Note: Descriptions are shown in the official language in which they were submitted.
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PAROXETINE COMPOSITIONS
The present invention relates to new formulations of a pharmaceutically active
compound,
and in particular to a novel formulation of paroxetine.
Pharmaceutical products with antidepressant and anti-Parkinson properties are
described
in US-A-3912743 and US-A-4007196. An especially important compound among those
disclosed is paroxetine, the (-)traps isomer of 4-(4'-fluorophenyl)-3-(3',4'-
methylenedioxy-phenoxymethyl)-piperidine.
In the literature this compound is usually isolated as an acid salt,
especially the
hydrochloride. Paroxetine is approved for human use as the hydrochloride salt,
and has
been proposed for the treatment and prophylaxis of inter alia depression,
obsessive
compulsive disorder (OCD) and panic.
Paroxetine hydrochloride has been described in the literature as a crystalline
hemihydrate
(see EP-A-0223403 of Beecham Group) and as various crystalline anhydrate forms
(see
W096/24595 of SmithKline Beecham).
Paroxetine free base has hitherto been disclosed in the literature as an oil,
and so the free
base has not itself been considered for therapeutic use, preference being
given to
crystalline forms which can be more easily purified and processes into dosage
forms.
The present invention is based on the discovery that paroxetine, for example
paroxetine
free base, is advantageously formulated into pharmaceutical compositions when
adsorbed
on or absorbed by a solid carrier.
The present invention provides a composition comprising paroxetine or a
pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a
pharmaceutically acceptable solid carrier, and the use of the composition as a
therapeutic
agent or for the manufacture of a medicament.
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By this invention paroxetine may be obtained as a free-flowing powder that can
be used
directly (for example by direct compression into tablet form) or with further
compounding
ingredients in therapy.
The paroxetine used in carrying out this invention is preferably paroxetine
free base, but
may alternatively be a pharmaceutically acceptable derivative such as a salt,
more
especially the hydrochloride.
The composition of this invention is simply obtained by combining a solution
of
paroxetine with a suitable adsorbent or absorbent material and evaporating the
solvent, for
example by spray drying. The solvent is suitably toluene, ethanol, acetone,
propan-2-ol,
or ethyl acetate, or any other suitable solvent or mixture of solvents, in a
paroxetine
concentration of between 1 and 20%, more preferably between 1 and 4%.
Alternatively an oil obtained by removal of solvent from a solution may be
blended with a
solid adsorbent or absorbent material.
Typically the material selected as carrier for the paroxetine is an excipient
suitable for
tablet formation or as a fill material for gelatine capsules, such as
cyclodextrin (beta and
/or gamma), porous silicates, starch, lactose or calcium phosphate, silica,
sorbitol,
maltodextrin, microcrystalline or powdered cellulose, sodium or calcium
carboxymethylcellulose, calcium carbonate, kaolin, magnesium aluminium
silicate.
Additionally, soluble excipients such as magnesium stearate may form part of
the solution
phase.
Advantageously the carrier is one that also has a taste-masking effect, for
example ion-
exchange resins.
A solution of paroxetine free base may be prepared by addition of a base such
as
triethylamine to a solution of a crystalline paroxetine salt especially the
hydrochloride or
acetate. Alternatively the solution may be prepared by basifying a solution of
an
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WO 99/4$499 PCT/GB99/00922
amorphous paroxetine hydrochloride or a crystalline anhydrate or hydrated form
of
paroxetine hydrochloride.
The preparation of the free base and the malefic acid salt are described in
Example 2 of US
4007196. The acetate salt may also be used as a starting material. Procedures
for
forming salts are described in EP-A-0223403.
Additionally the paroxetine free base may be prepared as a solution or oil by
adding a
base such as potassium hydroxide to a solution of a N-protected paroxetine
compound
such as N-phenoxycarbonyl paroxetine.
The composition of this invention comprising paroxetine adsorbed on or
absorbed by a
solid carrier may be formulated with or without conventional excipients for
tablet
formation or used as a powder fill for capsules.
The amount of paroxetine used is adjusted such that in a single unit dose
there is a
therapeutically effective amount of paroxetine. Preferably the unit dose
contains from 10
to 100 mg paroxetine (as measured in terms of the free base). More preferable
the amount
of paroxetine in a unit dose is lOmg, 20mg, 30mg, 40mg or SOmg. The most
preferred
amount of paroxetine in a unit dose is 20mg.
Therapeutic uses of the paroxetine product of this invention include treatment
o~
alcoholism, anxiety, depression, obsessive compulsive disorder, panic
disorder, chronic
pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia,
pre-menstrual
syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and
substance
abuse, referred to below as "the disorders".
Accordingly, the present invention also provides:
a pharmaceutical composition for treatment or prophylaxis of the disorders
comprising
paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or
absorbed
by a solid carrier and, optionally, at least one further pharmaceutically
acceptable
excipient;
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the use of paroxetine or a pharmaceutically acceptable derivative thereof
adsorbed on or
absorbed by a solid carrier to manufacture a medicament for the treatment or
prophylaxis
of the disorders; and
a method of treating the disorders which comprises administering an effective
or
prophylactic amount of paroxetine or a pharmaceutically acceptable derivative
thereof
adsorbed on or absorbed by a solid carrier to a person suffering from one or
more of the
disorders.
The invention is illustrated by the following Examples:
Example 1. Preparation of tablet pre-mix containing paroxetine free base.
