U.S. patent application number 16/664984 was filed with the patent office on 2020-09-17 for carbostyril derivatives and serotonin reuptake inhibitors for treatment of mood disorders.
The applicant listed for this patent is Otsuka Pharmaceutical Co., Ltd.. Invention is credited to Tsuyoshi Hirose, Taro Iwamoto, Tetsuro Kikuchi.
Application Number | 20200289501 16/664984 |
Document ID | / |
Family ID | 1000004858689 |
Filed Date | 2020-09-17 |
United States Patent
Application |
20200289501 |
Kind Code |
A1 |
Kikuchi; Tetsuro ; et
al. |
September 17, 2020 |
CARBOSTYRIL DERIVATIVES AND SEROTONIN REUPTAKE INHIBITORS FOR
TREATMENT OF MOOD DISORDERS
Abstract
The pharmaceutical composition of the present invention
comprises (1) a carbostyril derivative and (2) a serotonin reuptake
inhibitor in a pharmaceutically acceptable carrier. The carbostyril
derivative may be aripiprazole or a metabolite thereof, which is a
dopamine-serotonin system stabilizer. The serotonin reuptake
inhibitor may be fluoxetine, duloxetine, venlafaxine, milnacipran,
citalopram, fluvoxamine, paroxetine, sertraline or escitalopram.
The pharmaceutical composition of the present invention is useful
for treating patients with mood disorders, particularly depression
or major depressive disorder.
Inventors: |
Kikuchi; Tetsuro;
(Tokushima, JP) ; Iwamoto; Taro; (Princeton,
NJ) ; Hirose; Tsuyoshi; (Tokushima-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Otsuka Pharmaceutical Co., Ltd. |
Tokyo |
|
JP |
|
|
Family ID: |
1000004858689 |
Appl. No.: |
16/664984 |
Filed: |
October 28, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16242315 |
Jan 8, 2019 |
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16664984 |
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15604720 |
May 25, 2017 |
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16242315 |
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15176464 |
Jun 8, 2016 |
9694009 |
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15604720 |
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14252907 |
Apr 15, 2014 |
9387182 |
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15176464 |
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10540577 |
Dec 16, 2005 |
8759350 |
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PCT/JP2003/016724 |
Dec 25, 2003 |
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14252907 |
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60470481 |
May 14, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/381 20130101;
A61P 25/24 20180101; A61K 31/135 20130101; A61K 31/138 20130101;
A61K 31/496 20130101; A61K 31/165 20130101; A61K 31/137 20130101;
A61P 25/28 20180101; A61K 31/4525 20130101; A61K 31/343 20130101;
A61K 31/15 20130101; A61P 25/18 20180101 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/135 20060101 A61K031/135; A61K 31/15 20060101
A61K031/15; A61K 31/165 20060101 A61K031/165; A61K 31/343 20060101
A61K031/343; A61K 31/381 20060101 A61K031/381; A61K 31/4525
20060101 A61K031/4525; A61K 31/137 20060101 A61K031/137; A61K
31/138 20060101 A61K031/138; A61P 25/28 20060101 A61P025/28; A61P
25/18 20060101 A61P025/18; A61P 25/24 20060101 A61P025/24 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 27, 2002 |
JP |
2002-379003 |
Claims
1-36. (canceled)
37. A pharmaceutical composition comprising (a) a compound selected
from aripiprazole or a metabolite of aripiprazole wherein the
metabolite of aripiprazole is selected from the group consisting of
dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 and DCPP in
combination with (b) at least one serotonin reuptake inhibitor
selected from the group consisting of fluoxetine, duloxetine,
venlafaxine, milnacipran, citalopram, fluvoxamine, paroxetine,
sertraline, escitalopram and salts thereof.
38. The composition of claim 37, wherein compound (a) is
aripiprazole.
39. The composition of claim 37, wherein compound (a) is a
metabolite of aripiprazole selected from the group consisting of
dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 and
DCPP.
40. The composition of claim 37, wherein the at least one serotonin
reuptake inhibitor is citalopram.
41. The composition of claim 37, wherein the at least one serotonin
reuptake inhibitor is escitalopram.
42. The composition of claim 37, further comprising at least one
pharmaceutically acceptable carrier.
43. The composition of claim 37, wherein the composition is useful
for treatment of mood disorders.
44. The composition of claim 43, wherein the mood disorder is
depression or major depressive disorder.
45. The composition of claim 43, wherein the mood disorder is major
depressive disorder, all mood disorders, schizoaffective disorder
or dementia with depressive symptoms.
46. The composition of claim 37, wherein the composition is useful
for treatment of major depressive disorder, endogenous depression,
melancholia, depression in combination with psychotic episodes,
bipolar disorder with depressive phase, refractory depression,
dementia of the Alzheimer s type with depressive symptoms,
Parkinson's disease with depressive symptoms, senile dementia, mood
disorder associated with blood vessels and mood disorder following
head injury.
47. A method of treating a disorder in a patient selected from the
group consisting of major depressive disorder, endogenous
depression, melancholia, depression in combination with psychotic
episodes, bipolar disorder with depressive phase, refractory
depression, dementia of the Alzheimer s type with depressive
symptoms, Parkinson's disease with depressive symptoms, senile
dementia, mood disorder associated with blood vessels and mood
disorder following head injury, comprising administration of an
effective amount of a pharmaceutical composition which comprises
(a) a compound selected from aripiprazole or a metabolite of
aripiprazole wherein the metabolite of aripiprazole is selected
from the group consisting of dehydroaripiprazole, DM-1458, DM-1451,
DM-1452, DM-1454 and DCPP in combination with (b) at least one
serotonin reuptake inhibitor selected from the group consisting of
fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram,
fluvoxamine, paroxetine, sertraline, escitalopram and salts
thereof.
48. The method of claim 47, wherein compound (a) is
aripiprazole.
49. The method of claim 47, wherein compound (a) is a metabolite of
aripiprazole selected from the group consisting of
dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 and
DCPP
50. The method of claim 47, wherein the at least one serotonin
reuptake inhibitor is citalopram.
51. The method of claim 47, wherein the pharmaceutical composition
further comprises at least one pharmaceutically acceptable
carrier.
52. The method of claim 47, wherein the disorder is depression or
major depressive disorder.
Description
TECHNICAL FIELD
[0001] The present invention provides pharmaceutical compositions
comprising carbostyril derivatives that act as dopamine-serotonin
system stabilizers in combination with serotonin reuptake
inhibitors in a pharmaceutically acceptable carrier. Further, the
present invention provides methods of using the compositions of the
present invention to treat mood disorders such as depression and
major depressive disorder.
BACKGROUND ART
[0002] The number of people with mood disorders such as major
depressive disorder, and exhibiting various symptoms of depressions
is increasing every year for numerous reasons such as social
stress, unemployment, disease, and poverty. Depression is a major
social problem throughout the world. For example, in Japan the
occurrence rate of depression in the generation older than 65 years
is 5% or more, including major depressive disorder. Some of the
depression in this population is associated with mental
disturbances representing senile diseases associated with dementia
and neurosis. Many depressed patients show high recurrence rate,
and severe depressive symptoms are major causes of suicide and drug
abuse (Nishimura Ken, "NIPPON RONEN IGAKUZASSHI", Vol. 33, pp
503-504 (1996)).
[0003] Since the period of 1950, tricyclic antidepressant drugs
(e.g., imipramine, desipramine, amitriptyline, etc.) have been
developed that act to inhibit monoamine reuptake. They are
frequently used for treating patients suffering from mood
disorders, such as depression and major depressive disorder.
However, these drugs have side-effects such as the following: dry
mouth, hazy eyes, dysuria, constipation, recognition disturbance
and the like due to anticholinergic activity; cardiovascular
side-effects such as, orthostatic hypotension, tachycardia and the
like on the basis of .alpha..sub.1-adrenoreceptor antagonist
activity; side-effects such as, sedation, increase in the body
weight and the like on the basis of histamine-H.sub.1 receptor
antagonist activity.
[0004] Since 1980, serotonin reuptake inhibitors have been
developed, including but not limited to fluoxetine, duloxetine,
venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine,
paroxetine and sertraline, and these inhibitors have side-effects
such as recognition disturbance, sleep disturbance, and excerbation
of anxiety and agitation. Additionally, these inhibitors also have
other side effects in the digestive organs, such as nausea,
vomiting and the like.
[0005] For the reason that the mood disorders such as depressive
symptoms, depression and the like are diseases with severely strong
psychalgalia, the manifestation of new symptoms on the basis of
these side-effects are quite serious problems in the therapy of
mood disorders (Shioe Kunihiko, Kariya Tetsuhiko, "SHINKEI SEISHIN
YAKURI", Vol. 11, pp 37-48 (1989); Yamada Mitsuhiko, Ueshima
Kunitoshi, "RINSHOU SEISHIN YAKURI", Vol. 1, pp 355-363
(1998)).
[0006] Although the mood disorders including depression and major
depressive disorder are heterogeneous diseases, and the causes of
these diseases are not been fully understood, it is likely that the
abnormalities of monoaminergic central nervous system caused by
serotonin, norepinephrine and dopamine and the like, and the
abnormality of various hormones and peptides as well as various
stressors are causes of depression and various mood disorders
(Kubota Masaharu et al., "RINSHOU SEISHIN IGAKU", Vol. 29, pp
891-899 (2000)). For these reasons, even though antidepressant
drugs, such as tricyclic antidepressants and serotonin reuptake
inhibitors were used, these drugs are not always effective in
treating all depressed patients. About 30% of the depressed
patients do not respond to the primarily selected antidepressants
(Nelson, J. C, et al., J. Clin. Psychiatry, 55, pp 12-19 (1994)).
Further, when a second or third antidepressant is administered to
these patients, insufficient improvements of the symptoms occurs in
about 10% of these patients (Inoeu Takeshi, Koyama Tsukasa,
"RINSHOU SEISHIN IGAKU", Vol. 38, pp 868-870 (1996)). These
patients are called as refractory depression patients.
[0007] In some cases, electric shock therapy is used to treat
refractory depression, and the efficacy of this treatment has been
reported. However, in fact, the condition of numerous patients is
not improved (Inoue Takeshi, Koyama Tsukasa, "RINSHOU SEISHIN
YAKURI", Vol. 2, pp 979-984 (1999)). Additionally, psychological
anguish experienced by these patients and their families concerning
the use of the electric shock therapy can be severe.
