U.S. patent application number 15/305782 was filed with the patent office on 2017-02-16 for combination of brexpiprazole and nalmefene and use thereof for treating substance-related disorders.
This patent application is currently assigned to OTSUKA PHARMACEUTICAL. CO., LTD.. The applicant listed for this patent is H. LUNDBECK A/S, OTSUKA PHARMACEUTICAL. CO., LTD.. Invention is credited to Kenji MAEDA, Mai NAKAMURA.
Application Number | 20170042887 15/305782 |
Document ID | / |
Family ID | 53191808 |
Filed Date | 2017-02-16 |
United States Patent
Application |
20170042887 |
Kind Code |
A1 |
MAEDA; Kenji ; et
al. |
February 16, 2017 |
Combination of Brexpiprazole and Nalmefene and Use Thereof for
Treating Substance-Related Disorders
Abstract
A medicament comprising (I) brexpiprazole or a pharmaceutically
acceptable salt thereof, and (II) nalmefene or a pharmaceutically
acceptable salt thereof in combination, wherein brexpiprazole or a
pharmaceutically acceptable salt thereof, and nalmefene or a
pharmaceutically acceptable salt thereof are contained in a single
preparation, or a pharmaceutical composition containing
brexpiprazole or a pharmaceutically acceptable salt thereof and a
pharmaceutical composition containing nalmefene or a
pharmaceutically acceptable salt thereof are formulated for use in
combination. The medicament is used for the prophylaxis or
treatment of a substance-related disorder, preferably an
alcohol-related disorder.
Inventors: |
MAEDA; Kenji; (Osaka-shi,
Osaka, JP) ; NAKAMURA; Mai; (Osaka-shi, Osaka,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA PHARMACEUTICAL. CO., LTD.
H. LUNDBECK A/S |
Tokyo
Valby |
|
JP
DK |
|
|
Assignee: |
OTSUKA PHARMACEUTICAL. CO.,
LTD.
Tokyo
JP
H. LUNDBECK A/S
Valby
DK
|
Family ID: |
53191808 |
Appl. No.: |
15/305782 |
Filed: |
April 22, 2015 |
PCT Filed: |
April 22, 2015 |
PCT NO: |
PCT/JP2015/062913 |
371 Date: |
October 21, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/32 20180101;
A61K 31/496 20130101; A61K 31/485 20130101; A61K 31/485 20130101;
A61P 43/00 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/496 20130101; A61P 25/30 20180101 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/485 20060101 A61K031/485 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 22, 2014 |
JP |
2014-088148 |
Claims
1. A medicament comprising (I) brexpiprazole or a pharmaceutically
acceptable salt thereof, and (II) nalmefene or a pharmaceutically
acceptable salt thereof in combination, wherein brexpiprazole or a
pharmaceutically acceptable salt thereof, and nalmefene or a
pharmaceutically acceptable salt thereof are contained in a single
preparation, or a pharmaceutical composition containing
brexpiprazole or a pharmaceutically acceptable salt thereof and a
pharmaceutical composition containing nalmefene or a
pharmaceutically acceptable salt thereof are formulated for use in
combination.
2. The medicament according to claim 1, wherein (I) brexpiprazole
or a pharmaceutically acceptable salt thereof, and (II) nalmefene
or a pharmaceutically acceptable salt thereof are contained in a
single preparation.
3. The medicament according to claim 1, wherein a pharmaceutical
composition containing brexpiprazole or a pharmaceutically
acceptable salt thereof and a pharmaceutical composition containing
nalmefene or a pharmaceutically acceptable salt thereof are
formulated for use in combination.
4. The medicament according to any one of claims 1 to 3, for use in
the prophylaxis or treatment of a substance-related disorder.
5. The medicament according to claim 4, wherein the
substance-related disorder is an alcohol-related disorder.
6. The medicament according to claim 5, wherein the alcohol-related
disorder is selected from the group consisting of an alcohol use
disorder, an alcohol-induced disorder, alcohol abuse, alcohol
dependence, alcohol intoxication and an alcohol withdrawal
symptom.
7. The medicament according to claim 5, for use in the prophylaxis
or treatment of an impulsive symptom in an alcohol-related
disorder.
8. The medicament according to claim 7, wherein the alcohol-related
disorder is selected from the group consisting of an alcohol use
disorder, an alcohol-induced disorder, alcohol abuse, alcohol
dependence, alcohol intoxication and an alcohol withdrawal
symptom.
9. The medicament according to claim 8, wherein the alcohol-related
disorder is alcohol dependence.
10. A medicament comprising brexpiprazole or a pharmaceutically
acceptable salt thereof, for a combined use with nalmefene or a
pharmaceutically acceptable salt thereof.
11. A medicament comprising nalmefene or a pharmaceutically
acceptable salt thereof, for a combined use with brexpiprazole or a
pharmaceutically acceptable salt thereof.
12. Use of (I) brexpiprazole or a pharmaceutically acceptable salt
thereof in combination with (II) nalmefene or a pharmaceutically
acceptable salt thereof for the production of a medicament for the
prophylaxis or treatment of a substance-related disorder.
13. A method for preventing or treating a substance-related
disorder, comprising administering (I) brexpiprazole or a
pharmaceutically acceptable salt thereof, and (II) nalmefene or a
pharmaceutically acceptable salt thereof to a subject in need
thereof, wherein brexpiprazole or a pharmaceutically acceptable
salt thereof, and nalmefene or a pharmaceutically acceptable salt
thereof are administered as a single preparation or separate
preparations simultaneously or separately in a staggered
manner.
14. A pharmaceutical composition comprising (I) brexpiprazole or a
pharmaceutically acceptable salt thereof, (II) nalmefene or a
pharmaceutically acceptable salt thereof, and (III) a
pharmacologically acceptable carrier.
15. A method for producing a pharmaceutical composition, comprising
mixing (I) brexpiprazole or a pharmaceutically acceptable salt
thereof and (II) nalmefene or a pharmaceutically acceptable salt
thereof with a pharmacologically acceptable carrier.
16. A kit comprising (I) a medicament containing brexpiprazole or a
pharmaceutically acceptable salt thereof, and (II) a medicament
containing nalmefene or a pharmaceutically acceptable salt
thereof.
17. The medicament according to any one of claims 1 to 3, for
treating a patient for whom an existing therapeutic drug for
alcohol-related disorder provides only an insufficient effect.
18. The medicament according to claim 17, wherein the existing
therapeutic drug for alcohol-related disorder is selected from the
group consisting of cyanamide, disulfiram, acamprosate, nalmefene
and naltrexone.
