT2 inhibitor based on the patient's ability to tolerate exposure-related adverse effects.

Also provided is a method of administering to a patient in need thereof an inhibitor of vesicular monoamine transporter 2(VMAT2) selected from the group consisting of valiphenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or pharmaceutically acceptable salts and/or isotopic variants thereof, comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor, and subsequently determining that said patient will begin treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6), and administering to said patient a reduced amount of said VMAT2 inhibitor.

In certain embodiments, the method further comprises monitoring the patient for or more exposure-related adverse events.

In certain embodiments, the method further comprises reducing the amount of the VMAT2 inhibitor based on the patient's ability to tolerate exposure-related adverse effects.

In certain embodiments, the method further comprises informing the patient or healthcare worker that administration of the VMAT2 inhibitor to a patient who is also being administered a strong CYP2D6 inhibitor results in an increased exposure to (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol.

In certain embodiments, the method further comprises informing the patient or healthcare worker that administration of the VMAT2 inhibitor to a patient who is also being administered a strong inhibitor of CYP2D6 may result in an increased risk of or more exposure-related adverse reactions.

In certain embodiments, the method further comprises informing the patient or a health care provider that co-administration of the VMAT2 inhibitor and a strong CYP2D6 inhibitor may prolong QT interval in the patient.

In certain embodiments, the or more exposure-related adverse effects are selected from lethargy, anticholinergic effects, balance impairment or falls, headache, akathisia, vomiting, nausea, joint pain, QT prolongation, elevated blood glucose, elevated body weight, respiratory infections, salivation, movement disorders, extrapyramidal symptoms (akathisia), anxiety, insomnia, elevated prolactin, elevated alkaline phosphatase, and elevated bilirubin.

In certain embodiments, the adverse effects associated with exposure are selected from lethargy and QT prolongation.

In certain embodiments, the therapeutically effective amount is less than the amount administered to a patient not being administered a strong inhibitor of CYP2D 6.

In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is 10% -90% less than the amount that would be administered to a patient not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is 20% -80% less than the amount that would be administered to a patient that is not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is 30% -70% less than the amount that would be administered to a patient that is not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is 40% -60% less than the amount that would be administered to a patient not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

In certain embodiments, the therapeutically effective amount of the VMAT2 inhibitor is about 50% less than the amount that would be administered to a patient not being administered a strong inhibitor of cytochrome P4502D6(CYP2D 6).

For example, where the dose administered to a patient not being administered a strong inhibitor of CYP2D6 is 40 mg/day, the individual may receive the following reduced dose: 4-36 mg/day, e.g., 8-32 mg/day, such as 12-28 mg/day, e.g., 16-24 mg/day, or in certain embodiments, about 20 mg/day. Similarly, the dose administered to a patient not being administered a strong inhibitor of CYP2D6 is 80 mg/day and the individual may receive the following reduced dose: 8-72 mg/day, e.g., 16-64 mg/day, such as 24-56 mg/day, e.g., 32-48 mg/day, or in certain embodiments, about 24 mg/day.

In certain embodiments, the dose of VMAT2 inhibitor administered to a patient is reduced, e.g., to 75% or less, 50% or less, or 25% or less of the amount that would be administered to a patient not being administered a strong inhibitor of CYP2D 6. For example, where the amount to be administered to a patient who is not being administered a strong inhibitor of CYP2D6 is 40 mg/day, the individual may receive a reduced dose of 30, 20 or 10 mg/day. Likewise, where the amount to be administered to a patient not being administered a strong inhibitor of CYP2D6 is 80 mg/day, the individual may receive a reduced dose of 60, 40 or 20 mg/day.

In certain embodiments, the therapeutically effective amount is the same amount as that administered to a patient not being administered a strong inhibitor of CYP2D 6.

In certain embodiments, the CYP2D6 strong inhibitor is selected from the group consisting of bupropion, fluoxetine, metoclopramide, paroxetine, terbinafine, duloxetine, sertraline, and quinidine. In certain embodiments, the strong CYP2D6 inhibitor is selected from the group consisting of bupropion, fluoxetine, metoclopramide, paroxetine, and quinidine. In certain embodiments, the strong CYP2D6 inhibitor is selected from fluoxetine, paroxetine, and quinidine. In certain embodiments, the strong CYP2D6 inhibitor is quinidine.

In certain embodiments, the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder. In certain embodiments, the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder, a mood disorder, a bipolar disorder, schizophrenia, schizoaffective disorder, mania in a mood disorder, depression in a mood disorder, treatment of refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, mania associated with alzheimer's disease, fragile X syndrome or fragile X associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthosis.