[0008] New therapeutic trials involve proposed combined therapies
using an atypical antipsychotic drug, such as olanzapine, which is
an agent for treating for schizophrenia (antipsychotic drug),
together with an antidepressant drug such as serotonin reuptake
inhibitor (EP 0 367 141, WO 98/11897, WO99/61027, WO99/62522, U.S.
2002/0123490A1 and the like). However, commercially available
atypical antipsychotic drugs have significant problems relating to
their safety. For example, clozapine, olanzapine and quetiapine
increase body weight and enhance the risk of diabetes mellitus
(Newcomer, J. W. (Supervised Translated by Aoba Anri), "RINSHOU
SEISHIN YAKURI", Vol. 5, pp 911-925 (2002); Haupt, D. W. and
Newcomer, J. W (Translated by Fuji Yasuo and Misawa Fuminari),
"RINSHOU SEISHIN YAKURI", Vol. 5, pp 1063-1082 (2002)). In fact,
urgent safety alerts have been issued in Japan relating to
hyperglycemia, diabetic ketoacidosis and diabetic coma caused by
olanzapine and quetiapine, indicating that these drugs were
subjected to dosage contraindication to the patients with diabetes
mellitus and patients having anamnesis of diabetes mellitus.
Risperidone causes increases serum prolactin levels and produces
extrapyramidal side effects at high dosages. Ziprasidone enhances
the risk of severe arrhythmia on the basis of cardio-QTc
prolongation action. Further, clozapine induces agranulocytosis, so
that clinical use thereof is strictly restricted (van Kammen, D. P.
(Compiled under Supervision by Murasaki Mitsuroh), "RINSHOU SEISHIN
YAKURI", Vol. 4, pp 483-492 (2001)).
[0009] Accordingly what is needed are new compositions useful for
treating mood disorders, particularly, depression and major
depressive disorder, which are efficacious and do not cause the
deleterious side effects associated with prior art compounds.
DISCLOSURE OF THE INVENTION
[0010] The present invention solves the problem described above by
providing novel compositions and methods of using these
compositions for treating mood disorders, particularly depression
and major depressive disorder.
[0011] The present invention provides solutions to the
above-mentioned problems, and demonstrates that the mood disorders
such as depression, major depressive and the like can be treated
effectively by administering to a patient with such disorder a
pharmaceutical composition comprising at least one carbostyril
derivative that is a dopamine-serotonin system stabilizer in
combination with at least one serotonin reuptake inhibitor in a
pharmaceutically acceptable carrier.
[0012] A preferred carbostyril derivative of the present invention
that is a dopamine-serotonin system stabilizer is aripiprazole or a
metabolite thereof. Another preferred carbostyril derivative of the
present invention that is a dopamine-serotonin system stabilizer is
a metabolite of aripiprazole called dehydroaripiprazole, also known
as OPC-14857. Other such metabolites of aripiprazole included
within the present invention are shown in FIG. 8. Preferred
metabolites are shown in FIG. 8 indicated by the following
designations: OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 and
DCPP.
[0013] Aripiprazole, also called
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quin-
olinone, is a carbostyril compound and is useful for treating
schizophrenia (EP 0 367 141, U.S. Pat. No. 5,006,528). Aripiprazole
is also known as
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril-
, Abilify, OPC-14597, OPC-31 and BMS-337039. Aripiprazole possesses
5-HT1A receptor agonist activity, and is known as useful compound
for treating types of depression and refractory depressions, such
as endogeneous depression, major depression, melancholia and the
like (WO 02/060423, U. S. Patent Application 2002/0173513A1).
Aripiprazole has activity as an agonist at the serotonin receptors
and dopamine receptors, and acts as an agonist or partial agonist
at the serotonin 5-HT1A receptor and as an agonist or partial
agonist at the dopamine D.sub.2 receptor. Aripiprazole is a
dopamine-serotonin system stabilizer. Metabolites of aripiprazole
are included within the scope of the present invention. One such
metabolite of aripiprazole is called dehydroaripiprazole. Other
such metabolites of aripiprazole included within the present
invention are shown in FIG. 8. Preferred metabolites are shown in
FIG. 8 indicated by the following designations: OPC-14857, DM-1458,
DM-1451, DM-1452, DM-1454 and DCPP.
[0014] The at least one serotonin reuptake inhibitor used in the
present invention includes but is not limited to the following:
fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram,
fluvoxamine, paroxetine, sertraline, escitalopram and salts
thereof. In a preferred embodiment, the pharmaceutical composition
comprises aripiprazole and citalopram in a pharmaceutically
acceptable carrier.
[0015] The novel compositions of present invention comprising at
least one carbostyril derivative with activity as a
dopamine-serotonin system stabilizer and at least one serotonin
reuptake inhibitor in a pharmaceutically acceptable carrier may be
combined in one dosage form, for example a pill. Alternatively the
at least one carbostyril derivative with activity as a
dopamine-serotonin system stabilizer and the at least one serotonin
reuptake inhibitor may be in separate dosage forms, each in a
pharmaceutically acceptable carrier. These compositions are
administered to a patient with a mood disorder, particularly
depression or major depressive disorder, in an amount and dosage
regimen effective to treat the mood disorder.
[0016] Accordingly, it is an object of the present invention to
provide a pharmaceutical composition useful for treating a mood
disorder.
[0017] It is an object of the present invention to provide a
composition useful for treating a mood disorder, wherein the mood
disorder is depression or major depressive disorder.
[0018] It is another object of the present invention to provide a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier.
[0019] Yet another object of the present invention is to provide a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier, wherein the carbostyril derivative is aripiprazole or a
metabolite thereof.
[0020] Yet another object of the present invention is to provide a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier, wherein the carbostyril derivative is aripiprazole and the
serotonin reuptake inhibitor is citalopram.
[0021] Yet another object of the present invention is to provide a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor, wherein the carbostyril derivative
with activity as a dopamine-serotonin system stabilizer is a
metabolite of aripiprazole and is dehydroaripiprazole (OPC-14857),
DM-1458, DM-1451, DM-1452, DM-1454 or DCPP.
[0022] Yet another object of the present invention is to provide a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor, wherein the carbostyril derivative is
dehydroaripiprazole.
[0023] It is an object of the present invention to provide a use of
a composition useful for treating a mood disorder in the
preparation of a medicament for treatment of a mood disorder,
wherein the mood disorder is depression or major depressive
disorder.
[0024] It is another object of the present invention to provide a
use of a composition comprising at least one carbostyril derivative
with activity as a dopamine-serotonin system stabilizer and at
least one serotonin reuptake inhibitor in a pharmaceutically
acceptable carrier in the preparation of a medicament for treatment
of a mood disorder.
[0025] Yet another object of the present invention is to provide a
use of a composition comprising a carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier in the preparation of a medicament for treatment of mood
disorders, wherein the carbostyril derivative is aripiprazole or a
metabolite thereof.
[0026] Yet another object of the present invention is to provide a
use of a composition comprising a carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier in the preparation of a medicament for treatment of mood
disorders, wherein at least one carbostyril derivative is
aripiprazole and at least one serotonin reuptake inhibitor is
citalopram.
[0027] Yet another object of the present invention is to provide a
use of a composition comprising at least one carbostyril derivative
with activity as a dopamine-serotonin system stabilizer and at
least one serotonin reuptake inhibitor pharmaceutically acceptable
carrier in the preparation of a medicament for treatment of mood
disorders, wherein the carbostyril derivative with activity as a
dopamine-serotonin system stabilizer is a metabolite of
aripiprazole and is dehydroaripiprazole (OPC-14857), DM-1458,
DM-1451, DM-1452, DM-1454 or DCPP.
[0028] Yet another object of the present invention is to provide a
use of a composition comprising a carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier in the preparation of a medicament for treatment of mood
disorders, wherein the carbostyril derivative is
dehydroaripiprazole.
[0029] It is an object of the present invention to provide a method
for treating a mood disorder.
[0030] It is an object of the present invention to provide a method
for treating a mood disorder wherein the mood disorder is
depression or major depressive disorder.
[0031] It is another object of the present invention to provide a
method for treating a mood disorder comprising administration to a
patient with a mood disorder of a composition comprising at least
one carbostyril derivative with activity as a dopamine-serotonin
system stabilizer and at least one serotonin reuptake inhibitor in
a pharmaceutically acceptable carrier.
[0032] It is another object of the present invention to provide a
method for treating a mood disorder comprising administration to a
patient with a mood disorder of a composition comprising at least
one carbostyril derivative with activity as a dopamine-serotonin
system stabilizer and at least one serotonin reuptake inhibitor
together in a pharmaceutically acceptable carrier, wherein the
carbostyril derivative is aripiprazole or a metabolite thereof.
[0033] It is another object of the present invention to provide a
method for treating major depressive disorder comprising
administration to a patient with major depressive disorder of a
composition comprising a carbostyril derivative with activity as a
dopamine-serotonin system stabilizer and at least one serotonin
reuptake inhibitor together with a pharmaceutically acceptable
carrier, wherein the carbostyril derivative is aripiprazole and the
serotonin reuptake inhibitor is citalopram.
[0034] Still another object of the present invention is to provide
a method for treating a mood disorder comprising administration to
a patient with a mood disorder of a composition comprising at least
one carbostyril derivative with activity as a dopamine-serotonin
system stabilizer and at least one serotonin reuptake inhibitor in
a pharmaceutically acceptable carrier, wherein the carbostyril
derivative is a metabolite of aripiprazole and is
dehydroaripiprazole (OPC-14857), DM-1458, DM-1451, DM-1452, DM-1454
or DCPP.
[0035] Yet another object of the present invention is to provide a
method for treating major depressive disorder comprising
administration to a patient with major depressive disorder of a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier, wherein the mood disorder is major depressive
disorder.
[0036] It is another object of the present invention to provide a
method for treating major depressive disorder comprising
administration to a patient with major depressive disorder of a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier.
[0037] It is another object of the present invention to provide a
method for treating major depressive disorder comprising
administration to a patient with major depressive disorder of a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor together with a pharmaceutically
acceptable carrier, wherein the carbostyril derivative is
aripiprazole or a metabolite thereof.
[0038] Still another object of the present invention is to provide
a method for treating major depressive disorder comprising
administration to a patient with major depressive disorder of a
composition comprising at least one carbostyril derivative with
activity as a dopamine-serotonin system stabilizer and at least one
serotonin reuptake inhibitor in a pharmaceutically acceptable
carrier, wherein the carbostyril derivative is a metabolite of
aripiprazole and is dehydroaripiprazole (OPC-14857), DM-1458,
DM-1451, DM-1452, DM-1454 or DCPP.
