U.S. patent application number 16/646866 was filed with the patent office on 2020-09-03 for high dosage valbenazine formulation and compositions, methods, and kits related thereto.
The applicant listed for this patent is Neurocrine Biosciences, Inc.. Invention is credited to Gregory A. McClelland, Richard Alexander Moore, Jr., Christopher F. O`Brien.
Application Number | 20200276184 16/646866 |
Document ID | / |
Family ID | 1000004838148 |
Filed Date | 2020-09-03 |
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United States Patent
Application |
20200276184 |
Kind Code |
A1 |
Moore, Jr.; Richard Alexander ;
et al. |
September 3, 2020 |
High Dosage Valbenazine Formulation and Compositions, Methods, and
Kits Related Thereto
Abstract
Solid pharmaceutical compositions with high drug loading are
provided. A formulation useful for the solid pharmaceutical
composition includes valbenazine, or a pharmaceutically acceptable
salt thereof, silicified microcrystalline cellulose, isomalt,
hydroxypropyl methylcellulose, partially pregelatinized maize
starch, and magnesium stearate.
Inventors: |
Moore, Jr.; Richard Alexander;
(San Diego, CA) ; McClelland; Gregory A.; (San
Diego, CA) ; O`Brien; Christopher F.; (Vashon,
WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Neurocrine Biosciences, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000004838148 |
Appl. No.: |
16/646866 |
Filed: |
September 18, 2018 |
PCT Filed: |
September 18, 2018 |
PCT NO: |
PCT/US2018/051579 |
371 Date: |
March 12, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62564951 |
Sep 28, 2017 |
|
|
|
62561629 |
Sep 21, 2017 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/38 20130101;
A61K 47/02 20130101; A61K 9/0053 20130101; A61K 31/4745 20130101;
A61K 9/48 20130101; A61K 47/12 20130101; A61K 47/36 20130101; A61K
47/26 20130101 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; A61K 47/38 20060101 A61K047/38; A61K 47/26 20060101
A61K047/26; A61K 47/36 20060101 A61K047/36; A61K 47/02 20060101
A61K047/02; A61K 47/12 20060101 A61K047/12; A61K 9/00 20060101
A61K009/00; A61K 9/48 20060101 A61K009/48 |
Claims
1. A solid pharmaceutical composition comprising: valbenazine, or a
pharmaceutically acceptable salt thereof; silicified
microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose;
partially pregelatinized maize starch; and magnesium stearate.
2. The solid pharmaceutical composition of claim 1, wherein the
pharmaceutically acceptable salt of valbenazine is valbenazine
ditosylate.
3. The solid pharmaceutical composition of claim 1 or 2, wherein
valbenazine, or a pharmaceutically acceptable salt thereof, is
present at a level ranging from about 20-160 mg as measured as the
free base.
4. The solid pharmaceutical composition of any one of claims 1-3,
wherein valbenazine, or a pharmaceutically acceptable salt thereof,
is present at a level of about 20 mg as measured as the free
base.
5. The solid pharmaceutical composition of any one of claims 1-3,
wherein valbenazine, or a pharmaceutically acceptable salt thereof,
is present at a level of about 40 mg as measured as the free
base.
6. The solid pharmaceutical composition of any one of claims 1-3,
wherein valbenazine, or a pharmaceutically acceptable salt thereof,
is present at a level of about 60 mg as measured as the free
base.
7. The solid pharmaceutical composition of any one of claims 1-3,
wherein valbenazine, or a pharmaceutically acceptable salt thereof,
is present at a level of about 80 mg as measured as the free
base.
8. The solid pharmaceutical composition of any one of claims 1-3,
wherein valbenazine, or a pharmaceutically acceptable salt thereof,
is present at a level of about 120 mg as measured as the free
base.
9. The solid pharmaceutical composition of any one of claims 1-3,
wherein valbenazine, or a pharmaceutically acceptable salt thereof,
is present at a level of about 160 mg as measured as the free
base.
10. The solid pharmaceutical composition of any one of claims 1-9,
wherein valbenazine ditosylate is present at a level of at least
30% by weight of the total weight of the unit dosage form.
11. The solid pharmaceutical composition of any one of claims 1-9,
wherein valbenazine ditosylate is present at a level of at least
35% by weight of the total weight of the unit dosage form.
12. The solid pharmaceutical composition of any one of claims 1-9,
wherein valbenazine ditosylate is present at a level of at least
38% by weight of the total weight of the unit dosage form.
13. The solid pharmaceutical composition of any one of claims 1-9,
wherein valbenazine ditosylate is present at a level of at least
40% by weight of the total weight of the unit dosage form.
14. The solid pharmaceutical composition of any one of claims 1-9,
wherein valbenazine ditosylate is present at a level of at least
45% by weight of the total weight of the unit dosage form.
15. The solid pharmaceutical composition of any one of claims 1-14,
wherein the solid pharmaceutical composition is in unit dosage form
suitable for oral administration.
16. The solid pharmaceutical composition of any one of claims 1-15,
wherein the unit dosage form is formulated for dosing once
daily.
17. The solid pharmaceutical composition of any one of claims 1-16,
wherein the unit dosage form is in capsule form.
18. The solid pharmaceutical composition of any one of claims 1-17,
wherein the capsule form comprises a capsule of size 0 or
smaller.
19. The solid pharmaceutical composition of any one of claims 1-18,
wherein the capsule form comprises a capsule of size 1.
20. The solid pharmaceutical composition of any one of claims 1-19,
wherein the capsule has at least 80% dissolution at 30 minutes in a
USP Paddle Dissolution Method 2 apparatus and 0.1 N HCl medium.
21. The solid pharmaceutical composition of any one of claims 1-20,
wherein the solid pharmaceutical composition has a bulk density of
at least about 0.5 mg/mL.
22. The solid pharmaceutical composition of any one of claims 1-21,
wherein the solid pharmaceutical composition has a tapped density
of at least about 0.6 mg/mL.
23. The solid pharmaceutical composition of any one of claims 1-22,
wherein the valbenazine ditosylate has a d(0.9) particle size
distribution less than 100 .mu.m.
24. An oral dosage product comprising the pharmaceutical
composition of any one of claims 1-23.
25. A unit dosage form comprising a capsule of size 1 or smaller
and at least 80 mg of valbenazine, or a pharmaceutically acceptable
salt thereof, as measured as the free base.
26. The unit dosage form of claim 25 comprising a capsule of size 2
or smaller.
27. The unit dosage form of claim 25 or 26, wherein the
pharmaceutically acceptable salt of valbenazine is valbenazine
ditosylate.
28. A unit dosage form comprising a capsule of size 2 or smaller
and at least 20 mg of valbenazine, or a pharmaceutically acceptable
salt thereof, as measured as the free base.
29. The unit dosage form of claim 28 comprising at least 40 mg
valbenazine, or a pharmaceutically acceptable salt thereof, as
measured as the free base.
30. The unit dosage form of claim 28 comprising at least 60 mg
valbenazine, or a pharmaceutically acceptable salt thereof, as
measured as the free base.
31. The unit dosage form of any one of claims 28-30, wherein the
pharmaceutically acceptable salt of valbenazine is valbenazine
ditosylate.
32. A unit dosage form comprising a capsule of size 0 or smaller
and at least 120 mg of valbenazine, or a pharmaceutically
acceptable salt thereof, as measured as the free base.
33. A unit dosage form comprising valbenazine ditosylate having a
w/w % of at least 35%.
34. The unit dosage form of claim 32, wherein the valbenazine
ditosylate has a w/w % of at least 38%.
35. The unit dosage form of claim 32, wherein the valbenazine
ditosylate has a w/w % of at least 40%.
36. The unit dosage form of any one of claims 33-35, further
comprising: silicified microcrystalline cellulose; isomalt;
hydroxypropyl methylcellulose; partially pregelatinized maize
starch; and magnesium stearate.
37. A unit dosage form of a pharmaceutical composition comprising:
valbenazine ditosylate having a w/w % of about 40%; silicified
microcrystalline cellulose having a w/w % of about 25%; isomalt
having a w/w % of about 20%; hydroxypropyl methylcellulose having a
w/w % of about 5%; partially pregelatinized maize starch having a
w/w % of about 7.5%; and magnesium stearate having a w/w % of about
2.5%.
38. A method comprising orally administering a unit dosage form of
the solid pharmaceutical composition of any one of claims 1-37 to a
subject in need thereof.
39. The method of claim 38, wherein the subject has a neurological
or psychiatric disease or disorder.
40. The method of claim 38, wherein the subject has a hyperkinetic
movement disorder.
41. The method of claim 38, wherein the subject has tardive
dyskinesia.
42. The method of claim 38, wherein the subject has Tourette's
syndrome.
43. The method of claim 38, wherein the subject has Huntington's
disease.
44. The method of claim 38, wherein the subject has tics.
45. The method of claim 38, wherein the subject has chorea
associated with Huntington's disease.
46. The method of claim 38, wherein the subject has ataxia, chorea,
dystonia, hemifacial spasm, ton's disease, myoclonus, restless leg
syndrome, or tremors.
47. The method of claim 38 wherein the subject has hyperkinetic
movement disorder, mood disorder, bipolar disorder, schizophrenia,
schizoaffective disorder, mania in mood disorders, depression in
mood disorder, treatment-refractory 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.
48. The method of any one of claims 38-47, wherein oral
administration comprises administering a first unit dosage form to
the subject followed by administration of a second unit dosage form
to the subject, wherein valbenazine or pharmaceutically acceptable
salt thereof is present in the first unit dosage form at a lower
level than present in the second unit dosage form.
49. The method of claim 48, wherein valbenazine or pharmaceutically
acceptable salt thereof is present in the first unit dosage form at
a level of about 40 mg as measured as the free base.
50. The method of any one of claims 48-49 wherein valbenazine or
pharmaceutically acceptable salt thereof is present in the second
unit dosage form at a level of about 80 mg as measured as the free
base.
51. The method of any one of claims 48-50, wherein the first unit
dosage form is administered to the subject for days, weeks or
months prior to administration of the second unit dosage form to
the subject.
52. The method of any one of claims 48-51, wherein the first unit
dosage form is administered to the subject daily for one week prior
to administration of the second unit dosage form to the
subject.
53. A method for treating a neurological or psychiatric disease or
disorder in a patient in need thereof comprising administering to
the patient a therapeutically effective amount of the solid
pharmaceutical composition of any one of claims 1-23, the oral
dosage product of claim 24, or the unit dosage form of any one of
claims 25-37.
54. A method for treating a hyperkinetic movement disorder in a
patient in need thereof comprising administering to the patient a
therapeutically effective amount of the solid pharmaceutical
composition of any one of claims 1-23, the oral dosage product of
claim 24, or the unit dosage form of any one of claims 25-37.
55. The method of claim 53 wherein the neurological or psychiatric
disease or disorder is a hyperkinetic movement disorder, mood
disorder, bipolar disorder, schizophrenia, schizoaffective
disorder, mania in mood disorder, depression in mood disorder,
treatment-refractory 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.
56. The method of claim 54, wherein the hyperkinetic movement
disorder is tardive dyskinesia.
57. The method of claim 54, wherein the hyperkinetic movement
disorder is Tourette's syndrome.
58. The method of claim 54, wherein the hyperkinetic movement
disorder is Huntington's disease.
59. The method of claim 54, wherein the hyperkinetic movement
disorder is tics.
60. The method of claim 54, wherein the hyperkinetic movement
disorder is chorea associated with Huntington's disease.
61. The method of claim 54, wherein the hyperkinetic movement
disorder is ataxia, chorea, dystonia, Huntington's disease,
hemifacial spasm, myoclonus, restless leg syndrome, or tremors.
62. The method of claim 54, wherein the patient has been determined
to have 22q11.2 deletion syndrome.
63. The method of claim 54, wherein the patient is predisposed to
developing a psychiatric disorder due to the patient having 22q11.2
deletion syndrome.
64. The method of claim 54, wherein the patient has been determined
to have COMT haploinsufficiency.
65. The method of claim 54, wherein the patient is predisposed to
developing a psychiatric disorder due to the subject having COMT
haploinsufficiency.
66. The method of any one of claims 53-65, wherein valbenazine or
pharmaceutically acceptable salt thereof is administered to the
patient for a first period of time followed by a second period of
time, and wherein valbenazine or pharmaceutically acceptable salt
is administered at a lower level during the first period of time
than the second period of time.
67. The method of claim 66, wherein valbenazine or pharmaceutically
acceptable salt thereof is administered during the first period of
time in a daily unit dosage form comprising valbenazine or
pharmaceutically acceptable salt at a level of about 40 mg as
measured as the free base.