In certain embodiments, the neurological or psychiatric disease or disorder is hyperkinetic movement disorder. In certain embodiments, the hyperkinetic movement disorder is tardive movement disorder. In certain embodiments, the hyperkinetic movement disorder is tourette's syndrome. In certain embodiments, the hyperkinetic movement disorder is huntington's disease. In certain embodiments, the hyperkinetic movement disorder is a tic. In certain embodiments, the hyperkinetic movement disorder is chorea associated with huntington's disease. In certain embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, huntington's disease, myoclonus, restless leg syndrome, or tremor.

In certain embodiments, the VMAT2 inhibitor is administered orally.

In certain embodiments, the VMAT2 inhibitor is administered in the form of a tablet or capsule.

In certain embodiments, the VMAT2 inhibitor is administered with or without food.

In certain embodiments, the VMAT2 inhibitor is valiphenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof. In certain embodiments, the VMAT2 inhibitor is valiphenazine or a pharmaceutically acceptable salt thereof. In certain embodiments, the VMAT2 inhibitor is valiphenazine tosylate. In certain embodiments, the VMAT2 inhibitor is a xylene sulfonate salt of valiphenazine.

In certain embodiments, the VMAT2 inhibitor is an isotopic variant which is (2R,3R,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-bis (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-yl L-valine esters or pharmaceutically acceptable salts thereof.

In certain embodiments, the VMAT2 inhibitor is (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a pharmaceutically acceptable salt and/or isotopic variant thereof.

In certain embodiments, the VMAT2 inhibitor is (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the VMAT2 inhibitor is an isotopic variant, which is (+) - α -3-isobutyl-9, 10-bis (methoxy-d)₃) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ]]Isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 20mg to about 160mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 20mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 40mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 60mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 80mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 120mg of valbenazine free base. In certain embodiments, the VMAT2 inhibitor is administered in an amount equivalent to about 160mg of valbenazine free base.

In certain embodiments, the VMAT2 inhibitor is administered at amount for a period of and then the amount is increased to a second amount in certain embodiments, the period is weeks in certain embodiments, the amount is equivalent to about 40mg of the valphenazine free base in certain embodiments, the second amount is equivalent to about 80mg of the valphenazine free base.

In certain embodiments, the maximum plasma concentration (C) of (+) - α -DHTBZ of about 15ng to about 60ng per mL of plasma is achieved for a period of 8 hours_max) And a minimum plasma concentration (C) of at least 15ng (+) - α -DHTBZ per mL of plasma_min) In an amount sufficient to administer the VMAT2 inhibitor.

In certain embodiments, the maximum plasma concentration (C) of (+) - α -DHTBZ of about 15ng to about 60ng per mL of plasma is achieved for a period of 12 hours_max) And said C_maxApproximately at least about 33% -50% of the minimum plasma concentration (C)_min) In an amount sufficient to administer the VMAT2 inhibitor.

In certain embodiments, the VMAT2 inhibitor is administered in an amount sufficient to achieve (i) a therapeutic concentration range of about 15ng to about 60ng (+) - α -DHTBZ per mL of plasma and (ii) a threshold concentration of at least 15ng (+) - α -DHTBZ per mL of plasma for a period of time of about 8 hours to about 24 hours.

In certain embodiments, C of R, R, R-DHTBZ_maxIs about 15ng/mL, about 20ng/mL, about 25ng/mL, about 30ng/mL, about 35ng/mL, about 40ng/mL, about 45ng/mL, about 50ng/mL, about 55ng/mL, or about 60ng/mL of plasma. In certain embodiments, the C of R, R-DHTBZ is at a time period of 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 28 hours, or 32 hours duration_minIs at least 15ng/mL, at least 20ng/mL, at least 25ng/mL, at least 30ng/mL, or at least 35ng/mL of plasma. In certain embodiments, C of R, R, R-DHTBZ_minFrom about 15ng/mL to about 35 ng/mL.

In certain embodiments, the C of R, R, R-DHTBZ is provided in an amount sufficient to provide about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma for a 24 hour period_maxAnd said C_maxApproximately at least 33% of C_minAdministering the pharmaceutical composition. In certain embodiments, the C of R, R, R-DHTBZ is provided in an amount sufficient to provide about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma for a 24 hour period_maxAnd said C_maxApproximately at least 50% of C_minAdministering the pharmaceutical composition. In certain embodiments, the C of R, R, R-DHTBZ is provided in an amount sufficient to provide about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma for a 24 hour period_maxAnd said C_maxApproximately at least about 33% -50% of C_minAdministering the pharmaceutical composition.

In certain embodiments, the C of R, R, R-DHTBZ is provided in an amount sufficient to provide about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma for a 12 hour period_maxAnd said C_maxApproximately at least 33% of C_minAdministering the pharmaceutical composition. In certain embodiments, the C of R, R, R-DHTBZ is provided in an amount sufficient to provide about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma for a 12 hour period_maxAnd said C_maxApproximately at least 50% of C_minAdministering the pharmaceutical composition. In certain embodiments, the C of R, R, R-DHTBZ is provided in an amount sufficient to provide about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma for a 12 hour period_maxAnd said C_maxApproximately at least about 33% -50% of C_minAdministering the pharmaceutical composition.

