Note: Descriptions are shown in the official language in which they were submitted.
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
1
TREATMENT OF DEPRESSION AND OTHER AFFECTIVE DISORDERS
Field of invention
The present invention relates to the use of gaboxadol for the preparation of
medicaments
useful for the treatment of depression. The present invention also relates to
the use of a
combination of gaboxadol and a serotonin reuptake inhibitor (SRI), or any
other compound,
which causes an elevation in the level of extracellular serotonin, for the
treatment of
depression and other affective disorders.
Background of the Invention
Gaboxadol (THIP), described in EP patent 0000338 B1 and in EP Patent 0840601
B1, have
shown great potential in the treatment of sleep disorders.
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs)
have become first
choice therapeutics in the treatment of depression, certain forms of anxiety
and social
phobias, because they are effective, well tolerated and have a favourable
safety profile
compared to the classic tricyclic antidepressants.
However, clinical studies on depression and aiixiety disorders indicate that
non-response to
SSRIs is substantial, up to 30%. Another, often neglected, factor in
antidepressant treatment
is compliance, which has a rather profound effect on the patient's motivation
to continue
pharmacotherapy.
Description of the Invention
According to the present invention a phannaceutical composition for the
treatment of
depression is provided.
Gaboxadol has the general formula
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
2
OH
\ N
HN 0 /
and throughout the description "gaboxadol" is intended to include any form of
the
compound, such as the base (zwitter ion), pharmaceutically acceptable salts,
e.g.
pharmaceutically acceptable acid addition salts, hydrates or solvates of the
base or salt, as
well as anhydrates, and also amorphous, or crystalline forms.
More specifically, the present invention relates to the use of gaboxadol
having the general
formula
OH
\ N
HN
0
for the preparation of a pharmaceutical composition for the treatment of
depression.
In a further aspect, the present invention relates to a method for the
treatment of depression
comprising administering to an individual in need thereof a pharmaceutically
acceptable
amount of gaboxadol. Such individual is preferably a human, such as male or
female human,
child, adult or elderly.
According to the invention, gaboxadol may be used as the base (the zwitter
ion) or as a
pharmaceutically acceptable acid addition salt thereof or as an anhydrate or
hydrate of such
salt or base. The salts of the compound used in the invention are salts formed
with non-toxic
organic or inorganic acids. Exemplary of such organic salts are those with
maleic, fumaric,
benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic,
ethane-
disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic,
malic, mandelic,
cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-
benzoic,
glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-
halotheophyllines,
for example 8-bromo-theophylline. Exemplary of such inorganic salts are those
with
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
3
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
Gaboxadol may
also be used as the zwitter ion, e.g. the mono hydrate thereof.
The acid addition salts according to the invention may be obtained by
treatinent of
gaboxadol with the acid in an inert solvent followed by precipitation,
isolation and
optionally re-crystallisation by lalown methods and if desired micronisation
of the
crystalline product by wet or dry milling or another convenient process, or
preparation of
particles from a solvent-emulsification process. Suitable methods are
described in EP patent
0000338.
Precipitation of the salt is typically carried out in an inert solvent, e.g.
an inert polar solvent
such as an alcohol (e.g. ethanol, 2-propanol and n-propanol), but water or
mixtures of water
and inert solvent may also be used.
In an embodiment, gaboxadol is used in the form of an acid addition salt, or a
zwitter ion
hydrate or zwitter ion anhydrate. In a further embodiment, gaboxadol is used
in the form of
the pharmaceutically acceptable acid addition salt selected from the
hydrochloride or
hydrobromide salt, or in the form of the zwitter ion monohydrate. Most
conveniently,
gaboxadol is in a crystalline form.
According to the invention, gaboxadol may be administered in any suitable way
e.g. orally
or parenterally, and it may be presented in any suitable form for such
administration, e.g. in
the foim of tablets, capsules, powders, syrups or solutions or dispersions for
injection.
Preferably, and in accordance with the purpose of the present invention,
gaboxadol is
administered in the form of a solid pharmaceutical entity, suitably as a
tablet or a capsule or
in the form of a suspension, solution or dispersion for injection.