68. The method of any one of claims 66-67, wherein valbenazine or
pharmaceutically acceptable salt thereof is administered during the
second period of time in daily unit dosage form comprising
valbenazine or a pharmaceutically acceptable salt at a level of
about 80 mg as measured as the free base.
69. The method of any one of claims 66-68, wherein the first period
of time is days, weeks or months.
70. The method of any one of claims 66-69, wherein the first period
of time is one week.
71. A kit comprising a plurality of the oral dosage product of
claim 24 or the unit dosage form of any one of claims 25-37 in
combination with instructions for administration.
72. A method for producing a unit dosage form of valbenazine
ditosylate comprising the steps of FIG. 1.
73. A composition comprising: valbenazine, or a pharmaceutically
acceptable salt thereof, silicified microcrystalline cellulose;
isomalt; hydroxypropyl methylcellulose; partially pregelatinized
maize starch; and magnesium stearate.
74. A solid composition of valbenazine, or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable excipient, wherein the solid composition has a bulk
density of at least about 0.5 mg/mL.
75. A solid composition of valbenazine, or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable excipient, wherein the solid composition has a tapped
density of at least about 0.6 mg/mL.
76. A solid composition of valbenazine, or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable excipient, wherein the solid composition has a d(0.9)
particle size distribution less than 100 m.
77. A solid composition of valbenazine, or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable excipient, wherein the solid composition has a blend
uniformity between about 90% and about 110% with a relative
standard deviation of the blend uniformity of less than about
2%.
78. The solid composition of claim 77, wherein the solid
composition has a blend uniformity between about 95% and about 105%
with a relative standard deviation of the blend uniformity of less
than about 2%.
79. A solid composition of valbenazine, or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable excipient, wherein the solid composition has a blend
uniformity between about 90% and about 110% with a standard
deviation of the blend uniformity of less than about 2%.
80. The solid composition of claim 79, wherein the solid
composition has a blend uniformity between about 95% and about 105%
with a standard deviation of the blend uniformity of less than
about 2%.
81. The solid composition of any one of claims 74-80, wherein the
valbenazine, or a pharmaceutically acceptable salt thereof, is
present at a level ranging from about 20-160 mg as measured as the
free base.
82. The solid composition of claim 81, wherein the valbenazine, or
a pharmaceutically acceptable salt thereof, is present at a level
of about 20 mg as measured as the free base.
83. The solid composition of claim 81, wherein the valbenazine, or
a pharmaceutically acceptable salt thereof, is present at a level
of about 40 mg as measured as the free base.
84. The solid composition of claim 81, wherein the valbenazine, or
a pharmaceutically acceptable salt thereof, is present at a level
of about 60 mg as measured as the free base.
85. The solid composition of claim 81, wherein the valbenazine, or
a pharmaceutically acceptable salt thereof, is present at a level
of about 80 mg as measured as the free base.
86. The solid composition of claim 81, wherein the valbenazine, or
a pharmaceutically acceptable salt thereof, is present at a level
of about 120 mg as measured as the free base.
87. The solid composition of claim 81, wherein the valbenazine, or
a pharmaceutically acceptable salt thereof, is present at a level
of about 160 mg as measured as the free base.
88. The solid composition of any one of claims 74-87, wherein the
solid composition comprises valbenazine, or a pharmaceutically
acceptable salt thereof, as measured by the free base, at a level
of at least about 35% w/w.
89. The solid composition of claim 88, wherein the solid
composition comprises valbenazine, or a pharmaceutically acceptable
salt thereof, as measured by the free base, at a level of at least
about 38% w/w.
90. The solid composition of claim 88, wherein the solid
composition comprises valbenazine, or a pharmaceutically acceptable
salt thereof, as measured by the free base, at a level of at least
about 40% w/w.
91. The solid composition of claim 88, wherein the solid
composition comprises valbenazine, or a pharmaceutically acceptable
salt thereof, as measured by the free base, at a level of at least
about 45% w/w.
92. The solid composition of claim 88, wherein the solid
composition comprises valbenazine, or a pharmaceutically acceptable
salt thereof, as measured by the free base, at a level of about 40%
w/w.
93. The solid composition of any one of claims 74-92, wherein the
pharmaceutically acceptable salt of valbenazine is a tosylate
salt.
94. The solid composition of claim 93, wherein the pharmaceutically
acceptable salt of valbenazine is valbenazine ditosylate.
95. The solid composition of any of claims 74-94, wherein the solid
composition comprises granules of the valbenazine, or a
pharmaceutically acceptable salt thereof, and the at least one
pharmaceutically acceptable excipient.
96. The solid composition of claim 95, wherein the granules are
prepared by dry granulation.
97. The solid composition of claim 96, wherein the granules are
prepared by roller compaction.
98. The solid composition of any of claims 95-97, wherein the solid
composition comprises a blend of the granules of valbenazine, or a
pharmaceutically acceptable salt thereof, and the at least one
pharmaceutically acceptable excipient with at least one
lubricant.
99. The solid composition of any of claims 74-98, wherein the at
least one pharmaceutically acceptable excipient is at least one
lubricant.
100. The solid composition of claim 99, wherein the solid
composition comprises at least one lubricant in an amount of
between about 0.25% and about 5% w/w.
101. The solid composition of claim 99 or 100, wherein the at least
one lubricant is chosen from magnesium stearate, calcium stearate,
stearic acid, talc, starch, and fumed silica (silicon dioxide).
102. The solid composition of claim 101, wherein the at least one
lubricant is magnesium stearate.
103. The solid composition of any of claims 74-102, wherein the at
least one pharmaceutically acceptable excipient is at least one
disintegrant.
104. The solid composition of claim 103, wherein the at least one
disintegrant is present in an amount of between about 1% and about
10% w/w.
105. The solid composition of claim 103 or 104, wherein the at
least one disintegrant is chosen from starch, alginic acid, sodium
starch glycolate, croscarmellose, crospovidone, cellulose, and
acid-carbonate effervescent systems.
106. The solid composition of claim 105, wherein the at least one
disintegrant is starch.
107. The solid composition of any of claims 74-106, wherein the at
least one pharmaceutically acceptable excipient is at least one
binder.
108. The solid composition of claim 107, wherein the at least
binder is present in an amount of between about 0.5% and about 5%
w/w.
109. The solid composition of claim 107 or 108, wherein the at
least one binder is chosen from hypromellose, polyvinylpyrrolidone,
natural gums (e.g. acacia gum), microcrystalline cellulose,
methylcellulose, ethylcellulose, sucrose, starch, and gelatin.
110. The solid composition of claim 109, wherein the at least one
binder is hypromellose.
111. The solid composition of any of claims 74-110, wherein the at
least one pharmaceutically acceptable excipient is at least one
water soluble diluent.
112. The solid composition of claim 111, wherein the at least one
water soluble diluent is present in an amount of between about 20%
and about 95% w/w.
113. The solid composition of claim 111 or 112, wherein the at
least one water soluble diluent is chosen from lactose, mannitol,
isomalt, sucrose, dextrose, and sorbitol.
114. The solid composition of claim 113, wherein the at least one
water soluble diluent is isomalt.
115. The solid composition of any of claims 74-114, wherein the at
least one pharmaceutically acceptable excipient is at least one
water insoluble filler.
116. The solid composition of claim 115, wherein the at least one
insoluble filler is present in an amount of between about 20% and
about 95% w/w.
117. The solid composition of claim 114 or 115, wherein the at
least one water soluble filler is chosen from microcrystalline
cellulose, starch, dicalcium phosphate dihydrate, and calcium
carbonate.
118. The solid composition of claim 116, wherein the at least one
water soluble filler is microcrystalline cellulose.
119. A solid pharmaceutical composition comprising: valbenazine, or
a pharmaceutically acceptable salt thereof, at least one water
insoluble filler; at least one water soluble diluent; at least one
binder; at least one disintegrant; and at least one lubricant.
120. The solid pharmaceutical composition of claim 119, wherein the
pharmaceutically acceptable salt of valbenazine is a tosylate
salt.
121. The solid pharmaceutical composition of claim 120, wherein the
pharmaceutically acceptable salt of valbenazine is valbenazine
tosylate.
122. The solid pharmaceutical composition of any one of claims
119-121, wherein the solid pharmaceutical composition has a bulk
density of at least about 0.5 mg/mL.
123. The solid pharmaceutical composition of any one of claims
119-122, wherein the solid pharmaceutical composition has a tapped
density of at least about 0.6 mg/mL.
124. The solid pharmaceutical composition of any one of claims
119-123, wherein the solid pharmaceutical composition has a d(0.9)
particle size distribution less than 100 .mu.m.
125. The solid pharmaceutical composition of any one of claims
119-124, wherein the solid pharmaceutical composition has a blend
uniformity between about 90% and about 110% with a relative
standard deviation of the blend uniformity of less than about
2%.
126. The solid pharmaceutical composition of claim 125, wherein the
solid pharmaceutical composition has a blend uniformity between
about 95% and about 105% with a relative standard deviation of the
blend uniformity of less than about 2%.
127. The solid pharmaceutical composition of any one of claims
119-124, wherein the solid pharmaceutical composition has a blend
uniformity between about 90% and about 110% with a standard
deviation of the blend uniformity of less than about 2%.
128. The solid composition of claim 127, wherein the solid
pharmaceutical composition has a blend uniformity between about 95%
and about 105% with a standard deviation of the blend uniformity of
less than about 2%.
129. An oral dosage product comprising the composition of any one
of claims 74-128.
130. A unit dosage form comprising the solid composition of any one
of claims 74-128.
131. A unit dosage form of a pharmaceutical composition comprising:
valbenazine ditosylate having a w/w % of about 40%; at least one
water insoluble filler having a w/w % of about 25%; at least one
water soluble diluent having a w/w % of about 20%; at least one
binder having a w/w % of about 5%; at least one disintegrant having
a w/w % of about 7.5%; and at least one lubricant having a w/w % of
about 2.5%.
132. The unit dosage form of claim 130 or 131, comprising a capsule
of size 1 or smaller and at least 80 mg of valbenazine, or a
pharmaceutically acceptable salt thereof, as measured as the free
base.
133. The unit dosage form of claim 130 or 131, comprising a capsule
of size 2 or smaller.
134. The unit dosage form of claim 130 or 131, comprising a capsule
of size 2 or smaller and at least 20 mg of valbenazine, or a
pharmaceutically acceptable salt thereof, as measured as the free
base.
135. The unit dosage form of claim 130 or 131, comprising at least
40 mg valbenazine, or a pharmaceutically acceptable salt thereof,
as measured as the free base.
136. The unit dosage form of claim 130 or 131, comprising a capsule
of size 0 or smaller and at least 120 mg of valbenazine, or a
pharmaceutically acceptable salt thereof, as measured as the free
base.
137. The unit dosage form of any one of claim 130-136, having an
average stratified content uniformity of between about 99% and
about 100% with a standard deviation of the mean of less than about
3.5%.
138. The unit dosage form of any one of claim 130-136, having an
average stratified content uniformity of between about 99% and
about 100% with a standard error of the mean of less than about
3.5%.
139. The unit dosage form of any one of claim 130-138, having a
dissolution profile of at least 80% dissolution at 30 minutes in a
USP Paddle Dissolution Method 2 apparatus and 0.1 N HCl medium.
140. The unit dosage form of any one of claims 130-139, wherein the
pharmaceutically acceptable salt of valbenazine is a tosylate
salt.
141. The unit dosage form of claim 140, wherein the
pharmaceutically acceptable salt of valbenazine is valbenazine
tosylate.
142. A process for preparing a solid composition of valbenazine, or
a pharmaceutically acceptable salt thereof, wherein the process
comprises: a) subjecting a blend of valbenazine, or a
pharmaceutically acceptable salt thereof, at least one water
insoluble filler, and at least one water soluble diluent to
comminution; b) blending the product of step a) with at least one
binder and at least one disintegrant; c) determining the blend
uniformity of the product of step b); and d) blending the product
of step b) with at least one lubricant only if the blend uniformity
satisfies a predetermined criteria to produce a solid composition
of valbenazine, or a pharmaceutically acceptable salt thereof.
143. The process of claim 142, further comprising, e) determining
density and/or particle size distribution of the product of step
d); and f) subjecting the product of step d) to dry granulation to
produce granules of valbenazine, or a pharmaceutically acceptable
salt thereof, only if the density and/or particle size distribution
satisfies a predetermined criteria.