In some instancesIn embodiments, the C of R, R, R-DHTBZ is provided in an amount sufficient to provide about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma for a 24 hour period_maxAnd a Cc of about 5ng to about 30ng per mL of plasma_minAdministering the pharmaceutical composition. In certain embodiments, the C of R, R, R-DHTBZ is provided in an amount sufficient to provide about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma for a 24 hour period_maxAnd a Cc of about 7.5ng to about 30ng per mL of plasma_minAdministering the pharmaceutical composition.

In certain embodiments, provided herein are methods of treating a neurological or psychiatric disease or disorder comprising administering to a subject a pharmaceutical composition comprising the VMAT2 inhibitor as an active pharmaceutical ingredient in an amount sufficient to provide, for a period of time lasting from about 8 hours to about 24 hours: (i) a therapeutic concentration range of about 15ng to about 60ng of R, R, R-DHTBZ per mL of plasma; and (ii) a threshold concentration of at least 15ng R, R, R-DHTBZ per mL of plasma.

In certain embodiments, the therapeutic concentration ranges from about 15ng to about 35ng, about 15ng to about 40ng, about 15ng to about 45ng, about 15ng to about 50ng, or about 15ng to about 55ng R, R-DHTBZ per mL of plasma.

In certain embodiments, the threshold concentration of R, R-DHTBZ is about 15ng/mL, about 20ng/mL, about 25ng/mL, about 30ng/mL, about 35ng/mL, about 40ng/mL, about 45ng/mL, about 50ng/mL, about 55ng/mL, or about 60ng/mL plasma for a period of about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, or about 32 hours. In certain embodiments, the threshold concentration of R, R-DHTBZ is about 15ng/mL to about 35ng/mL for a period of time ranging from about 8 hours to about 24 hours.

Plasma concentrations can be measured by methods known in the art and are typically measured by tandem mass spectrometry.

Also provided is a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, wherein said patient has previously been determined to have been administered a strong inhibitor of CYP2D6, said method comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor.

Also provided is a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor, subsequently determining that said patient will begin treatment with a CYP2D6 strong inhibitor, and continuing to administer to said patient a therapeutically effective amount of said VMAT2 inhibitor.

Also provided is a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valphenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, wherein said patient has previously been determined to have been administered a CYP2D6 strong inhibitor, said method comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor, followed by selecting a patient who is unable to tolerate or more exposure-related adverse effects, and administering to said patient a reduced amount of said VMAT2 inhibitor, for example times 40mg daily.

Also provided is a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valphenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, wherein said patient has previously been determined to have been administered a strong inhibitor of CYP2D6, said method comprising administering to said patient a therapeutically effective amount of said VMAT2 inhibitor, followed by selecting a patient capable of tolerating or more exposure-related adverse effects, and continuing to administer to said patient a therapeutically effective amount of said VMAT2 inhibitor.

Valiphenazine may be prepared according to U.S. patent nos. 8,039,627 and 8,357,697, the disclosures of each of which are incorporated herein by reference in their entirety. Tetrabenazine may be administered by a variety of methods, including the formulations disclosed in PCT publication nos. WO 2010/018408, WO 2011/019956, and WO 2014/047167, the disclosures of each of which are incorporated herein by reference in their entirety. In certain embodiments, the valbenazines used in the compositions and methods provided herein are polymorph I as disclosed in U.S. serial No. 15/338,214, the disclosure of which is incorporated herein by reference in its entirety.

Pharmaceutical composition

Also provided is a composition for treating a patient in need of a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, and administered a potent inhibitor of cytochrome P4502D6(CYP2D6), comprising a therapeutically effective amount of said VMAT2 inhibitor.

In certain embodiments, the patient is monitored for or more exposure-related adverse reactions.

In certain embodiments, after administering a composition comprising a therapeutically effective amount of the VMAT2 inhibitor, administering a composition comprising a reduced amount of the VMAT2 inhibitor based on the patient's ability to tolerate or more exposure-related adverse effects.

Also provided are compositions for treating a patient in need of a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising said VMAT2 inhibitor, characterized in that a composition comprising a therapeutically effective amount of said VMAT2 inhibitor is administered to a patient who is subsequently determined to commence treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6) after administration of a composition comprising a therapeutically effective amount of said VMAT2 inhibitor.