Methods for the preparation of solid pharmaceutical preparations are well
known in the art.
Tablets may thus be prepared by mixing the active ingredients with ordinary
adjuvants
and/or diluents and subsequently compressing the mixture in a convenient
tabletting
machine. Examples of adjuvants or diluents comprise: corn starch, lactose,
talcum,
magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant
or additive
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
4
such as colourings, aroma, preservatives, etc. may also be used provided that
they are
compatible with the active ingredients.
A suitable formulation of gaboxadol is described in WO 02/094225 filed May 17,
2002.
Without limiting the invention in any way, it is intended that any one of the
aspects or
embodiments of this patent application is suitable embodiments of the
medicament or
pharmaceutical compositions herein.
Gaboxadol is typically adininistered as an oral dose form, such as a solid
oral dose form,
typically tablets or capsules, or as a liquid oral dose foim. Gaboxadol is
most conveniently
administered orally in unit dosage forms such as tablets or capsules,
containing the active
ingredient in an amount from about 0.1 to about 150 mg/day, such as from about
0.1 to
about 100 mg/day, typically from about 0.5 to about 50 mg/day, preferably from
about 2.5
to about 20 mg/day, e.g. from about 5 to about 15 mg/day. The amount of
gaboxadol is
calculated based on the free base form.
Gaboxadol may be administered as monotherapy or as combination therapy with
other
drugs. In a particular aspect, gaboxadol may be combined with a serotonin
reuptake
inhibitor as described below.
The combination of gaboxadol with a serotonin reuptake inhibitor
In addition, gaboxadol may be used to augment and provide faster onset of the
therapeutic
effect of serotonin reuptake inhibitors, in particular citalopram and
escitalopram.
It has now surprisingly been found that gaboxadol may be used to augment and
provide
faster onset of the therapeutic effect of serotonin reuptake inhibitors.
In one aspect, the invention relates to use of gaboxadol for the preparation
of a
phannaceutical composition to be used in combination with a serotonin reuptake
inhibitor or
any other compound, which causes an elevation in the level of extracellular
serotonin.
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
In another aspect, the invention relates to use of gaboxadol for the
preparation of a
pharmaceutical composition useful for augmenting and/or providing faster onset
of the
therapeutic effect of a serotonin reuptake inhibitor or any other compound,
which causes an
elevation in the level of extracellular serotonin.
5
In a further aspect, the invention relates to a pharmaceutical composition or
kit comprising
gaboxadol and a compound, which is a serotonin reuptake inhibitor, or any
other compound
which causes an elevation in the level of extracellular serotonin, and
optionally
pharmaceutically acceptable carriers or diluents.
In a further aspect, the invention relates to a method for the treatment of
diseases or
disorders responsive to a serotonin reuptake inhibitor or any other compound
which causes
an elevation in the level of extracellular serotonin, comprising administering
gaboxadol and
a serotonin reuptake inhibitor, or a compound which causes an elevation in the
level
extracellular serotonin, to an individual in need thereof.
In a fiuther aspect, the invention relates to use of gaboxadol and a compound,
which is a
serotonin reuptake inhibitor, or any other compound which causes an elevation
in the level
of extracellular serotonin, for the preparation of a pharmaceutical
composition for the
treatment of diseases or disorders responsive to the therapeutic effect of a
serotonin reuptake
inhibitor or any other compound causing an elevation in the level of
extracellular serotonin.
In a further aspect, the invention relates to use of gaboxadol for the
preparation of a
pharmaceutical composition for the treatment of an individual to be treated
with or
undergoing treatment with the serotonin reuptake inhibitor, or any other
compound which
causes an elevation in the level of extracellular serotonin, wherein said
individual suffers
from diseases or disorders responsive to the therapeutic effect of a serotonin
reuptalce
inhibitor or any other compound causing an elevation in the level of
extracellular serotonin.
In a further aspect, the invention relates to use of gaboxadol and a compound,
which is a
serotonin reuptake inhibitor, or any other compound which causes an elevation
in the level
of extracellular serotonin, for the preparation of a kit for the treatment of
diseases or
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
6
disorders responsive to the therapeutic effect of a serotonin reuptake
inhibitor or any other
compound causing an elevation in the level of extracellular serotonin.