[0039] These and other objects, advantages, and uses of the present
invention will reveal themselves to one of ordinary skill in the
art after reading the detailed description of the preferred
embodiments and the attached claims.
BRIEF DESCRIPTION OF DRAWINGS
[0040] FIG. 1 is the thermogravimetric/differential thermogram of
the aripiprazole hydrate A obtained in Reference Example 4.
[0041] FIG. 2 is the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the aripiprazole hydrate A obtained in Reference Example 4.
[0042] FIG. 3 is the powder X-ray diffraction diagram of the
aripiprazole hydrate A obtained in Reference Example 4.
[0043] FIG. 4 is the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the Anhydrous Aripiprazole Crystals B obtained in Example 1.
[0044] FIG. 5 is the powder X-ray diffraction diagram of the
Anhydrous Aripiprazole Crystals B obtained in Example 1.
[0045] FIG. 6 is the thermogravimetric/differential thermogram of
the aripiprazole hydrate A obtained in Reference Example 3.
[0046] FIG. 7 is the powder X-ray diffraction diagram of
aripiprazole hydrate obtained in Reference Example 3.
[0047] FIG. 8 is a schematic representation of the chemical
structures of aripiprazole and metabolites thereof. Some of the
metabolites may be formed through other possible pathways; for
example, DM-1431 could be formed by N-dealkylation of DM-1451 and
DM-1459.
DETAILED DESCRIPTION OF THE INVENTION
[0048] The pharmaceutical composition of the present invention
comprises a first ingredient comprising a carbostyril derivative
active as a dopamine-serotonin system stabilizer and a second
ingredient comprising a serotonin reuptake inhibitor, in a
pharmaceutically acceptable carrier. The pharmaceutical
compositions of the present invention are useful in treating mood
disorders, including depression and major depressive disorder.
The Pharmaceutical Composition: The First Ingredient
[0049] The first ingredient comprises a carbostyril derivative
active as a dopamine-serotonin system stabilizer. Such carbostyril
derivative has activity as an agonist or partial agonist at some
serotonin receptors and some dopamine receptors, preferably as an
agonist or partial agonist at the serotonin 5-HT1A receptor and as
an agonist or partial agonist at the dopamine D.sub.2 receptor.
Carbostyril derivatives are described in U.S. Pat. No. 5,006,528
and U.S. published patent application 2002/0173513A1. In one
embodiment of the present invention, the carbostyril derivatives
represented by the following formula (1) are used:
##STR00001##
wherein the carbon-carbon bond between 3- and 4-positions in the
carbostyril skeleton is a single or a double bond.
[0050] In a preferred embodiment, this activity of the carbostyril
derivative is as an agonist or partial agonist at the 5-HT1A
receptor and an agonist or partial agonist at the dopamine D.sub.2
receptor subtype. In another preferred embodiment, the carbostyril
derivative to be used as a first component in the present invention
is aripiprazole, or a metabolic derivative thereof. Metabolic
derivatives of aripiprazole include but are not limited to
dehydroaripiprazole, also called OPC-14857. Other metabolic
derivatives of aripiprazole include but are not limited to the
chemical structures shown in FIG. 8 as OPC-14857, DM-1458, DM-1451,
DM-1452, DM-1454 and DCPP. All of the aforementioned carbostyril
derivatives may be used as a first component in the practice of the
present invention.
[0051] Aripiprazole, also called
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quin-
olinone, is a carbostyril compound useful as the effective
ingredient for treating schizophrenia (JP-A-2-191256, U.S. Pat. No.
5,006,528). Aripiprazole is also known as
7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril-
, Abilify, OPC-14597, OPC-31 and BMS-337039. Aripiprazole possesses
5-HT1A receptor agonist activity, and is known as a useful compound
for treating types of depression and refractory depression, such as
endogenous depression, major depression, melancholia and the like
(WO 02/060423A2; Jordan et al. U.S. Patent Application
2002/0173513A1). Aripiprazole has activity as an agonist at
serotonin receptors and dopamine receptors, and acts as an agonist
or partial agonist at the serotonin 5-HT1A receptor and as an
agonist or partial agonist at the dopamine D.sub.2 receptor.
Aripiprazole is an antipsychotic drug having new mechanism of
action which is different from that of other atypical antipsychotic
drugs (Grunder, G. et al., Arch Gen Psychiatry, 60(10), pp 974-977,
2003). The available typical and atypical antipsychotic drugs act
as antagonists at the dopamine-D.sub.2 receptors. In contrast,
aripiprazole acts as a partial agonist at the dopamine D.sub.2
receptor (By Ishigooka Jyunya and Inada Ken, RINSHO SEISHIN YAKURI,
Vol. 4, pp 1653-1664 (2001); Burris, K. D. et al., J. Pharmacol.
Exp. Ther., 302, pp 381-389 (2002)). In addition to the partial
agonist action at dopamine-D.sub.2 receptors, aripiprazole has
activity as a partial agonist at the serotonin 5-HT1A receptors, as
well as antagonist action at serotonin 5-HT2A receptors.
Accordingly, aripiprazole is a drug belonging to new category
defined as a dopamine-serotonin system stabilizer
(dopamine-serotonin stabilizer (Burris, K. D. et al., J. Pharmacol,
Exp. Ther., 302, pp 381-389, 2002; Jordan, S. et al., Eur. J.
Pharmacol. 441, pp 137-140, 2002; Grunder, G. et al., Arch Gen
Psychiatry, 60(10), pp 974-977, 2003).
Methods of Preparing Aripiprazole
[0052] Aripiprazole and aripiprazole metabolites to be used in the
present invention may be any of form, for example, free bases,
polymorphisms of every type of crystal, hydrate, salts (acid
addition salts, etc.) and the like. Among of these forms, Anhydrous
Aripiprazole Crystals B is a preferred form.
[0053] As to method for preparing the Anhydrous Aripiprazole
Crystals B, for example it is prepared by heating aripiprazole
hydrate A as follows.
Aripiprazole Hydrate A
[0054] The aripiprazole hydrate A having the physicochemical
properties shown in (1)-(5) as follows:
[0055] (1) It has an endothermic curve which is substantially
identical to the thermogravimetric/differential thermal analysis
(heating rate 5.degree. C./min) endothermic curve shown in FIG. 1.
Specifically, it is characterized by the appearance of a small peak
at about 71.degree. C. and a gradual endothermic peak around
60.degree. C. to 120.degree. C.
[0056] (2) It has an .sup.1H-NMR spectrum which is substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 2. Specifically, it has characteristic peaks at 1.55-1.63 ppm
(m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56
ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6
Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),
6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),
7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s,
1H).
[0057] (3) It has a powder x-ray diffraction spectrum which is
substantially identical to the powder x-ray diffraction spectrum
shown in FIG. 3. Specifically, it has characteristic peaks at
2.theta.=12.6.degree., 15.4.degree., 17.3.degree., 18.0.degree.,
18.6.degree., 22.5.degree. and 24.8.degree..
[0058] (4) It has clear infrared absorption bands at 2951, 2822,
1692, 1577, 1447, 1378, 1187, 963 and 784 cm' on the IR (KBr)
spectrum.
[0059] (5) It has a mean particle size of 50 .mu.m or less.
Method for Preparing Aripiprazole Hydrate A
[0060] Aripiprazole hydrate A is prepared by milling conventional
aripiprazole hydrate. Conventional milling methods can be used to
mill conventional aripiprazole hydrate. For example, conventional
aripiprazole hydrate can be milled in a milling machine. A widely
used milling machine such as an atomizer, pin mill, jet mill or
ball mill can be used. Among of these, the atomizer is preferably
used.
[0061] Regarding the specific milling conditions when using an
atomizer, a rotational speed of 5000-15000 rpm could be used for
the main axis, for example, with a feed rotation of 10-30 rpm and a
screen hole size of 1-5 mm.
[0062] The mean particle size of the aripiprazole hydrate A
obtained by milling may be normally 50 .mu.m or less, preferably 30
.mu.m or less. Mean particle size can be ascertained by the
particle size measuring method described hereinafter.
Anhydrous Aripiprazole Crystals B
[0063] "Anhydrous Aripiprazole Crystals B" of the present invention
have the physicochemical properties given in (6)-(10) below.
[0064] (6) They have an .sup.1H-NMR spectrum which is substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 4. Specifically, they have characteristic peaks at 1.55-1.63
ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),
2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm
(brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4
Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1
Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm
(s, 1H).
[0065] (7) They have a powder x-ray diffraction spectrum which is
substantially identical to the powder x-ray diffraction spectrum
shown in FIG. 5. Specifically, they have characteristic peaks at
2.theta.=11.0.degree., 16.6.degree., 19.3.degree., 20.3.degree. and
22.1.degree..
[0066] (8) They have clear infrared absorption bands at 2945, 2812,
1678, 1627, 1448, 1377, 1173, 960 and 779 cm.sup.-1 on the IR (KBr)
spectrum.
[0067] (9) They exhibit an endothermic peak near about
141.5.degree. C. in thermogravimetric/differential thermal analysis
(heating rate 5.degree. C./min).
[0068] (10) They exhibit an endothermic peak near about
140.7.degree. C. in differential scanning calorimetry (heating rate
5.degree. C./min).
[0069] When the small particle size is required for solid
preparation, such as tablets and other solid dose formulations
including for example flash melt formulations, the mean particle
size is preferably 50 .mu.m or less.
Method for Preparing Anhydrous Aripiprazole Crystals B
[0070] The Anhydrous Aripiprazole Crystals B of the present
invention are prepared for example by heating the aforementioned
aripiprazole hydrate A at 90-125.degree. C. The heating time is
generally about 3-50 hours, but cannot be stated unconditionally,
because it differs depending on heating temperature. The heating
time and heating temperature are inversely related, so that for
example when the heating time is longer, then the heating
temperature is lower, and when the heating temperature is higher
then the heating time is shorter. Specifically, if the heating
temperature of aripiprazole hydrate A is 100.degree. C., the
heating time may be 18 hours or more, or preferably about 24 hours.
If the heating temperature of aripiprazole hydrate A is 120.degree.
C., on the other hand, the heating time may be about 3 hours. The
Anhydrous Aripiprazole Crystals B of the present invention can be
prepared with certainty by heating aripiprazole hydrate A for about
18 hours at 100.degree. C., and then heating it for about 3 hours
at 120.degree. C. The Anhydrous Aripiprazole Crystals B of the
present invention can also be obtained if the heating time is
extended still further, but this method may not be economical.