Also provided are compositions for treating a patient in need of a vesicular monoamine transporter 2(VMAT2) inhibitor selected from valbenazine and (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising said VMAT2 inhibitor, characterized in that the composition comprising a reduced amount of said VMAT2 inhibitor is administered to a patient who is subsequently determined to commence treatment with a strong inhibitor of cytochrome P4502D6(CYP2D6) after administration of the composition comprising a therapeutically effective amount of said VMAT2 inhibitor.

In certain embodiments, the patient is monitored for or more exposure-related adverse reactions.

In certain embodiments, after administering a composition comprising a therapeutically effective amount of the VMAT2 inhibitor or a composition comprising a reduced amount of the VMAT2 inhibitor, administering a composition comprising a reduced amount of the VMAT2 inhibitor based on the patient's ability to tolerate or more exposure-related adverse effects.

In certain embodiments, the patient or healthcare worker is informed that administration of the composition to a patient who is also being administered a strong inhibitor of CYP2D6 can result in an increased exposure to (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol.

In certain embodiments, the patient or healthcare worker is informed that administration of the composition to a patient who is also being administered a strong inhibitor of CYP2D6 may result in an increased risk of exposure-related adverse reactions.

In certain embodiments, the patient or healthcare worker is informed that co-administration of the composition with a CYP2D6 inhibitor may prolong QT interval in the patient.

In certain embodiments, the adverse effects associated with exposure are selected from lethargy and QT prolongation.

In certain embodiments, the therapeutically effective amount is less than the amount administered to a patient not being administered a strong inhibitor of CYP2D 6.

In certain embodiments, the therapeutically effective amount is the same amount as that administered to a patient not being administered a strong inhibitor of CYP2D 6.

In certain embodiments, the compositions are used to treat a neurological or psychiatric disease or disorder.

In certain embodiments, the composition is administered orally.

In certain embodiments, the composition is administered in the form of a tablet or capsule.

In certain embodiments, the composition is administered with or without food.

In certain embodiments, the VMAT2 inhibitor is valiphenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof.

In certain embodiments, the VMAT2 inhibitor is valiphenazine or a pharmaceutically acceptable salt thereof.

In certain embodiments, the VMAT2 inhibitor is valiphenazine tosylate.

In certain embodiments, the VMAT2 inhibitor is a xylene sulfonate salt of valiphenazine.

In certain embodiments, the VMAT2 inhibitor is (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the composition is administered in an amount equivalent to about 20mg to about 120mg of the valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 20mg of the valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 40mg of the valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 80mg of the valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 120mg of the valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 160mg of the valbenazine free base of the VMAT2 inhibitor.

In certain embodiments, the composition is administered at the amount of the VMAT2 inhibitor for a time period and then the amount is increased to a second amount in certain embodiments, the time period is weeks in certain embodiments, the amount is equivalent to about 40mg of valphenazine free base in certain embodiments, the second amount is equivalent to about 80mg of valphenazine free base.

Also provided herein are pharmaceutical compositions for treating a neurological or psychiatric disease or disorder comprising said VMAT2 inhibitor as an active pharmaceutical ingredient in combination with or more pharmaceutically acceptable carriers or excipients.

The choice of excipient will depend in large part on a variety of factors such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

The pharmaceutical compositions provided herein can be provided in unit dose form or in multi-dose form. As used herein, unit dosage forms refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined amount of the active ingredient sufficient to produce the desired therapeutic effect, in association with a desired pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. The unit dosage form may be administered in portions or multiple portions thereof. A multi-dose form is a plurality of identical unit dose forms packaged in a single container for administration as separate unit dose forms. Examples of multi-dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

The pharmaceutical compositions provided herein can be administered alone, or in combination with or more other compounds, or more other active ingredients provided herein the pharmaceutical compositions provided herein can be formulated into a variety of dosage forms for oral, parenteral, and topical administration.

Oral administration

Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, pastilles, cachets, pellets, medicated chewing gums, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.

Binders or granulating agents impart cohesiveness to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches, such as corn STARCH, potato STARCH, and pregelatinized STARCH (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, carrageen's extract, panval gum, ghatti gum, psyllium mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), magnesium aluminum silicate, larch gum arabic hemi-lactose, tragacanth gum powder, and guar gum; cellulose such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105(FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillers include, but are not limited to: talc, calcium carbonate, microcrystalline cellulose, cellulose powder, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein from about 50% to about 99% by weight.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and sugar powders. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, can impart to certain compressed tablets the property of allowing disintegration in the mouth by chewing. Such compressed tablets may be used as chewable tablets.