In a further aspect, the invention relates to a method for augmenting and/or
providing faster
onset of the therapeutic effect of a serotonin reuptake inhibitor, or any
other compound
which causes an elevation in the level of extracellular serotonin, comprising
administering
gaboxadol to an individual to be treated with or undergoing treatment with the
serotonin
reuptalce inhibitor, or any other compound which causes an elevation in the
level of
extracellular serotonin. Such individual is preferably a human, such as male
or female
human, child, adult or elderly.
In an embodiment, the serotonin reuptake inhibitor or the compound which
causes an
elevation in the level of extracellular serotonin is used in the treatment of
depression,
anxiety disorders and other affective disorders, eating disorders such as
bulimia, anorexia
and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders,
iunpulse
control disorders, attention deficit hyperactivity disorder and drug abuse, in
particular
depression.
In a fizrther embodiment, the serotonin reuptake inhibitor or the compound
which causes an
elevation in the level of extracellular serotonin is used in the treatment of
anxiety disorders
including general anxiety disorder, panic anxiety, obsessive compulsive
disorder, acute
stress disorder, post trauma stress disorder or social anxiety disorder.
In a further embodiment, the serotonin reuptake inhibitor is selected from
citalopram,
escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine,
duloxetine,
dapoxetine, nefazodone, imipramin, femoxetine and clomipramine or a
pharmaceutically
acceptable salt of any of these compounds. Just to clarify, each of the
serotonin reuptake
inhibitors specified above is intended to be an individual embodiment.
Accordingly, each of
them and the use thereof may be claimed individually.
In a further embodiment, the serotonin reuptake inhibitor is a selective
serotonin reuptake
inhibitor (SSRI).
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
7
In a further embodiment, the pharmaceutical composition or kit prepared is
adapted for
simultaneous administration of the active ingredients. In an embodiment, the
active
ingredients are contained in the same unit dosage form.
In a further embodiment, the pharmaceutical composition or kit prepared is
adapted for
sequential administration of the active ingredients. In an embodiment, the
active ingredients
are contained in discrete unit dosage forms.
In a further aspect, the present invention relates to the use of gaboxadol for
the preparation
of a pharmaceutical composition to be used in combination with a serotonin
reuptake
inhibitor or any other compound which causes an elevation in the level of
extracellular
serotonin.
In particular, the present invention relates to the use of gaboxadol for the
preparation of a
pharmaceutical composition useful for augmenting and/or providing faster onset
of the
therapeutic effect of a serotonin reuptake inhibitor or any other compound
which causes an
elevation in the level of extracellular serotonin.
More particularly, the present invention relates to the use as above, of
gaboxadol, for the
treatment of depression, anxiety disorders and other affective disorders, such
as generalized
anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress
disorder, post
traumatic stress disorder and social anxiety disorder eating disorders such as
bulimia,
anorexia and obesity, phobias, dysthymia, premenstraal syndrome, cognitive
disorders,
impulse control disorders, attention deficit hyperactivity disorder and drug
abuse, in
particular depression with a serotonin reuptake inhibitor or any other
compound which
causes an elevation in the level of extracellular serotonin.
The anxiety disorders mentioned above include general anxiety disorder, panic
anxiety,
obsessive compulsive disorder, acute stress disorder, post trauma stress
disorder or social
anxiety disorder.
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
8
As used herein, the term augmenting covers improving the therapeutic effect
and/or
potentiating the therapeutic effect of an SRI or a compound which causes an
elevation in the
level of extracellular 5-HT.
In a further embodiment, the invention relates to the use of gaboxadol and a
compound,
which is a serotonin reuptake inhibitor, or a compound, which causes an
elevation in the
level of extracellular serotonin, for the preparation of a pharmaceutical
composition for the
treatment of diseases or disorders responsive to the therapeutic effect of a
serotonin reuptake
inhibitor, or any other compound, which causes an elevation in the level of
extracellular
serotonin.