[0071] When small particle size is not required for the
formulation, e.g., when drug substance is being prepared for
injectable or oral solution formulations, Anhydrous Aripiprazole
Crystals B can be also obtained by the following process.
[0072] Anhydrous Aripiprazole Crystals B of the present invention
are prepared for example by heating conventional anhydrous
aripiprazole crystals at 90-125.degree. C. The heating time is
generally about 3-50 hours, but cannot be stated unconditionally
because it differs depending on heating temperature. The heating
time and heating temperature are inversely related, so that for
example if the heating time is longer, the heating temperature is
lower, and if the heating time is shorter, the heating temperature
is higher. Specifically, if the heating temperature of the
anhydrous aripiprazole crystals is 100.degree. C., the heating time
may be about 4 hours, and if the heating temperature is 120.degree.
C. the heating time may be about 3 hours.
[0073] Furthermore, Anhydrous Aripiprazole Crystals B of the
present invention are prepared for example, by heating conventional
aripiprazole hydrate at 90-125.degree. C. The heating time is
generally about 3-50 hours, but cannot be stated unconditionally
because it differs depending on heating temperature. The heating
time and heating temperature are inversely related, so that for
example, if the heating time is longer, the heating temperature is
lower, and if the heating time is shorter, the heating temperature
is higher. Specifically, if the heating temperature of the
aripiprazole hydrate is 100.degree. C., the heating time may be
about 24 hours, and if the heating temperature is 120.degree. C.
the heating time may be about 3 hours.
[0074] The anhydrous aripiprazole crystals which are the raw
material for preparing the Anhydrous Aripiprazole Crystals B of the
present invention are prepared for example by Method a or b
below.
"Method a": Process for Preparing Crude Crystals of
Aripiprazole
[0075] Conventional anhydrous aripiprazole crystals are prepared by
well-known methods, as described in Example 1 of Japanese
Unexamined Patent Publication No. 191256/1990.
[0076] 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, is reacted with
1-(2,3-dichlorophenyl)piperazine and the thus obtained crude
aripiprazole crystals are recrystallized from ethanol.
"Method b": Process for Preparing Conventional Anhydrous
Aripiprazole
[0077] The Method b is described in the Proceedings of the 4th
Joint Japanese-Korean Symposium on Separation Technology (Oct. 6-8,
1996).
[0078] The aripiprazole hydrate which is the raw material for
preparing the Anhydrous Aripiprazole Crystals B of the present
invention is prepared for example by Method c below.
"Method c": Method for Preparing Conventional Aripiprazole
Hydrate
[0079] Aripiprazole hydrate is easily obtained by dissolving the
anhydrous aripiprazole crystals obtained by Method a above in a
hydrous solvent, and heating and then cooling the resulting
solution. Using this method, aripiprazole hydrate is precipitated
as crystals in the hydrous solvent.
[0080] An organic solvent containing water is usually used as the
hydrous solvent. The organic solvent may be preferable one which is
miscible with water, for example an alcohol such as methanol,
ethanol, propanol or isopropanol, a ketone such as acetone, an
ether such as tetrahydrofuran, dimethylformamide, or a mixture
thereof, ethanol is particularly desirable. The amount of water in
the hydrous solvent may be 10-25% by volume of the solvent, or
preferably close to 20% by volume.
[0081] Aripiprazole can easily form an acid addition salt with a
pharmaceutically acceptable acid. As to such acid, for example, an
inorganic acid, such as sulfuric acid, nitric acid, hydrochloric
acid, phosphoric acid, hydrobromic acid, etc.; an organic acid such
as, acetic acid, p-toluenesulfonic acid, methanesulfonic acid,
oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid,
citric acid, benzoic acid, succinic acid, etc. can be exemplified.
Similar to aripiprazole of free forms, these acid addition salts
can also be used as the active ingredient compounds in the present
invention.
[0082] The objective compound thus obtained through each one of
production steps, is separated from the reaction system by usual
separation means, and can be further purified. As to the separation
and purification means, for example, distillation method, solvent
extraction method, dilution method, recrystallization method,
column chromatography, ion-exchange chromatography, gel
chromatography, affinity chromatography, preparative thin-layer
chromatography and the like can be exemplified.
The Pharmaceutical Composition: The Second Ingredient
[0083] In the composition of the present invention, a serotonin
reuptake inhibitor is used as the second ingredient. Compounds
which function as serotonin reuptake inhibitors can be widely used
as the serotonin reuptake inhibitors and are known to one of
ordinary skill in the art.
[0084] Among the serotonin reuptake inhibitors, those having
IC.sub.50 value (a concentration of the drug that inhibits
serotonin reuptake by about 50%), measured by the method of Wong et
al. (Neuropsychopharmacology, 8, pp 337-344 (1993)), the standard
pharmacological assay method, is about 1000 nM or lower is
preferable.
[0085] As to such serotonin reuptake inhibitors, for example,
fluvoxamine
(5-methoxy-1-[4-(trifluoro-methyl)phenyl]-1-pentanone-O-(2-aminoethyl)oxi-
me), fluoxetine
(N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine),
paroxetine
(trans-(-)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-piperid-
ine), sertraline
(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylyla-
mine hydrochloride), venlafaxine, milnacipran
(N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxyamide),
citalopram, escitalopram, duloxetine and the like may be used.
[0086] The serotonin reuptake inhibitor may be either in the form
of a free base or a salt (an acid addition salt or the like).
Further, the serotonin reuptake inhibitor may be either a racemic
modifications or R and S enantiomers.
[0087] The serotonin reuptake inhibitors may be either a single use
of one serotonin reuptake inhibitor, and in case of need, two or
more of the serotonin reuptake inhibitors may be used in
combination. Use of one serotonin reuptake inhibitor is
preferred.
[0088] The serotonin reuptake inhibitor can easily form an acid
addition salt with a pharmaceutically acceptable acid. As to such
acid, for example, an inorganic acid, such as sulfuric acid, nitric
acid, hydrochloric acid, phosphoric acid, hydrobromic acid, etc.;
an organic acid such as, acetic acid, p-toluenesulfonic acid,
methanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic
acid, tartaric acid, citric acid, benzoic acid, succinic acid, etc.
can be exemplified. Similar to the reuptake inhibitor of free
forms, these acid addition salts can be also used as the active
ingredient compounds in the present invention.
[0089] Among the serotonin reuptake inhibitors, a compound having
acidic group can easily form salt by reacting with a
pharmaceutically acceptable basic compound. As to such basic
compound, a metal hydroxide, for example, sodium hydroxide,
potassium hydroxide, lithium hydroxide, calcium hydroxide and the
like; an alkali metal carbonate or bicarbonate, for example sodium
carbonate, potassium carbonate, sodium hydrogencabonate, potassium
hydrogencarbonate and the like; a metal alcoholate, for example
sodium methylate, potassium ethylate and the like can be
exemplified.
[0090] The thus obtained salt form of serotonin reuptake inhibitor
is separated from the reaction system by usual separation means,
and can be further purified. As to the separation and purification
means, for example, distillation method, solvent extraction method,
dilution method, recrystallization method, column chromatography,
ion-exchange chromatography, gel chromatography, affinity
chromatography, preparative thin-layer chromatography and the like
can be exemplified.
Combination of the First Ingredient with the Second Ingredient
[0091] As to combination of carbostyril derivatives with activity
as dopamine-serotonin system stabilizers, non-limiting examples of
aripiprazole and dehydroaripiprazole are described herein. When
aripiprazole is combined with at least one serotonin reuptake
inhibitor, the following are non-limiting examples of such
combinations: aripiprazole/fluoxetine, aripiprazole/duloxetine,
aripiprazole/venlafaxine, aripiprazole/milnacipran,
aripiprazole/citalopram, aripiprazole/fluvoxamine,
aripiprazole/paroxetine, and aripiprazole/sertraline. A preferred
embodiment comprises a combination of aripiprazole/citalopram.
[0092] In another embodiment of the present invention,
aripiprazole, or a metabolite thereof may be combined with more
than one serotonin reuptake inhibitor. Metabolites of aripiprazole
that may be used in the present invention include but are not
limited to OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 and DCPP
as shown in FIG. 8. Any one of these metabolites may be used in the
present invention. The following sentences describe a combination
of dehydroaripiprazole with specific serotonin reuptake inhibitors,
however it is to be understood that any one of DM-1458, DM-1451,
DM-1452, DM-1454 or DCPP, as shown in FIG. 8, could be substituted
for dehydroaripiprazole in these disclosed combinations.
Dehydroaripiprazole (also called OPC-14857 in FIG. 8) is a
preferred metabolite of aripiprazole. As to combination of
dehydroaripiprazole with serotonin reuptake inhibitor, the
following are non-limiting examples of such combinations:
dehydroaripiprazole/fluoxetine, dehydroaripiprazole/duloxetine,
dehydroaripiprazole/venlafaxine, dehydroaripiprazole/milnacipran,
dehydroaripiprazole/citalopram, dehydroaripiprazole/fluvoxamine,
dehydroaripiprazole/paroxetine, and dehydroaripiprazole/sertraline.
A preferred embodiment comprises a combination of
dehydroaripiprazole and citalopram.
Method of Treating a Mood Disorder, Especially Major Depressive
Disorder
[0093] Patients with mood disorders may be treated with the
compositions of the present invention. A preferred disorder treated
with the method and compositions of the present invention is
depression or major depressive disorder. Treatment comprises
administration of the compositions of the present invention to a
patient with a mood disorder such as depression or major depressive
disorder, in an amount and dose regimen effective to treat the mood
disorder.
Dosage
[0094] Dosage of the drug used in the present invention is decided
by considering the properties of each constituting drug to be
combined, the properties of drugs being after combination and
symptoms of the patient (existence of other diseases beside mood
disorders such as depression or major depressive disorder). General
outlines of the dosage can be applied the following guidelines.
[0095] Aripiprazole or a metabolite, such as dehydroaripiprazole,
DM-1458, DM-1451, DM-1452, DM-1454 or DCPP: generally about 0.1 to
100 mg/once a day (or about 0.05 to about 50 mg/twice a day),
preferably about 1 to 30 mg/once a day (or about 0.5 to about 15
mg/twice a day).