19. A medicament for use in the treatment of an alcohol-related
disorder, comprising brexpiprazole or a pharmaceutically acceptable
salt thereof as an active ingredient, which is used for a patient
receiving a treatment with a preparation of nalmefene or a
pharmaceutically acceptable salt thereof.
20. A medicament for use in the treatment of an alcohol-related
disorder, comprising nalmefene or a pharmaceutically acceptable
salt thereof as an active ingredient, which is used for a patient
receiving a treatment with a preparation of brexpiprazole or a
pharmaceutically acceptable salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to a medicament using
brexpiprazole or a pharmaceutically acceptable salt thereof and
nalmefene or a pharmaceutically acceptable salt thereof in
combination.
BACKGROUND ART
[0002] It is known that brexpiprazole
(7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one)
or a pharmaceutically acceptable salt thereof has a dopamine
D.sub.2 receptor partial agonist activity (D.sub.2 receptor partial
agonist activity), a serotonin 5-HT.sub.2A receptor antagonist
activity (5-HT.sub.2A receptor antagonist activity) and an
adrenergic .alpha..sub.1 receptor antagonist activity
(.alpha..sub.1 receptor antagonist activity) and, in addition
thereto, concurrently has a serotonin uptake inhibitory action (or
serotonin reuptake inhibitory action) (patent document 1 and patent
document 2). In addition, it is known that brexpiprazole has a
serotonin 5-HT.sub.1A receptor antagonist activity (5-HT.sub.1A
receptor antagonist activity) (non-patent document 1).
[0003] Nalmefene
(17-(cyclopropylmethyl)-4,5.alpha.-epoxy-6-methylenemorphinan-3,14-diol)
has the following formula
##STR00001##
and can be prepared using methods that are well known in the art
e.g. starting by manufacturing of naltrexone from noroxymorphone as
described in WO2012/059103 (patent document 3) and subsequently
manufacturing nalmefene from naltrexone e.g. by the Wittig reactin
as described in WO2010/136039 (patent document 4).
[0004] Nalmefene is an opioid system modulator with a distinct
.mu., .delta. and .kappa. receptor profile. In vitro studies have
demonstrated that nalmefene is a selective opioid receptor ligand
with antagonist activity at the .mu. and .delta. receptors and
partial agonist activity at the .kappa. receptor. Acute alcohol
intake was shown to result in mesolimbic dopamine release
(facilitated by the release of .beta.-endorphins), which can
provide positive reinforcement. Nalmefene is thought to counteract
the reinforcement effects and to reduce alcohol consumption,
possibly by modulating these cortico-mesolimbic functions.
[0005] The efficacy and tolerability of nalmefene in the treatment
of alcohol dependence have been evaluated in three phase III
studies (two confirmatory 6-month efficacy studies and one 1-year
safety study) conducted by Lundbeck (non-patent 25 documents 2 to
4) and 5 studies in alcohol use disorders conducted by the company
Biotie (non-patent document 5).
[0006] In February 2013, a marketing authorization has been granted
for oral nalmefene in the European Union (EU) under the tradename
Selincro (registered trademark) for the reduction of alcohol
consumption in adult patients with alcohol dependence.
[0007] WO2005/089486 (patent document 5) discloses that when
coadministered with an opioid antagonist naltrexone, a dopamine
D.sub.2 receptor partial agonist aripiprazole does not affect
(i.e., neither impairs nor enhances) naltrexone's ability to
decrease ethanol intake.
DOCUMENT LIST
Patent Documents
[0008] patent document 1: WO2006/112464 [0009] patent document 2:
JP-A-2008-115172 [0010] patent document 3: WO2012/059103 [0011]
patent document 4: WO2010/136039 [0012] patent document 5:
WO2005/089486
Non-Patent Documents
[0012] [0013] non-patent document 1: Maeda et al., Brexpiprazole I:
In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine
Activity Modulator. J Pharmacol Exp Ther (2014); 350:589-604 [0014]
non-patent document 2: Mann et al., Extending the Treatment Options
in Alcohol Dependence: A Randomized Controlled Study of As-Needed
Nalmefene. Biol. Psychiatry (2013); 73: 706-713 [0015] non-patent
document 3: Gual et al., A randomised, double-blind,
placebo-controlled, efficacy study of nalmefene, as-needed use, in
patients with alcohol dependence. European Neuropsychopharmacology
(2013); 23(11): 1432-1442 [0016] non-patent document 4: van den
Brink et al., Long-term efficacy, tolerability and safety of
nalmefene as-needed in patients with alcohol dependence: A 1-year,
randomised controlled study. J. Psychopharmacol., published online
before print Mar. 26, 2014, doi: 10.1177/0269881114527362 [0017]
non-patent document 5: Karhuvaara et al., Alcohol. Clin. Exp. Res.
(2007); 31: 1179-1187
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0018] The object of the present invention is to provide a
medicament for use in the prophylaxis or treatment of
substance-related disorders such as alcohol-related disorder and
the like.
Means of Solving the Problems
[0019] As mentioned above, a combined administration of naltrexone
which is an opioid antagonist and aripiprazole which is a dopamine
D.sub.2 receptor partial agonist does not affect the ability of
both drugs. That is, it is disclosed that such combined
administration does not show a synergistic effect or even an
additive effect. In such situation, the present inventors have
conducted intensive studies in an attempt to solve the
aforementioned problems and found that the use of nalmefene which
is an opioid antagonist and brexpiprazole which is a dopamine
D.sub.2 receptor partial agonist in combination surprisingly
affords not only an additive effect but also a synergistic effect.
The present invention has been completed based on such finding.
[0020] The present invention preferably provides medicaments, use,
methods for preventing or treating diseases, a pharmaceutical
composition, a production method of a pharmaceutical composition
and kits shown in item 1 to item 63 below.
Item 1.
[0021] A medicament comprising (I) brexpiprazole or a
pharmaceutically acceptable salt thereof, and (II) nalmefene or a
pharmaceutically acceptable salt thereof in combination, wherein
brexpiprazole or a pharmaceutically acceptable salt thereof, and
nalmefene or a pharmaceutically acceptable salt thereof are
contained in a single preparation, or a pharmaceutical composition
containing brexpiprazole or a pharmaceutically acceptable salt
thereof and a pharmaceutical composition containing nalmefene or a
pharmaceutically acceptable salt thereof are formulated for use in
combination.
Item 2.
[0022] The medicament according to item 1, wherein (I)
brexpiprazole or a pharmaceutically acceptable salt thereof, and
(II) nalmefene or a pharmaceutically acceptable salt thereof are
contained in a single preparation.
Item 3.