144. The process of claim 143, further comprising, g) determining
density and/or particle size distribution of the product of step
f); and h) blending the granules of step f) with at least one
lubricant only if the density and/or particle size distribution
satisfies a predetermined criteria.
145. The process of claim 144, further comprising, i) determining
density and/or blend uniformity of the product of step h); j)
encapsulating the product of step h) to produce a unit dosage form
comprising valbenazine, or a pharmaceutically acceptable salt
thereof, only if the density and/or blend uniformity satisfies a
predetermined criteria.
146. The process of claim 145, further comprising determining the
disintegration and/or content uniformity of the unit dosage
form.
147. A unit dosage form prepared by the process of claim 146.
148. A process for preparing a unit dosage form comprising
valbenazine, or a pharmaceutically acceptable salt thereof, wherein
the process comprises: encapsulating the solid composition of any
one of claims 74-128, to produce the unit dosage form comprising
valbenazine, or a pharmaceutically acceptable salt thereof.
149. A unit dosage form comprising valbenazine, or a
pharmaceutically acceptable salt thereof, prepared by the process
of claim 148.
150. A process for preparing a unit dosage form comprising
valbenazine, or a pharmaceutically acceptable salt thereof, wherein
the process comprises: encapsulating a lubricated blend to produce
a solid composition comprising valbenazine, or a pharmaceutically
acceptable salt thereof, wherein the lubricated blend comprises
granules of valbenazine, or a pharmaceutically acceptable salt
thereof, and at least one lubricant.
151. The process of claim 150, wherein the lubricated blend is
prepared by a process comprising the steps of: blending at least
one lubricant with granules of valbenazine, or a pharmaceutically
acceptable salt thereof, to produce a lubricated blend.
152. The process of claim 151, wherein the granules of valbenazine,
or a pharmaceutically acceptable salt thereof, is prepared by a
process comprising the steps of: dry granulating a blend to produce
granules of valbenazine, or a pharmaceutically acceptable salt
thereof.
153. The process of claim 152, wherein dry granulating a blend
comprises gravity feeding the blend through the roller
compactor.
154. The process of claim 152 or 153, wherein the blend is prepared
by a process comprising the steps of: blending at least one
lubricant with an intragranular blend to produce the blend.
155. The process of claim 154, wherein the intragranular blend is
prepared by a process comprising blending a pre-blend with at least
one disintegrant and at least one binder to produce the
intragranular blend.
156. The process of claim 155, wherein the pre-blend is prepared by
a process comprising the steps of: blending valbenazine, or a
pharmaceutically acceptable salt thereof, with at least one
water-insoluble filler and at least one water soluble diluent to
produce the pre-blend.
157. A unit dosage form comprising valbenazine, or a
pharmaceutically acceptable salt thereof, prepared by the process
of claim 150.
158. A process for preparing a unit dosage form comprising
valbenazine, or a pharmaceutically acceptable salt thereof, wherein
the process comprises: preparing a dispersion of valbenazine, or a
pharmaceutically acceptable salt thereof, in at least one
water-insoluble filler and at least one water soluble diluent to
produce a pre-blend; blending the pre-blend with one or more
excipients to produce a blend; granulating the blend to produce a
granulated blend; optionally blending the granulated blend with one
or more excipients to produce a lubricated blend; and encapsulating
the lubricated blend.
159. A unit dosage form comprising valbenazine, or a
pharmaceutically acceptable salt thereof, prepared by the process
of claim 158.
160. A method comprising orally administering a unit dosage form of
the solid composition of any one of claims 74-118, or a solid
pharmaceutical composition of any one of claims 119-128, or a unit
dosage form of any one of claims 130-141, 147, 149, 157, or 159 to
a patient in need thereof.
161. The method of claim 160, wherein the unit dosage form of the
solid composition is administered to the patient to treat a
neurological or psychiatric disease or disorder.
162. The method of claim 161, wherein the neurological or
psychiatric disease or disorder is a hyperkinetic movement
disorder, mood disorder, bipolar disorder, schizophrenia,
schizoaffective disorder, mania in mood disorder, depression in
mood disorder, treatment-refractory 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.
163. The method of claim 162, wherein the neurological or
psychiatric disease or disorder is a hyperkinetic movement
disorder.
164. The method of claim 163, wherein the hyperkinetic movement
disorder is tardive dyskinesia.
165. The method of claim 163, wherein the hyperkinetic movement
disorder is Tourette's syndrome.
166. The method of claim 163, wherein hyperkinetic movement
disorder is Huntington's disease.
167. The method of claim 163, wherein hyperkinetic movement
disorder is tics.
168. The method of claim 163, wherein the hyperkinetic movement
disorder is chorea associated with Huntington's disease.
169. The method of claim 163, wherein the hyperkinetic movement
disorder is ataxia, chorea, dystonia, Huntington's disease,
myoclonus, restless leg syndrome, or tremors.
170. The method of any one of claims 160-169, wherein the patient
has been determined to have 22q11.2 deletion syndrome.
171. The method of any one of claims 160-169, wherein, the patient
is predisposed to developing a psychiatric disorder due to the
patient having 22q11.2 deletion syndrome.
172. The method of any one of claims 160-169, wherein the patient
has been determined to have COMT haploinsufficiency.
173. The method of any one of claims 160-169, wherein the patient
is predisposed to developing a psychiatric disorder due to the
patient having COMT haploinsufficiency.
174. A kit comprising a plurality of oral unit dosage forms of any
one of the claims 130-141, 147, 149, 157, or 159, in combination
with instructions for administration.
175. A unit dosage form of any one of claims 130-141, 147, 149,
157, or 159, for use in a method of treating a neurological or
psychiatric disease or disorder of a patient in need thereof.
176. The unit dosage form of claim 175, wherein the neurological or
psychiatric disease or disorder is a hyperkinetic movement
disorder, mood disorder, bipolar disorder, schizophrenia,
schizoaffective disorder, mania in mood disorder, depression in
mood disorder, treatment-refractory 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.
177. The unit dosage form of claim 176, wherein the neurological or
psychiatric disease or disorder is a hyperkinetic movement
disorder.
178. The unit dosage form of claim 177, wherein the hyperkinetic
movement disorder is tardive dyskinesia.
179. The unit dosage form of claim 177, wherein the hyperkinetic
movement disorder is Tourette's syndrome.
180. The unit dosage form of claim 177, wherein hyperkinetic
movement disorder is Huntington's disease.
181. The unit dosage form of claim 177, wherein hyperkinetic
movement disorder is tics.
182. The unit dosage form of claim 177, wherein the hyperkinetic
movement disorder is chorea associated with Huntington's
disease.
183. The unit dosage form of claim 177, wherein the hyperkinetic
movement disorder is ataxia, chorea, dystonia, Huntington's
disease, myoclonus, restless leg syndrome, or tremors.
184. The unit dosage form of any one of claims 175-183, wherein the
patient has been determined to have 22q11.2 deletion syndrome.
185. The unit dosage form of any one of claims 175-183, wherein,
the patient is predisposed to developing a psychiatric disorder due
to the patient having 22q11.2 deletion syndrome.
186. The unit dosage form of any one of claims 175-183, wherein the
patient has been determined to have COMT haploinsufficiency.
187. The unit dosage form of any one of claims 175-183, wherein the
patient is predisposed to developing a psychiatric disorder due to
the patient having COMT haploinsufficiency.
Description
BACKGROUND
Technical Field
[0001] This invention related to a novel pharmaceutical composition
of L-Valine,
(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methyl-
propyl)-2H-benzo[a]quinolizin-2-yl ester (referred to herein as
"valbenazine") and pharmaceutically acceptable salts, as well as to
compositions, method, and kits relating to the same.
Description of the Related Art
[0002] Dysregulation of dopaminergic systems is integral to several
central nervous system (CNS) disorders, including neurological and
psychiatric diseases and disorders. These neurological and
psychiatric diseases and disorders include hyperkinetic movement
disorders, and conditions such as schizophrenia and mood disorders.
The transporter protein vesicular monoamine transporter-2 (VMAT2)
plays an important role in presynaptic dopamine release and
regulates monoamine uptake from the cytoplasm to the synaptic
vesicle for storage and release.
[0003] Despite the advances that have been made in this field,
there remains a need for new therapeutic products useful to
treatment of neurological and psychiatric diseases and disorders
and other related diseases or conditions described herein. One such
promising agent is valbenazine. The free base form of valbenazine
has the following chemical structure:
##STR00001##
[0004] Many different factors are considered in the selection of a
counter-ion for the formation of a salt. Only the
4-toluenesulfonate salt had the combination of properties that made
it a developable form of valbenazine. A formulation of
valbenazine:4-toluenesulfonate (1:2) (referred to herein as
"valbenazine ditosylate") has been previously reported in the FDA
approved drug label for valbenazine ditosylate (Ingrezza.RTM.). It
is manufactured in the form of size 1 hard gelatin capsule for a 40
mg unit dosage, as measured as the free base.
[0005] With an increase in dose, the high molecular weight of two
4-toluenesulfonic acid counter-ions in the salt form of valbenazine
creates a unique challenge to develop a formulation with acceptable
powder flow properties. The prior art does not provide for
valbenazine or valbenazine ditosylate in a form suitable for
solid-dosing at preferred high loading drug levels, particularly
with regard to capsule formation. Therapeutically acceptable
capsules according to the known formulation and procedure
containing more than about 30% valbenazine ditosylate were not
manufacturable. Single dosage units are unavailable to patients in
need of high doses of valbenazine
[0006] Many patients experience difficulty swallowing tablets and
capsules. This problem can lead to a variety of adverse events and
patient noncompliance with treatment regimens. A survey of adults
on difficulties swallowing tablets and capsules suggests that this
problem may affect as many as 40 percent of Americans. (Harris
Interactive Inc. for Schwarz Pharma, 2003, Pill-Swallowing Problems
in America: A National Survey of Adults. 1-39.) Individuals who
find it difficult to swallow tablets and capsules frequently cite
the size as the main reason for the difficulty in swallowing.
(Fields, J. et al., Pill Properties that Cause Dysphagia and
Treatment Failure, Curr. Ther. Res. Clin. Exp., 2015,
77:79-82.)
[0007] Larger tablets and capsules have also been shown to affect
the transit of drug products through the pharynx and esophagus.
Larger tablets and capsules have been shown to have a prolonged
esophageal transit time and may directly affect a patient's ability
to swallow a particular drug product. This can lead to
disintegration of the product in the esophagus and/or cause injury
to the esophagus. The United States Food and Drug Administration
("FDA") has indicated "that size should be considered as part of a
single product risk/benefit profile." (FDA Guidance for Industry on
Size, Shape, and Other Physical Attributes of Generic Tablets and
Capsules at 5, 1-7, June 2015.) The FDA further recommends "that
the largest dimension of a tablet or capsule should not exceed 22
mm and that capsules should not exceed a standard 00 size." Id.
[0008] There remains a substantial need for improved techniques and
products for the oral administration of valbenazine, or a
pharmaceutically acceptable salt thereof, to patients in need
thereof, including patients having neurological and psychiatric
diseases and disorders such as hyperkinetic movement disorders,
schizophrenia, and mood disorders The present disclosure fulfills
these and other needs, as evident in reference to the following
disclosure.
BRIEF SUMMARY
[0009] The present invention generally provides a novel solid drug
form of valbenazine or valbenazine ditosylate, as well as to
compositions, methods, and/or kits for oral administration of the
same.
[0010] Valbenazine has particular utility in the treatment of
hyperkinetic movement disorders, including tardive dyskinesia and
other conditions as described in greater detail below. The solid
drug form of valbenazine provided herein provides for high loading
capacity, thus allowing formulations of valbenazine in a form
suitable for oral dosing. In some embodiments, the solid drug form
is a solid pharmaceutical composition. In some embodiments, the
solid drug form is a unit dosage form. In some embodiments, the
solid drug form is a solid composition.
[0011] In one embodiment a solid pharmaceutical composition is
provided of valbenazine, or a pharmaceutically acceptable salt
thereof, silicified microcrystalline cellulose, isomalt,
hydroxypropyl methylcellulose, partially pregelatinized maize
starch, and magnesium stearate. In one embodiment, the
pharmaceutically acceptable salt is valbenazine ditosylate.
[0012] In another embodiment, a unit dosage form of a
pharmaceutical composition is provided having a capsule of size 1
or smaller and at least 80 mg of valbenazine, or a pharmaceutically
acceptable salt thereof, as measured as the free base.