Suitable disintegrants include, but are not limited to: agar; soap clay; cellulose such as methyl cellulose and carboxymethyl cellulose; a wood product; a natural sponge; a cation-exchange resin; alginic acid; gums such as guar gum and magnesium aluminum silicate HV; citrus pulp; cross-linked cellulose, such as cross-linked carboxymethylcellulose; crosslinked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; potassium polacrilin; starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; alginic acid (aligns); and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily identifiable by one of ordinary skill in the art. The pharmaceutical compositions provided herein can contain from about 0.5% to about 15% or from about 1% to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to: calcium stearate; magnesium stearate; mineral oil; light mineralAn oil; glycerol; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium clavatum powder (lycopodium); silicon dioxide or silica gel, e.g.200(w.r.grace co., Baltimore, MD) and

(Cabot co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein can contain from about 0.1% to about 5% by weight of a lubricant. Suitable glidants include colloidal silicon dioxide,(Cabot Co. of Boston, MA) and asbestos-free talc the colorant comprises any of approved, certified, water-soluble FD&C dye, and water-insoluble FD suspended on alumina hydrate&C dyes, and lakes and mixtures thereof. Lakes are a combination formed by adsorbing a water-soluble dye to a hydrated oxide of a heavy metal, thereby producing an insoluble form of the dye. Flavors include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant taste sensation, such as mint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include gelatin, gum acacia, gum tragacanth, bentonite and surfactants, such as polyoxyethylene sorbitan monooleate

Polyoxyethylene sorbitan monooleate 80

And triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, magnesium aluminium silicate, acacia, sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Preservatives include glycerol, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethanol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

It will be appreciated that many carriers and excipients may serve several functions even within a formulation of . the pharmaceutical compositions provided herein may be provided as compressed tablets, molded tablets (table tritrates), chewable lozenges, fast dissolving tablets, compressed tablets, or enteric coated tablets, sugar coated or film coated tablets enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine thereby protecting the active ingredient from the acidic environment of the stomach.

The tablet dosage form may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with or more of the carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or coloring agents.

The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate.A hard gelatin capsule, also known as a Dry Fill Capsule (DFC), consists of two parts, parts slip over another parts, thereby completely encapsulating the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups, emulsions are two-phase systems in which liquids are dispersed in the form of globules throughout another liquids, which may be oil-in-water or water-in-oil.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients provided herein, as well as dialkylated mono-or polyalkylene glycols including 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 represent the approximate average molecular weight of the polyethylene glycol these formulations may further comprise step or more antioxidants such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems.

The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients for use in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients for use in effervescent granules or powders may include organic acids and sources of carbon dioxide. Colorants and flavors may be used in all of the above dosage forms. The pharmaceutical compositions provided herein can be formulated as immediate release dosage forms or modified release dosage forms, including delayed release forms, sustained release forms, pulsed release forms, controlled release forms, targeted release forms, and programmed release forms.

The pharmaceutical compositions provided herein may be combined with other active ingredients that do not impair the desired therapeutic effect, or with substances that supplement the desired effect (such as antacids, proton pump inhibitors and H)₂Receptor antagonist) co-formulationAnd (5) preparing.

The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

Parenteral administration

The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for formulation into a solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in the art of pharmaceutical science.

Pharmaceutical compositions intended for parenteral administration may comprise or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial or preservative agents to combat microbial growth, stabilizers, pro-solvents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous vehicles include, but are not limited to, water, saline, physiological or Phosphate Buffered Saline (PBS), sodium chloride injection, ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactate ringer's injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercuric preparations, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propyl p-hydroxybenzoate, and sorbic acid suitable isotonicizing agents include, but are not limited to, sodium chloride, glycerol, and dextrose suitable buffering agents include, but are not limited to, phosphates and citrates suitable antioxidants are those described herein, including bisulfite and sodium metabisulfite suitable local anesthetics include, but are not limited to, procaine hydrochloride suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate suitable sequestering or chelating agents include, but are not limited to, edta suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid suitable complexing agents include, but are not limited to, cyclodextrin, including α -cyclodextrin, β - β -cyclodextrin, sulfocyclodextrin- β -butyl- β -cyclodextrin and sulfoether-3624

CyDex,Lenexa,KS)。

The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of an antimicrobial agent. As is known and practiced in the art, all parenteral formulations must be sterile.

In certain embodiments, the pharmaceutical composition is provided as a sterile solution ready for use. In certain embodiments, the pharmaceutical compositions are provided as sterile, dry, soluble products, including lyophilized powders and subcutaneous tablets, for reconstitution with a vehicle prior to use. In certain embodiments, the pharmaceutical composition is provided as a sterile suspension ready for use. In certain embodiments, the pharmaceutical composition is provided as a sterile, dry, insoluble product for reconstitution with a vehicle prior to use. In certain embodiments, the pharmaceutical composition is provided as a sterile emulsion that is ready-to-use.

The pharmaceutical compositions provided herein can be formulated as immediate release dosage forms or modified release dosage forms, including delayed release forms, sustained release forms, pulsed release forms, controlled release forms, targeted release forms, and programmed release forms.

