Note: Descriptions are shown in the official language in which they were submitted.
CA 02295822 2000-O1-10
WO 99/02142 PCT/EP98/04971
NOVEL COMPOSITION
This invention is concerned with novel formulations of selective serotonin re-
uptake
inhibitors (SSRI's}. In particular the present invention provides formulations
that
potentiate the therapeutic activity of an SSRI, and especially that improve
the onset of the
therapeutic effect.
Artigas et al (Arch. Gen Psychiatry, Vol. 51, pp 248-251, Mar. 1994) have
reported that
administration of pindolol (2.5 mg. three times a day) during treatment with
the SSRI
paroxetine (20 mg once per day) relieved depression in patients previously
showing no
benefit from treatment with paroxetine.
Subsequently, it has been proposed in EP-A-0714663 that the effect of the
SSRIs
citaloprolam, fluvoxamine and paroxetine can be potentiated by co-
administration in
~5 certain combinations with inter alia pindolol, penbutolol, propranol and
tertatolol and
other compounds known to be serotonin IA receptor antagonists, but excluding
the
combination paroxetine-pindolol.
A problem with any co-administration regime is ensuring patient compliance,
particularly
2o in a regime such as proposed by Artigas which involves taking medication on
three
occasions during the day (assuming that the paroxetine dose and the first
pindolol dose
are taken simultaneously).
The present invention aims to overcome the problems associated with co-
administration
25 of SSRIs and potentiating compounds.
In its broadest aspect, the present invention provides an SSRI composition
comprising an
SSRI in quick release form and a ~i-blocker in sustained release form. The
composition is
conveniently in tablet or capsule form.
Typical SSRIs used in this invention are paroxetine, fluvoxamine, citalopram
and
sertraline. Preferably the SSRI is paroxetine. The co-administered (3-blocker
is
preferably pindolol.
The preferred combination of SSRI and ~i-blocker is paroxetine and pindolol.
Preferably
the tablet or capsule contains 20 mg of paroxetine in an immediate release
form and 7.~
mg of pindolol in a sustained release form.
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Typically the sustained release form of the (3-blocker is provided to release
the equivalent
of a three times daily dose continuously over a period of 12-16 hours.
Alternatively, the
dose may be released in three spaced tranches.
When the SSRI is combined with a (3-blocker in a continuous release
formulation, then
the composition of the invention is preferably presented as a bi-layer tablet
in which one
layer contains an SSRI in a conventional quick release formulation and the
other layer
contains a (3-blocker in a sustained release formulation.
1o The sustained release may be provided by formulating the (3-Mocker with any
conventional sustained release excipient or blend of excipients that does not
interact with
the (3-Mocker or the SSRI.
Suitably, the sustained release properties are provided by incorporating the
(3-blocker in
~ 5 an excipient which swells in gastric juice, typically forming a gel which
dissolves and/or
is abraded as the tablet passes through the patient's gut, releasing the
active ingredient.
The rate of release may be controlled in a conventional manner by varying the
molecular
weight of the excipient and/or co-formulating a primary excipient with
materials that
dissolve or disintegrate at a different rate than the primary excipient, to
form micropores
2o in a swollen or gelled primary excipient.
Suitable primary excipients may be selected from swellable binders such as
methyl
cellulose for example as sold under the trade mark Methocel K4M and E5, ethyl
cellulose, polyacrylic acid for example as sold under the trade mark Carbopol
974P,
25 polyacrylic esters for example as sold under the trade mark Eudragit L30D
and RS30D,
xanthan gum, and starch.
The release profile of the primary excipient may be varied by incorporating
fillers and
disintegrants such as lactose especially lactose monohydrate, microcrystalline
cellulose
3o for example as sold under the trade mark Avicel pH102, calcium sulphate,
dicalcium
phosphate for example as sold under the trade mark Encompress, polyvinyl
pyrrolidone
for example as sold under the trade mark Povidone 30, hydrogenated vegetable
oils for
example as sold under the trade mark Lubritab.
35 Conventional tableting excipients may also be included to assist tablet
manufacture, for
example as die lubricants etc., such as magnesium stearate, glyceryl behenate
for example
as sold under the trade mark Compritol 888.