[0096] The aripiprazole, or a metabolite thereof, may be combined
with at least one of any of the following SRIs at the dosage ranges
indicated:
[0097] Fluoxetine: generally about 1 to about 80 mg/once a day,
preferably about 10 to about 40 mg/once a day;
[0098] Duloxetine: generally about 1 to 160 mg/once a day (or 80
mg/twice a day), preferably about 5 to about 20 mg/once a day;
[0099] Venlafaxine: generally about 10 to 150 mg/1 to 3 times a
day, preferably about 25 to 125 mg/3 times a day;
[0100] Milnacipran: generally about 10 to 100 mg/1 to 2 times a
day, preferably about 25 to about 50 mg/twice a day;
[0101] Citalopram: generally about 5 to about 50 mg/once a day,
preferably about 10 to about 30 mg/once a day;
[0102] Escitalopram: generally about 5 to about 30 mg/once a day,
preferably about 10 to about 20 mg/once a day;
[0103] Fluvoxamine: generally about 20 to 500 mg/once a day,
preferably about 50 to 300 mg/once a day;
[0104] Paroxetine: generally about 20 to about 50 mg/once a day,
preferably about 20 to about 30 mg/once a day; or
[0105] Sertraline: generally, about 20 to about 500 mg/once a day,
preferably about 50 to about 200 mg/once a day.
[0106] Generally, the weight ratio of the first ingredient to the
second ingredient is selected in accordance with the
above-mentioned guideline. As to the ratio of the first ingredient
and the second ingredient, if the first ingredient is about 1 part
by weight of the former, the second ingredient is used about 0.01
to about 500 parts by weight, preferably about 0.1 to about 100
parts by weight.
Pharmaceutically Acceptable Carriers
[0107] Pharmaceutically acceptable carriers include diluents and
excipients generally used in pharmaceutical preparations, such as
fillers, extenders, binders, moisturizers, disintegrators,
surfactant, and lubricants.
[0108] The pharmaceutical composition of the present invention may
be formulated as an ordinary pharmaceutical preparation, for
example in the form of tablets, flash melt tablets, pills, powder,
liquid, suspension, emulsion, granules, capsules, suppositories or
injection (liquid, suspension, etc.), troches, intranasal spray
percutaneous patch and the like.
[0109] In case of shaping to tablet formulation, a wide variety of
carriers that are known in this field can be used. Examples include
lactose, saccharose, sodium chloride, glucose, urea, starch,
xylitol, mannitol, erythritol, sorbitol, calcium carbonate, kaolin,
crystalline cellulose, silic acid and other excipients; water,
ethanol, propanol, simple syrup, glucose solution, starch solution,
gelatin solution, carboxymethyl cellulose, shellac, methyl
cellulose, potassium phosphate, polyvinyl pyrrolidone and other
binders; dried starch, sodium alginate, agar powder, laminaran
powder, sodium hydrogencarbonate, calcium carbonate,
polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,
stearic acid monoglyceride, starch, lactose and other
disintegrators; white sugar, stearin, cacao butter, hydrogenated
oil and other disintegration inhibitors; quaternary ammonium salt,
sodium lauryl sulfate and other absorption accelerator; glycerine,
starch and other moisture retainers; starch, lactose, kaolin,
bentonite, colloidal silic acid and other adsorbents; and refined
talc, stearate, boric acid powder, polyethylene glycol and other
lubricants and the like. Tablets can also be formulated if
necessary as tablets with ordinary coatings, such as sugar-coated
tablets, gelatin-coated tablets, enteric coated tablets and film
coated tablets, as well as double tablets and multilayered
tablets.
[0110] In case of shaping to pills, a wide variety of carriers that
are known in this field can be used. Examples include glucose,
lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc
and other excipients; gum arabic powder, traganth powder, gelatin,
ethanol and other binders; and laminaran, agar and other
disintegrators and the like.
[0111] In case of shaping to a suppository formulation, a wide
variety of carriers that are known in the field can be used.
Examples include polyethylene glycol, cacao butter, higher alcohol,
esters of higher alcohol, gelatin semi-synthetic glyceride and the
like.
[0112] Capsules are prepared according to ordinary methods by
mixing carbostyril derivatives such as anhydrous aripiprazole
crystals as the first ingredient and serotonin reuptake inhibitor
as the second ingredient, and the various carriers described above
and packing them in hard gelatin capsules, soft capsules
hydroxypropylmethyl cellulose capsules (HPMC capsules) and the
like.
[0113] In addition, colorants, preservatives, perfumes, flavorings,
sweeteners and the like as well as other drugs may be contained in
the pharmaceutical composition.
[0114] The amounts of the first ingredient and the second
ingredient to be contained in the pharmaceutical composition of the
present invention are suitably selected from a wide range depending
on the diseases to be treated. Generally, about 1 to 70 parts by
weight, preferably about 1 to 30 parts by weight of the first
ingredient and the second ingredient in the total amount on the
basis of the pharmaceutical composition.
[0115] The methods for administration of the pharmaceutical
composition of the present invention are not specifically
restricted. The composition is administered depending on each type
of preparation forms, and the age, gender and other condition of
the patient (degree and conditions of the disease, etc.). For
example, tablets, pills, liquids, suspensions, emulsions, granules
and capsules are administered orally. In case of injection
preparation, it is administered intravenously by either singly or
mixed with a common auxiliary liquid such as solutions of glucose
or amino acid. Further, if necessary, the injection preparation is
singly administered intracutaneously, subcutaneously or
intraperitoneally. In case of a suppository, it is administered
intrarectally.
[0116] Administration forms of the pharmaceutical composition of
the present invention may be any type by which the effective levels
of both carbostyril derivatives and serotonin reuptake inhibitors
can be provide in vivo at the same time. In one embodiment, a
carbostyril derivative together with a serotonin reuptake inhibitor
are contained in one pharmaceutical composition and this
composition may be administered. On the other hand, each one of
carbostyril derivative and a serotonin reuptake inhibitor are
contained individually in a pharmaceutical preparation
respectively, and each one of these preparations may be
administered at the same time or in suitable intervals.
[0117] Dosage of the pharmaceutical composition of the present
invention for treating and improving depression or major depressive
disorder may be used relatively in a small amount, because the
composition possesses excellent efficacy. Therefore the composition
has fewer side-effects and an excellent safety profile.
[0118] The pharmaceutical composition of the present invention is
quite effective for treating or improving mood disorders such as
depressive symptoms, depression, refractory depression, major
depressive disorder and the like.
[0119] The pharmaceutical composition of the present invention can
be manifest in a wide range of neurotransmission accommodation
actions. As a result, the composition of the present invention
establishes pseudo-homeostatic dopaminergic and serotoninergic
neurotransmission (as a result of partial agonism), which, as a
result of neuropathophysiological processes has ceased to function
normally.
[0120] The mood disorders which can be treated by the
pharmaceutical composition of the present invention includes the
mood disorders being classified in "Diagnostic and Statistical
Manual of Mental Disorders" Fourth Edition (DSM-IV) published by
the American Psychiatric Association. These mood disorders include,
for example, major depressive disorder, all mood disorders,
schizoaffective disorder, dementia with depressive symptoms and the
like. A preferred disorder to be treated with the present invention
is major depressive disorder.
[0121] The pharmaceutical composition of the present invention is
useful for treating major depressive disorder, endogenous
depression, melancholia, depression in combination with psychotic
episodes, bipolar disorder with depressive phase, refractory
depression, dementia of the Alzheimer's type with depressive
symptoms, Parkinson's disease with depressive symptom, senile
dementia, mood disorder associated with cerebral blood vessels and
mood disorder following head injury and the like. In addition to
the methods for treatment described herein, additional disclosure
for designing clinical studies is provided in J. Clin. Psychiatry,
2002, 63:(12), pp 1164-1170; J. Clin. Psychiatry, 2002, 63:(8), pp
733-736; and J. Clin. Psychiatry, 2002, 63:(5), pp 391-395.
EXAMPLES
[0122] The present invention will be explained more in detail by
illustrating Reference Examples, Example and Formulation Sample
Examples. First, analytical methods are explained.
Analytical Methods
[0123] (1) The .sup.1H-NMR spectrum was measured in DMSO-d.sub.6 by
using TMS as the standard.
[0124] (2) Powder X-ray Diffraction
[0125] By using RAD-2B diffraction meter manufactured by Rigaku
Denki, the powder x-ray diffraction pattern was measured at room
temperature by using a Cu Ka filled tube (35 kV 20 mA) as the x-ray
source with a wide-angle goniometer, a 1.degree. scattering slit,
an 0.15 mm light-intercepting slit, a graphite secondary
monochromator and a scintillation counter. Data collection was done
in 2.theta.-continuous scan mode at a scan speed of
5.degree./minute in scan steps of 0.02.degree. in the range of
3.degree. to 40.degree..
[0126] (3) The IR spectrum was measured by the KBr method.
[0127] (4) Thermogravimetric/Differential Thermal Analysis
[0128] Thermogravimetric/differential thermal analysis was measured
by using SSC 5200 control unit and TG/DTA 220 simultaneous
differential thermal/thermogravimetric measuring unit manufactured
by Seiko Corp. Samples (5-10 mg) were placed in open aluminum pans
and heated at from 20.degree. C. to 200.degree. C. in a dry
nitrogen atmosphere at a heating rate of 5.degree. C./minute.
.alpha.-Alumina was used as the standard substance.
[0129] (5) Differential Scanning calorimetry
[0130] Thermogravimetric/differential thermal analysis was measured
by using SSC 5200 control unit and DSC 220C differential scanning
calorimeter manufactured by Seiko Corp. Samples (5-10 mg) were
placed in crimped aluminum pans and heated from 20.degree. C. to
200.degree. C. in a dry nitrogen atmosphere at a heating rate of
5.degree. C./minute. .alpha.-Alumina was used as the standard
substance.
[0131] (6) Particle Size Measurement
[0132] The particles (0.1 g) to be measured were suspended in a 20
ml n-hexane solution of 0.5 g soy lecithin, and particle size was
manufactured by using a size distribution measuring meter
(Microtrack HRA, manufactured by Microtrack Co.).
Reference Example 1
[0133] 7-(4-Cholorobutoxy)-3,4-dihydrocarbostyril (19.4 g) and
monohydrochloride 16.2 g of 1-(2,3-dichlorophenyl)piperadine 1
hydrochloride were added to a solution of 8.39 g of potassium
carbonate dissolved in 140 ml of water, and refluxed for 3 hours
under agitation. After the reaction was complete, the mixture was
cooled and the precipitated crystals collected by filtration. These
crystals were dissolved in 350 ml of ethyl acetate, and about 210
ml of water/ethyl acetate azeotrope was removed under reflux. The
remaining solution was cooled, and the precipitated crystals were
collected by filtration. The resulting crystals were dried at
60.degree. C. for 14 hours to obtain 20.4 g (74.2%) of crude
product of aripiprazole.