The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implant reservoir. In certain embodiments, a pharmaceutical composition provided herein is dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids, but allows the active ingredient in the pharmaceutical composition to diffuse through.

Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.

Topical application

The pharmaceutical compositions provided herein can be topically applied to the skin, opening, or mucosa. Topical administration as used herein includes dermal (intra), conjunctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, respiratory and rectal administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for topical administration for a local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, rinses, sprays, suppositories, bandages, dermal patches. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial or preservative agents to combat microbial growth, stabilizers, solubilizing agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, thickening agents, and inert gases.

The pharmaceutical composition may also be administered topically by: electroporation, iontophoresis, sonophoresis and micro-needle or needle-free injection, such as POWDERJECT^TM(Chiron Corp., Emeryville, Calif.), and BIOJECT^TM(Bioject Medical Technologies Inc.，Tualatin，OR)。

The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon bases including, for example, lard, benzoic lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsifiable or absorbent bases such as hydrophilic petrolatum, glyceryl hydroxystearate sulfate, and anhydrous lanolin; water-removing bases, such as hydrophilic ointments; water-soluble ointment bases including polyethylene glycols of varying molecular weights; emulsion base, water-in-oil (W/O) emulsion or oil-in-water (O/W) emulsion, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. These vehicles are emollients, but generally require the addition of antioxidants and preservatives.

Suitable cream bases may be oil-in-water or water-in-oil. The cream vehicle may be water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase often, although not necessarily, exceeds the oil phase in volume and typically contains a humectant. The emulsifier in the cream formulation may be a nonionic surfactant, an anionic surfactant, a cationic surfactant, or an amphoteric surfactant.

Gels are semisolid suspension type systems. Single phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers such as carbomers, carboxy polyolefins, poly (vinyl alcohol), poly (vinyl alcohol,

Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymer and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose phthalate and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, a dispersing agent such as an alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and/or stirring.

The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally or perivaginally in the form of a suppository, pessary, stick, compress or poultice, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, suspension, tampon, gel, foam, spray or enema. These dosage forms can be prepared using conventional methods.

Rectal, urethral and vaginal suppositories are solid bodies for insertion into body openings which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient within the opening. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include vehicles (such as sclerosing agents) that when formulated with the pharmaceutical compositions provided herein produce a melting point near body temperature; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerol-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and suitable mixtures of mono-, di-and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of various vehicles may be used. Rectal and vaginal suppositories may be prepared by compression methods or molding. The typical weight of rectal and vaginal suppositories is about 2 to 3 g.

The pharmaceutical compositions provided herein can be administered to the eye in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, nebulizer, atomizer (such as one that generates a fine mist using electrohydrodynamic techniques) or nebulizer, alone or in combination with a suitable propellant (such as 1,1,1, 2-tetrafluoroethane or 1,1,1,2,3,3, 3-heptafluoropropane). The pharmaceutical compositions may also be provided as a dry powder for insufflation, either alone or in combination with an inert carrier (such as lactose or a phospholipid); and nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.

Solutions or suspensions for pressurized containers, pumps, sprayers, atomizers, or sprayers can be formulated to contain: ethanol, aqueous ethanol, or suitable alternative agents for dispersing, dissolving, or extending the release of the active ingredients provided herein, as a propellant for the solvent; and/or surfactants such as sorbitan trioleate, oleic acid or oligolactic acid.

The pharmaceutical compositions provided herein can be micronized into a size suitable for delivery by inhalation, such as 50 microns or less, or 10 microns or less. Particles of such size can be prepared using size reduction methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules, blisters and cartridges (cartridges) for use in an inhaler or insufflator may be formulated containing a powder mix of the pharmaceutical composition provided herein, a suitable powder base such as lactose or starch, which may be anhydrous or in the form of hydrate, and a performance modifier such as l-leucine, mannitol or magnesium stearate.

The pharmaceutical compositions provided herein for topical administration may be formulated for immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

Modified release

The pharmaceutical compositions provided herein can be formulated as modified release dosage forms. The term "modified release" as used herein refers to dosage forms that: wherein the rate or location of release of the active ingredient is different from that of an immediate release dosage form when administered by the same route. Modified release dosage forms include delayed release, extended release, sustained release, pulsatile or pulsed release, controlled release, accelerated and rapid release, targeted release, programmed release and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms may be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. By varying the particle size and polymorphism of the active ingredient, the release rate of the active ingredient can also be varied.

The pharmaceutical compositions provided herein can be manufactured in modified release dosage forms using matrix controlled release devices known to those skilled in the art.