[0013] In another embodiment, a unit dosage form of a
pharmaceutical composition is provided having a capsule of size 2
or smaller and at least 20 mg of valbenazine, or a pharmaceutically
acceptable salt thereof, as measured as the free base. In one
embodiment, the unit dosage form has at least 40 mg of valbenazine,
or a pharmaceutically acceptable salt thereof, as measured as the
free base.
[0014] In one embodiment, a unit dosage form of a pharmaceutical
composition is provided having a capsule of size 0 or smaller and
at least 120 mg of valbenazine, or a pharmaceutically acceptable
salt thereof, as measured as the free base.
[0015] In another embodiment, a unit dosage form of a
pharmaceutical composition is provided with valbenazine ditosylate
having a w/w % of at least 35%.
[0016] In one embodiment, a unit dosage form of a pharmaceutical
composition is provided with valbenazine ditosylate having a w/w %
of about 40%, silicified microcrystalline cellulose having a w/w %
of about 25%, isomalt having a w/w % of about 20%, hydroxypropyl
methylcellulose having a w/w % of about 5%, partially
pregelatinized maize starch having a w/w % of about 7.5%, and
magnesium stearate having a w/w % of about 2.5%.
[0017] In one embodiment is provided a method of orally
administering a unit dosage form valbenazine or valbenazine
ditosylate to a subject in need thereof.
[0018] In one embodiment is provided a method for treating a
hyperkinetic movement disorder in a patient in need thereof by
administering to the patient a therapeutically effective amount of
the solid drug form of valbenazine or valbenazine ditosylate.
[0019] In one embodiment is provided a method for treating a
hyperkinetic movement disorder in a patient in need thereof by
administering to the patient a therapeutically effective amount of
the solid pharmaceutical composition of valbenazine or valbenazine
ditosylate.
[0020] In one embodiment, a kit is provided with a plurality of
oral unit dosage forms of a solid pharmaceutical composition of
valbenazine or valbenazine ditosylate in combination with
instructions for administration.
[0021] In one embodiment, a kit is provided with a plurality of
oral unit dosage forms of a solid composition of valbenazine or
valbenazine ditosylate in combination with instructions for
administration.
[0022] In one embodiment, a method for producing a unit dosage form
of valbenazine ditosylate is provided.
[0023] In one embodiment, a composition is provided of valbenazine,
or a pharmaceutically acceptable salt thereof, silicified
microcrystalline cellulose, isomalt, hydroxypropyl methylcellulose,
partially pregelatinized maize starch, and magnesium stearate.
[0024] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a bulk density of at least about 0.5 mg/mL.
[0025] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a tapped density of at least about 0.6 mg/mL.
[0026] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a d(0.9) particle size distribution less than 100
.mu.m.
[0027] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a blend uniformity between about 90% and about 110%
with a relative standard deviation of the blend uniformity of less
than about 2%.
[0028] A solid composition of valbenazine, or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable excipient, wherein the solid composition has a blend
uniformity between about 90% and about 110% with a standard
deviation of the blend uniformity of less than about 2%.
[0029] Also provided is a process for preparing a unit dosage form
comprising valbenazine, or a pharmaceutically acceptable salt
thereof, wherein the process comprises:
[0030] encapsulating the solid composition described herein, to
produce the unit dosage form comprising valbenazine, or a
pharmaceutically acceptable salt thereof.
[0031] Also provided is a process for preparing a unit dosage form
comprising valbenazine, or a pharmaceutically acceptable salt
thereof, wherein the process comprises:
[0032] encapsulating a lubricated blend to produce a solid
composition comprising valbenazine, or a pharmaceutically
acceptable salt thereof,
[0033] wherein the lubricated blend comprises granules of
valbenazine, or a pharmaceutically acceptable salt thereof, and at
least one lubricant.
[0034] Also provided is a unit dosage form, for use in a method of
treating a neurological or psychiatric disease or disorder of a
patient in need thereof.
[0035] Also provided is a solid pharmaceutical composition
comprising:
[0036] valbenazine, or a pharmaceutically acceptable salt
thereof,
[0037] at least one water insoluble filler;
[0038] at least one water soluble diluent;
[0039] at least one binder;
[0040] at least one disintegrant; and
[0041] at least one lubricant.
[0042] Also provided is a unit dosage form of a pharmaceutical
composition comprising:
[0043] valbenazine ditosylate having a w/w % of about 40%;
[0044] at least one water insoluble filler having a w/w % of about
25%;
[0045] at least one water soluble diluent having a w/w % of about
20%;
[0046] at least one binder having a w/w % of about 5%;
[0047] at least one disintegrant having a w/w % of about 7.5%;
and
[0048] at least one lubricant having a w/w % of about 2.5%.
[0049] 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 their entirety.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0050] FIG. 1 shows a process flow diagram for the production of
high drug loading valbenazine capsules.
DETAILED DESCRIPTION
[0051] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
embodiments. However, one skilled in the art will understand that
the 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 descriptions of the
embodiments. Unless the context requires otherwise, throughout the
specification and claims which follow, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is, as "including, but
not limited to." Further, headings provided herein are for
convenience only and do not interpret the scope or meaning of the
claimed invention.
[0052] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment. Thus, the appearances of the
phrases "in one embodiment" or "in an embodiment" in various places
throughout this specification are not necessarily all referring to
the same embodiment. Furthermore, the particular features,
structures, or characteristics may be combined in any suitable
manner in one or more embodiments. Also, as used in this
specification and the appended claims, the singular forms "a,"
"an," and "the" include plural referents unless the content clearly
dictates otherwise. It should also be noted that the term "or" is
generally employed in its sense including "and/or" unless the
content clearly dictates otherwise.
[0053] As used herein, "about" means.+-.20% of the stated value,
and includes more specifically values of .+-.10%, .+-.5%, .+-.2%
and .+-.1% of the stated value.
[0054] Hyperkinetic movement disorders represent a category of
neurological disorders that are characterized by unwanted and
uncontrollable, or poorly controllable, involuntary movements. The
phenomenology of these disorders is quite variable encompassing
chorea, tremor, dystonia, myoclonus, tics, other dyskinesias, jerks
and shakes. Hyperkinetic movement disorders include ataxia, chorea,
dystonia, hemifacial spasm, Huntington's disease, chorea associated
with Huntingon's disease, myoclonus, restless leg syndrome, tardive
dyskinesia, tics, Tourette's syndrome, and tremors.
[0055] Mood disorders represent a category of mental disorders in
which the underlying problem primarily affects a person's
persistent emotional state (their mood). Mood disorders include:
major depressive disorder (also called major depression), bipolar
disorder, persistent depressive disorder (long lasting low grade
depression), cyclothymia (a mild form of bipolar disorder),
catatonic depression, post-partum depression, mania, and seasonal
affective disorder (SAD). Mood disorders include substance-induced
mood disorders and mood disorders due to a medical condition, e.g.,
hypothyroidism or Parkinson's disease.
[0056] Bipolar disorder, also known as bipolar affective disorder
or manic-depressive illness, is a mental disorder characterized by
periods of elevated mood and periods of depression. The periods of
elevated mood is known as mania or hypomania depending on the
severity or whether psychosis is present. Symptoms of mania or a
manic episode include a long period of feeling "high" or an overly
happy or outgoing mood, extreme irritability, talking very fast,
racing thoughts, jumping from one idea to another, being easily
distracted, increasing activities, being overly restless, sleeping
little, having an unrealistic belief in one's abilities, impulsive
behavior, and engaging in pleasurable, high-risk behaviors.
Symptoms of depression or a depressive episode include: an overly
long period of sadness or hopelessness, loss of interest in
activities, feeling tired, problems with concentration or memory,
difficulty making decisions, being restless or irritable, change in
eating or sleeping habits, and suicide ideation. Patients with
bipolar disorder have a high risk of suicide and self-harm. The
cause of bipolar disorder is not completely understood, but both
genetic and environmental factors are thought to play a role.
Environmental factors include long term stress and a history of
child abuse.
[0057] Medications for treatment of the manic, psychotic, or
depressive aspects of bipolar disorder generally include mood
stabilizers, atypical antipsychotics, or antidepressants, in
combination with psychotherapy. Sleep medications may also be used
to help with sleep disturbances. For severe cases in which
medication and psychotherapy does not work, electroconvulsive
therapy may be used. Bipolar disorder usually is a lifelong illness
and can worsen if left untreated. Long-term, continuous treatment
is needed to control symptoms, and even with proper treatment mood
changes can still occur. Patients frequently need to try several
different medications before finding ones that help control
symptoms. Given the unpleasant and potentially severe side effects
associated with these medications, particularly anti-psychotic
medications, a need exists to develop new therapeutics for treating
mania in mood disorders and their related symptoms.
[0058] Schizophrenia affects approximately 1% of the adult
population and reduces life expectancy by an average of 20 to 25
years through the impact of the disorder on self-care and physical
health, as well as through suicide. At the present time the
etiological mechanisms underlying schizophrenia are poorly
understood. Schizophrenia is diagnosed clinically, based on
characteristic symptoms of psychosis, disorganization and so called
`negative` symptoms (representing a reduced range of emotional
expression, reduced production of speech and a lack of
volition/motivation); duration of illness; impaired functioning;
and the exclusion of other disorders such as autism and bipolar
disorder. For clinicians, identifying which psychotic patients have
schizophrenia requires clinical acumen and familiarity with the
DSM-IV or ICD-10 diagnostic manuals [see, e.g., Corvin, BMC Biol.
2011; 9: 77].
[0059] Schizoaffective disorder is a mental health condition
characterized primarily by symptoms of schizophrenia, such as
hallucinations or delusions, and symptoms of a mood disorder, such
as mania and depression. Diagnosis may be difficult as symptoms of
schizophrenia and mood disorders are both present and many people
are incorrectly diagnosed with schizophrenia or mood disorder.
Treatment for schizoaffective disorder includes medications,
typically antipsychotics and antidepressants and psychotherapy.
[0060] Antipsychotic drug therapy is a pillar in the treatment of
schizophrenia. These antipsychotic drugs, also known as
neuroleptics, generally cause a reduction of the `positive`
symptoms of schizophrenia, namely psychosis, thought disorders, and
disorganized behavior. Antipsychotics generally have a lesser
influence on cognition and on the `negative` symptoms of the
disease, which include lack of motivation and emotion, social
withdrawal, lack of interest in everyday activities, and the
reduced ability to plan or carry out activities.
[0061] Obsessive-compulsive disorder (OCD) is an anxiety disorder
characterized by recurrent and persistent anxiety-provoking
thoughts (obsessions) that lead to repetitive behaviors
(compulsions) that focus on alleviating distress caused by
obsessive thoughts. Patients may or may not recognize that the
obsessions and compulsions are unreasonable, and these thoughts and
behaviors can become time-consuming and impair function.
[0062] OCD is generally treated with psychotherapy, medication or
both. Cognitive behavior therapy (CBT), which teaches a person
different ways of thinking, behaving, and reacting to situations
that help him or her to feel less anxious or fearful without having
obsessive thoughts or acting compulsively (cognitive restructuring
and exposure response prevention). However, CBT takes effort and
practice to learn healthy ways to cope with anxiety. Medications
may also be prescribed to treat OCD. The most commonly prescribed
medications are anti-anxiety medications and anti-depressants.
Anti-anxiety medications begin working right away, but should not
be taken for long periods of time. Anti-depressants may take 10 to
12 weeks to start working and can cause side effects such as
headache, nausea, sleep disturbance, and reduced libido. Atypical
anti-psychotics may also be prescribed. It is not unusual for OCD
patients to have to try several medications before finding one that
controls OCD symptoms.
[0063] However, even when OCD is appropriately diagnosed and
treated, many OCD patients are "treatment-resistant" or
"treatment-refractory" and do not adequately respond to standard
therapies. An estimated 10% to 40% of OCD patients are
treatment-refractory (Bystritsky, Mol. Psychiatry 11:805-814).
Treatment resistance generally refers to a lack of sufficient
improvement despite multiple adequate and appropriate treatment
trials. For mood disorders, it may be defined by failure to remit
or respond clinically (50% reduction in symptoms) despite .gtoreq.2
adequate antidepressant trials or failure to respond clinically
despite adequate medication trials across several neurotransmitter
classes. Pallanti and Quercioli (Neuropsychopharmacol. Biol.
