Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02374931 2001-12-31
1
SOLID PREPARATIONS CONTAINING PAROXETINE
The present invention relates to solid or semisolid preparations
of paroxetine or one of its physiologically active salts in the
form of a molecular dispersion in a pharmaceutically acceptable
matrix material. The invention further relates to a process for
producing such preparations.
Paroxetine is the generic name for
(-)-traps-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxy-
methyl)piperidine, which is described, for example, in US-A 4 007
196.
Paroxetine belongs to the class of 5-hydroxytryptamine inhibitors
and is used as antidepressant.
Because of its basicity, paroxetine is employed in the form of
its acid addition salts for therapeutic use, in particular in the
form of the particularly physiologically acceptable
hydrochloride. However, paroxetine hydrochloride anhydrate shows
a tendency to polymorphism. Thus, DE-C 196 03 797 describes four
polymorphic forms of paroxetine hydrochloride anhydrate.
Polymorphic forms are, however, problematical for therapeutic use
since different polymorphs may have different solubilities and
consequently differences in the bioavailability.
One possible solution to the polymorphism problem is to prepare
the active ingredient in amorphous form. Thus, WO 99/16440
describes the production of amorphous, i.e. noncrystalline,
paroxetine hydrochloride formulations by dissolving in_a
hydroxyl-containing compound such as ethanol and then removing
this compound. Likewise, EP-A 0 810 224 describes the production
of amorphous paroxetine hydrochloride by dissolving the active
ingredient in water or a lower alcohol and then removing the
solvent, for example by spray drying.
Dispersions, i.e. homogeneous microdisperse phases, of two or
more solids, and the special case of "solid solutions" (molecular
dispersion systems), and their use in pharmaceutical technology
are generally known (cf. Chiou and Riegelman, J. Pharm. Sci., 60,
1281-1300 (1971)).
WO 99/00131 describes the production of solid dispersions of
substances of low solubility in water using a solvent process or
a melt process. This makes it possible, for example, to produce a
solid dispersion of paroxetine hydrochloride in a solid carrier
material by melting the free paroxetine base in the presence of
X480/01221 CA 02374931 2001-12-31
2
the carrier material, and then passing dry hydrogen chloride gas
through the melt. The melt is then cooled to room temperature,
for example by leaving to stand overnight, and is ground.
However, the procedure described in this document is likely to be
confined to the laboratory scale, and is still unsatisfactory in
relation to the homogeneity of the mixtures. An additional factor
is that the hydrogen chloride gas is very chemically reactive and
may react with the excipients and form toxicologically
unacceptable products.
EP-A 665 009 discloses the possibility of altering the
crystalline state of active ingredients by processing in an
extruder, the active ingredients being processed essentially
without other excipients.
In addition, EP-A 760 654 discloses the possibility of producing
acid addition salts directly by a melt extrusion process by
reacting the free base in the presence of a salt.
WO 99/26625 discloses paroxetine formulations in which the active
ingredient is dissolved in a copolymer and mixed with a molten
polymer. Formulations of this type can also be extruded. However,
such formulations are prone to recrystallization, because of the
use of a cosolvent.
It is an object of the present invention to find improved
preparations of paroxetine and its physiologically acceptable
salts which, on the one hand, help to avoid the polymorphism
problem, but, on the other hand, also have an improved solubility
and storage stability for the active ingredient paroxetine which
is of low solubility per se. It was a further object of the
invention to provide a simplified process for producing such
preparations.
We have found that this object is achieved by solid preparations
of paroxetine and its physiologically acceptable salts in which
the active ingredient is embedded as a molecular dispersion in a
pharmaceutically acceptable carrier material which comprises a
completely synthetic polymer having a glass transition
temperature of >90~C.
The preparations may also be semisolid, although solid forms are
preferred.
048U/01221 CA 02374931 2001-12-31
3
Suitable pharmaceutically acceptable salts of paroxetine are not
only salts such as, for example, the fumarate or the maleate but
also, in particular, the hydrochloride and the corresponding
hydrochloride anhydrate.
Pharmaceutically acceptable matrix or carrier materials which are
suitable in principle are all materials which can be processed by
a melt process to give a homogeneous matrix with the active
ingredient.
Suitable matrix polymers have a glass transition temperature of
>90~C, preferably >90 to 110~C, in the anhydrous state and are
completely synthetic polymers. Particularly suitable ones are
melt-processable water-soluble polymers such as the homo- or
copolymers of N-vinylpyrrolidone with Fikentscher K values in the
range from 19 to 100.
Preferred matrix materials are polyvinylpyrrolidones or
copolymers of N-vinylpyrrolidone and vinyl acetate such as VP/VAc
60/40 (copovidone).
It is also possible to add to the matrix conventional
pharmaceutical excipients such as bulking agents, release agents,
disintegrants, stabilizers, flavor-improvers, antioxidants or
colors.
The novel preparations may contain paroxetine or one of its salts
in amounts of from 0.1 to 50% by weight, preferably 5 to 30% by
weight, based on the total weight of the preparation.
The novel preparations are preferably produced by a melt process,
in particular by producing and processing the melt using an
extruder.