In a further embodiment, the invention relates to the use of gaboxadol and a
compound,
which is a serotonin reuptake inhibitor, or a compound, which causes an
elevation in the
level of extracellular serotonin, for the preparation of a kit-of-parts (kit)
for the treatment of
diseases or disorders responsive to the therapeutic effect of a serotonin
reuptake inhibitor, or
any other compound, which causes an elevation in the level of extracellular
serotonin.
The diseases responsive to a serotonin reuptake inhibitor include depression,
anxiety
disorders and other affective disorders, eating disorders such as bulimia,
anorexia and
obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders,
impulse control
disorders, attention deficit hyperactivity disorder and drug abuse, in
particular depression.
The term anxiety disorders is as defined above.
In one embodiment, the present invention relates to the use of gaboxadol for
the preparation
of a pharmaceutical composition as above, which is adapted for simultaneous
administration
of the active ingredients. In particular, such pharmaceutical compositions may
contain the
active ingredients within the same unit dosage fonn, e.g. in the same tablet
or capsule. Such
unit dosage forms may contain the active ingredients as a homogenous mixture
or in
separate compartments of the unit dosage form.
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
9
In another embodiment, the present invention relates to the use of gaboxadol
for the
preparation of a pharmaceutical composition or kit as above, which is adapted
for sequential
administration of the active ingredients. In particular, such pharmaceutical
compositions
may contain the active ingredients in discrete unit dosage forms, e.g.
discrete tablets or
capsules containing either of the active ingredients. These discrete unit
dosage forms may
be contained in the same container or package, e.g. a blister pack.
As used herein the term kit means a pharmaceutical composition containing each
of the
active ingredients, but in discrete unit dosage forms.
The invention also relates to a pharmaceutical composition or kit comprising
gaboxadol and
a compound, which is a serotonin reuptalce inhibitor, or any other compound
which causes
an elevation in extracellular 5-HT, and optionally phannaceutically acceptable
carriers or
diluents.
The pharmaceutical composition or kit of the invention may be adapted for
simultaneous
administration of the active ingredients or for sequential administration of
the active
ingredients, as described above.
Finally, the present invention relates to a method for the treatment of
diseases or disorders
responsive to a serotonin reuptake nihibitor or any other compound which
causes an
elevation in the level of extracellular serotonin, comprising administering
gaboxadol and a
serotonin reuptalce inhibitor, or a compound which causes an elevation in the
level
extracellular serotonin, to an individual in need thereof.
In particular, the present invention relates to a method for augmenting and/or
providing
faster onset of the therapeutic effect of a serotonin reuptake inhibitor or
any other compound
wliich causes an elevation in the level extracellular serotonin, comprising
administering
gaboxadol to an individual to be treated with or undergoing treatment with the
serotonin
reuptake inhibitor or any other compound which causes an elevation in the
level of
extracellular serotonin.
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
The individuals, which may benefit fiom treatment with a combination as above,
may suffer
from depression, anxiety disorders and other affective disorders, eating
disorders such as
bulimia, anorexia and obesity, phobias, premenstrual syndrome, dysthymia,
cognitive
disorders, iinpulse control disorders, attention deficit hyperactivity
disorder and drug abuse,
5 in particular depression.
As mentioned above, anxiety disorder includes general anxiety disorder, panic
anxiety,
obsessive compulsive disorder, acute stress disorder, post trauma stress
disorder or social
anxiety disorder.
Gaboxadol and the serotonin reuptake inhibitor may be administered
simultaneously as
described above.
Alternatively, the active ingredients may be administered sequentially, e.g.
in two discrete
unit dosage forms as described above.
It has now, surprisingly, been found that co-administration of gaboxadol and a
serotonin
reuptake inhibitor produces a significant increased response in an animal
model predictive
of antidepressant effect, the mouse forced swim test, compared to the
administration of the
serotonin reuptake inhibitor alone.
As mentioned above, serotonin reuptake inhibitors show delayed onset of
action. Even in
responders to SSRIs, several weelcs of treatment are necessary to achieve a
relief in symptoms.
Gaboxadol may provide fast onset of therapeutic effect of serotonin reuptake
inhibitors.