[0023] The medicament according to item 1, wherein a pharmaceutical
composition containing brexpiprazole or a pharmaceutically
acceptable salt thereof and a pharmaceutical composition containing
nalmefene or a pharmaceutically acceptable salt thereof are
formulated for use in combination.
Item 4.
[0024] The medicament according to any one of items 1 to 3, for use
in the prophylaxis or treatment of a substance-related
disorder.
Item 5.
[0025] The medicament according to item 4, wherein the
substance-related disorder is an alcohol-related disorder.
Item 6.
[0026] The medicament according to item 5, wherein the
alcohol-related disorder is selected from the group consisting of
an alcohol use disorder, an alcohol-induced disorder, alcohol
abuse, alcohol dependence, alcohol intoxication and an alcohol
withdrawal symptom.
Item 7.
[0027] The medicament according to item 5, for use in the
prophylaxis or treatment of an impulsive symptom in an
alcohol-related disorder.
Item 8.
[0028] The medicament according to item 7, wherein the
alcohol-related disorder is selected from the group consisting of
an alcohol use disorder, an alcohol-induced disorder, alcohol
abuse, alcohol dependence, alcohol intoxication and an alcohol
withdrawal symptom.
Item 9.
[0029] The medicament according to item 8, wherein the
alcohol-related disorder is alcohol dependence.
Item 10.
[0030] A medicament comprising brexpiprazole or a pharmaceutically
acceptable salt thereof, for a combined use with nalmefene or a
pharmaceutically acceptable salt thereof.
Item 11.
[0031] A medicament comprising nalmefene or a pharmaceutically
acceptable salt thereof, for a combined use with brexpiprazole or a
pharmaceutically acceptable salt thereof.
Item 12.
[0032] Use of (I) brexpiprazole or a pharmaceutically acceptable
salt thereof in combination with (II) nalmefene or a
pharmaceutically acceptable salt thereof for the production of a
medicament for the prophylaxis or treatment of a substance-related
disorder.
Item 13.
[0033] Use according to item 12, wherein the substance-related
disorder is an alcohol-related disorder.
Item 14.
[0034] Use according to item 13, wherein the alcohol-related
disorder is selected from the group consisting of an alcohol use
disorder, an alcohol-induced disorder, alcohol abuse, alcohol
dependence, alcohol intoxication and an alcohol withdrawal
symptom.
Item 15.
[0035] Use according to item 13, wherein the medicament is for use
in the prophylaxis or treatment of an impulsive symptom in an
alcohol-related disorder.
Item 16.
[0036] Use according to item 15, wherein the alcohol-related
disorder is selected from the group consisting of an alcohol use
disorder, an alcohol-induced disorder, alcohol abuse, alcohol
dependence, alcohol intoxication and an alcohol withdrawal
symptom.
Item 17.
[0037] Use according to item 16, wherein the alcohol-related
disorder is alcohol dependence.
Item 18.
[0038] A method for preventing or treating a substance-related
disorder, comprising administering (I) brexpiprazole or a
pharmaceutically acceptable salt thereof, and (II) nalmefene or m a
pharmaceutically acceptable salt thereof to a subject in need
thereof, wherein brexpiprazole or a pharmaceutically acceptable
salt thereof, and nalmefene or a pharmaceutically acceptable salt
thereof are administered as a single preparation or separate
preparations simultaneously or separately in a staggered
manner.
Item 19.
[0039] The method according to item 18, wherein the
substance-related disorder is an alcohol-related disorder.
Item 20.
[0040] The method according to item 19, wherein the alcohol-related
disorder is selected from the group consisting of an alcohol use
disorder, an alcohol-induced disorder, alcohol abuse, alcohol
dependence, alcohol intoxication and an alcohol withdrawal
symptom.
Item 21.
[0041] The method according to item 19, which is a method for
preventing or treating an impulsive symptom in an alcohol-related
disorder.
Item 22.
[0042] The method according to item 21, wherein the alcohol-related
disorder is selected from the group consisting of an alcohol use
disorder, an alcohol-induced disorder, alcohol abuse, alcohol
dependence, alcohol intoxication and an alcohol withdrawal
symptom.
Item 23.
[0043] The method according to item 22, wherein the alcohol-related
disorder is alcohol dependence.
Item 24.
[0044] A pharmaceutical composition comprising (I) brexpiprazole or
a pharmaceutically acceptable salt thereof, (II) nalmefene or a
pharmaceutically acceptable salt thereof, and (III) a
pharmacologically acceptable carrier.
Item 25.
[0045] A method for producing a pharmaceutical composition,
comprising mixing (I) brexpiprazole or a pharmaceutically
acceptable salt thereof and (II) nalmefene or a pharmaceutically
acceptable salt thereof with a pharmacologically acceptable
carrier.
Item 26.
[0046] A kit comprising (I) a medicament containing brexpiprazole
or a pharmaceutically acceptable salt thereof, and (II) a
medicament containing nalmefene or a pharmaceutically acceptable
salt thereof.
Item 27.
[0047] The kit according to item 26, for use in the prophylaxis or
treatment of a substance-related disorder.
Item 28.
[0048] The kit according to item 27, wherein the substance-related
disorder is an alcohol-related disorder.
Item 29.
[0049] The medicament according to any one of items 1 to 11,
wherein brexpiprazole or a pharmaceutically acceptable salt thereof
is a solvate of brexpiprazole or of a pharmaceutically acceptable
salt thereof.
Item 30.
[0050] The medicament according to item 29, wherein the solvate is
dihydrate.
Item 31.
[0051] The medicament according to any one of items 1 to 11, 29 and
30, wherein nalmefene or a pharmaceutically acceptable salt thereof
is monohydrate or dihydrate of nalmefene or of a pharmaceutically
acceptable salt thereof.
Item 32.
[0052] The medicament according to item 31, wherein nalmefene or a
pharmaceutically acceptable salt thereof is dihydrate of nalmefene
or of a pharmaceutically acceptable salt thereof.
Item 33.
[0053] The medicament according to item 32, wherein nalmefene or a
pharmaceutically acceptable salt thereof is nalmefene hydrochloride
dihydrate.
Item 34.
[0054] Use according to any one of items 12 to 17, wherein
brexpiprazole or a pharmaceutically acceptable salt thereof is a
solvate of brexpiprazole or of a pharmaceutically acceptable salt
thereof.
Item 35.
[0055] Use according to item 34, wherein the solvate is
dihydrate.
Item 36.
[0056] Use according to any one of items 12 to 17, 34 and 35,
wherein nalmefene or a pharmaceutically acceptable salt thereof is
monohydrate or dihydrate of nalmefene or of a pharmaceutically
acceptable salt thereof.
Item 37.