Psychiatry 30:400-412) proposed categorizing obsessive-compulsive
disorder treatment response into several stages along a spectrum,
ranging from complete recovery (or remission) to full or partial
response to non-response (or completely refractory). Whichever
definition is used, patients with treatment resistance in anxiety
disorders experience minimal restoration of function despite
several appropriate treatment exposures. Factors that contribute to
treatment resistance in OCD include, but are not limited to,
disease severity, medical comorbidity, psychiatric comorbidity,
treatment non-compliance, cultural factors, childhood stressors,
long-term persistent stressors, life stage, and limitations of
clinician/health system (Khalsa et al., Curr. Psychiatry, 2011,
10:45-52). Invasive therapies, including some that are
irreversible, such as electroconvulsive therapy, vagal nerve
stimulation, repetitive transcranial magnetic stimulation, and
surgical methods, are reserved for patients with the strongest
treatment resistance. More effective treatments are therefore
needed to treat the symptoms associated with treatment refractory
OCD.
[0064] Lesch-Nyhan syndrome is characterized by neurologic
dysfunction, cognitive and behavioral disturbances, and uric acid
overproduction and has a prevalence of 1:380,000. Patients with
this syndrome suffer from cognitive deficits, movement disorders,
and self-injurious behavior. The most common presenting feature of
Lesch-Nyhan syndrome is developmental delay during the first year
of life; hypotonia and delayed motor skills are usually evident by
age 3-6 months. Children with Lesch-Nyhan syndrome typically fail
to sit, crawl, and walk, and are ultimately confined to a
wheelchair. Even with effective management of symptoms, most
affected individuals survive only into their second or third
decade.
[0065] Lesch-Nyhan syndrome is inherited in an X-linked recessive
pattern and is caused by deficiency of the enzyme
hypoxanthine-guanine phosphoribosyltransferase (HPRT) that
catalyzes the conversion of hypoxanthine to inosine monophosphate
(inosinic acid, IMP) and guanine to guanine monophosphate (guanylic
acid, GMP) in the presence of phosphoribosyl pyrophosphate. To
treat hyperuricemia and thereby reduce the risk for
nephrolithiasis, urate nephropathy, gouty arthritis, and tophi,
overproduction of uric acid is controlled with allopurinol, which
blocks the metabolism of hypoxanthine and xanthine into uric acid
catalyzed by xanthine oxidase.
[0066] Agitation in Alzheimer's disease refers to a cluster of
several behavioral symptoms associated with the disease. Agitation
develops as the disease progresses and occurs in addition to
cognitive loss. The cluster of symptoms includes anxiety,
depression, irritability, and motor restlessness (such as pacing,
wandering, constant movement). Other symptoms that may occur
include sleep disturbances, delusions, hallucinations, compulsive
behaviors, aggression, and general emotional distress. Agitation
may occur in as many as half of all individuals with Alzheimer's
disease. Agitation is associated with patients who have a poor
quality of life, deteriorating family relationships and
professional caregivers, ultimately leading to admission to a
residential care facility.
[0067] Fragile X syndrome (also called Martin-Bell syndrome) is a
genetic condition that causes a range of developmental problems
including learning disabilities and cognitive impairment. Usually,
males are more severely affected by this disorder than females.
Fragile X syndrome is inherited in an X-linked dominant pattern.
Fragile X syndrome occurs in approximately 1 in 4,000 males and 1
in 8,000 females. This syndrome is caused by loss of the fragile X
mental retardation protein (FMRP), generally due to transcriptional
silencing from a CGG repeat expansion in the 5' untranslated region
of the FMR1 gene (see, e.g., Verkerk et al., Cell 65:905-14
(1991)).
[0068] Affected individuals usually have delayed development of
speech and language by the age of 2 years. Most males with Fragile
X syndrome have mild to moderate intellectual disability, while
about one-third of affected females are intellectually disabled.
Children with Fragile X syndrome may also exhibit behavioral
problems, including anxiety, attentional deficits, anxiety, and
hyperactive behaviors, such as fidgeting or impulsive actions.
Children with Fragile X syndrome and who have attentional deficits
may be diagnosed with attention deficit disorder (ADD), which
includes an impaired ability to maintain attention and difficulty
focusing on specific tasks. About one-third of individuals with
Fragile X syndrome have features of autism spectrum disorders that
affect communication and social interaction, for example, anxiety
and repetitive, stereotyped behaviors (i.e., stereotypies).
Seizures occur in about 15 percent of males and about 5 percent of
females with this syndrome.
[0069] The CGG repeat expansion in patients with Fragile X syndrome
occurs more than 200 times. When the repeat expansion occurs to a
lesser degree (i.e., between about 50-200 times), an FMR1 gene
permutation occurs and FMRP is produced to some degree. FMR1 gene
permutation may result in another genetic condition called Fragile
X-associated tremor-ataxia syndrome (FXTAS). FXTAS is characterized
by movement difficulties and cognition problems. FXTAS is a
late-onset disorder, usually occurring after age 50; symptoms
worsen with age. This condition also affects males more frequently
and severely than females with about 1 in 3000 men affected.
[0070] Characteristics of FXTAS include problems with coordination
and balance (ataxia) and intention tremor, which is trembling or
shaking of a limb when the affected individual is trying to perform
a voluntary movement, such as reaching for an object. Most often,
intention tremors develop first, followed a few years later by
ataxia. Not all persons with FXTAS have both features. Many
affected individuals develop other movement problems, such as
parkinsonism, which includes tremors when not moving (resting
tremor), rigidity, and unusually slow movement (bradykinesia). In
addition, affected individuals may have reduced sensation, numbness
or tingling, pain, or muscle weakness in the lower limbs. Some
people with FXTAS experience problems with the autonomic nervous
system, leading to the inability to control the bladder or
bowel.
[0071] Women who have a pre-mutation in their FMR1 gene are at
higher risk for primary ovarian insufficiency (Fragile X-Associated
Primary Ovarian Insufficiency) and are at higher risk for having
children who have Fragile X syndrome. Fragile X-Associated Primary
Ovarian Insufficiency is a cause of infertility and early
menopause.
[0072] No uniformly effective intervention for managing the
neurobehavioral aspects of Fragile X syndrome or FXTAS exists. More
effective treatments are therefore needed to manage the conditions
associated with these genetic diseases.
[0073] Autism spectrum disorder (ASD) is a range of complex
neurodevelopment disorders, characterized by social impairments;
communication difficulties; and restricted, repetitive, and
stereotyped patterns of behavior (stereotypies). Autistic disorder,
sometimes called autism or classical ASD, is the most severe form
of ASD. Other conditions include a milder form known as Asperger
syndrome, childhood disintegrative disorder, pervasive
developmental disorder, which is not otherwise specified (usually
referred to as PDD-NOS). Although ASD varies significantly in
character and severity, it occurs in all ethnic and socioeconomic
groups and affects every age group. Based on current data, experts
estimate that about one of 70 children who are age eight will have
an ASD. Males are four-five times more likely to have an ASD than
females. The hallmark feature of ASD is impaired social
interaction. Many children with an ASD engage in repetitive
movements, such as rocking and twirling, or exhibit self-abusive
behavior, such as biting or head-banging.
[0074] Depression is a common feature of mental illness, whatever
its nature and origin. A person with a history of any serious
psychiatric disorder has almost as high a chance of developing
major depression as someone who has had major depression itself in
the past. About 20% of the U.S. population reports at least one
depressive symptom in a given month, and 12% report two or more in
a year. Mood disorders represent a category of mental disorders in
which the underlying problem primarily affects a person's
persistent emotional state (their mood). Bipolar disorder is less
common, occurring at a rate of 1% in the general population, but
some believe the diagnosis is often overlooked because manic
elation is too rarely reported as an illness. Bipolar disorder is
an illness involving one or more episodes of serious mania and
depression. Sometimes a person might only experience symptoms of
mania. If a person only experiences feelings of sadness, this is
considered depression. During episodes of bipolar disorder, a
person's mood can swing from excessively "high" and/or irritable to
sad and hopeless, with periods of a normal mood in between.
[0075] Major depressive disorder is one of the most common mental
illnesses. Depression causes people to lose pleasure from daily
life, can complicate other medical conditions, and can even be
serious enough to lead to suicide. Depression can occur to anyone,
at any age, and to people of any race or ethnic group. Depression
is usually treated with medications, psychotherapy, or a
combination of the two. Medications for major depressive disorder
fall in multiple drug classes, including tricyclic antidepressants,
monoamine oxidase inhibitors, selective serotonin reuptake
inhibitors, and atypical antidepressants. However, most
antidepressants require at least 4-6 weeks for onset of
effectiveness, and many antidepressants have unpleasant side
effects. Moreover, as many as two-thirds of patients with
depression experience treatment failure with the first
anti-depressant, and up to a third of patients with depression
don't respond to several attempts at treatment. Given the
unpleasant and potentially severe side effects associated with
these medications, a need exists to develop new therapeutics for
treating depression in mood disorders and their related
symptoms.
[0076] Rett syndrome (RTT), originally termed cerebroatrophic
hyperammonemia, is a rare genetic postnatal neurological disorder
of the grey matter of the brain that affects both females and male
patients, with predominance of female ones. Rett syndrome causes
problems in brain function that are responsible for cognitive,
sensory, emotional, motor, and autonomic function. Most frequent
problems that occur include those involving learning, speech,
sensory sensations, mood, movement, breathing, cardiac function,
chewing, swallowing, and digestion. It is characterized by normal
early growth and development followed by a slowing of development,
loss of purposeful use of the hands, distinctive hand movements,
slowed brain and head growth, problems with walking, seizures, and
intellectual disability. In particular, repetitive stereotyped hand
movements, such as wringing and/or repeatedly putting hands into
the mouth, are usual symptoms. Apraxia--the inability to perform
motor functions--is perhaps the most severely disabling feature of
Rett syndrome, interfering with every body movement, including eye
gaze and speech. Children with Rett syndrome often exhibit
autistic-like behaviors in the early stages
(http://www.ninds.nih.gov/disorders/rett/detail_rett.htm).
[0077] Nearly all cases of Rett syndrome are caused by a mutation
in the methyl CpG binding protein 2, or MECP2 gene. The MECP2 gene
contains instructions for the synthesis of a protein called methyl
cytosine binding protein 2 (MeCP2), which is needed for brain
development and acts as one of the many biochemical switches that
can either increase gene expression or tell other genes when to
turn off and stop producing their own unique proteins. Because the
MECP2 gene does not function properly in individuals with Rett
syndrome, insufficient amounts or structurally abnormal forms of
the protein are produced and can cause other genes to be abnormally
expressed. However, not everyone who has an MECP2 mutation has Rett
syndrome. Although Rett syndrome is a genetic disorder, less than 1
percent of recorded cases are inherited or passed from one
generation to the next. Most cases are spontaneous, which means the
mutation occurs randomly. Rett syndrome is estimated to affect one
in every 10,000 to 15,000 live female births and in all racial and
ethnic groups worldwide.
[0078] Chorea-acanthocytosis (ChAc) is a neurological disorder that
affects movements in many parts of the body. Chorea refers to the
involuntary jerking movements made by people with this disorder.
People with this condition also have abnormal star-shaped red blood
cells (acanthocytosis). This disorder is one of a group of
conditions called neuroacanthocytoses that involve neurological
problems and abnormal red blood cells. Clinically is characterized
by a Huntington disease-like phenotype with progressive
neurological symptoms including movement disorders, psychiatric
manifestations and cognitive disturbances. Chorea may also be
associated with Huntington's disease, and the methods and
compositions provided herein may be employed to treat the same.
[0079] Prevalence and incidence of chorea-acanthocytosis are not
known, but it is estimated that there are around 1,000 cases
worldwide. Onset is in early adulthood and the initial presentation
is often subtle cognitive or psychiatric symptoms. During the
course of the disease, most patients develop a characteristic
phenotype including chorea. Most patients develop generalized
chorea and some degree of parkinsonism. Impairment of memory and
executive functions is frequent. Psychiatric manifestations are
common and may present as schizophrenia-like psychosis or obsessive
compulsive disorder (OCD). Chorea-acanthocytosis usually progresses
slowly over 15-30 years, but sudden death, presumably caused by
seizures or autonomic involvement, may occur.
[0080] Chorea-acanthocytosis is caused by various mutations in the
VPS13A gene coding for chorein. No obvious genotype-phenotype
correlations have been observed. This condition is inherited in an
autosomal recessive pattern, which means both copies of the gene in
each cell have mutations. The parents of an individual with an
autosomal recessive condition each carry one copy of the mutated
gene, but they typically do not show signs and symptoms of the
condition.