The use of a combination of gaboxadol and a serotonin reuptake inhibitor may
greatly
reduce the amount of serotonin reuptake inhibitor necessary to treat
depression and other
affective disorders and may thus reduce the side effects caused by the
serotonin reuptake
inhibitor. In particular, the combination of a reduced amount of SRI and
gaboxadol may
reduce the rislc of SSRI-induced sexual dysfunction and sleep disturbances.
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
11
Co-administration of gaboxadol and a serotonin reuptake inhibitor may also be
useful for the
treatment of refractory depression, i.e. depression, which cannot be treated
appropriately by
administration of a serotonin reuptake inhibitor alone. Typically, gaboxadol
may be used as
add-on therapy for the augmentation of the response to SRIs in patients where
at least 40-60%
reduction in symptoms has not been achieved during the first 6 weeks of
treatment with an
SRI.
Typically, gaboxadol is used in the form of an acid addition salt, or a
zwitter ion hydrate or
zwitter ion anhydrate. In a further embodiment, gaboxadol is used in the form
of the
pharmaceutically acceptable acid addition salt selected from the hydrochloride
or
hydrobromide salt, or in the form of the zwitter ion monohydrate. Most
conveniently,
gaboxadol is in a crystalline form.
Many antidepressants with serotonin reuptake inhibiting -effect have been
described in the
literature. Any pharmacologically active compound, which primarily or partly
exert its
therapeutic effect via inhibition of serotonin reuptake in the central nervous
system (CNS),
may benefit from augmentation with gaboxadol.
The following list contains a number of serotonin reuptake inhibitors which
may benefit
from augmentation with gaboxadol: citalopram, escitalopram, fluoxetine, R-
fluoxetine,
sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine,
nefazodone,
imipramine, imipramine N-oxide, desipramine, pirandamine, dazepinil, nefopam,
befuraline,
fezolamine, femoxetine, clomipramine, cianoimipramine, litoxetine,
cericlamine,
seproxetine, WY 27587, WY 27866, imeldine, ifoxetine, tiflucarbine, viqualine,
milnacipran, bazinaprine, YM 922, S 33005, F 98214-TA, OPC 14523, alaproclate,
cyanodothepine, trimipramine, quinupramine, dothiepin, amoxapine,
nitroxazepine, McN
5652, McN 5707, 0177, Org 6582, Org 6997, Org 6906, amitriptyline,
amitriptyline N-
oxide, nortriptyline, CL 255.663, pirlindole, indatraline, LY 113.821, LY
214.281, CGP
6085 A, RU 25.591, napamezole, diclofensine, trazodone, EMD 68.843, BMY
42.569, NS
2389, sercloremine, nitroquipazine, ademethionine, sibutramine, clovoxamine,
desinethylsubitramine, didesmethylsubitramine, clovoxamine vilazodone,
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
12
N-[( 1-[(6-Fluoro-2-naphthalenyl)methyl]- 4-piperidinyl]amino]carbonyl]-3-
pyridine
carboxamide, [trans-6-(2-chlorophenyl)-1,2,3,5,6,10b-hexahydropyrrolo- (2,1-
a)isoquinoline] (McN 5707),
(dl-4-exo-amino-8-chloro-benzo-(b)-bicyclo[3.3.1]nona-2-6 alpha(10 alpha)-
diene
hydrochloride)(Org 6997),
(dl)-(5 alpha,8 alpha,9 alpha)-5,8,9,10-Tetrahydro-5,9- methanobenzocycloocten-
8-amine
hydrochloride (Org 6906),
-[2-[4-(6-fluoro-lH-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-isopropyl-
6-
(methylsulphonyl)-3,4-dihydro-lH-2,1,3-benzothiadiazine-2,2-dioxide
(LY393558), [4-
(5,6-dimethyl-2-benzofuranyl)-piperidine] (CGP 6085),
dimethyl-[5-(4-nitro-phenoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl]-
amine (RU
25.591),
.r'
(A 80426),
i5
I l a
fl-~~
~ ""_
N
(EMD 86006),
" õ~-
~
~ (S33005),
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
13
ci
I
N O
(OPC 14523),
/ I = H
oN/,o
HO'('
(McN 5652),
.,,,~.-,~.,~ .