[0057] Use according to item 36, wherein nalmefene or a
pharmaceutically acceptable salt thereof is dihydrate of nalmefene
or of a pharmaceutically acceptable salt thereof.
Item 38.
[0058] Use according to item 37, wherein nalmefene or a
pharmaceutically acceptable salt thereof is nalmefene hydrochloride
dihydrate.
Item 39.
[0059] The method according to any one of items 18 to 23, wherein
brexpiprazole or a pharmaceutically acceptable salt thereof is a
solvate of brexpiprazole or of a pharmaceutically acceptable salt
thereof.
Item 40.
[0060] The method according to item 39, wherein the solvate is
dihydrate.
Item 41.
[0061] The method according to any one of items 18 to 23, 39 and
40, wherein nalmefene or a pharmaceutically acceptable salt thereof
is monohydrate or dihydrate of nalmefene or of a pharmaceutically
acceptable salt thereof.
Item 42.
[0062] The method according to item 41, wherein nalmefene or a
pharmaceutically acceptable salt thereof is dihydrate of nalmefene
or of a pharmaceutically acceptable salt thereof.
Item 43.
[0063] The method according to item 42, wherein nalmefene or a
pharmaceutically acceptable salt thereof is nalmefene hydrochloride
dihydrate.
Item 44.
[0064] The pharmaceutical composition according to item 24, wherein
brexpiprazole or a pharmaceutically acceptable salt thereof is a
solvate of brexpiprazole or of a pharmaceutically acceptable salt
thereof.
Item 45.
[0065] The pharmaceutical composition according to item 44, wherein
the solvate is dihydrate.
Item 46.
[0066] The pharmaceutical composition according to any one of items
24, 44 and 45, wherein nalmefene or a pharmaceutically acceptable
salt thereof is monohydrate or dihydrate of nalmefene or of a
pharmaceutically acceptable salt thereof.
Item 47.
[0067] The pharmaceutical composition according to item 46, wherein
nalmefene or a pharmaceutically acceptable salt thereof is
dihydrate of nalmefene or of a pharmaceutically acceptable salt
thereof.
Item 48.
[0068] The pharmaceutical composition according to item 47, wherein
nalmefene or a pharmaceutically acceptable salt thereof is
nalmefene hydrochloride dihydrate.
Item 49.
[0069] The kit according to any one of items 26 to 28, wherein
brexpiprazole or a pharmaceutically acceptable salt thereof is a
solvate of brexpiprazole or of a pharmaceutically acceptable salt
thereof.
Item 50.
[0070] The kit according to item 49, wherein the solvate is
dihydrate.
Item 51.
[0071] The kit according to any one of items 26 to 28, 49 and 50,
wherein nalmefene or a pharmaceutically acceptable salt thereof is
monohydrate or dihydrate of nalmefene or of a pharmaceutically
acceptable salt thereof.
Item 52.
[0072] The kit according to item 51, wherein nalmefene or a
pharmaceutically acceptable salt thereof is dihydrate of nalmefene
or of a pharmaceutically acceptable salt thereof.
Item 53.
[0073] The kit according to item 52, wherein nalmefene or a
pharmaceutically acceptable salt thereof is nalmefene hydrochloride
dihydrate.
Item 54.
[0074] The medicament according to any one of items 1 to 3, for
treating a patient for whom an existing therapeutic drug for
alcohol-related disorder provides only an insufficient effect.
Item 55.
[0075] The medicament according to item 54, wherein the existing
therapeutic drug for alcohol-related disorder is selected from the
group consisting of cyanamide, disulfiram, acamprosate, nalmefene
and naltrexone.
Item 56.
[0076] A medicament for use in the treatment of an alcohol-related
disorder, comprising brexpiprazole or a pharmaceutically acceptable
salt thereof as an active ingredient, which is used for a patient
receiving a treatment with a preparation of nalmefene or a
pharmaceutically acceptable salt thereof.
Item 57.
[0077] A medicament for use in the treatment of an alcohol-related
disorder, comprising nalmefene or a pharmaceutically acceptable
salt thereof as an active ingredient, which is used for a patient
receiving a treatment with a preparation of brexpiprazole or a
pharmaceutically acceptable salt thereof.
Item 58.
[0078] The medicament according to item 6, wherein brexpiprazole or
a pharmaceutically acceptable salt thereof is brexpiprazole, and
nalmefene or a pharmaceutically acceptable salt thereof is
nalmefene hydrochloride dihydrate.
Item 59.
[0079] The medicament according to item 8, wherein brexpiprazole or
a pharmaceutically acceptable salt thereof is brexpiprazole, and
nalmefene or a pharmaceutically acceptable salt thereof is
nalmefene hydrochloride dihydrate.
Item 60.
[0080] Use according to item 14, wherein brexpiprazole or a
pharmaceutically acceptable salt thereof is brexpiprazole, and
nalmefene or a pharmaceutically acceptable salt thereof is
nalmefene hydrochloride dihydrate.
Item 61.
[0081] Use according to item 16, wherein brexpiprazole or a
pharmaceutically acceptable salt thereof is brexpiprazole, and
nalmefene or a pharmaceutically acceptable salt thereof is
nalmefene hydrochloride dihydrate.
Item 62.
[0082] The method according to item 20, wherein brexpiprazole or a
pharmaceutically acceptable salt thereof is brexpiprazole, and
nalmefene or a pharmaceutically acceptable salt thereof is
nalmefene hydrochloride dihydrate.
Item 63.
[0083] The method according to item 22, wherein brexpiprazole or a
pharmaceutically acceptable salt thereof is brexpiprazole, and
nalmefene or a pharmaceutically acceptable salt thereof is
nalmefene hydrochloride dihydrate.
Item 64.
[0084] The pharmaceutical composition according to item 24, wherein
brexpiprazole or a pharmaceutically acceptable salt thereof is
brexpiprazole, and nalmefene or a pharmaceutically acceptable salt
thereof is nalmefene hydrochloride dihydrate.
Item 65.
[0085] The method for producing a pharmaceutical composition
according to item 25, wherein brexpiprazole or a pharmaceutically
acceptable salt thereof is brexpiprazole, and nalmefene or a
pharmaceutically acceptable salt thereof is nalmefene hydrochloride
dihydrate.
Item 66.
[0086] The kit according to item 28, wherein brexpiprazole or a
pharmaceutically acceptable salt thereof is brexpiprazole, and
nalmefene or a pharmaceutically acceptable salt thereof is
nalmefene hydrochloride dihydrate.