[0134] The crude product of aripiprazole (30 g) obtained above was
recrystallized from 450 ml of ethanol according to the methods
described in Japanese Unexamined Patent Publication No.
191256/1990, and the resulting crystals were dried at 80.degree. C.
for 40 hours to obtain anhydrous aripiprazole crystals. The yield
was 29.4 g (98.0%).
[0135] The melting point (mp) of these anhydrous aripiprazole
crystals was 140.degree. C., which is identical to the melting
point of the anhydrous aripiprazole crystals described in Japanese
Unexamined Patent Publication No. 191256/1990.
Reference Example 2
[0136] The crude product of aripiprazole (6930 g) obtained in
Reference Example 1 was heat dissolved by heating in 138 liters of
hydrous ethanol (water content 20% by volume) according to the
method presented at the 4th Joint Japanese-Korean Symposium on
Separation Technology, the solution was gradually (2-3 hours)
cooled to room temperature, and then was chilled to near 0.degree.
C. The precipitated crystals were collected by filtration, about
7200 g of aripiprazole hydrate (wet-state).
[0137] The wet-state aripiprazole hydrate crystals obtained above
were dried at 80.degree. C. for 30 hours to obtain 6480 g (93.5%)
of anhydrous aripiprazole crystals. The melting point (mp) of these
crystals was 139.5.degree. C.
[0138] Further, the crystalline form of these crystals was
colorless flake.
[0139] The water content of the crystals were confirmed by the Karl
Fischer method, the moisture value was 0.03%, thus the crystals
were confirmed as anhydrous product.
Reference Example 3
[0140] The aripiprazole hydrate (820 g) in wet state obtained from
Reference Example 2 was dried at 50.degree. C. for 2 hours to
obtain 780 g of aripiprazole hydrate crystals. The moisture value
of the crystals had a moisture value was 3.82% measured according
to the Karl Fischer method. As shown in FIG. 6,
thermogravimetric/differential thermal analysis revealed
endothermic peaks at 75.0, 123.5 and 140.5.degree. C. Because
dehydration began near at 70.degree. C., there was no clear melting
point (mp) was observed.
[0141] As shown in FIG. 7, the powder x-ray diffraction spectrum of
aripiprazole hydrate obtained by this method exhibited
characteristic peaks at 20=12.6.degree., 15.1.degree.,
17.4.degree., 18.2.degree., 18.7.degree., 24.8.degree. and
27.5.degree..
[0142] The powder x-ray diffraction spectrum of this aripiprazole
hydrate was identical to the powder x-ray diffraction spectrum of
aripiprazole hydrate presented at the 4th Joint Japanese-Korean
Symposium on Isolation Technology.
Reference Example 4
[0143] The aripiprazole hydrate crystals (500.3 g) obtained in
Reference Example 3 were milled by using a sample mill (small size
atomizer). The main axis rotation rate was set to 12,000 rpm and
the feed rotation rate to 17 rpm, and a 1.0 mm herringbone screen
was used. Milling was finished in 3 minutes, and obtained 474.6 g
(94.9%) of powder of aripiprazole hydrate A.
[0144] The aripiprazole hydrate A (powder) obtained in this way had
a mean particle size of 20-25 .mu.m. The melting point (mp) was
undetermined because dehydration was observed beginning near at
70.degree. C.
[0145] The aripiprazole hydrate A (powder) obtained above exhibited
an .sup.1H-NMR (DMSO-d.sub.6, TMS) spectrum which was substantially
identical to the .sup.1H-NMR spectrum shown in FIG. 2.
Specifically, it had characteristic peaks at 1.55-1.63 ppm (m, 2H),
1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,
4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H),
3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm
(dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17
ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).
[0146] The aripiprazole hydrate A (powder) obtained above had a
powder x-ray diffraction spectrum which was substantially identical
to the powder x-ray diffraction spectrum shown in FIG. 3.
Specifically, it had characteristic peaks at 2.theta.=12.6.degree.,
15.4.degree., 17.3.degree., 18.0.degree., 18.6.degree.,
22.5.degree. and 24.8.degree.. This pattern is different from the
powder x-ray spectrum of unmilled aripiprazole hydrate shown in
FIG. 7.
[0147] The aripiprazole hydrate A (powder) obtained above had
infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378,
1187, 963 and 784 cm.sup.-1 on the IR (KBr) spectrum.
[0148] As shown in FIG. 1, the aripiprazole hydrate A (powder)
obtained above had a weak peak at 71.3.degree. C. in
thermogravimetric/differential thermal analysis and a broad
endothermic peak (weight loss observed corresponding to one
molecule of water) between 60-120.degree. C. which was clearly
different from the endothermic curve of unmilled aripiprazole
hydrate (see FIG. 6).
[0149] It will be appreciated that other embodiments and uses will
be apparent to those skilled in the art and that the invention is
not limited to these specific illustrative examples.
Example 1
[0150] The aripiprazole hydrate A (powder) (44.29 kg) obtained in
the Reference Example 4 was dried at 100.degree. C. for 18 hours by
using a hot air dryer and further heated at 120.degree. C. for 3
hours, to obtain 42.46 kg (yield; 99.3%) of Anhydrous Aripiprazole
Crystals B. These Anhydrous Aripiprazole Crystals B had a melting
point (mp) of 139.7.degree. C.
[0151] The Anhydrous Aripiprazole Crystals B obtained above had an
.sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was substantially
identical to the .sup.1H-NMR spectrum shown in FIG. 4.
Specifically, they had characteristic peaks at 1.55-1.63 ppm (m,
2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm
(m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz,
4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49
ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),
7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s,
1H).
[0152] The Anhydrous Aripiprazole Crystals B obtained above had a
powder x-ray diffraction spectrum which was substantially the
identical to the powder x-ray diffraction spectrum shown in FIG. 5.
Specifically, they had characteristic peaks at
2.theta.=11.0.degree., 16.6.degree., 19.3.degree., 20.3.degree. and
22.1.degree..
[0153] The Anhydrous Aripiprazole Crystals B obtained above had
remarkable infrared absorption bands at 2945, 2812, 1678, 1627,
1448, 1377, 1173, 960 and 779 cm.sup.-1 on the IR (KBr)
spectrum.
[0154] The Anhydrous Aripiprazole Crystals B obtained above
exhibited an endothermic peak near about at 141.5.degree. C. in
thermogravimetric/differential thermal analysis. The Anhydrous
Aripiprazole Crystals B obtained above exhibited an endothermic
peak near about at 140.7.degree. C. in differential scanning
calorimetry.
Example 2
Receptor Binding at the 5-HT1A Receptor
1. Materials and Methods
[0155] 1.1 Test Compound
[0156]
7-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarb-
ostyril (aripiprazole) was used as test compound.
[0157] 1.2 Reference Compounds
[0158] Serotonin (5-HT) and WAY-100635
(N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)-cyclohexane-
carboxamide, a 5-HT1A receptor antagonist, manufactured by RBI
(Natick, Mass.) were used as reference compounds.
[0159] 1.3 Vehicle
[0160] Dimethyl sulfoxide (DMSO) manufactured by Sigma Chemical Co.
(St. Louis, Mo.) was used as vehicle.
[0161] 1.4 Preparation of Test and Reference Compounds
[0162] Test compound was dissolved in 100% dimethyl sulfoxide
(DMSO) to yield 100 .mu.M stock solutions (final concentration of
DMSO in all tubes containing test compound was 1%, v/v). All other
reference compounds were prepared by the same method using
double-distilled water rather than DMSO.
[0163] 1.5 Experimental Procedure for the
[.sup.35S]GTP.sub..gamma.S Binding Assay
[0164] Test and reference compounds were studied in triplicate at
10 different concentrations (0.01, 0.1, 1, 5, 10, 50, 100, 1000,
10000 and 50000 nM) for their effects upon basal
[.sup.35S]GTR.sub..gamma.S binding to h5-HT1A CHO cell membranes.
Reactions were performed in 5 ml glass test tubes containing 8
.mu.l of test/reference drug mixed with 792 .mu.l of buffer (25 mM
Tris HCl, 50 mM NaCl, 5 mM MgCl.sub.2, 0.1 mM EGTA, pH=7.4)
containing GDP (1 .mu.M), [.sup.35S]GTP.sub..gamma.S (0.1 nM) and
h5-HT1A CHO cell membranes (10 .mu.g protein/reaction; NEN Life
Science Products, Boston, Mass.; catalog # CRM035, lot #501-60024,
GenBank # X13556). Reactions proceeded for 60 min at room
temperature and were terminated by rapid filtration through Whatman
GF/B filter paper, using a Brandel harvester and 4.times.3 ml
ice-cold buffer washes. S radio-activity bound to the filter paper
was measured using liquid scintillation counting (1272 Clinigamma,
LKB/Wallach).
[0165] 1.6 Experimental Procedure to Determine the Binding Affinity
of Test Compound (Aripiprazole) at the h5-HT1A Receptor
[0166] Test compound was studied in triplicate at 10 different
concentrations (0.01, 0.1, 1, 10, 50, 100, 500, 1000, 5000 and
10000 nM) to determine its displacement of [.sup.3H]8-OH-DPAT (1
nM; NEN Life Sciences; catalog # NET 929, lot #3406035, Specific
Activity=124.9 Ci/mmol) binding to h5-HT1A receptors in CHO cell
membranes (15-20 .mu.g protein; NEN Life Science Products, catalog
# CRM035, lot #501-60024). Membranes (396 .mu.l) were incubated in
5 ml glass tubes containing [.sup.3H]8-OH-DPAT (396 .mu.l), test
compound or vehicle (8 .mu.l) and buffer A (50 mM Tris.HCl, 10 mM
MgSO.sub.4, 0.5 mM EDTA, 0.1% (w/v) ascorbic acid, pH=7.4). All
assays proceeded for 60 min at room temperature and were terminated
by rapid filtration through Whatman GF/B filter paper (presoaked in
buffer B; 50 mM Tris.HCl, pH=7.4), using a Brandel harvester and
4.times.1 ml ice-cold washes with buffer B. Non-specific binding
was determined in the presence of 10 .mu.M (+)8-OH-DPAT.