CIH
F (YM 35992),
CA 02692334 2010-02-04
WO 2004/112786 PCTIDK2004/000459
14
N-OH
CI (Org 6582).
The compounds mentioned above may be used in the form of the base or a
pharmaceutically
acceptable salt, such as acid addition salt, thereof. Each of the serotonin
reuptake inhibitors
specified above is intended to be an individual embodiment. Accordingly, each
of them and
the use thereof may be claimed individually.
Other therapeutic compounds, which may benefit from augmentation with
gaboxadol,
include compounds which causes an elevation in the extracellular level of 5-HT
in the
synaptic cleft, although they are not serotonin reuptake inhibitors. One such
compound is
tianeptine.
The above list of serotonin reuptake inhibitors and other compouiids which
causes an
increase in the extracellular level of serotonin, may not be construed as
limiting.
In an embodiment, the SRIs is selected from citalopram, escitalopram,
fluoxetine, sertraline,
paroxetine, fluvoxamine, duloxetine, venlafaxine, duloxetine, dapoxetine,
nefazodone,
imipramin, femoxetine and clomipramine. Just to clarify, each of these SRIs
constitute
individual embodiments, and may be the subject of individual claims.
The term selective serotonin reuptake inhibitor (SSRI) means an inhibitor of
the monoamine
transporters which has stronger inhibitory effect at the serotonin transporter
than the
dopamine and the noradrenaline transporters.
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
Selective serotonin reuptake inhibitors (SSRIs) are among the most preferred
serotonin
reuptake inhibitors used according to the present invention. Thus, in a
further embodiment
the SRI is selected from SSRIs, such as citalopram, escitalopram, fluoxetine,
fluvoxamine,
sertraline or paroxetine.
5
The active ingredients according to the invention, i.e. gaboxadol and the SRI
or a compound
causing an increase in extracellular serotonin levels, may be used in the free
base form or in
the form of a pharmaceutically acceptable acid addition salt thereof, the
latter being
obtainable by reaction of the base form with an appropriate acid.
Citalopram is preferably used in the form of the hydrobromide or as the base,
escitalopram
in the form of the oxalate, fluoxetine, sertraline and paroxetine in the form
of the
hydrochloride and fluvoxamine in the form of the maleate. -
As mentioned above, the combination of gaboxadol with a serotonin reuptake
inhibitor
unexpectedly shows a synergistic effect on the CNS. As a consequence,
combination
therapy using gaboxadol and lower doses of the serotonin reuptake inhibitor
than normally
used in monotherapy, may be effective, and side-effects associated with the
larger amounts
of serotonin reuptake inhibitor used in monotherapy may be reduced or
prevented
altogether.
Additionally, combination therapy with gaboxadol using a normal dose of
serotonin
reuptake inhibitor has the advantage that an effective CNS effect may be
obtained in the
often large number of patients who do not respond to conventional monotherapy
with
SSRIs.
The amount of gaboxadol used in combination therapy may range from about 0.1
to about
150 mg/day, such as from about 0.1 to about 100 mg/day, from about 0.5 to
about 50
mg/day, from about 5 to about 50 mg/day, or from about 1 to about 5 mg/day.
Low amounts
of gaboxadol having no significant effect on sleep disorders have shown clear
and
significant effect in combination therapy with a serotonin reuptake inhibitor,
such as
escitalopram. Low amounts are typically selected from about 0.1 to about 2.5
mg/day, such
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
16
as from about 0.1 to about 2.0 mg/day, whereas higher amounts are typically
selected from
about 2.5 to about 150 mg/day.
Serotonin reuptake inhibitors, including the SSRIs specifically mentioned
hereinabove,
differ both in molecular weight and in activity. As a consequence, the amount
of serotonin
reuptake inhibitor used in combination therapy depends on the nature of said
serotonin
reuptake inhibitor. In one embodiment of the invention, the serotonin reuptake
inhibitor or
the compound causing an increase in the level of extracellular 5-HT, is
administered at
lower doses than required when the compound is used alone. In another
embodiment, the
serotonin reuptake inhibitor or the compound causing an increase in the level
of
extracellular 5-HT, is administered in normal doses.