Production can take place by initially producing a powdered
premix of all the starting materials and introducing it into an
extruder. This premix is processed to a homogeneous melt by
introducing shear forces and thermal energy and is subsequently
shaped. The melt is preferably produced at temperatures in the
range from 80 to 100°C, preferably 80 to 150~C. It is also
possible initially to melt only the matrix materials and then to
meter the active ingredient in through suitable devices.
The extruder employed is preferably a corotating twin screw
extruder. The homogeneous melt produced in this way can either be
extruded through a die or a breaker plate, or else be conveyed
through the open extruder head and, in this case, where
0480/01221 CA 02374931 2001-12-31
4
appropriate, be conveyed directly as granules through grinding
elements disposed in the screw channel. The shaping can also take
place by conventional pelletizing techniques, for example by hot
cut or cold cut or using compressed air.
The shaping of the extruded and still plastic melt can also take
place by passing the extrudate between counter-rotating calender
rolls with depressions, in which case tablet shapes can be
produced directly.
The novel preparations are preferably produced in the absence of
solvents. However, if the starting materials contain solvents,
these can be removed in the extruder by applying a vacuum. It is
also possible in this way to remove water of crystallization if
still present in the active ingredient employed. Suitable
solvents are, for example, volatile organic solvents or water.
In a particularly preferred embodiment of the invention, the
paroxetine salt is produced by processing the free paroxetine
base together with a compound which is suitable for forming an
appropriate acid addition salt, and the appropriate matrix
materials, by a melt extrusion process in an extruder. Ammonium
chloride is preferably employed as salt-forming component to
produce the corresponding hydrochloride.
Preferred novel preparations have instant release of the active
ingredient. Instant release means that the release of active
ingredient measured in a paddle apparatus at pH 1.2, 50 rpm and
37~C, is at least 80~ after 30 min.
The novel solid preparations comprise the active ingredient
embedded in the form of a molecular dispersion in a matrix. The
matrix behaves like a true solvent, i.e. every active ingredient
molecule is surrounded by molecules of the matrix materials. This
is visually evident from the transparency of the resulting cooled
melts. This state of molecular dispersion in the cooled melt is
moreover thermodynamically stable, i.e. no recrystallization
processes occur. As a consequence of the molecular dispersion of
the active ingredient in the matrix, the preparations show
instant and uniform release of active ingredient. The active
ingredient is essentially released from the solidified melt after
30 min.
048/01221 CA 02374931 2001-12-31
Examination of the extruded melts by differential scanning
calorimetry (DSC) no longer shows any melting signals in the
region of the active ingredient melting point. In the case of
polymeric matrix materials, only broad polymer glass transition
5 steps are evident.
It is also possible according to the invention to employ
amorphous paroxetine or its salts. The amorphous forms dissolve
more quickly in the matrix because no lattice energy must be
supplied for the melting. This makes processing at lower
temperatures possible.
The novel preparations are moreover stable to uptake of moisture,
i.e. no recrystallization occurs. This is all the more surprising
since extremely hydrophilic polymers are employed. The products
also show improved storage stability. Surprisingly, paroxetine
can be extruded without decomposition despite the sensitive
acetal group. This is all the more surprising since PvP and its
copolymers have an acidic pH.
The novel preparations can be obtained in the form of granules
and be used as such to fill capsules or be compressed to tablets
or, as described above, be calendered directly to tablet form or
else be used as semisolid preparations to fill capsules.
Examples
Powdered premixes of the following composition were processed,
employing in each case anhydrous paroxetine hydrochloride:
Example 1
Paroxetine hydrochloride 30% by weight
copovidone 70% by weight
finely dispersed silica
(1% by weight based on
active ingredient/polymer)
The powdered premix was melted and extruded in a twin screw
extruder with a screw diameter of 16 mm at a material temperature
of 145°C. The resulting slightly yellowish transparent melt
remained transparent even after cooling. Even after storing per 9
months at 40°C and at 45% relative humidity, the transparency was
retained.
~48~/01221 CA 02374931 2001-12-31
_ 6
Example 2
A mixture as in Example 1 was extruded analogously through a
round-section die with a diameter of 3 mm. To determine the
active ingredient release, the cooled, transparent extrudate was
divided into pieces weighing 133 mg (paroxetine hydrochloride
content of 40 mg). The release was determined by the USP XXII
method in a paddle apparatus at pH 1.2, 50 rpm and 37°C:
Time [min] Active ingredient release [% by weight]
0 0
5 19
10 42
82
15 30 96
60 99
Example 3
Production of tablets
Biconvex tablets with a diameter of 9 mm and a weight of 200 mg
were produced by compressing the starting materials in a
conventional tablet press (Fette E2 eccentric press) under a
pressure of 6.5 kN. The tablet had the following composition:
paroxetine hydrochloride extrudate from Ex. 1 38~ by weight
microcrystalline cellulose 15~ byweight
calcium hydrogen phosphate (anhydrous) 35~ byweight
Na croscarmellose 10~ byweight
highly disperse silica 1% byweight
magnesium stearate 1~ byweight
The tablets had completely disintegrated in water at 37~C in
5 min.
40