Effect of the Invention
[0087] A combined administration of brexpiprazole and nalmefene can
afford a synergistic effect as compared to single administration of
each medicament. A combined use of extremely low doses of
brexpiprazole and nalmefene can suppress an impulsive
ethanol-intake behavior. In addition, the combined use of the both
medicaments is shown to enable brexpiprazole to enhance the
treatment effect of nalmefene. In addition, the combined use of the
both medicaments is shown to enable nalmefene to enhance the
treatment effect of brexpiprazole. Lower side effects are expected
as a result of the lower doses that may be applied.
BRIEF DESCRIPTION OF THE DRAWING
[0088] FIG. 1 is a graph showing the test results of Example 1.
DESCRIPTION OF EMBODIMENTS
[0089] Preferable examples of the pharmaceutically acceptable salt
of brexpiprazole usable in the present invention include salt with
inorganic acid such as sulfate, nitrate, hydrochloride, phosphate,
hydrobromide and the like; salt with organic acid such as acetate,
sulfonate (e.g., p-toluenesulfonate, methanesulfonate,
ethanesulfonate etc.), oxalate, maleate, fumarate, malate,
tartrate, citrate, succinate, pamoate, benzoate and the like.
Brexpiprazole or a pharmaceutically acceptable salt thereof may be
a solvate. The preferred example of the solvate is dihydrate of
brexpiprazole or of a pharmaceutically acceptable salt thereof
(WO2013/162046).
[0090] Brexpiprazole or a pharmaceutically acceptable salt thereof
usable in the present invention is also encompasses the same
isotopically-labeled compounds, wherein one or plural atoms is(are)
replaced by one or plural atoms having a particular atomic mass or
mass number. Examples of the isotope that can be incorporated into
brexpiprazole or a pharmaceutically acceptable salt thereof include
hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine
isotopes such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.18F, .sup.36Cl and the like. Certain
isotopically-labeled brexpiprazole or a pharmaceutically acceptable
salt thereof, which contains the above-mentioned isotope and/or
other isotope of other atom, for example, brexpiprazole or a
pharmaceutically acceptable salt thereof incorporating a
radioactive isotope such as .sup.3H, .sup.14C and the like, is
useful for drug tissue distribution assay and/or substrate tissue
distribution assay. Tritiated (i.e., .sup.3H) or carbon-14 (i.e.,
.sup.4C) isotope are particularly preferred because of easiness of
preparation and detectability. Furthermore, substitution with a
heavier isotope such as deuterium (i.e., .sup.2H) and the like is
expected to provide improved metabolic stability and particular
therapeutic advantage attributable to increased in vivo half-life
or decreased amount necessary for administration. An
isotopically-labeled compound of brexpiprazole or a
pharmaceutically acceptable salt thereof can be generally prepared
according to the method disclosed in WO2006/112464 and
WO2013/162046, by substituting a non-isotopically-labeled reagent
with an easily available isotopically-labeled reagent.
[0091] Brexpiprazole or a pharmaceutically acceptable salt thereof,
a production method thereof, a dose to be used thereof and the like
are disclosed in WO2006/112464 and WO2013/162046, and the
disclosure thereof is incorporated herein by reference.
[0092] Nalmefene or a pharmaceutically acceptable salt thereof, a
production method thereof, a dose to be used thereof and the like
are disclosed in U.S. Pat. No. 3,814,768, U.S. Pat. No. 4,751,307,
U.S. Pat. No. 4,535,157 and WO2010/063292, and the disclosure
thereof is incorporated herein by reference.
[0093] Examples of the pharmaceutically acceptable salt of
nalmefene include hydrochloride, hydrochloride monohydrate,
hydrochloride dihydrate and the like. A more preferable example is
nalmefene hydrochloride dihydrate.
[0094] A medicament using brexpiprazole or a pharmaceutically
acceptable salt thereof in combination with nalmefene or a
pharmaceutically acceptable salt thereof has an excellent effect.
Therefore, such medicament is expected to cause a fewer side
effects and has an excellent safety profile as a results of lower
doses that may be applied.
[0095] Brexpiprazole or a pharmaceutically acceptable salt thereof
and nalmefene or a pharmaceutically acceptable salt thereof may be
administered orally or parenterally.
[0096] In the present specification, when a medicament comprising
brexpiprazole or a pharmaceutically acceptable salt thereof in
combination with nalmefene or a pharmaceutically acceptable salt
thereof is used, the administration period of brexpiprazole or a
pharmaceutically acceptable salt thereof and nalmefene or a
pharmaceutically acceptable salt thereof is not limited, and
brexpiprazole or a pharmaceutically acceptable salt thereof and
nalmefene or a pharmaceutically acceptable salt thereof may be
simultaneously formulated into a single preparation, or
brexpiprazole or a pharmaceutically acceptable salt thereof or a
pharmaceutical composition thereof and nalmefene or a
pharmaceutically acceptable salt thereof or a pharmaceutical
composition thereof may be administered to a subject of
administration simultaneously or in a staggered manner. When
brexpiprazole or a pharmaceutically acceptable salt thereof and
nalmefene or a pharmaceutically acceptable salt thereof are
administered, they may be administered simultaneously.
Alternatively, nalmefene or a pharmaceutically acceptable salt
thereof may be administered in advance, and then brexpiprazole or a
pharmaceutically acceptable salt thereof may be administered, or
brexpiprazole or a pharmaceutically acceptable salt thereof may be
administered in advance, and then nalmefene or a pharmaceutically
acceptable salt thereof may be administered. For administration in
a staggered manner, the time difference varies depending on the
dosage form and administration method. For example, when
brexpiprazole or a pharmaceutically acceptable salt thereof is to
be administered in advance, a method including administering
nalmefene or a pharmaceutically acceptable salt thereof within 1
min-3 days, preferably 10 min-1 day, more preferably 15 min-1 hr,
after the administration of brexpiprazole or a pharmaceutically
acceptable salt thereof can be mentioned. The dose of nalmefene or
a pharmaceutically acceptable salt thereof may be similar to the
dose clinically used, and can be appropriately determined according
to the subject of administration, administration route, disease and
the like.