To prepare the pharmaceutical compositions of this invention, an appropriate
amount of the
active ingredient(s), in salt form or base form, is combined in an intimate
admixture with a
pharmaceutically acceptable carrier, which can take a wide variety of forms
depending on
the form of preparation desired for administration. These pharmaceutical
compositions are
desirably in unitary dosage form suitable for administration orally, rectally,
percutaneously
or by parenteral injection. For example, in preparing the compositions in oral
dosage form,
any of the usual pharmaceutical media may be employed, such as, for example,
water,
glycols, oils, alcohols and the like in the case of oral liquid preparations
such as
suspensions, syrups, elixirs and solutions; or solid carriers such as
starches, sugars, kaolin,
lubricants, binders, disintegrating agents and the like in the case of
powders, pills, capsules
and tablets. Because of their ease in administration, tablets and capsules
represent the most
advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are
obviously employed.
It is especially advantageous to formulate the aforementioned pharmaceutical
compositions
in dosage unit form for ease of administration and uniformity of dosage. As
used in the
specification and claims, unit dosage form refers to physically discrete units
suitable as
unitary dosages, each unit containing a predetermined quantity of active
ingredient(s)
calculated to produce the desired therapeutic effect, in association with the
required
pharmaceutical carrier. Examples of such dosage unit forms are tablets
(including scored or
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
17
coated tablets), capsules, pills, powder packets, wafers, injectable solutions
or suspensions,
teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Gaboxadol may be administered before, during or after the administration of
the serotonin
reuptake inhibitor provided that the time between the administration of
gaboxadol and the
administration of the serotonin reuptake inhibitor is such that ingredients
are allowed to act
synergistically on the CNS. When simultaneous administration of gaboxadol and
a serotonin
reuptake inhibitor is envisaged, a composition containing both a serotonin
reuptake inhibitor
and gaboxadol may be particularly convenient. Alternatively, gaboxadol and the
serotonin
reuptake inhibitor may be administered separately in the form of suitable
compositions. The
compositions may be prepared as described hereinabove.
The present invention also comprises products containing gaboxadol and a
serotonin
reuptalce inhibitor as a combination preparation for simultaneous, separate or
sequential use
in psychiatric drug therapy. Such products may comprise, for example, a kit
comprising
discrete unit dosage forms containing gaboxadol and discrete unit dosage forms
containing a
serotonin reuptake inhibitor, all contained in the same container or paclc,
e.g. a blister pack.
The above mentioned preparations for simultaneous or sequential administration
may
instead of a serotonin reuptake inhibitor contain another compound causing an
elevation in
the level of extracellular 5-HT.
Pharmacological Test of antidepressant effect of gaboxadol
The rat chronic mild stress (CMS) model of depression has a high degree of
preditive
validity for antidepressant activity (Willner (1997), Psychopharmacol 134:319-
329).
Furthermore the procedure is an appropriate model to study onset of
antidepressant action in
anhnals. (Behavioural Pharmacology 14:465-470, 2003, Sanchez, C. et al). The
principle of
the model is based on the relation between stress and affective disorders.
Rats exposed to
chronic stress will show a reduced sensitivity to rewards (e.g. a palatable
sucrose solution).
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
18
Experimental Procedure chronic mild stress
Male Wistar rats (Gorzkowska, Warsaw) were brought into the laboratory two
months
before the start of the experiment. The animals were singly housed with food
and water
freely available, and maintained on a 12-h light/dark cycle at a temperature
of 22 ~: 2 C,
except as described below.
