Note: Descriptions are shown in the official language in which they were submitted.
CA 02342341 2001-02-28
WO 00/15218 PCT/SE99/01597
A NEW COMPOSTTION
Field of the Invention
s The present invention relates to a composition which comprises a first
component (a)
which is (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-
carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second component (b)
which is
paroxetine, or a pharmaceutically acceptable salt and/or solvate thereof. The
present
invention also relates to a process for the preparation of the inventive
composition,
io pharmaceutical formulations containing said composition and to the use of
said
composition either by concomitant administration or by separate administration
as an
improvement of the treatment of affective disorders such as depression,
anxiety, obsessive
compulsive disorder (OCD), etc.
~s Background of the Invention
Today, it is generally considered that antidepressants take 2-4 weeks to reach
full clinical
effect. In contrast, the side effects occur immediately. Thus, slow onset of
action of
antidepressants leads to a vulnerable period for patients in which they
experience the side
~o effects, but riot the therapeutic effects of drugs. There is often a heavy
burden on the
treating physician to persuade the patient to continue with the treatment
during this period.
Furthermore, in suicidal patients, as the onset of action is gradual,
initiative may be
regained without the experiencing of full reversal of symptoms, leaving a
window of risk
for suicide and a frequent requirement for hospitalization. An antidepressant
with fast onset
zs of action would not only be beneficial due to the faster symptom reduction,
but would also
be more acceptable to patients and physicians and reduce the need for and
duration of
hospitalization. The same long period to reach full clinical effect has been
shown in the
treatment of other affective disorders such as anxiety and OCD.
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2
Prior art
In WO 96/33710 is disclosed that the compound (R)-5-carbamoyl-8-fluoro-3-N,N
dicyclobutylamino-3,4-dihydro-2H 1-benzopyran which has high affinity to 5-HT
receptors
and antagonizes 5-HT,,~ mediated responses induces a rapid improvement of
depressed
patients treated with serotonin reuptake inhibitors.
Summary of the Invention
io The present invention is directed to a new composition comprising of a
first component (a)
which is the specific 5-HTlpantagonist (R)-3-N,N dicyclobutylamino-8-fluoro-
3,4-
dihydro-2H 1-benzopyran-~-carboxamide hydrogen (2R,3R)-tartrate monohydrate
and a
second component (b) which is paroxetine, in the form of the free base, or a
pharmaceutically acceptable salt and/or solvate thereof. Said composition
attains a faster
~s onset of action and consequently, provides a more efficacious treatment of
the patients
suffering form affective disorders, particularly depression.
It has been shown in animal studies that acute administration of selective 5-
HT reuptake
inhibitors (SSRIs) decreases the electrical impulse propagation in 5-HT
neurones via a
Zo negative feedback reaction probably mediated by collateral 5-HT axons
releasing S-HT in
raphe nuclei. By inhibiting the somatodendritic 5-HT,A autoreceptors in the
raphe nuclei
the selective antagonists counteract the decrease in propagetion caused by 5-
HT reuptake
inhibitors. This indicates that a selective blockade of somatodendritic
autoreceptor i.e. 5-
HTtA antagonist may have a clinical potential to improve the efficacy of 5-HT
reuptake
Zs inhibitors (SSRIs) and offer a new rationale for rapid onset of effect in
the treatment of
affective disorders, for instance the antidepressant actions.
The compound (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1=benzopyran-
5-
carboxanude hydrogen (2R,3R)-tartrate monohydrate (NAD 299) disclosed herein
is
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3
described in J. Pharmacol. Exp. Ther., 283, 216-225, (1997) as a selective 5-
HT~p receptor
antagonist.
(R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide
hydrogen (2R,3R)-tartrate monohydrate possesses a high affinity to the
specific subgroup of
5-HT,A receptor in the CNS and acts as an antagonist on that 5-HT,A receptor,
and also
shows favourable bioavailability after oral administration.
Paroxetine is a 5-HT reuptake inhibitor (SSRn which is commercially available.
~o Pharmaceutically acceptable salts of paroxetine such as the hydrochloride,
hydrobromide,
maleate, tartrate, acetate etc. are also included in the inventive
composition. Also solvate
forms such as the hydrate and hemihydrate of the salts are included.
The composition according to the present invention may exist in one
pharmaceutical
~s formulation comprising the component (a) and component (b), or in two
different
pharmaceutical formulations, one for component (a) and one for component (b).
The
pharmaceutical formulation may be in the form of tablets or capsules, powders,
mixtures,
solutions or other suitable pharmaceutical formulation forms such as patches
and nasal
formulations.