[0167] 1.7 Parameters Determined
[0168] Serotonin (5-HT) is a full 5-HT1A receptor agonist which
stimulates increases in basal [.sup.35S]GTP.sub..gamma.S binding to
h5-HT1A receptors in recombinant CHO cell membranes. The test
compound was studied at 10 concentrations to determine effects upon
basal [.sup.35S]GTP.sub..gamma.S binding relative to that produced
by 10 .mu.M 5-HT. The relative potency (EC.sub.50, 95% confidence
interval) and intrinsic agonist activity (% of E.sub.max for 10
.mu.M 5-HT) was calculated for each compound by computerized
non-linear regression analysis of complete concentration-effect
data. The binding affinity of test compound at the h5-HT1A receptor
was determined by its ability to prevent [.sup.3H]8-OH-DPAT binding
to CHO cell membranes that express this receptor. Non-linear
regression analysis of the competition binding data was used to
calculate an inhibition constant (IC.sub.50, 95% confidence
interval), which is the concentration of test compound that
occupies half of the h5-HT1A sites specifically bound by
[.sup.3H]8-OH-DPAT. The affinity of h5-HT1A receptors for test
compound (Ki, 95% confidence interval) was calculated by the
equation, Ki=(IC.sub.50)/(1+([[.sup.3H]8-OH-DPAT]/Kd), where the Kd
for [.sup.3H]8-OH-DPAT at h5-HT1A=0.69 nM (NEN Life Sciences). All
estimates of drug binding affinity, potency and intrinsic efficacy
at the h5-HT1A receptor were calculated using GraphPad Prism
version 3.00 for Windows (GraphPad Software, San Diego,
Calif.).
2. Results
[0169] The test compound and 5-HT produced concentration-dependent
increases above basal [.sup.35S]GTP.sub..gamma.S binding. 1% DMSO
tested alone had no effect upon basal or drug-induced
[.sup.35S]GTP.sub..gamma.S binding.
[0170] The test compound (EC.sub.50=2.12 nM), 5-HT (EC.sub.50=3.67
nM), potently stimulated basal [.sup.35S]GTP.sub..gamma.S binding.
Potency and intrinsic agonist efficacy estimates were derived by
non-linear regression analysis with correlation coefficients
(r.sup.2)>0.98 in each case (Table 1). The test compound exerted
partial agonist efficacies in the 65-70% range. WAY-100635 produced
no significant change (unpaired Student's t-test) in basal
[.sup.35S]GTP.sub..gamma.S binding at all concentrations tested
(Table 1). WAY-100635 did, however, completely inhibit the effects
of 5-HT and test compound upon [.sup.35S]GTP.sub..gamma.S binding
to h5-HT1A receptors in CHO cell membranes (Table 2). Tables 1 and
2 are shown below.
[0171] The test compound demonstrated high affinity binding to
h5-HT1A receptors in CHO cell membranes (IC.sub.50=4.03 nM, 95%
confidence interval=2.67 to 6.08 nM; Ki=1.65 nM, 95% confidence
interval=1.09 to 2.48 nM).
TABLE-US-00001 TABLE 1 Potency (EC.sub.50) and Intrinsic Agonist
Efficacy (E.sub.max) of Test compound and Reference Drugs in a
h5-HT1A [.sup.35S]GTP.gamma.S CHO-cell Membrane Binding Assay.
EC.sub.50, nM (95% Confidence E.sub.max Goodness of Fit Drug
Interval) (% .+-. SEM) (r.sup.2) Test 2.12 68.13 .+-. 3.16 0.986
Compound (0.87 to 5.16) 5-HT 3.67 98.35 .+-. 4.47 0.986 (1.56 to
8.63) WAY-100635 -- -- --
TABLE-US-00002 TABLE 2 Inhibitory Potency (IC.sub.50) of WAY-100635
versus 1 .mu.M Concentration of 5-HT and Test compound in a h5-HT1A
[.sup.35S]GTP.gamma.S CHO-cell Membrane Binding Assay. WAY-100635
Inhibition Potency, IC.sub.50, nM (95% Confidence Goodness of Fit
Drug Combination Interval) (r.sup.2) 5-HT + WAY-100635 217.1 0.988
(127.4 to 369.7) Test compound + 392.2 0.989 WAY-100635 (224.1 to
686.2)
Example 3
Pharmacological Test
[0172] The forced swimming test proposed by Porsolt et al.
(Porsolt, R. D. et al.: Arch. Int. Pharmacodyn., 229, 327-336,
1977) is widely used as to an experimental animal model for
predicting the antidepressant activity in clinical settings. In
this experimental model, a test mouse is put in a cylinder in which
a suitable amount of water is contained, and the antidepressant
action of a test drug is detected by measuring the immobility time,
as the indication, shown by the mouse. It was reported that the
action of shortening the immobility time is correlated with
clinically observed antidepressive action (Willner, P.:
Psychopharmacology, 83: 1-16, 1984). The crisis of depression is
closely concerned with lowering of serotonin 5-HT1A receptor
neurotransmission action, and the present inventors have found the
facts that antidepressive action of antidepressants which affect to
serotonin system can be detected more precisely using prolongation
of the immobility time performed with WAY-100635, which is a
selective serotonin 5-HT1A receptor antagonist. The prolongation of
the immobility time performed by WAY-100635 is defined as the
indication. In this manner, the antidepressive action of test
antidepressants was determined by taking the prolongation of
immobility time performed by WAY-100635 in the forced swimming test
as the indication.
[0173] In a cylinder (diameter: 9 cm, height 20 cm), water was
poured therein up to the height of 9.5 cm, from the bottom, then a
mouse of ICR strain is placed in the cylinder. After placing the
mouse in the cylinder, an immobility time of 6 minutes is measured.
During the test, the water temperature is maintained at 23 to
24.degree. C. A test drug is orally administered to the mouse at 1
or 2 hours before placing the mouse in the water. WAY-100635 is
administered subcutaneously to the mouse 30 minutes before placing
the mouse in the water.
[0174] During this test, aripiprazole is used in combination
together with citalopram, escitalopram, fluoxetine, venlafaxine or
milnacipran. Following such combination administration, a decrease
in the immobility time (the antidepressant activity) is observed in
comparison with the case of single use of each one of aripiprazole,
citalopram, escitalopram, fluoxetine, venlafaxine or milnacipran,
respectively.
[0175] Further, when aripiprazole is used in combination with
citalopram, escitalopram, fluoxetine, venlafaxine or milnacipran, a
decrease in the immobility time (the antidepressant activity) is
observed in comparison to administration of the available atypical
antipsychotic drugs such as olanzapine, quetiapine, risperidone in
combination with citalopram, fluoxetine, venlafaxine or
milnacipran.
Example 4
Formulation Examples
[0176] Several non-limiting formulation examples of aripiprazole,
dehydroaripiprazole and other metabolites with serotonin reuptake
inhibitors are presented below.
Formulation Sample Example 1
TABLE-US-00003 [0177] Anhydrous Aripiprazole Crystals B 5 mg
Fluoxetine 20 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 220 mg
[0178] According to a preparation method which is well-known to a
person having an ordinary skill in the art, the tablet containing
the above mentioned formulation was prepared.
Formulation Sample Example 2
TABLE-US-00004 [0179] Anhydrous Aripiprazole Crystals B 5 mg
Duloxetine 20 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 220 mg
[0180] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 3
TABLE-US-00005 [0181] Anhydrous Aripiprazole Crystals B 5 mg
Venlafaxine 75 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 275 mg
[0182] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 4
TABLE-US-00006 [0183] Anhydrous Aripiprazole Crystals B 5 mg
Milnacipran 50 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 250 mg
[0184] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 5
TABLE-US-00007 [0185] Anhydrous Aripiprazole Crystals B 5 mg
Citalopram 20 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 220 mg
[0186] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 6
TABLE-US-00008 [0187] Anhydrous Aripiprazole Crystals B 5 mg
Fluvoxamine 50 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 250 mg
[0188] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 7
TABLE-US-00009 [0189] Anhydrous Aripiprazole Crystals B 5 mg
Paroxetine 20 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 220 mg
[0190] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 8
TABLE-US-00010 [0191] Anhydrous Aripiprazole Crystals B 5 mg
Sertraline 50 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 250 mg
[0192] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 9
TABLE-US-00011 [0193] Anhydrous Aripiprazole Crystals B 5 mg
Escitalopram 10 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 210 mg
[0194] According to a common method, the tablet containing the
above mentioned formulation was prepared.
[0195] Several non-limiting formulation examples of
dehydroaripiprazole and serotonin reuptake inhibitors are presented
below. It is to be understood that any one of DM-1458, DM-1451,
DM-1452, DM-1454 or DCPP, as shown in FIG. 8, could be substituted
for dehydroaripiprazole in these disclosed formulations.
Formulation Sample Example 10
TABLE-US-00012 [0196] Dehydroaripiprazole 5 mg Fluoxetine 20 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 220
mg
[0197] According to a preparation method which is well-known to a
person having an ordinary skill in the art, the tablet containing
the above mentioned formulation was prepared.
Formulation Sample Example 11
TABLE-US-00013 [0198] Dehydroaripiprazole 5 mg Duloxetine 20 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 220
mg
[0199] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 12
TABLE-US-00014 [0200] Dehydroaripiprazole 5 mg Venlafaxine 75 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 275
mg
[0201] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 13
TABLE-US-00015 [0202] Dehydroaripiprazole 5 mg Milnacipran 50 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 250
mg
[0203] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 14
TABLE-US-00016 [0204] Dehydroaripiprazole 5 mg Citalopram 20 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 220
mg
[0205] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 15
TABLE-US-00017 [0206] Dehydroaripiprazole 5 mg Fluvoxamine 50 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 250
mg
[0207] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 16
TABLE-US-00018 [0208] Dehydroaripiprazole 5 mg Paroxetine 20 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 220
mg
[0209] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 17
TABLE-US-00019 [0210] Dehydroaripiprazole 5 mg Sertraline 50 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 250
mg
[0211] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Formulation Sample Example 18
TABLE-US-00020 [0212] Dehydroaripiprazole 5 mg Escitalopram 10 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 210
mg
[0213] According to a common method, the tablet containing the
above mentioned formulation was prepared.
Example 5
[0214] Method of Treatment of Patients Diagnosed with Major
Depressive Disorder Who were Previously Non-Responsive or Partially
Responsive to Anti-Depressant Medication
[0215] Aripiprazole is evaluated as an augmentation therapy in
depressed patients with major depressive disorder who were
previously non-responsive or partially responsive to
anti-depressant medication comprising serotonin reuptake
inhibitors. These patients currently receive therapy through
administration of serotonin reuptake inhibitors.