The animals were first trained to consume a 1% sucrose solution; training
consisted of eight
lh baseline tests in which sucrose was presented, in the home cage, following
14h food and
water deprivation; intake was measured by weighing pre-weighed bottles
containing the
sucrose solution, at the end of the test. Subsequently, sucrose consumption
was monitored,
under similar conditions, throughout the whole experiment. On the basis of
their sucrose
intakes in the final baseline test, the animals were divided into two matched
groups. One
group of animals was subjected to a chronic mild stress procedure for a period
of 8
consecutive weeks. The weekly stress regime coxnsisted of 2 periods of food or
water
deprivation, 45 degree cage tilt, intermittent illumination (lights on and off
every 2 h), soiled
cage (250 ml water in sawdust bedding), paired housing and low intensity
stroboscopic
illumination (150 flashes/min), and 2 periods of no stress. .All stressors
were 10 - 14 h of
duration and were applied individually and continuously, day and night. The
other groups of
animals, the unstressed controls, were housed in separate rooms and had no
contact with the
stressed animals. The rats were deprived of food and water for the 14 h
preceding each
sucrose test, but otherwise food and water were freely available in the home
cage. On the
basis of their sucrose intake scores following 3 weeks of stress, both
stressed and control
animals were divided into matched subgroups, and for the subsequent five weeks
they
received twice daily intraperitoneal drug injections (at approximately 10.00
and 17.00).
Sucrose tests were performed at 10 a.m. on a weekly basis (Tuesdays).
Different groups of
animals (n = 8) were administered vehicle (1 mUkg per day) or test drug.
Before test
sessions drugs were administered at approximately 10.OOh and the sucrose tests
were carried
out 24h following the previous drug injection. Stress was continued throughout
the entire
treatment period. Body weights were assessed a baseline and by the end of drug
treatment.
CA 02692334 2010-02-04
WO 2004/112786 PCT/DK2004/000459
19
Results chronic mild stress
The testing of gaboxadol in the rat chronic mild stress model showed that the
compound had
a significant anti-depressant-like effect. The dose of 2.5 mg/kg per day had a
clear and
significant effect in this model.
Gaboxadol in combination with escitalopram
In order to modulate the activity of systems, responsible for antidepressants
activity, we
have characterized the interaction between gaboxadol and escitalopram (an
SSRI) in a
behavioural model of serotonin reuptake inhibition, the mouse 5-HTP
potentiation test, and
a model that is predictive of antidepressant activity, the mouse forced swim
test (cf. C.
S'anchez et al, Psychopharmacology (2003), 167:353-362).
Experimental Procedures
Male NMRJUBOM mice (18-25 g; Bomholtgaard, Denmark) were used. The mice were
housed in plastic cages (35 x 30 x 12 cm), 10 in each and habituated to the
animal facilities
for at least a week before test. The room temperature (21 2 C), relative
humidity (55 -+
5%), and air exchange (16 times per h) were automatically controlled. The
animals had free
access to commercial food pellets and tap water before test.
Potentiation of 5-HTP-induced behaviour.
The test procedure for studies in mice is described in detail by Hyttel et al
(1992). Briefly,
min after s.c. administration of test compound mice were given 5-HTP (100
mg/kg, i.v.).
Thereafter the animals were evaluated in their home cage during a 15-min
observation
period with respect to stereotypy (lateral head movements), tremor, and hind
limb
25 abduction. One point was given for each symptom being present. A total of 8-
16 mice were
used per dose.
Inhibition of forced swimming-induced immobility.
A mouse that is forced to swim in a spatially constrained container will exert
a characteristic
immobile posture. Pretreatment with an antidepressant will counteract this
effect. The test
CA 02692334 2010-02-04
, = WO 2004/112786 PCT/DK2004/000459
was conducted as described in detail by Sanchez and Meier (Psychopharmacol
129:197-205;
1997). Briefly, a fally automated test system with 6 swim units (2000 ml glass
jars filled
with 1200 mi soiled water (23 - 25 C) in which a mouse had been placed
previously) was
used. The assessment of immobility was performed by image analysis. Thirty
minutes after
5 drug or vehicle treatment the mouse was placed into the glass jar and left
in the water for a
total of 6 min. The accumulated duration of immobility was measured during the
last 3 min.
A total of 9-18 mice were tested per dose.
Results
10 Gaboxadol (2.5 mg/kg) strongly potentiated the acute effects of
escitalopram ( 0.5 to 0.025
mg/kg) in the 5-HTP potentiation test and a gaboxadol dose (2.5 mg/kg) that
was not active
by itself in the forced swim test potentiated the antidepressant-like effect
of escitalopram
(2.5 and 5 mg/lcg) significantly.