The composition of the present invention can be prepared such that component
(a) is
incorporated into the same pharmaceutical formulation as component (b) by e.g.
mixing in
a conventional way.
Zs The present invention also includes a method of improving the onset of
therapeutic action
by concomitant administration of a composition comprising of (R)-3-N,N
dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen
(2R,3R)-tartrate monohydrate and paroxetine.
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A further embodiment of the present invention is a kit containing a dosage
unit of (R)-3-
N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide
hydrogen
{2R,3R)-tartrate monohydrate and a dosage unit of a paroxetine, optionally
with
instructions for use.
Pharmaceutical formulations
According to the present invention the compounds in the composition will
normally be
administered orally, rectally, transdermally, nasally or by injection, in the
form of
~o pharmaceutical formulations comprising the active ingredients in a
pharmaceutically
acceptable dosage form . The dosage form may be a solid, semisolid or liquid
formulation.
Usually the active substances will constitute between 0.1 and 99% by weight of
the
formulation, more specifically between 0.5 and 20% by weight for formulations
intended
for injection and between 0.2 and 50% by weight for formulations suitable for
oral
is administration.
The pharmaceutical formulation comprises the active ingredients, optionally in
association
with adjuvants, excipients e.g. diluents, and/or inert carriers.
zo To produce pharmaceutical formulations of the composition of the invention
in the form of
dosage units for oral application, the selected compounds may be mixed with a
solid
excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as
potato starch, corn
starch or amylopectin, cellulose derivatives, a binder such as gelatin or poly-
vinylpyrrolidone, disintegrants e.g. sodium starch glycolate, cross-linked PVP
and cross-
zs caramellose sodium and a lubricant such as magnesium stearate, calcium
stearate,
polyethylene glycol, waxes, paraffin, and the like, and an antisticking agent
such as talc or
colloidal silicon dioxide, and then compressed into tablets. If coated tablets
are required,
the cores, prepared as described above, may be coated with a polymer known to
the man
skilled in the art e.g. HPMC, HC or other cellulose derivatives or PVP,
wherein the
3o polymer is dissolved in water or a readily volatile organic solvent or
mixture of organic
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solvents. Alternatively, the tablets can be coated with a concentrated sugar
solution which
may contain e.g. gum arabic, gelatin, talcum, titanium dioxide, and the like.
Dyestuffs may
be added to these coatings for instance in order to readily distinguish
between tablets
containing different active substances or different amounts of the active
compounds.
For the formulation of soft gelatin capsules, the active substances may be
admixed with
e.g. a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain
granules of
the active substances using any of the above mentioned excipients for tablets
e.g. lactose,
saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or
amylopectin),
io cellulose derivatives, plasticizers, polyetheneglycol, waxes, lipids or
gelatin. Also liquids
or semisolids of the drug can be filled into hard gelatin capsules.
Dosage units for rectal application can be solutions or suspensions or can be
prepared in
the form of suppositories comprising the active substances in a mixture with a
neutral fatty
~s base, or gelatine rectal capsules comprising the active substances in
admixture with veget
able oil or paraffin oil. Liquid formulations for oral application may be in
the form of
solutions, syrups or suspensions, for examplc'solutions containing from about
0.2% to
about 20% by weight of the active substances herein described, the balance
being sugar and
mixture of ethanol, water, glycerol and propylene glycol. Optionally such
liquid
2o formuiationSmay contain colouring agents, flavouring agents, saccharin and
carboxymethyl-cellulose as a thickening agent or other excipients known to a
person
skilled in the art.
Solutions for parenteral applications by injection can be prepared in an
aqueous solution of
2s a water-soluble pharmaceutically acceptable salt of the.active substances,
preferably in a
concentration of from about 0.5% to about 10% by weight. These solutions may
also
contain stabilizing agents and/or buffering agents and may conveniently be
provided in
various dosage unit ampoules.
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Suitable daily doses of the active compounds in the composition of the
invention in
therapeutic treatment of humans are about 0.01-100 mg/kg bodyweight for
peroral
administration and 0.001-100 mg/kg bodyweight for parenteral administration.
The daily
doses of the active ingredient (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-
dihydro-2H 1-
benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate may very well
differ
from the daily doses of the active ingredient paroxetine but the doses can
also be the same
for both of the active ingredients.