[0081] As used herein, "22q11.2 Deletion Syndrome (22q11.2 DS) is
also known as Velocardiofacial syndrome ("VCFS"), DiGeorge
syndrome, CATCH 22 and less often referred to as DiGeorge sequence,
Microdeletion 22q11.2, Monosomy 22q11, Conotruncal anomaly face
syndrome, Sedlaikova syndrome, Shprintzen syndrome, Takao syndrome,
or Cayler cardiofacial syndrome. It is an autosomal dominant
genetic condition that arises from the deletion of genes on
chromosome 22 at band q11.2. Approximately 90% of individuals with
VCFS have a 3 Mb deletion with the deletion of two genes, COMT and
TBX1, being specifically associated with VCFS. Only .about.10% of
individuals have a smaller 1.5 Mb deletion, which also typically
includes the deletion of TBX1 and COMT. However, not all genes
related to VCFS have been identified.
[0082] As used herein, "COMT" is a key enzyme for regulating
catechol compounds, including dopamine, epinephrine and
norepinephrine. Individuals with VCFS have approximately 50% less
COMT mRNA, COMT protein expression, and enzyme activity compared to
normal subjects. The characteristic behavioral manifestations of
VCFS may be related to dopamine dysregulation resulting from COMT
haploinsufficiency. However, that can be compounded by the presence
of a low-activity COMT allele, leading to further dysregulation in
patients with VCFS. COMT contains a common functional polymorphism,
Val158Met (rs4680), which leads to alterations in enzyme activity.
Individuals with VCFS who have a single copy of the Met allele have
markedly low COMT activity. Compared with VCFS adults carrying the
COMT Val allele, those carrying the Met allele tend to have
increased risk for psychotic disorders, other neuropsychiatric
syndromes, and have more severe cognitive deficits.
[0083] Accordingly, in various embodiments as disclosed herein,
methods are provided for treating a hyperkinetic movement disorder
in a subject in need thereof by administering to the patient a
therapeutically effective amount of the solid drug form of
valbenazine or valbenazine ditosylate. In one embodiment, the
hyperkinetic movement disorder is tardive dyskinesia, Tourette's
syndrome, Huntington's disease, chorea associated with Huntington's
disease, or tics. In other embodiments, the hyperkinetic movement
disorder is ataxia, chorea, dystonia, hemifacial spasm, myoclonus,
restless leg syndrome, or tremors.
[0084] In other embodiments, methods are provided for treating a
neurological and/or psychiatric diseases and disorders in a subject
in need thereof by administering to the patient a therapeutically
effective amount of the solid drug form of valbenazine or
valbenazine ditosylate. In one embodiment, the neurological and/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-refractory 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.
[0085] As used herein, "subject" means a mammal, including a human.
The term "patient" is used synonymously with "subject" within this
disclosure.
[0086] As used herein, the phrase term "therapeutically effective
amount" refers to an amount of a therapeutic agent to treat,
ameliorate, or prevent a disease or condition, or to exhibit a
detectable therapeutic or preventative effect. The effect is
detected by, for example, a reduction in tumor size. The effect is
also detected by, for example, chemical markers, steroid levels, or
antigen levels. Therapeutic effects also include reduction in
physical symptoms, such as decreased body temperature. The precise
effective amount for a subject will depend upon the subject's size
and health, the nature and extent of the condition, the
therapeutics or combination of therapeutics selected for
administration, and other variables known to those of skill in the
art. The effective amount for a given situation is determined by
routine experimentation and is within the judgment of the
clinician.
[0087] As used herein, "treatment" includes therapeutic
applications to slow or stop progression of a disorder,
prophylactic application to prevent development of a disorder,
and/or reversal of a disorder. Reversal of a disorder differs from
a therapeutic application which slows or stops a disorder in that
with a method of reversing, not only is progression of a disorder
completely stopped, cellular behavior is moved to some degree,
toward a normal state that would be observed in the absence of the
disorder.
[0088] As used herein, "capsule size" or "capsule size number"
refers to the internationally accepted numbering system for capsule
sizes used in approved U.S. drug products, as shown in Table 1
below.
TABLE-US-00001 TABLE 1 Capsule Size 000 00E 00 0E 0 1 2 3 4 5 Empty
Capsule Volume Capacity (ml) Capacity 1.37 1.00 0.90 0.78 0.68 0.48
0.36 0.27 0.20 0.13 Empty Capsule Overall Closed Length (mm) 26.1
25.3 23.4 23.5 21.6 19.4 17.6 15.7 14.3 11.1 Tolerance .+-.0.3
.+-.0.3 .+-.0.3 .+-.0.3 .+-.0.3 .+-.0.3 .+-.0.3 .+-.0.3 .+-.0.3
.+-.0.4 (mm) Empty Capsule Individual Lengths (Cap) Cap (mm) 12.95
12.95 11.80 11.68 10.85 9.85 8.80 8.00 7.20 6.20 Tolerance .+-.0.35
.+-.0.35 .+-.0.35 .+-.0.35 .+-.0.35 .+-.0.35 .+-.0.35 .+-.0.35
.+-.0.35 .+-.0.29 Empty Capsule Individual Lengths (Body) Body (mm)
22.20 22.20 20.22 20.19 18.35 16.40 15.15 13.45 12.10 9.30
Tolerance .+-.0.35 .+-.0.35 .+-.0.35 .+-.0.35 .+-.0.35 .+-.0.35
.+-.0.35 .+-.0.35 .+-.0.35 .+-.0.29 Empty Capsule External Diameter
Cap (mm) 9.91 8.58 8.56 7.65 7.64 6.96 6.39 5.85 5.33 4.91 Body
(mm) 9.55 8.25 8.23 7.36 7.35 6.63 6.12 5.6 5.08 4.68
[0089] As used herein, "blend uniformity" refers to the homogeneity
of a solid and can represent either one sample or the average of
more than one sample.
[0090] As used herein, "content uniformity" refers to the
homogeneity of the valbenazine content among unit dosage forms,
e.g. capsules, after formulation.
[0091] As used herein, "stratified sampling" refers to a process of
selecting units deliberately from various locations within a lot or
batch or from various phases or periods of a process to obtain a
sample. In some embodiments, stratified sampling of the blend and
dosage units specifically targets locations either in the blender
or throughout the compression/filling operation, which have a
higher risk of producing failing content uniformity results.
[0092] In various embodiments a solid pharmaceutical composition is
provided of valbenazine, or a pharmaceutically acceptable salt
thereof, silicified microcrystalline cellulose, isomalt,
hydroxypropyl methylcellulose, partially pregelatinized maize
starch, and magnesium stearate. In one embodiment, the
pharmaceutically acceptable salt is valbenazine ditosylate.
[0093] In various embodiments, valbenazine, or a pharmaceutically
acceptable salt thereof, is present in the solid pharmaceutical
composition at a level ranging from about 20-160 mg as measured as
the free base. In one embodiment, valbenazine, or a
pharmaceutically acceptable salt thereof, is present at a level of
about 20 mg as measured as the free base. In one embodiment,
valbenazine, or a pharmaceutically acceptable salt thereof, is
present at a level of about 40 mg as measured as the free base.
[0094] In one embodiment, valbenazine, or a pharmaceutically
acceptable salt thereof, is present at a level of about 60 mg as
measured as the free base. In one embodiment, valbenazine, or a
pharmaceutically acceptable salt thereof, is present at a level of
about 80 mg as measured as the free base. In one embodiment,
valbenazine, or a pharmaceutically acceptable salt thereof, is
present at a level of about 100 mg as measured as the free base. In
one embodiment, valbenazine, or a pharmaceutically acceptable salt
thereof, is present at a level of about 120 mg as measured as the
free base. In one embodiment, valbenazine, or a pharmaceutically
acceptable salt thereof, is present at a level of about 140 mg as
measured as the free base. In one embodiment, valbenazine, or a
pharmaceutically acceptable salt thereof, is present at a level of
about 160 mg as measured as the free base.
[0095] In one embodiment, valbenazine ditosylate is present in a
unit dosage form of a solid pharmaceutical composition at a level
of at least 30% by weight of the total weight of the unit dosage
form. In one embodiment, valbenazine ditosylate is present at a
level of at least 35% by weight of the total weight of the unit
dosage form. In one embodiment, valbenazine ditosylate is present
at a level of at least 38% by weight of the total weight of the
unit dosage form. In one embodiment, valbenazine ditosylate is
present at a level of at least 40% by weight of the total weight of
the unit dosage form. In one embodiment, valbenazine ditosylate is
present at a level of at least 45% by weight of the total weight of
the unit dosage form.
[0096] In one embodiment, a solid pharmaceutical composition of
valbenazine, or a pharmaceutically acceptable salt thereof, is
provided where the solid pharmaceutical composition is in unit
dosage form suitable for oral administration. In one embodiment,
the unit dosage form is formulated for dosing once daily. In
another embodiment, the unit dosage form is formulated for dosing
twice, three times, or four times daily.
[0097] In one embodiment, a unit dosage form of a solid
pharmaceutical composition of valbenazine, or a pharmaceutically
acceptable salt thereof, as presented herein, is provided where the
unit dosage form is in capsule form. In one embodiment, the unit
dosage form is an oral dosage product. In one embodiment, the
capsule is size 0 or smaller. In one embodiment, the capsule is
size 1 or smaller. In one embodiment, the capsule is size 2 or
smaller. In one embodiment, the capsule is size 3 or smaller.
[0098] In one embodiment, the unit dosage form capsule of the solid
pharmaceutical composition of valbenazine, or a pharmaceutically
acceptable salt thereof, as presented herein, has at least 80%
dissolution at 30 minutes in a USP Paddle Dissolution Method 2
apparatus and 0.1 N HCl medium.
[0099] In another embodiment, the solid pharmaceutical composition
of valbenazine or valbenazine ditosylate as presented herein has a
bulk density of at least about 0.5 mg/mL. In another embodiment,
the solid pharmaceutical composition of valbenazine or valbenazine
ditosylate as presented herein has a tapped density of at least
about 0.6 mg/mL. In another embodiment, valbenazine ditosylate in
the solid pharmaceutical composition has a d(0.9) particle size
distribution less than 100 .mu.m.
[0100] In another embodiment, a unit dosage form of a
pharmaceutical composition is provided having a capsule of size 1
or smaller and at least 80 mg of valbenazine, or a pharmaceutically
acceptable salt thereof, as measured as the free base. In another
embodiment, the valbenazine 80 mg unit dosage form has a capsule of
size 2 or smaller. In another embodiment, the valbenazine 80 mg
unit dosage form has a capsule of size 3 or smaller.
[0101] In another embodiment, a unit dosage form of a
pharmaceutical composition is provided having a capsule of size 2
or smaller and at least 20 mg of valbenazine, or a pharmaceutically
acceptable salt thereof, as measured as the free base. In another
embodiment, the valbenazine 20 mg unit dosage form has a capsule of
size 3 or smaller.
[0102] In another embodiment, a unit dosage form of a
pharmaceutical composition is provided having a capsule of size 2
or smaller and at least 40 mg of valbenazine, or a pharmaceutically
acceptable salt thereof, as measured as the free base. In another
embodiment, the valbenazine 40 mg unit dosage form has a capsule of
size 3 or smaller.
[0103] In one embodiment, a unit dosage form of a pharmaceutical
composition is provided having a capsule of size 0 or smaller and
at least 120 mg of valbenazine, or a pharmaceutically acceptable
salt thereof, as measured as the free base. In another embodiment,
the valbenazine 120 mg unit dosage form has a capsule of size 1 or
smaller. In another embodiment, the valbenazine 80 mg unit dosage
form has a capsule of size 2 or smaller.
[0104] In another embodiment, a unit dosage form of a
pharmaceutical composition is provided with valbenazine ditosylate
having a w/w % of at least 35%. In another embodiment, the
valbenazine ditosylate has a w/w % of at least 38%. In another
embodiment, the valbenazine ditosylate has a w/w % of at least 40%.
In another embodiment, the unit dosage form further comprises
silicified microcrystalline cellulose, isomalt, hydroxypropyl
methylcellulose, partially pregelatinized maize starch, and
magnesium stearate.
[0105] In one embodiment, a unit dosage form of a pharmaceutical
composition is provided with valbenazine ditosylate having a w/w %
of about 40%, silicified microcrystalline cellulose having a w/w %
of about 25%, isomalt having a w/w % of about 20%, hydroxypropyl
methylcellulose having a w/w % of about 5%, partially
pregelatinized maize starch having a w/w % of about 7.5%, and
magnesium stearate having a w/w % of about 2.5%.
[0106] Also provided is a unit dosage form comprising a solid
composition described herein.
[0107] In some embodiments, the unit dosage form has an average
stratified content uniformity of between about 99% and about 100%
with a standard deviation of the mean of less than about 3.5%.
[0108] In some embodiments, the unit dosage form has an average
stratified content uniformity of between about 99% and about 100%
with a standard error of the mean of less than about 3.5%.