[0097] The administration form of the medicament of the present
invention is not particularly limited, and brexpiprazole or a
pharmaceutically acceptable salt thereof and nalmefene or a
pharmaceutically acceptable salt thereof only need to be combined
on administration. Examples of such administration form include (1)
administration of a single preparation obtained by simultaneously
formulating brexpiprazole or a pharmaceutically acceptable salt
thereof and nalmefene or a pharmaceutically acceptable salt
thereof, (2) simultaneous administration of two kinds of
preparations obtained by separately formulating brexpiprazole or a
pharmaceutically acceptable salt thereof and nalmefene or a
pharmaceutically acceptable salt thereof by the same administration
route, (3) administration of two kinds of preparations obtained by
separately formulating brexpiprazole or a pharmaceutically
acceptable salt thereof and nalmefene or a pharmaceutically
acceptable salt thereof by the same administration route in a
staggered manner (e.g., administration in the order of
brexpiprazole or a pharmaceutically acceptable salt thereof;
nalmefene or a pharmaceutically acceptable salt thereof, or
administration in the reverse order), (4) simultaneous
administration of two kinds of preparations obtained by separately
formulating brexpiprazole or a pharmaceutically acceptable salt
thereof and nalmefene or a pharmaceutically acceptable salt thereof
by different administration routes, (5) administration of one or
more kinds of preparations obtained by separately formulating
brexpiprazole or a pharmaceutically acceptable salt thereof and
nalmefene or a pharmaceutically acceptable salt thereof by
different administration routes in a staggered manner (e.g.,
administration in the order of brexpiprazole or a pharmaceutically
acceptable salt thereof; nalmefene or a pharmaceutically acceptable
salt thereof, or in the reverse order) and the like.
[0098] The medicaments of the present invention comprising
brexpiprazole or a pharmaceutically acceptable salt thereof,
nalmefene or a pharmaceutically acceptable salt thereof and/or
brexpiprazole or a pharmaceutically acceptable salt thereof and
nalmefene or a pharmaceutically acceptable salt thereof in
combination, which are constituent components of the present
invention, show low toxicity and, for example, brexpiprazole or a
pharmaceutically acceptable salt thereof and/or nalmefene or a
pharmaceutically acceptable salt thereof can be mixed with a
pharmacologically acceptable carrier according to a known method to
give a pharmaceutical composition, such as tablets (including
sugar-coated tablet, film-coated tablet), powders, granules,
capsules (including soft capsule), liquids, injections,
suppositories, sustained-release preparations and the like, which
can be safely administered orally or parenterally (e.g., local,
rectum, vein, and the like). An injection can be administered by
intravenous, intramuscular, subcutaneous or intraorgan
administration or directly to the lesion. As a pharmacologically
acceptable carrier which may be used for producing the
pharmaceutical composition of the present invention, excipient,
disintegrant, binder, glidant, lubricant, coating agent, colorant,
suspending agent, sweetening agent or surfactant is appropriately
used, and a general pharmaceutical preparation is formed according
to a known method. Examples of the form of the pharmaceutical
preparation include powder, tablet, pill, capsule and the like.
[0099] Examples of the excipient include lactose, anhydrous
lactose, purified sucrose, sucrose, D-mannitol, D-sorbitol,
xylitol, erythritol, dextrin, crystalline cellulose,
microcrystalline cellulose, cornstarch, potato starch, anhydrous
calcium hydrogen phosphate and the like.
[0100] Examples of the disintegrant include sodium carboxymethyl
starch, carmellose, carmellose calcium, carmellose sodium,
croscarmellose sodium, crospovidone, low-substituted
hydroxypropylcellulose, partially pregelatinized starch and the
like.
[0101] Examples of the binder include hydroxypropylcellulose,
hydroxypropylmethylcellulose, polyvinylpyrrolidone, pregelatinized
starch, syrup, starch syrup and the like.
[0102] Examples of the glidant include light anhydrous silicic
acid, synthetic aluminum silicate, hydrated silicon dioxide,
calcium stearate, magnesium aluminometasilicate, talc and the
like.
[0103] Examples of the lubricant include magnesium stearate,
calcium stearate, magnesium silicate, magnesium oxide, talc,
hydrogenated oil, sucrose fatty acid ester, sodium stearyl fumarate
and the like.
[0104] Examples of the coating agent include
hydroxypropylmethylcellulose, polyvinyl alcohol, polysorbate,
macrogol, talc and the like.
[0105] Examples of the colorant include yellow iron sesquioxide,
brown iron oxide, iron sesquioxide, black iron oxide, titanium
oxide, Food Blue No. 1, Food Red No. 2, Food Red No. 3, Food Yellow
No. 4 and the like.
[0106] Examples of the suspending agent include polysorbate,
polyethylene glycol, gum arabic, glycerol, gelatin and the
like.
[0107] Examples of the sweetening agent include aspartame,
saccharin, saccharin sodium, starch syrup, fructose and the
like.
[0108] Examples of the surfactant include sodium lauryl sulfate,
polysorbate, polyoxyethylene hydrogenated castor oil and the
like.
[0109] A capsule is prepared by filling a hard capsule such as
gelatin capsule, hydroxypropylmethylcellulose capsule, polyvinyl
alcohol capsule and the like or a soft capsule based on gelatin,
according to a known method. Conventional various organic or
inorganic carrier substances can be used as preparation starting
materials and examples thereof include excipient, lubricant, binder
and disintegrant for solid preparations, and solvent, solubilizing
agent, suspending agent, isotonic agent, buffering agent and
soothing agent for liquid preparations and the like. Furthermore,
where necessary, additives such as general preservative,
antioxidant, colorant, sweetening agent, adsorbent, wetting agent
and the like can be appropriately used in an appropriate
amount.
Dose
[0110] The dose of brexpiprazole or a pharmaceutically acceptable
salt thereof and nalmefene or a pharmaceutically acceptable salt
thereof to be used in the present invention is determined in
consideration of the properties of the drug after combination, and
the condition of the patients. As shown above, brexpiprazole or a
pharmaceutically acceptable salt thereof and nalmefene or a
pharmaceutically acceptable salt thereof may be separately
administered without being combined in one composition. As the
general outline of the dose, for example, the following guideline
can be applied.
[0111] In the following description of the dose, for example,
"about 0.005-about 50 mg/2 times/1 day" means administration of
about 0.005-about 50 mg per administration twice a day.
[0112] Brexpiprazole or a pharmaceutically acceptable salt thereof:
generally about 0.01-about 100 mg/l time/1 day (or about
0.005-about 50 mg/2 times/1 day), preferably about 0.1-about 4 mg/l
time/1 day (or about 0.05-about 2 mg/2 times/1 day). The dose may
be 0.05-2 mg/l time/1 day on an as-needed basis.
[0113] Nalmefene or a pharmaceutically acceptable salt thereof:
generally about 0.1-about 100 mg/l time/1 day (or about 0.05-about
50 mg/2 times/1 day), preferably about 1-about 20 mg/l time/1 day
(or about 0.5-about 10 mg/2 times/1 day). The dose may be 0.5-10
mg/l time/1 day on an as-needed basis.
[0114] In the present invention, the proportion of brexpiprazole or
a pharmaceutically acceptable salt thereof and nalmefene or a
pharmaceutically acceptable salt thereof to be used may be
generally about 0.01-about 500 parts by weight, preferably about
0.1-about 100 parts by weight, of the latter relative to 1 part by
weight of the former.