In certain embodiments, the pharmaceutical compositions provided herein are formulated in a modified release dosage form using erodable matrix devices which are water swellable, erodable or soluble polymers, including synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

Materials that may be used to form the erodable matrix include, but are not limited to: chitin, chitosan, dextran, and pullulan; agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenan, gum ghatti, guar gum, xanthan gum and scleroglucan; starches, such as dextrin and maltodextrin; hydrocolloids, such as pectin; phospholipids, such as lecithin; an alginate; propylene glycol alginate; gelatin; collagen; and cellulosic materials such as Ethyl Cellulose (EC), Methyl Ethyl Cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), Cellulose Acetate (CA), Cellulose Propionate (CP), Cellulose Butyrate (CB), Cellulose Acetate Butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerin fatty acid ester; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (A)

Rohm America, inc., Piscataway, NJ); poly (2-hydroxyethyl-methacrylate); a polylactide; a copolymer of L-glutamic acid and ethyl L-glutamate; degradable lactic glycolic acid copolymers; poly(s) are polymerized-D- (-) -3-hydroxybutyric acid; and other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl acrylate, 2-dimethylaminoethyl methacrylate and (trimethylaminoethyl) methacrylate chloride.

In certain embodiments, the pharmaceutical composition is formulated with a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and is released primarily after application by diffusion in the inert matrix. Materials suitable for use as a non-erodible matrix device include, but are not limited to: insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methylmethacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer and ethylene/ethyleneoxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, polyisobutylene, polybutadiene, styrene-butadiene-styrene copolymer, styrene-isoprene, A silicone carbonate copolymer, and; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

In matrix controlled release systems, the desired release kinetics can be controlled, for example, by the type of polymer employed, the viscosity of the polymer, the particle size of the polymer and/or active ingredient, the ratio of active ingredient to polymer, and other excipients in the composition.

The pharmaceutical compositions provided herein can be prepared in modified release dosage forms by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt granulation followed by compression.

The pharmaceutical compositions provided herein can be manufactured in modified release dosage forms using a controlled osmotic device comprising an compartment system, a two compartment system, Asymmetric Membrane Technology (AMT), and an Extruded Core System (ECS). such a device has at least two components, (a) a core containing an active ingredient, and (b) a semipermeable membrane having at least delivery ports that encapsulates the core.

The -type osmotic agent is a water-swellable hydrophilic polymer, also referred to as "osmopolymer" and "hydrogel," including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides (such as calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, copolymers of PVA/PVP and hydrophobic monomers (such as methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, crosslinked sodium carboxymethylcellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium glycolate.

Another class of osmotic agents are osmogens (osmogens) that are capable of absorbing water to affect the osmotic pressure gradient across the surrounding coating barrier suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate, sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol, organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-methylbenzenesulfonic acid, succinic acid, and tartaric acid, urea, and mixtures thereof.

Different dissolution rates of the osmotic agent may be used to affect the rate of initial delivery of the active ingredient from the dosage form. For example, amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, DE) may be used to provide faster delivery over the first few hours to immediately produce the desired therapeutic effect, and to gradually and continuously release the remaining amount over an extended period of time to maintain the desired level of therapeutic or prophylactic effect. In this case, the active ingredient is released at such a rate as to replace the amount of metabolized and excreted active ingredient.

The core may also include a variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.

Examples of suitable polymers that may be used to form the coating include plasticized, unplasticized, and reinforced Cellulose Acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, Cellulose Acetate Butyrate (CAB), CA urethane, CAP, CA methyl carbamate, CA succinate, Cellulose Acetate Trimellitate (CAT), CA dimethyl aminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, CA agar, amylose triacetate, β glycan acetate, β dextran triacetate, acetaldehyde dimethyl acetate, dextran triacetate of dextran gum, hydrated ethylene-vinyl acetate, EC, PEG/PEG copolymer, PVP, HEC, polysulfone, CMC, MCP, MCAS, HPCA, CPPS, HPPS, CPPS, HPPS, CPPS.

The semi-permeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and are not wetted by aqueous media, but are permeable to water, as disclosed in U.S. patent No. 5,798,119. Such hydrophobic, but water permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluorides, polyvinyl esters and ethers, natural and synthetic waxes. The delivery openings in the semi-permeable membrane may be formed by mechanical or laser drilling after coating. The delivery openings may also be formed in situ by etching a plug of water soluble material or by rupturing a thinner portion of the film at the notch of the core. In addition, the delivery openings may be formed during the coating process.

The total amount of active ingredient released and the release rate can be substantially adjusted by the thickness and porosity of the semi-permeable membrane, the composition of the core, and the number, size and location of the delivery openings.

The pharmaceutical composition in an osmotic controlled release dosage form may further comprise additional conventional excipients described herein to facilitate performance or processing of the formulation.

The osmotic controlled release dosage form may be prepared according to conventional methods and techniques known to those skilled in the art.

In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled release dosage forms comprising asymmetric osmotic membranes coating a core comprising the active ingredient and other pharmaceutically acceptable excipients, which AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating methods.