[0109] In one embodiment is provided a method of orally
administering a unit dosage form valbenazine or valbenazine
ditosylate to a subject in need thereof. In some embodiments, the
subject has a neurological or psychiatric disease or disorder. In
one embodiment, the subject has a hyperkinetic movement disorder.
In another embodiment, the hyperkinetic movement disorder is
tardive dyskinesia, Tourette's syndrome, Huntington's disease, or
tics.
[0110] In some embodiments, the hyperkinetic movement disorder is
tardive dyskinesia. In some embodiments, the hyperkinetic movement
disorder is Tourette's syndrome. In some embodiments, the
hyperkinetic movement disorder is Huntington's disease. In some
embodiments, the hyperkinetic movement disorder is tics.
[0111] In some embodiments, the hyperkinetic movement disorder is
chorea associated with Huntington's disease. In some embodiments,
the hyperkinetic movement disorder is ataxia, chorea, dystonia,
Huntington's disease, myoclonus, restless leg syndrome, or
tremors.
[0112] In some embodiments, the patient has been determined to have
22q11.2 deletion syndrome. In some embodiments, the patient is
predisposed to developing a psychiatric disorder due to the patient
having 22q11.2 deletion syndrome. In some embodiments, the patient
has been determined to have COMT haploinsufficiency. In some
embodiments, the patient is predisposed to developing a psychiatric
disorder due to the patient having COMT haploinsufficiency.
[0113] In some embodiments, the neurological or psychiatric disease
or disorder is a hyperkinetic movement disorder, mood disorder,
bipolar disorder, schizophrenia, schizoaffective disorder, mania in
mood disorder, depression in mood disorder, treatment-refractory
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.
[0114] In one embodiment is provided a method for treating a
hyperkinetic movement disorder in a patient in need thereof by
administering to the patient a therapeutically effective amount of
the solid drug form of valbenazine or valbenazine ditosylate, as
presented herein. In another embodiment, the hyperkinetic movement
disorder is tardive dyskinesia, Tourette's syndrome, Huntington's
disease, or tics.
[0115] Also provided is a unit dosage form, as described herein,
for use in a method of treating a neurological or psychiatric
disease or disorder of a patient in need thereof.
[0116] In the practice of the methods disclosed herein, valbenazine
or pharmaceutically acceptable salt thereof may be administered to
the patient for a first period of time followed by a second period
of time, wherein valbenazine or pharmaceutically acceptable salt is
administered at a lower level during the first period of time than
the second period of time. The first period of time may be, for
example, days, weeks or months. In one embodiment, the first period
of time is one week. When administered daily in oral unit dosage
form, valbenazine or pharmaceutically acceptable salt thereof may
be present in a first unit dosage form at a level of about 40 mg as
measured as the free base. Following a period of time, such as one
week, a second daily oral unit dosage form may then be
administered. For example, valbenazine or pharmaceutically
acceptable salt thereof may be present in the second unit dosage
form at a level of about 80 mg as measured as the free base.
[0117] In one embodiment, a kit is provided with a plurality of
oral unit dosage forms of a solid pharmaceutical composition of
valbenazine or valbenazine ditosylate in combination with
instructions for administration.
[0118] In one embodiment, a kit is provided with a plurality of
oral unit dosage forms of a solid composition of valbenazine or
valbenazine ditosylate in combination with instructions for
administration.
[0119] In one embodiment, a method for producing a unit dosage form
of valbenazine ditosylate is provided according to FIG. 1.
[0120] Also provided is a process for preparing a solid composition
of valbenazine, or a pharmaceutically acceptable salt thereof,
wherein the process comprises:
[0121] a) subjecting a blend of valbenazine, or a pharmaceutically
acceptable salt thereof, at least one water insoluble filler, and
at least one water soluble diluent to comminution;
[0122] b) blending the product of step a) with at least one binder
and at least one disintegrant;
[0123] c) determining the blend uniformity of the product of step
b); and
[0124] d) blending the product of step b) with at least one
lubricant only if the blend uniformity satisfies a predetermined
criteria to produce a solid pharmaceutical composition of
valbenazine, or a pharmaceutically acceptable salt thereof.
[0125] In some embodiments, the process further comprises the steps
of: e) determining density and/or particle size distribution of the
product of step d); and f) subjecting the product of step d) to dry
granulation to produce granules of valbenazine, or a
pharmaceutically acceptable salt thereof, only if the density
and/or particle size distribution satisfies a predetermined
criteria.
[0126] In some embodiments, the process further comprises the steps
of: g) determining density and/or particle size distribution of the
product of step f); and h) blending the granules of step f) with at
least one lubricant only if the density and/or particle size
distribution satisfies a predetermined criteria.
[0127] In some embodiments, the process further comprises the steps
of: i) determining density and/or blend uniformity of the product
of step h); and j) encapsulating the product of step h) to produce
a unit dosage form comprising valbenazine, or a pharmaceutically
acceptable salt thereof, only if the density and/or blend
uniformity satisfies a predetermined criteria.
[0128] In some embodiments, the process further comprises the step
of: determining the disintegration and/or content uniformity of the
unit dosage form.
[0129] Methods for determining disintegration, content uniformity,
density, particle size distribution, and blend uniformity are known
in the art, including the methods described in U.S. Pharmacopeia
("USP") 905 (Uniformity of Dosage Units (2016)); USP 711
(Dissolution (2011)); USP 616 (Bulk Density and Tapped Density of
Powders (2015)); USP 429 (Light Diffraction Measurement of Particle
Size (2016)); and USP 701 (Disintegration (2016)), each of which is
incorporated herein by reference for all purposes.
[0130] Also provided is a process for preparing a unit dosage form
comprising valbenazine, or a pharmaceutically acceptable salt
thereof, wherein the process comprises: encapsulating solid
composition as described herein, to produce the unit dosage form
comprising valbenazine, or a pharmaceutically acceptable salt
thereof.
[0131] Also provided is a process for preparing a unit dosage form
comprising valbenazine, or a pharmaceutically acceptable salt
thereof, wherein the process comprises: encapsulating a lubricated
blend to produce a solid composition comprising valbenazine, or a
pharmaceutically acceptable salt thereof, wherein the lubricated
blend comprises granules of valbenazine, or a pharmaceutically
acceptable salt thereof, and at least one lubricant.
[0132] In some embodiments, the lubricated blend is prepared by a
process comprising the steps of: blending at least one lubricant
with granules of valbenazine, or a pharmaceutically acceptable salt
thereof, to produce a lubricated blend.
[0133] In some embodiments, the granules of valbenazine, or a
pharmaceutically acceptable salt thereof, is prepared by a process
comprising the steps of: dry granulating a blend to produce
granules of valbenazine, or a pharmaceutically acceptable salt
thereof. In some embodiments, dry granulating a blend comprises
gravity feeding the blend through the roller compactor.
[0134] In some embodiments, the blend is prepared by a process
comprising the steps of: blending at least one lubricant with an
intragranular blend to produce the blend.
[0135] In some embodiments, the intragranular blend is prepared by
a process comprising blending a pre-blend with at least one
disintegrant and at least one binder to produce the intragranular
blend.
[0136] In some embodiments, the pre-blend is prepared by a process
comprising the steps of: blending valbenazine, or a
pharmaceutically acceptable salt thereof, with at least one
water-insoluble filler and at least one water soluble diluent to
produce the pre-blend.
[0137] Also provided is a process for preparing a unit dosage form
comprising valbenazine, or a pharmaceutically acceptable salt
thereof, wherein the process comprises:
[0138] preparing a dispersion of valbenazine, or a pharmaceutically
acceptable salt thereof, in at least one water-insoluble filler and
at least one water soluble diluent to produce a pre-blend;
[0139] blending the pre-blend with one or more excipients to
produce a blend;
[0140] granulating the blend to produce a granulated blend;
[0141] optionally blending the granulated blend with one or more
excipients to produce a lubricated blend; and
[0142] encapsulating the lubricated blend.
[0143] Also provided is a unit dosage form comprising valbenazine,
or a pharmaceutically acceptable salt thereof, prepared by any of
the processes described herein.
[0144] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a bulk density of at least about 0.5 mg/mL.
[0145] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a tapped density of at least about 0.6 mg/mL.
[0146] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a d(0.9) particle size distribution less than 100
.mu.m.
[0147] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a blend uniformity between about 90% and about 110%
with a relative standard deviation of the blend uniformity of less
than about 2%. In some embodiments, the solid composition has a
blend uniformity between about 95% and about 105% with a relative
standard deviation of the blend uniformity of less than about
2%.
[0148] Also provided is a solid composition of valbenazine, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, wherein the solid
composition has a blend uniformity between about 90% and about 110%
with a standard deviation of the blend uniformity of less than
about 2%. In some embodiments, the solid composition has a blend
uniformity between about 95% and about 105% with a standard
deviation of the blend uniformity of less than about 2%.
[0149] In some embodiments, the valbenazine, or a pharmaceutically
acceptable salt thereof, is present at a level ranging from about
20-160 mg as measured as the free base. In some embodiments, the
valbenazine, or a pharmaceutically acceptable salt thereof, is
present at a level of about 20 mg as measured as the free base. In
some embodiments, the valbenazine, or a pharmaceutically acceptable
salt thereof, is present at a level of about 40 mg as measured as
the free base. In some embodiments, the valbenazine, or a
pharmaceutically acceptable salt thereof, is present at a level of
about 60 mg as measured as the free base. In some embodiments, the
valbenazine, or a pharmaceutically acceptable salt thereof, is
present at a level of about 80 mg as measured as the free base. In
some embodiments, the valbenazine, or a pharmaceutically acceptable
salt thereof, is present at a level of about 120 mg as measured as
the free base. In some embodiments, the valbenazine, or a
pharmaceutically acceptable salt thereof, is present at a level of
about 160 mg as measured as the free base.
[0150] In some embodiments, the solid composition comprises
valbenazine, or a pharmaceutically acceptable salt thereof, as
measured by the free base, at a level of at least about 35% w/w. In
some embodiments, the solid composition comprises valbenazine, or a
pharmaceutically acceptable salt thereof, as measured by the free
base, at a level of at least about 38% w/w. In some embodiments,
the solid composition comprises valbenazine, or a pharmaceutically
acceptable salt thereof, as measured by the free base, at a level
of at least about 40% w/w. In some embodiments, the solid
composition comprises valbenazine, or a pharmaceutically acceptable
salt thereof, as measured by the free base, at a level of at least
about 45% w/w. In some embodiments, the solid composition comprises
valbenazine, or a pharmaceutically acceptable salt thereof, as
measured by the free base, at a level of about 40% w/w.
[0151] In some embodiments, the pharmaceutically acceptable salt of
valbenazine is a tosylate salt. In some embodiments, the
pharmaceutically acceptable salt of valbenazine is valbenazine
ditosylate.
[0152] In some embodiments, the solid composition comprises
granules of the valbenazine, or a pharmaceutically acceptable salt
thereof, and the at least one pharmaceutically acceptable
excipient. In some embodiments, the granules are prepared by dry
granulation. In some embodiments, the granules are prepared by
roller compaction.
[0153] In some embodiments, the solid composition comprises a blend
of the granules of valbenazine, or a pharmaceutically acceptable
salt thereof, and the at least one pharmaceutically acceptable
excipient with at least one lubricant.
[0154] In some embodiments, the at least one pharmaceutically
acceptable excipient is at least one lubricant. In some
embodiments, the solid composition comprises at least one lubricant
in an amount of between about 0.25% and about 5% w/w. In some
embodiments, the solid composition comprises at least one lubricant
in an amount of about 2.5% w/w. In some embodiments, the at least
one lubricant is chosen from magnesium stearate, calcium stearate,
stearic acid, talc, starch, and fumed silica (silicon dioxide). In
some embodiments, the at least one lubricant is magnesium
stearate.
[0155] In some embodiments, the at least one pharmaceutically
acceptable excipient is at least one disintegrant. In some
embodiments, the at least one disintegrant is present in an amount
of between about 1% and about 10% w/w, such as between about 2% and
about 9%, such as between about 3% and about 8%, such as between
about 4% and about 8%, such as between about 5% and about 8%, such
as between about 6% and about 8%, such as between about 7% and
about 8%. In some embodiments, the at least one disintegrant is
present in an amount of about 7.5% w/w. In some embodiments, the at
least one disintegrant is chosen from starch, alginic acid, sodium
starch glycolate, croscarmellose, crospovidone, cellulose, and
acid-carbonate effervescent systems. In some embodiments, the at
least one disintegrant is starch.