[0115] The mixing ratio of brexpiprazole or a pharmaceutically
acceptable salt thereof and nalmefene or a pharmaceutically
acceptable salt thereof in the medicament of the present invention
can be appropriately determined according to the subject of
administration, administration route, disease and the like. For
example, while the total proportion of brexpiprazole or a
pharmaceutically acceptable salt thereof and nalmefene or a
pharmaceutically acceptable salt thereof in the medicament of the
present invention varies depending on the preparation form, it is
generally about 0.01-about 99.99 wt %, preferably about 0.1-about
99.9 wt %, more preferably about 1-about 30 wt %, relative to the
whole preparation. The above-mentioned pharmacologically acceptable
carrier is used for the remaining part.
[0116] In addition, when brexpiprazole or a pharmaceutically
acceptable salt thereof and nalmefene or a pharmaceutically
acceptable salt thereof are to be separately formulated, a similar
content may be used.
[0117] The present invention may also be in the form of a kit
comprising a medicament containing brexpiprazole or a
pharmaceutically acceptable salt thereof and a medicament
containing nalmefene or a pharmaceutically acceptable salt thereof,
which are separately formulated. The kind of the preparation is not
particularly limited, and tablets (including sugar-coated tablet,
film-coated tablet), powder, granule, capsule (including soft
capsule), liquid, injection, suppository, sustained-release
preparation and the like can be mentioned. Preferred is, for
example, a kit comprising an oral preparation containing
brexpiprazole or a pharmaceutically acceptable salt thereof
(tablet, powder, granule, capsule or liquid), and an oral
preparation containing nalmefene or a pharmaceutically acceptable
salt thereof (tablet, powder, granule, capsule or liquid).
[0118] The medicament and pharmaceutical composition of the present
invention are useful for the prophylaxis or treatment of
substance-related disorders (e.g., alcohol-related disorder
(alcohol use disorder, alcohol-induced disorder, alcohol abuse,
alcohol dependence, alcohol intoxication, alcohol withdrawal
symptoms, etc.), amphetamine-related disorder (amphetamine use
disorder etc.), cannabis-related disorder (cannabis use disorder
etc.), cocaine-related disorder (cocaine use disorder etc.),
hallucinogen-related disorder (hallucinogen use disorder etc.) and
the like).
[0119] In addition, the medicament and pharmaceutical composition
of the present invention are useful for the prophylaxis or
treatment of an impulsive symptom in substance-related disorders
(e.g., alcohol-related disorder (alcohol use disorder,
alcohol-induced disorder, alcohol abuse, alcohol dependence,
alcohol intoxication, alcohol withdrawal symptoms, etc.),
amphetamine-related disorder (amphetamine use disorder etc.),
cannabis-related disorder (cannabis use disorder etc.),
cocaine-related disorder (cocaine use disorder etc.),
hallucinogen-related disorder (hallucinogen use disorder etc.) and
the like).
[0120] The medicament and pharmaceutical composition of the present
invention are particularly useful for the prophylaxis or treatment
of alcohol-related disorders, and the prophylaxis or treatment of
an impulsive symptom in alcohol-related disorders.
[0121] The impulsive symptom is a symptom associated with an
impulsive action. Specific examples of the impulsive behavior
include physical attack, wandering, restlessness, agitation,
senseless behavior and deviant behavior (e.g., sexual deviant
behavior), roaming, shrill voice, screaming, violent language, loss
of motivation, constant questioning, shadowing, suicide attempt and
suicide, self-injurious behavior, threat, stealing, overeating, act
of threatening, short-circuit reaction, panic reaction, property
damage, inappropriate dressing/undressing, underselling and the
like. Specific examples of the impulsive symptom in alcohol-related
disorders include not only impulsive drinking behavior wherein a
patient cannot suppress an intake action of alcohol, but also a
symptom to take quick action to satisfy the immediate desire even
though it can lead to an m undesirable effect in the future. In the
latter case, patients often commit a crime such as violent behavior
and the like.
[0122] The medicament and pharmaceutical composition of the present
invention can be used for treating a patient for whom an existing
therapeutic drug for alcohol-related disorder provides only an
insufficient effect.
[0123] The "patient for whom an existing therapeutic drug for
alcohol-related disorder provides only an insufficient effect"
means "those who could not achieve a Medium risk (male: 41 to 60
g/day, female: 21 to 40 g/day) or below in a sobriety treatment
according to the standard of WHO drinking classification
(WHO/MSD/MSB/00.4, INTERNATIONAL GUIDE FOR MONITORING ALCOHOL
CONSUMPTION AND RELATED HARM, chapter 2.2 and The quantification of
drug-caused mortality and morbidity in Australia, 1998, chapter
2.5.1), or those who could not achieve abstinence from alcohol by
an alcohol abstinence therapy".
[0124] Examples of the existing therapeutic drugs for
alcohol-related disorder includes
(1) antialcoholic drugs (cyanamide, disulfiram, etc.), (2)
therapeutic drugs for alcohol dependence (acamprosate etc.), (3)
drugs for reducing alcohol consumption (nalmefene, naltrexone
etc.), (4) antipsychotics (atypical antipsychotics such as
aripiprazole, quetiapine, olanzapine, risperidone, etc. and typical
antipsychotics), (5) antiepileptic agents (topiramate, zonisamide,
gabapentin, vigabatrin, lamotrigine, valproic acid, carbamazepine,
etc.), (6) antidepressants [selective serotonin reuptake inhibitors
(fluoxetine, citalopram, fluvoxamine, paroxetine, sertraline,
escitalopram, etc.), serotonin and norepinephrine reuptake
inhibitors (venlafaxine, duloxetine, milnacipran, desvenlafaxine,
etc.), noradrenergic and specific serotonergic antidepressants
(mirtazapine etc.), tricyclic and tetracyclic antidepressants
(desipramine etc.), monoamine oxidase inhibitors, etc.], (7)
antianxiety drugs or sleeping drugs (ethyl loflazepate, etizolam,
nitrazepam, flunitrazepam, zopiclone, mianserin, trazodone,
ramelteon, tandospirone, etc.), (8) others. (varenicline,
bupropion, atomoxetine, ibudilast, baclofen, buspirone, etc.), and
the like.
