Note: Descriptions are shown in the official language in which they were submitted.
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WO 00/15217 PCT/SE99/01596
A NEW COMPOSITION
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-2N 1-benzopyran-5-
carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second component (b)
which is
a 5-HT reuptake inhibitor excluding citalopram and paroxetine. The present
invention also
relates to a process for the preparation of the inventive composition,
pharmaceutical
io 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.
is 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 wlnerable period for patients in which they
experience the side
~o effects, but not 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
~s 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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Prior art
in WO 96/33710 is disclosed the combination of 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, with a serotonin
reuptake inhibitor.
Summary of the Invention
The present invention is directed to a new composition comprising of a first
component (a)
~o which is the specific 5-HTlAantagonist (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 a 5-HT reuptake inhibitor excluding citalopram
and
paroxetine. Said composition attains a faster onset of action and
consequently, provides a
more effcacious treatment of the patients suffering from affective disorders,
particularly
is 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
negative feedback reaction probably mediated by collateral 5-HT axons
releasing 5-HT in
~o raphe nuclei: By inhibiting the somatodendritic 5-HT,A autoreceptors in the
raphe nuclei
the selective antagonists counteract the decrease in propagation caused by 5-
HT reuptake
inhibitors. This indicates that a selective blockade of somatodendritic
autoreceptor i.e. 5-
HT,A antagonist may have a clinical potential to improve the efficacy of 5-HT
reuptake
inhibitors (SSRIs) and offer a new rationale for rapid onset of effect in the
treatment of
xs affective disorders, for instance the antidepressant actions.
The compound (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-
5-
carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299) disclosed herein
is
described in J. Pharmacol. Exp. Ther., 283, 216-225, (1997), as a selective 5-
HTIA
so receptor antagonist.
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(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 .
S-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.
Known 5-HT reuptake inhibitors (SSRIs) which may be used are norLimeldine,
fluoxetine,
ciomipramine, sertraline, fluvoxamine and alaproclate, preferably suitable are
fluoxetine,
clomipramine, sertraline, and fluvoxamine. However, component {b) in the
combination
io according to the invention is not limited only to those SSRIs.
The definitions and chemical names of the above-mentioned compounds (SSRIs)
can be
found in the Merck Index, 12th Edition, S Budavari et al (ed.) and are
incorporated herein
by reference.
is
The composition according to the present invention may exist in one
pharmaceutical
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,
~o 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 fonmulation as component (b) by e.g.
mixing in
zs a conventional way.
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-S-carboxamide hydrogen
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(2R,3R)-tartrate monohydrate and a 5-HT reuptake inhibitor excluding
citalopram and
paroxetine.
A further embodiment of the present invention is a kit containing a dosage
unit of 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 5-HT reuptake inhibitor
excluding
citalopram and paroxetine, optionally with instructions for use.
Pharmaceutical formulations
io
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
pharmaceutical formulations comprising the active ingredients in a
pharmaceutically
acceptable dosage form . The dosage form may be a solid, semisolid or liquid
formulation.
is 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
administration.
~o The pharmaceutical formulation comprises the active ingredicnts, optionally
in association
with adjuvants, excipients e.g. diluents, and/or inert carriers.
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
zs 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-
caramellose sodium; a lubricant such as magnesium stearate, calcium stearate,
polyethylene
glycol, waxes, paraffin, and the like, and an antisticking agent such as talc
or colloidal
so silicon dioxide, and then compressed into tablets. If coated tablets are
required, the cores,
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WO 00/15217 PCT/SE99/01596
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 polymer
is dissolved
in water or a readily volatile organic solvent or mixture of organic solvents.
Alternatively,
the tablets can be coated with a concentrated sugar solution which may contain
e.g. gum
arabic, gelatine, 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
io 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),
cellulose derivatives, plasticizers, polyetheneglycol, waxes, lipids or
gelatin. Also liquids
or semisolids of the drug can be filled into hard gelatin capsules.