In certain embodiments, the pharmaceutical compositions provided herein are formulated as a controlled-release ESC dosage form comprising a permeable membrane coating a core comprising the active ingredient, hydroxyethyl cellulose, and other pharmaceutically acceptable excipients.

The pharmaceutical compositions provided herein can be manufactured in a modified release dosage form using a multiparticulate controlled release device comprising a plurality of microparticles, granules or pellets of about 10pm to about 3mm, about 50pm to about 2.5mm, or about 100pm to 1mm diameter. Such multiparticulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion/spheronization, roller compaction, melt-congealing, and spray coating of the seed core.

The resulting particles may themselves constitute the multiparticulate device or may be coated with a variety of film forming materials, such as enteric polymers, water swellable and water soluble polymers, the multiparticulate may be further processed into capsules or tablets.

Targeted delivery

The pharmaceutical compositions provided herein may also be formulated to target specific tissues, receptors, or other areas of the body of the subject to be treated, including liposome-based, re-encapsulated red blood cell-based, and antibody-based delivery systems.

Dosage form

In treating, preventing or ameliorating the symptoms of tic disorders or other conditions, disorders or diseases associated with inhibition of VMAT2, suitable dosage levels are typically about 0.001-100mg/kg patient body weight per day (mg/kg/day), about 0.01 to about 80 mg/kg/day, about 0.1 to about 50 mg/kg/day, about 0.5 to about 25 mg/kg/day, or about 1 to about 20 mg/kg/day, which may be administered in a single dose or in multiple doses, within this range the dosage may be 0.005-0.05, 0.05-0.5, or 0.5-5.0, 1-15, 1-20, or 1-50 mg/kg/day.

In certain embodiments, the dosage level is about 25 to 100 mg/kg/day. In certain embodiments, the dosage level is from about 0.01 to about 40 mg/kg/day. In certain embodiments, the dosage level is from about 0.1 to about 80 mg/kg/day. In certain embodiments, the dosage level is from about 0.1 to about 50 mg/kg/day. In certain embodiments, the dosage level is from about 0.1 to about 40 mg/kg/day. In certain embodiments, the dosage level is from about 0.5 to about 80 mg/kg/day. In certain embodiments, the dosage level is from about 0.5 to about 40 mg/kg/day. In certain embodiments, the dosage level is from about 0.5 to about 25 mg/kg/day. In certain embodiments, the dosage level is from about 1 to about 80 mg/kg/day. In certain embodiments, the dosage level is from about 1 to about 75 mg/kg/day. In certain embodiments, the dosage level is from about 1 to about 50 mg/kg/day. In certain embodiments, the dosage level is from about 1 to about 40 mg/kg/day. In certain embodiments, the dosage level is from about 1 to about 25 mg/kg/day.

In certain embodiments, the dosage level is from about 5.0 to 150 mg/day, and in certain embodiments from 10 to 100 mg/day. In certain embodiments, the dosage level is about 80 mg/day. In certain embodiments, the dosage level is about 40 mg/day.

For oral administration, the pharmaceutical composition may be provided in the form of a tablet containing 1.0-1,000mg of active ingredient, in particular about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 75, about 80, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900 and about 1,000mg of active ingredient, as judged for the symptoms of the dose to the patient to be treated. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 100mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 80mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 75mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 50mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 40mg of the active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 25mg of the active ingredient. The composition may be administered on a regimen of 1-4 times per day, including 1,2,3, and 4 times per day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, -general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The compounds provided herein may also be used in combination or association with other agents useful in the treatment, prevention, or amelioration of or more symptoms of diseases or conditions for which the compounds provided herein are useful, including tic disorders and other conditions commonly treated with antipsychotic drugs.

In certain embodiments, the compounds provided herein may also be used in combination or association with typical antipsychotic agents. In certain embodiments, the typical antipsychotic agent is fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine, or trifluoperazine. In certain embodiments, the antipsychotic drug is an atypical antipsychotic drug. In certain embodiments, the atypical antipsychotic is aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone. In certain embodiments, the atypical antipsychotic is clozapine.

When a compound provided herein is used contemporaneously with or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound provided herein may be utilized, but is not required to be so.

Thus, for example, when a compound provided herein is used in combination with a second drug or a pharmaceutical composition containing such other drug, the weight ratio of the microparticles to the second drug can be from about 1,000:1 to about 1:1,000, or from about 200:1 to about 1: 200.

Combinations of microparticles and other active ingredients provided herein will also generally be within the aforementioned ranges, but in each case an effective dose of each active ingredient should be used.

Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented by way of illustration only and to assist one of ordinary skill in the art in utilizing the present disclosure. The examples are not intended in any way to otherwise limit the scope of the present disclosure.

Examples

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