Mcdical and Pharmaceutical Use
io
In a further aspect the present invention provides the use of the composition
comprising a
first component (a) which is (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-
2H 1-
benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second
component (b) which is paroxetine, in the treatment of 5-hydroxytryptanune
mediated
~s disorders, such as affective disorders. Examples of affective disorders are
disorders in the
CNS such as mood disorders (depression, major depressive episodes, dysthymia,
seasonal
affective disorder, depressive phases of bipolar disorder), anxiety disorders
(obsessive
compulsive disorder, panic disorder with/without agoraphobia, social phobia,
specific
phobia, generalized anxiety disorder, posttraumatic stress disorder),
personality disorders
io (disorders of impulse control, trichotellomania) and sleep disorders. Other
disorders in the
CNS such as eating disorders (obesity, anorexia, bulimia), premenstzual
syndrome, sexual
disturbances, alcoholism, tobacco abuse, autism, attention deficit,
hyperactivity disorder,
migraine, memory disorders (age associated memory impairment, presenile and
senile
dementia such as Alzheimer's disease), pathological aggression, schizophrenia,
endocrine
a disorders (e g hyperprolactinaemia), stroke, dyskinesia, Parkinson's
disease,
thermoregulatory disordcrs, pain and hypertension may also be treated with the
combination described herein. Examples of other hydroxytryptamine mediated
disorders
are urinary incontinence, vasospasm and growth control of tumors (e g lung
carcinoma)
and it may be possible to treat those with the combination described herein as
well:
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Pharmacolotv
Antagonism by (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-
S-carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299) of the
paroxetine
induced suppression of dorsal raphe firing.
Materials and methods
Adult male Sprague Dawley rats (B&K Universal, Sollentuna, Sweden) were used
and
were housed under controlled climate conditions. The animals were prepared for
to electrophysiological recordings according to standard procedures. Briefly,
the rats were
deeply anaesthetized with chloral hydrate and mounted in a stereotaxic frame.
Extracellular
recording electrodes were lowered into the dorsal raphe, guided by stereotaxic
co-ordinates,
and target neurones were identified by the firing characteristics of serotonin
neurones in
this nuceius. The animals were kept anaesthetized throughout the experiments
and drugs
~s were administered intravenously through a tail vein catheter. Paroxetine
(0.1 mg kg 1 i.v.}
was administered 3 min before NAD 299 (50 nmol kg I i.v.)
Results
It was also found that NAD 299 could antagonize the suppression of firing in
zo serotoniner~c dorsal raphe neurones in rats induced by paroxetine (Figure).
The figure
shows medians ~semi-interquartile range based on recordings from 5 animals per
group.
Statistical evaluation for differences between treatment groups and controls,
performed by
means of the Mann-Whitney It-test, is also shown in the figure. In addition,
the paroxetine-
induced suppression was statistically significantly antagonised by NAD 299
treatment
zs (p<0.05).
Discussion and conclusions
It is generally considered that selective serotonin reuptake inhibitors
(SSRIs), such as
paroxetine, owe their antidepressant efficacy to their ability to enhance the
synaptic
so availability of serotonin in forebrain target areas of serotoninergic
projections from the
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midbrain raphe nuclei. However, the 5-hydroxytryptamine (5-HT) transporter
protein
affected is present both in somatodendritic and terminal regions, and
initially the enhanced
availability of serotonin in the former areas will inhibit neuronal activity
as well as
forebrain synthesis and release of S-HT through activation of inhibitory 5-
HT1A
autoreceptors. As these receptors desensitize with time there is a gradual
increase in
forebrain serotonin release, as has been shown in animals studies, and the
time-course for
this phenomenon probably explains the delayed onset of antidepressant actions
clinically.
There exists the hypothesis that disinhibition of the self inhibitory effects
of SSRIs by
io blockade of inhibitory 5-HT~p autoreceptors should produce a faster onset
of action, and
also generally increase the efficacy of these agents.
The data show that (R)-3-~V.~V dicyclobutylaznino-8-fluoro-3,4-dihydro-2H 1-
benzopyran-
5-carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299) effectively
antagonizes
is the inhibition of firing in serotoninergic neurones produced by acute
administration of
paroxetine in the rat.
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The following non-limiting Example serves to illustrate the present invention.
Example
s A suitable pharmaceutical composition comprising a first component (a) and a
second
component (b) in a single dosage form include the following:
Composition mg/tablet
Active drug component (a) $
Active drug component {b) 20
Microcrystalline cellulose 100
Corn starch 40
Povidone 4
Water 50
Sodium starch glycolate 8
Magnesium stearate 1