EXAMPLE
Reference Example 1
1) Alcohol Withdrawal-Induced Locomotor Activity Increasing Action
in Alcohol Dependence Mice
[0125] In reference to a report that alcohol dependence can be
formed by breeding mice on a liquid diet containing ethanol for 5
days (Narita M et al., Eur J Pharmacol 401 (2000) 191-5), and based
on a report that rats bred on a liquid diet containing ethanol show
increase in locomotor activity along with withdrawal syndrome after
ethanol withdrawal (Iso H, Jpn J Psychopharmacol 3 (1983) 23-8),
locomotor activity after withdrawal was measured in alcohol
dependence mice. As a result, significant increase in locomotor
activity was confirmed. The alcohol withdrawal-induced locomotor
activity increasing action in the alcohol dependence mice may be
deeply involved in various symptoms, particularly impulsive
symptoms, associated with alcohol-related disorders.
[0126] The effect of combined use of brexpiprazole and nalmefene
can be confirmed by measuring alcohol withdrawal-induced locomotor
activity increasing action in alcohol dependence mice. Measurement
method: Alcohol dependence mice are generated by breeding C57BL/6J
mice (male) under individual housing for 5 days with free ingestion
of skimmed milk containing 3% ethanol. On day 6, locomotor activity
is measured after changing to an ethanol-free diet. An animal with
average ethanol intake on days 2 to 4 of not less than 20 g/kg/day,
and the body weight of not less than 14.5 g on day 5 is subjected
to the test.
2) Preparation of Drug, Administration Method and Determination of
Dose
[0127] Brexpiprazole is suspended in distilled water containing 5%
gum arabic. The drug is orally administered to each mouse
immediately before measurement of the locomotor activity on day 6.
The dose of brexpiprazole is set to 0.02 to 0.03 mg/kg.
3) Preparation of Drug, Administration Method and Determination of
Dose
[0128] Nalmefene hydrochloride monohydrate is dissolved in saline.
The drug is subcutaneously administered to each mouse immediately
before measurement of the locomotor activity on day 6. The dose of
nalmefene hydrochloride monohydrate is set to 0.08 to 0.12
mg/kg.
4) Measurement of Locomotor Activity
[0129] The ethanol withdrawal-induced locomotor activity increasing
action is measured by calculating difference between the locomotor
activity on day 5 and the locomotor activity on day 6 after ethanol
withdrawal in each animal.
Example 1
1) Measurement of Alcohol Intake by Limited Access Paradigm
[0130] Measurement method: An impulsive behavior of cravings for
drinking alcohol was evaluated as follows by reference to the
method of Sinclair et al. (Alcohol 1992; 9:441-44 and Alcohol &
Alcoholism 2001; 36:2-10). First, Wistar rats (male) were allowed
to freely drink 10% aqueous ethanol solution and tap water for
several weeks under isolated rearing. After the ethanol intake of
each animal became stable, limited access paradigm allowing ethanol
intake only for 1 hr per day was started, and the ethanol intake in
1 hr was measured every day. The ethanol intake was calculated from
the results of weight measurement of a water supply bottle filled
with 10% aqueous ethanol solution immediately before the start of
the limited access paradigm and immediately after the completion of
the limited access paradigm. Animals that showed an average ethanol
intake of not less than 0.4 g/kg/hr based on 100% ethanol in the
limited access paradigm for 4 days immediately before drug
evaluation were used. The limited access paradigm test was
performed during 9:00 AM-4:00 PM.
2) Preparation of Drug, Administration Method and Determination of
Dose
[0131] Brexpiprazole was suspended in distilled water containing 5%
gum arabic. The drug was orally administered to each rat once per
day for 4 days at 1 hr before the start of the limited access
paradigm. The dose of brexpiprazole was selected to be 0.01 mg/kg
that does not, by itself, influence the ethanol intake and the
spontaneous locomotor activity under novel environments (data not
shown).
3) Preparation of Drug, Administration Method and Determination of
Dose
[0132] Nalmefene hydrochloride monohydrate (Tocris Bioscience) was
dissolved in saline. The drug was subcutaneously administered to
each rat once per day for 4 days at 1 hr before the start of the
limited access paradigm. The dose of nalmefene hydrochloride
monohydrate was selected to be 0.04 mg/kg that does not, by itself,
influence the ethanol intake and the spontaneous locomotor activity
under novel environments (data not shown).
4) Number of Rats
[0133] Twelve rats were used in total. A test using 3 rats per
group was performed twice to make 6 rats for each group. The
animals were repeatedly used after a sufficient period of drug
cessation.
5) Statistical Analysis
[0134] The significance level of the test was set to 5%. As a
statistical software, SAS (R9.3, SAS Institute Japan) was used. The
difference between an average ethanol intake in the limited access
paradigm for 4 days immediately before drug evaluation and an
average ethanol intake in the limited access paradigm for 4 days
during the drug administration period was calculated for every
animal, and analyzed by two-way factorial analysis of variance by
using the presence or absence of brexpiprazole and the presence or
absence of nalmefene as factors.
6) Results
[0135] The test results are shown in FIG. 1.
[0136] To the rats confirmed to ingest ethanol at not less than 0.4
g/kg/hr on average of 4 days in the limited access paradigm were
administered brexpiprazole orally at 0.01 mg/kg at 1 hr before
ethanol intake and nalmefene hydrochloride monohydrate
subcutaneously at 0.04 mg/kg at 20 min before ethanol intake, both
for 4 days, and a difference between an average ethanol intake in
the limited access paradigm for 4 days before administration and an
average ethanol intake for 4 days during the dosing period was
calculated and analyzed by two-way factorial analysis of variance.
As a result, only the brexpiprazole and nalmefene combined use
group showed a significant decrease in the ethanol intake
(interaction: p=0.0033). This statistically shows that a combined
use of the both drugs has a synergistic effect.
[0137] From the above-mentioned results, it has been clarified
that, in the limited access paradigm to 10% aqueous ethanol
solution, brexpiprazole and nalmefene can suppress impulsive
ethanol intake behavior of Wistar rats by a combined use of
extremely low doses thereof. There is a report stating that
nalmefene, which has been clinically confirmed to suppress
impulsive drinking behavior of patients with alcohol dependence and
enable control of alcohol consumption, shows effects in this
evaluation system when used singly at a dose about 10 times higher
than the dose used in the present test (Alcohol & Alcoholism
2001; 36: 2-10). Therefore, the test results show that the combined
use of the both medicaments not only suppresses impulsive drinking
behavior of patients with alcohol dependence but also enables
brexpiprazole to enhance treatment effects of nalmefene.
Conversely, the test results show that the combined use of the both
medicaments enables nalmefene to enhance treatment effects of
brexpiprazole. Lower side effects are expected as a result of the
lower doses that may be applied.
[0138] This application is based on patent application No.
2014-88148 filed in Japan, the entire contents of which are
incorporated by reference herein.
* * * * *