~s
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
base, or gelatin 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
zo solutions, syrups or suspensions, for example solutions containing from
about 0.2% to
about 20% by weight of the active substances herein described, the balance
being sugar and
a mixture of ethanol, water, glycerol and propylene glycol. Optionally such
liquid
formulations may contain colouring agents, flavouring agents, saccharin and
carboxymethyl-cellulose as a thickening agent or other excipients known to a
person
is skilled in the art.
Solutions for parenteral applications by injection can be prepared in an
aqueous solution of
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
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contain stabilizing agents and/or buffering agents and may conveniently be
provided in
various dosage unit ampoules.
Suitable daily doses of the active compounds in the composition of the
invention in
s 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-S-carboxamide hydrogen (2R,3R)-tartrate monohydrate may very well
differ
from the daily doses of the active ingredient 5-HT reuptake inhibitor but the
doses can also
io be the same for both of the active ingredients.
Medical and Pharmaceutical Use
In a further aspect the present invention provides the use of the composition
comprising a
~s 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 a 5-HT reuptake inhibitor excluding citalopram and
paroxetine, in
the treatment of 5-hydroxytryptamine mediated disorders, such as affective
disorders.
Examples of affective disorders are disorders in the CNS such as mood
disorders
Zo (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 (disorders of
impulse control,
trichotellomania) and sleep disorders. Other disorders in the CNS such as
eating disorders
~s (obesity, anorexia, bulimia), premenstrual 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 disorders (e g
hypetprolactinaemia), stroke, dyskinesia, Parkinson's disease,
thermoregulatory disorders,
3o pain and hypertension may also be treated with the combination described
herein.
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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.
Pharmacology
Potentiation of the 5 HTIp autoreceptor blocking effekt of 5-HT of a 5-HT
reuptake
inhibitor by using of (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-
benzopyran-
5-carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299).
io
Materials and methods
Animals
The studies were carried out in male Sprague-Dawley rats (290-450g; B&K
Universal,
Sollentuna, Sweden). The animals were housed for at least 3 weeks after
arrival until used
is in the experiments.
Methods
The studies were carried out by means of intra-cerebral microdialysis in awake
rats. To
assess any putative regional differences between dorsal and median
rapheinnervated 5-HT
zo projection areas, dialysis probes were simultaneously implanted both into
the frontal cortex
(FCx) and dorsal hippocampus (DH).
Microdialysis
The rats were anaesthetised with a mixture of ketamine HCl (67 mg/kg
intraperitoneal (IP);
zs Ketalar~, Park-Davis) and xylazine HCl ( 13 mg/kg IP; Rompun~, Bayer-
Leverkusen). U-
shaped microdialysis probes (total dialysis fibre length 4 mm, OD 220N.m) were
stereotaxically implanted in the frontal cortex {FCx) and dorsal hippocampus
(DH); probe
tips at AP +3.5, ML -3.0, DV -4.2 and -4.3, ML +2.5, DV -4.2, respectively,
vs. bregma
and dura surface (Paxinos, et al, in The Rat Brain in Stereotaxic Coordinates,
2nd Ed.,
3o Academic Press, San Diego ( 1996)). The microdialysis studies were
performed in
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conscious animals after a 40-4.8 h recovery period, during which they were
kept
individually. Food and water were allowed ad libitum in the plastic cages
subsequently
used in the experimental sessions. On the day of the experiment, the probe
inlets were
connected to a syringe perfusion pump (CMA/100; CMA Microdialysis AB, Sweden),
s delivering artificial CSF (Hjorth, S., J. Neurochem. 60:776-779 ( 1993)) at
a speed of
1.3~t1/min. Twenty-min dialysate fractions were collected from the probe
outlet tubing, and
immediately analysed for 5-HT and 5-HIAA by standard HPLC-EC methods. After
the
perfusion was commenced, a period of 2-3 h was allowed to establish stable
baseline
dialysate levels of 5-HT, prior to drug treatment(s).
~o
The following non-limiting Example serves to illustrate the present invention.
Example
cs 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 5
(a)
Active drug component 20
(b)
Microcrystalline cellulose100
Corn starch 40
Povidone 4
Water 50
Sodium starch giycolate8
Magnesium stearate 1