[0156] In some embodiments, the at least one pharmaceutically
acceptable excipient is at least one binder. In some embodiments,
the at least binder is present in an amount of between about 0.5%
and about 5% w/w, such as between about 2 and about 5%, such as
between about 3% and about 5%, such as between about 4% and about
5%. In some embodiments, the at least binder is present in an
amount of about 5% w/w. In some embodiments, the at least one
binder is chosen from hypromellose, polyvinylpyrrolidone, natural
gums (e.g. acacia gum), microcrystalline cellulose,
methylcellulose, ethylcellulose, sucrose, starch, and gelatin. In
some embodiments, the at least one binder is hypromellose.
[0157] In some embodiments, the at least one pharmaceutically
acceptable excipient is at least one water soluble diluent. In some
embodiments, the at least one water soluble diluent is present in
an amount of between about 20% and about 95% w/w, such as between
about 20% and about 80%, such as between about 20% and about 60%,
such as between about 20% and about 40%. In some embodiments, the
at least one water soluble diluent is present in an amount of about
20% w/w. In some embodiments, the at least one water soluble
diluent is chosen from lactose, mannitol, isomalt, sucrose,
dextrose, and sorbitol. In some embodiments, the at least one water
soluble diluent is isomalt.
[0158] In some embodiments, the at least one pharmaceutically
acceptable excipient is at least one water insoluble filler. In
some embodiments, the at least one insoluble filler is present in
an amount of between about 20% and about 95% w/w, such as between
about 20% and about 80%, such as between about 20% and about 60%,
such as been about 20% and about 40%. In some embodiments, the at
least one insoluble filler is present in an amount of about 25%
w/w. In some embodiments, the at least one water soluble filler is
chosen from microcrystalline cellulose, starch, dicalcium phosphate
dihydrate, and calcium carbonate. In some embodiments, the at least
one water soluble filler is microcrystalline cellulose.
[0159] In some embodiments, the solid composition is a solid
pharmaceutical composition.
[0160] Also provided is an oral dosage product comprising the solid
composition described herein.
[0161] Also provided is a unit dosage form prepared from a solid
composition of valbenazine, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient,
wherein the solid composition has a bulk density of at least about
0.5 mg/mL.
[0162] Also provided is a unit dosage form prepared from a solid
composition of valbenazine, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient,
wherein the solid composition has a tapped density of at least
about 0.6 mg/mL.
[0163] Also provided is a unit dosage form prepared from a solid
composition of valbenazine, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient,
wherein the solid composition has a d(0.9) particle size
distribution less than 100 .mu.m.
[0164] Also provided is a unit dosage form prepared from a solid
composition of valbenazine, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient,
wherein the solid composition has a blend uniformity between about
90% and about 110% with a relative standard deviation of the blend
uniformity of less than about 2%.
[0165] Also provided is a unit dosage form prepared from a solid
composition of valbenazine, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient,
wherein the solid composition has a blend uniformity between about
90% and about 110% with a standard deviation of the blend
uniformity of less than about 2%.
[0166] In one embodiment, a composition is provided of valbenazine,
or a pharmaceutically acceptable salt thereof, silicified
microcrystalline cellulose, isomalt, hydroxypropyl methylcellulose,
partially pregelatinized maize starch, and magnesium stearate. In
another embodiment, the composition has appropriate properties for
unit dosage manufacture, including de-agglomeration, granule flow,
blending, uniformity, compression, encapsulation characteristics,
dry granulation parameters and granule characteristics.
[0167] Physical characteristics of the granules and a final
lubricated blend include bulk and tapped densities, flowdex, and
particle size distribution (PSD). In one embodiment, the
composition has blend uniformity for final lubricated blends,
encapsulation fill weight uniformity and dissolution profiles and
content uniformity. Content and uniformity of dosage units is
prepared by adequate de-agglomeration and subsequent dispersion of
the drug substance in isomalt and silicified microcrystalline
cellulose diluents. Improper processing parameters can result in
poor granule flow and compressibility which can impact
encapsulation.
[0168] Blending is performed in a controlled environment minimizing
moisture exposure. Inadequate blending can impact content and
uniformity of dosage units. Over blending with hydrophobic
magnesium stearate can impact dissolution.
[0169] Each and every process, method, composition, or use
described herein optionally includes the limitation "wherein the
oral dosage form is not a capsule comprising 80 mg valbenazine free
base in combination with hypromellose, isomalt, magnesium stearate,
pregelatinized starch, and silicified microcrystalline
cellulose."
[0170] Each and every process, method, composition, or use
described herein optionally includes the limitation "wherein the
oral dosage form is not a capsule comprising 40 mg valbenazine free
base in combination with colloidal silicon dioxide, magnesium
stearate, mannitol, and pregelatinized starch."
[0171] Each and every process, method, composition, or use
described herein optionally includes the limitation "wherein the
oral dosage form is not a capsule comprising 80 mg valbenazine free
base in combination with mannitol, partially pregelatinized maize
starch, fumed silica, and magnesium stearate."
[0172] Each and every process, method, composition, or use
described herein optionally includes the limitation "wherein the
oral dosage form is not a capsule comprising 40 mg valbenazine free
base in combination with mannitol, partially pregelatinized maize
starch, fumed silica, and magnesium stearate."
EXAMPLES
Example 1
Preparation of Capsule Containing 80 mg Valbenazine
[0173] Capsules containing 80 mg valbenazine (measured as the free
base) may be prepared according to the procedure set forth below,
and the makeup of exemplary tablets are listed in Table 2. A flow
diagram of the manufacturing process for Valbenazine Capsules, 80
mg, which comprises unit operations of low shear (tumble) blending,
screening, roller compaction and encapsulation, is presented in
FIG. 1.
TABLE-US-00002 TABLE 2 Quantity 80 mg capsule (mg/ % Component
capsule) (w/w) Function Valbenazine ditosylate 145.80 40.0 Active
Silicified Microcrystalline 91.25 25.0 Diluent Cellulose Isomalt
73.00 20.0 Diluent Partially pregelatinized 27.38 7.5 Disintegrant
maize starch Hydroxypropyl Methylcellulose 18.25 5.0 Binder
Magnesium stearate 9.12 2.5 Lubricant Total Capsule Fill Weight
364.80 100.00 -- Hard gelatin capsule - Size #1 1 -- Shell
[0174] Valbenazine ditosylate, silicified microcrystalline
cellulose (USP), isomalt (USNF), partially pregelatinized maize
starch (USNF), hydroxypropyl methylcellulose (USNF) and magnesium
stearate (USNF) were weighed according to the amounts in Table
2.
Wallpapering:
[0175] Isomalt was transferred through a screening mill equipped
with an 813 m or equivalent round-hole screen to a tote bin for
blending. The screened isomalt component was then blended.
Pre-Blending and Screening:
[0176] The following components were transferred into the tote bin
through a screening mill equipped with a .about.813 .mu.m or
equivalent round-hole screen:
[0177] a. Valbenazine ditosylate
[0178] b. Silicified microcrystalline cellulose ("SMCC")
The components were then blended.
Delumping:
[0179] The blend was vacuum transferred through a buffer tank
equipped with a .about.813 .mu.m or equivalent round-hole
screen.
Pre-Blending #2:
[0180] The screened components were again blended.
Intragranular Blending:
[0181] The following components were then transferred, into the
tote bin through a screening mill equipped with a .about.813 .mu.m
or equivalent round-hole screen:
[0182] a. Partially pregelatinized maize starch
[0183] b. Hydroxypropyl methylcellulose
The components were then blended. Inadequate de-agglomeration and
subsequent dispersion of valbenazine ditosylate in isomalt and SMCC
diluent can potentially impact content and uniformity of dosage
units.
Lubricant Blending:
[0184] Magnesium stearate was manually screened (.about.1 mm sieve)
(intragranular quantity adjusted as needed based on pre-lubricated
blend yield--limit 98%) into the opened tote bin for blending. The
components were then blended. The desired output for this step is
improved flowability with increased bulk and tapped density and
improved particle size distribution.
Roller Compaction:
[0185] The blend was then gravity fed through a roller compactor
with a mill screen of 0.8-1.0 mm. The blend characterisics are
important factors to consider for how well the blend will handle
during encapsulation. Improper processing parameters can result in
poor granule flow and compressibility which impacts encapsulation.
The high solubility of the API and excipients should not impact
dissolution. All roller compaction blends showed improvement over
the initial intragranular blend properties which supports better
capsule weight uniformity.
Final Lubricant Blending:
[0186] Magnesium stearate was manually screened (.about.1 mm sieve)
(quantity to be adjusted as needed based on pre-lubricated blend
yield--limit 98%) into the opened tote bin for blending. The
components were then blended. The desired output for this step is a
uniform and free flowing lubricated final blend for encapsulation.
Inadequate blending can impact content and uniformity of dosage
units. Over blending with hydrophobic magnesium stearate can impact
dissolution. Blending is performed in a controlled environment
minimizing moisture exposure.
Encapsulation:
[0187] The lubricated blend was transferred to an automatic
encapsulation machine and encapsulated into a size 1 capsule.
Improper encapsulation equipment setup can impact filled capsule
shell appearance. Capsule fill weight can impact content and dose
uniformity. Capsule fill plug compression could impact dissolution
and fill weight/content uniformity.
[0188] Encapsulation is performed in a controlled environment
minimizing moisture exposure.
[0189] Dedusting and metal detection of the encapsulated product
was performed, and the product was weight-checked.
Example 2
Preparation of 80 mg Valbenazine Capsule with Prior Art
Formulation
[0190] An 80 mg dose formulation strategy attempted to use the
known 40 mg capsule direct encapsulation formulation. Efforts were
made to fill a Size 0 capsule with twice the amount of the 40 mg
powder blend to yield an 80 mg strength capsule, as shown in Table
3.
TABLE-US-00003 TABLE 3 Quantity 80 mg capsule (mg/ % Component
capsule) (w/w) Function Valbenazine ditosylate 146.0 28.21 Active
Mannitol 320.0 61.82 Diluent Partially pregelatinized 40.0 7.73
Disintegrant maize starch Fumed silica 6.4 1.24 Glidant Magnesium
stearate 2.4 1.00 Lubricant Total Capsule Fill Weight 517.6 100.00
-- Hard gelatin capsule - Size #0 1 -- Shell
[0191] Valbenazine ditosylate, mannitol (USP), partially
pregelatinized maize starch (USNF), fumed silica (USNF) and
magnesium stearate (USNF) were weighed according to the amounts in
Table 3. A portion of the mannitol (1/4) was transferred through a
screening mill equipped with a .about.0.8 mm or equivalent
round-hole screen to a tote bin for blending. The screened mannitol
component was then blended.
Pre-Blending and Screening:
[0192] The following components were transferred into the tote bin
through a screening mill equipped with a .about.0.8 mm or
equivalent round-hole screen: [0193] a. Valbenazine ditosylate
[0194] b. Fumed silica [0195] c. Partially pregelatinized maize
starch [0196] d. Remaining mannitol (3/4)--(the adjustment of
mannitol weight to compensate DS assay is performed on this
fraction) The components were blended and then transferred into
polyethylene (PE) bags. The pre-blend was transferred through a
screening mill equipped with an .about.0.8 mm or equivalent
round-hole screen to a tote bin for blending.
Final Lubricant Blending:
[0197] Magnesium stearate (quantity to be adjusted as needed based
on pre-lubricated blend yield--limit 98%) was manually screened
(.about.1 mm sieve) into the opened tote bin for blending. The
components were then blended.
Encapsulation:
[0198] Efforts to fill a Size 0 capsule were unsuccessful. It was
not possible to compress enough powder into a compact that would
fit into a Size 0 capsule shell.
[0199] The various embodiments described above can be combined to
provide further embodiments. This application also claims the
benefit of U.S. Provisional Patent Application No. 62/561,629,
filed Sep. 21, 2017 and U.S. Provisional Patent Application No.
62/564,951, filed Sep. 28, 2017, and are incorporated herein by
reference in their entirety. All of the U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet are incorporated herein by reference, in their entirety.
Aspects of the embodiments can be modified, if necessary to employ
concepts of the various patents, applications and publications to
provide yet further embodiments.
[0200] These and other changes can be made to the embodiments in
light of the above-detailed description. In general, in the
following claims, the terms used should not be construed to limit
the claims to the specific embodiments disclosed in the
specification and the claims, but should be construed to include
all possible embodiments along with the full scope of equivalents
to which such claims are entitled. Accordingly, the claims are not
limited by the disclosure.
* * * * *
References