[0216] Patients ranging in age from 18 to 65 years who have been
diagnosed with major depressive disorder and are receiving therapy
with a serotonin reuptake inhibitor are evaluated to ensure that
they have a baseline Hamilton score for depression (item 17) of 14
or higher. Only patients with such Hamilton scores receive
treatment. These patients are interviewed to obtain a complete
medical and psychiatric history. Aripiprazole is first administered
at a dose of 10 mg/day and increased to 30 mg/day as needed in the
opinion of the monitoring psychiatrist. Aripiprazole is
administered to these patients at a dose of from 10 mg/day to 30
mg/day for a period of at least four weeks, and up to eight weeks
for patients who respond well to this treatment during the first
four weeks.
[0217] An improvement in alleviation of symptoms of depression is
observed in these patients following administration of aripiprazole
as shown by results of testing performed during and after the
duration of aripiprazole administration. The Hamilton test for
depression and other measures such as clinical global impression
(CGI), abnormal involuntary movement scale (AIMS), Simpson Angus
scale (SAS), and Barnes akathesia scale (Barnes), commonly known to
one of ordinary skill in the art, are administered to these
patients.
Example 6
[0218] Method of Treatment of Patients with a New Diagnosis of
Major Depressive Disorder
[0219] A combination of aripiprazole and at least one serotonin
reuptake inhibitor is evaluated as a therapy for depression in
patients newly diagnosed with major depressive disorder. Patients
ranging in age from 18 to 65 years who are diagnosed with major
depressive disorder are evaluated to ensure that they have a
baseline Hamilton score for depression (item 17) of 14 or higher.
Only patients with this Hamilton score receive treatment. These
patients are interviewed to obtain a complete medical and
psychiatric history. Aripiprazole is first administered at a dose
of 10 mg/day and increased to 30 mg/day as needed in the opinion of
the monitoring psychiatrist. Aripiprazole is administered to these
patients at a dose of from 10 mg/day to 30 mg/day for a period of
at least four weeks, and up to eight weeks for patients who respond
well to this treatment during the first four weeks. The
aripiprazole is administered together with at least one serotonin
reuptake inhibitor, wherein the serotonin reuptake inhibitor is
fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram,
fluvoxamine, paroxetine or sertraline. The dosages to be used for
these serotonin reuptake inhibitors are provided elsewhere in this
patent application.
[0220] The aripiprazole can be administered in one dosage form, for
example a tablet, and the serotonin reuptake inhibitor may be
administered in a separate one dosage form, for example a tablet.
The administration may occur at about the same time or at different
times during the day.
[0221] Alternatively, a dosage form containing aripiprazole in
combination with at least one serotonin reuptake inhibitor may be
administered. Such combinations include without limitation the
following: aripiprazole/fluoxetine, aripiprazole/duloxetine,
aripiprazole/venlafaxine, aripiprazole/milnacipran,
aripiprazole/citalopram, aripiprazole/fluvoxamine,
aripiprazole/paroxetine, and aripiprazole/sertraline. A preferred
embodiment comprises a combination of aripiprazole and
citalopram.
[0222] An improvement in alleviation of symptoms of depression is
observed in these patients following administration of aripiprazole
and the one or more serotonin reuptake inhibitors as shown by
results of testing performed during and after the duration of
aripiprazole and serotonin reuptake inhibitor administration. The
Hamilton test for depression and other measures such as CGI, AIMS,
SAS, Simpson & Angus and Barnes, commonly known to one of
ordinary skill in the art, are administered to these patients.
Results demonstrate an alleviation of the symptoms of
depression.
Example 7
[0223] Method of Treatment of Patients Diagnosed with Major
Depressive Disorder Who were Previously Non-Responsive or Partially
Responsive to Anti-Depressant Medication
[0224] Dehydroaripiprazole, an active metabolite of aripiprazole,
is evaluated as an augmentation therapy in depressed patients with
major depressive disorder who were previously non-responsive or
partially responsive to anti-depressant medication comprising
serotonin reuptake inhibitors. These patients currently receive
therapy through administration of serotonin reuptake
inhibitors.
[0225] Patients ranging in age from 18 to 65 years who have been
diagnosed with major depressive disorder and are receiving therapy
with a serotonin reuptake inhibitor are evaluated to ensure that
they have a baseline Hamilton score for depression (item 17) of 14
or higher. Only patients with such Hamilton scores receive
treatment. These patients are interviewed to obtain a complete
medical and psychiatric history. Dehydroaripiprazole is first
administered at a dose of 10 mg/day and increased to 30 mg/day as
needed in the opinion of the monitoring psychiatrist.
Dehydroaripiprazole is administered to these patients at a dose of
from 10 mg/day to 30 mg/day for a period of at least four weeks,
and up to eight weeks for patients who respond well to this
treatment during the first four weeks.
[0226] An improvement in alleviation of symptoms of depression is
observed in these patients following administration of aripiprazole
as shown by results of testing performed during and after the
duration of aripiprazole administration. The Hamilton test for
depression and other measures such as clinical global impression
(CGI), abnormal involuntary movement scale (AIMS), Simpson Angus
scale (SAS), and Barnes akathesia rating scale (BARS), commonly
known to one of ordinary skill in the art, are administered to
these patients.
Example 8
[0227] Method of Treatment of Patients with a New Diagnosis of
Major Depressive Disorder
[0228] A combination of dehydroaripiprazole and at least one
serotonin reuptake inhibitor is evaluated as a therapy for
depression in patients newly diagnosed with major depressive
disorder. Patients ranging in age from 18 to 65 years who are
diagnosed with major depressive disorder are evaluated to ensure
that they have a baseline Hamilton score for depression (item 17)
of 14 or higher. Only patients with this Hamilton score receive
treatment. These patients are interviewed to obtain a complete
medical and psychiatric history. Dehydroaripiprazole is first
administered at a dose of 10 mg/day and increased to 30 mg/day as
needed in the opinion of the monitoring psychiatrist.
Dehydroaripiprazole is administered to these patients at a dose of
from 10 mg/day to 30 mg/day for a period of at least four weeks,
and up to eight weeks for patients who respond well to this
treatment during the first four weeks. The dehydroaripiprazole is
administered together with at least one serotonin reuptake
inhibitor, wherein the serotonin reuptake inhibitor is fluoxetine,
duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine,
paroxetine or sertraline.
[0229] The dehydroaripiprazole can be administered in one dosage
form, for example a tablet, and the serotonin reuptake inhibitor
may be administered in a separate one dosage form, for example a
tablet. The administration may occur at about the same time or at
different times during the day.
[0230] Alternatively, a dosage form containing dehydroaripiprazole
in combination with at least one serotonin reuptake inhibitor may
be administered. Such combinations include without limitation the
following: dehydroaripiprazole/fluoxetine,
dehydroaripiprazole/duloxetine, dehydroaripiprazole/venlafaxine,
dehydroaripiprazole/milnacipran, dehydroaripiprazole/citalopram,
dehydroaripiprazole/fluvoxamine, dehydroaripiprazole/paroxetine,
and dehydroaripiprazole/sertraline. A preferred embodiment
comprises a combination of dehydroaripiprazole and citalopram.
[0231] An improvement in alleviation of symptoms of depression is
observed in these patients following administration of
dehydroaripiprazole and the one or more serotonin reuptake
inhibitors as shown by results of testing performed during and
after the duration of dehydroaripiprazole and serotonin reuptake
inhibitor administration. The Hamilton test for depression and
other measures such as CGI, AIMS, SAS, Simpson & Angus and
Barnes, commonly known to one of ordinary skill in the art, are
administered to these patients. Results demonstrate an alleviation
of the symptoms of depression.
[0232] All patents, patent applications, scientific and medical
publications mentioned herein are hereby incorporated in their
entirety. It should be understood, of course, that the foregoing
relates only to preferred embodiments of the present invention and
that numerous modifications or alterations may be made therein
without departing from the spirit and the scope of the invention as
set forth in the appended claims.
Example 9
Pharmacological Test
[0233] The tail suspension test (TST) was originally described by
Steru et al. (1985)..sup.1) A mouse suspended by its tail shows
periods of agitation and immobility. The antidepressant activity of
a test drug can be detected as an index of shortening the
immobility time. This test is widely used as to an experimental
animal model for predicting the antidepressant activity of a test
drug in clinical settings. An automated device for performing the
TST was developed by the authors of the TST (1989)..sup.2) We
improved this device and developed our own device incorporating an
electric balance, an A/D converter, a testing box
(30.times.25.times.25 cm), and a personal computer. The mouse was
suspended from a hook hanging from the ceiling in the testing box
by adhesive tape applied 20 mm from the tip of the tail. The
duration of immobility was measured by the computer for a period of
15 min following the start of suspension. The immobility time for a
period of 10 min (5-15 min) was evaluated. The experiments were
carried out in a sound-proof room.
[0234] Aripiprazole was suspended in 0.5% gum arabic-0.9% saline
solution and citalopram was dissolved in 0.9% saline solution.
Aripiprazole (3 mg/kg) and citalopram (3 mg/kg) were orally
administered to mice 60 min before the start of suspension. In this
test, the decrease in the immobility time of the combination of
aripiprazole with citalopram was statistically significant
synergistic effect in comparison with the effects of aripiprazole-
and citaroplam-treated groups (Table 3).
REFERENCES
[0235] 1) Steru L. et al.: The tail suspension test: A new method
for screening antidepressants in mice. Psychopharmacology
85,367(1985). [0236] 2) Steru L. and Porsolt R. D.: The automated
tail suspension test: A computerized device for evaluating
psychotropic activity profiles. Jpn J Clin Pharmacol Ther
20,77(1989).
TABLE-US-00021 [0236] TABLE 3 Effects of aripiprazole and
citalopram on duration of immobility in the tail suspension test in
mice Dose Immobility % of (mg/kg, time (sec, shortening for Drug
p.o.) mean .+-. SE) immobility time Vehicle -- 499.2 .+-. 13.6 --
Aripiprazole 3 486.4 .+-. 12.3 3 (Aripi.) Citalopram 3 468.7 .+-.
24.2 6 (Citalo.) Aripi. + Citalo. 3 + 3 .sup. 380.6 .+-.
19.2**.sup.##$ 24 N = 7-9, **p < 0.01 vs. vehicle group
(two-tailed t-test), .sup.##p < 0.01 vs. aripiprazole alone
(two-tailed t-test), .sup.$p < 0.05 vs. citalopram alone
(two-tailed t-test).
[0237] The decrease in the immobility time of the combination of
aripiprazole with citalopram was a statistically significant
synergistic effect in comparison with the effects of aripiprazole-
and citaroplam-treated groups (p<0.05, one-way ANOVA).
* * * * *