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WO 99/02142 PCT/EP98/04971
Alternatively, the composition may be a capsule presentation comprising coated
pellets of
a (3-blocker, which is a mixture of coated pellets having different
dissolution times,
dispersed in a powder formulation of an SSRI, all contained within a soluble
capsule.
Suitably, the coating of the pellets of the (3-Mocker is a material that is
resistant to gastric
juices but dissolves in the gut, for example. Dissolution times may be varied
by varying
the coating thickness. Preferably the coated pellets are mixed so as to
provide a
substantially continuous release of pindolol, but if desired the pellets may
be a mixture of
three coating thicknesses so that pindolol is released in three tranches over
a the desired
to dosage period such as 12-14 hours. A powdered formulation of the SSRI be be
made by
blending the SSRI with conventional excipients. Soluble capsules to contain
the
combination of active ingredients may be conventionally made from gelatine.
Typical sustained release formulations of the above described hydrophilic
matrix type and
enteric coating type that may be used in this invention are disclosed in
standard textbooks
on the subject.
VVe have found that a suitable release profile for clinical use is obtained
when the
sustained release (3-blocker formulation has a release profile measured in
vitro in
2o acid/buffer which has a dissolution time Tsooo of 1.73 hours, a T9oo~o of
8.45 hours and a
T~oooo of 14 hours.
Accordingly, a preferred embodiment of the invention provides a formulation of
an SSRI
and a (3-blocker in which the (3-blocker is in a sustained release form having
a release
profile in vitro in which the Tsoo~o is 1.73 hours + 20%, the T9ooa is 8.45
hours + 20% and
the T, oooo is 14 hours + 20%.
Preferably, the SSRI is paroxetine hydrochloride, most preferably at a dosage
of 20 mg,
and the ~3-blocker is pindolol, most preferably at a dosage of 7.5 mg.
The pindolol is typically used as the commercially available racemate.
However, active
isomers thereof may be used at a dosage adjusted for bioquivalence to a stated
dose of the
racemate.
Therapeutic uses of compositions of this invention, especially compositions of
paroxetine
hydrochloride and pindolol, include treatment of alcoholism, anxiety,
depression,
obsessive compulsive disorder (OCD), panic disorder, chronic pain, obesity,
senile
dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome
(PMS),
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adolescent depression, trichotillomania, dysthymia and substance abuse;
referred to
herein as "the Disorders".
Accordingly, the present invention also provides
use of an SSRI and a sustained release form of a (3-blocker for the
manufacture of a tablet
or capsule for the treatment or prophylaxis of the Disorders in humans and
animals, and
a method for the treatment or prophylaxis of the Disorders, which comprises
to administering a tablet or capsule comprising an SSRI and a sustained
release form of a ~i-
blocker to a person or animal in need thereof.
In the use and method of the invention, the tablet or capsule is preferably a
composition
of this invention having the preferred values indicated above.
is
The invention is illustrated by the following Example:
Example 1
2o Bi-layer tablets of paroxetine and sustained release pindolol were
manufactured as
follows.
Pindolol Component
A sustained release form of pindolol based upon a hydrophilic matrix with a
soluble
25 filler/disintegrant to increase the porosity of the matrix once hydrated
was prepared by
high shear wet granulation of a mixture of
pindolol base 7.5 parts by weight
methylcellulose (Methocel K4M) 35 parts by weight
30 lactose monohydrate 25 parts by weight
microcrystalline cellulose (Avicel pH102) 32 parts by weight
After drying and screening, O.s parts by weight of glyceryl behenate
(Compritol 888) as a
lubricant were incorporated by tumble blending.
3s
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WO 99/02142 PCT/EP98/04971
Paroxetine Component
An immediate release formulation of paroxetine was prepared by blending 20
parts per
weight of paroxetine hydrochloride and 80 parts per weight of conventional
excipients.
Tableting
100 mg. amounts of the sustained release pindolol formulation were charged
into tablet
moulds in a rotary tableting platen at a first charging station. After a
preliminary light
pressing to locate the powdered formulation in the tablet mould, the platen
was indexed to
a second charging station where 152 mg. of the paroxetine formulation were
introduced
1 o on top of the sustained release formulation. The two layer mixture in the
tablet mould was
then given a full press to prepare 252 mg. tablets containing 20 mg.
paroxetine
hydrochloride and 7.S mg. pindolol in a sustained release base, each active
component
being in separate layers of a bi-layer tablet.
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