A mixture of dibasic calcium phosphate dihydrate (408 g), hydroxypropylmethyl
cellulose (25 g) and sodium starch glycollate (25 g) was blended in a key
granulator for 3
minutes at a stir rate of 240 r.p.m. and an impeller rate of 3000 r.p.m.
Purified water (57
ml) was added at a rate of approximately 4 ml/minute for 13.5 minutes while
the key
granulator was set at a stir rate of 240 r.p.m. and the impeller rate was set
at 1500 r.p.m.
The mixture was stirred for a further 1 minute, and the resulting granules
dried in an air
oven at 50°C for 3 hours.
A portion of the granules prepared above (SO g) was added to a solution of
paroxetine free
base (2.0 g) in propan-2-of (50 ml) and the resulting slurry dried under
vacuum with
agitation at 50°C.
This product is suitable for direct compression into tablets containing 10,
20, or 30 mg
paroxetine.
Example 2. Preparation of a solid supported form of paroxetine free base.
A stirred mixture of N-phenoxycarbonyl paroxetine ( SO.Og ), potassium
hydroxide (45.Og) and toluene ( 750m1) was heated to reflux under a nitrogen
atmosphere for 3 hours. After allowing the mixture to cool to room
temperature,
distilled water (SOOmI) was added and the mixture stirred for 30 minutes. The
organic layer was separated, dried over magnesium sulfate and concentrated to
a
total volume of 85m1.
Toluene ( 1 OOmI) was added to an aliquot of the solution of paroxetine free
amine
in toluene ( 0.43g/ml) ( 2.4 ml) and to this solution was added Celite ( 25.Og
) and
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the mixture stirred for 5 minutes. Solvent was removed under reduced pressure
(water bath SS~C) to afford the Celite supported paroxetine free amine as a
free
moving powdery solid (26.Og).
S This product may be mixed with additional excipients and compressed into
tablets or
added directly to capsule shells to make a product containing a therapeutic
dose of
paroxetine.
Example 3
Spray drying of paroxetine hydrochloride solution onto a suspended carrier
material.
Anhydrous paroxetine hydrochloride (60 g) was dissolved in anhydrous ethanol
(725 ml)
and the clear solution slurried with maltodextrin DE4-6 (506 g). The uniform
suspension
was spray-dried in a Niro Mobile Minor (TM) closed cycle spray dryer using
nitrogen as
the process gas, a rotary atomiser wheel spinning at 27,000 r.p.m.
(alternatively a co-
current or fountain two-fluid nozzle could be used), an inlet temperature of
96-104 C and
outlet temperature of 44-50 C at a feed rate of 4.1 kg per hour. A white
free-flowing product was recovered (490 g) which was found to have a mean
particle size
of 84 microns.
Example 4
Preparation of tablet pre-mix containing paroxetine hydrochloride.
A mixture of dibasic calcium phosphate dihydrate (408 g), hydroxypropylmethyl
cellulose (25 g) and sodium starch glycollate (25 g) was blended in a key
granulator for 3
minutes at a stir rate of 240 r.p.m. and an impeller rate of 3000 r.p.m.
Purified water (57
ml) was added at a rate of approximately 4mllminute for 13.5 minutes while the
key
granulator was set at a stir rate of 240 r.p.m. and the impeller rate was set
at 1500 r.p.m.
The mixture was stirred for a further 1 minute, and the resulting granules
dried in an air
oven at SO°C for 3 hours.
A solution of paroxetine hydrochloride hemihydrate (2.0 g) in ethanol ( 100
ml) was added
to the granules prepared above (50 g) and the slurry dried under vacuum at
50°C.
Example 5
Preparation of tablet pre-mix containing paroxetine hydrochloride.
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A solution of paroxetine hydrochloride hemihydrate (2.0 g) in ethanol (150 ml)
was added
to celite (50 g), the mixture stirred and the slurry dried under vacuum at
50°C to afford a
free moving powdery solid, suitable for use as a component of a tablet or
capsule
formulation.
Example 6
Preparation of tablet pre-mix containing paroxetine hydrochloride.
A stirred mixture of N-phenoxycarbonyl paroxetine ( 50.0 g), potassium
hydroxide (45.0 g) and toluene ( 750 ml) was heated to reflux under a nitrogen
atmosphere for 3 hours. After allowing the mixture to cool to room
temperature,
distilled water (500 ml) was added and the mixture stirred for 30 minutes. The
organic layer was separated, dried over magnesium sulphate and filtered.
An aliquot of this solution of paroxetine free amine in toluene [ 0.048 g/ml]
( 21.0
ml) was diluted with a further 30 ml of toluene and heated to 60oC.
Concentrated
hydrochloric acid (0.34 ml) was added and the mixture stirred for 10 minutes.
Tablet granules ( 25.Og ), prepared as in Example 4, were added and the
mixture
stirred at 60oC for 5 minutes. Solvent was removed under reduced pressure at
70oC to afford a mobile powdery solid (26.Og).
Example 7
Preparation of tablet pre-mix containing paroxetine hydrochloride.
Concentrated hydrochloric acid (0.34m1) was added to a stirred solution of
paroxetine
acetate ( 1.18g) in toluene (SOmI) at 60oC and the mixture stirred for 10
minutes. Tablet
granules ( 25.Og ), prepared as in Example 4, were added and the mixture
stirred at 60oC
for S minutes. Solvent was removed under reduced pressure at 70oC to afford a
free
flowing powdery solid (26.Og).
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