Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02352874 2001-05-30
WO 00/32169 PCT/EP99/09309
Method for Producing Solid Forms of Administration by Melt
Extrusion
' The present invention relates to a method for produeiag
solid forms of administration by melt extrusion.
In contrast to conventional tableting methods, which are
based on compacting powders or granules, in melt extrusion a melt
of a polymer of thermoplastic material, which is water-soluble or
capable of swelling in water and contains active ingredients, is
processed. Methods for producing tablets and other forms of
administration by means of melt extrusion are knoatn, for example,
from EP-A 0 240 904, EP-~A 0 240 906, 8P-A 0 337 256, US-A
4,880,585 and EP-A 0 358 105.
There, an extrudable pharmaceutical mixture is created by
mixing and melting a polymeric binder agent, at least one active
pharmaceutical ingredient and possibly further additives. An
extruder is customarily employed for mixing and melting. However,
the individual components can also be mixed prior to their
introduction into the extruder. The melt containing active
ingredients is pressed out through one or several extrusion dies,
for example slot dies in the extzuder head, in the form of product
strings or tapes. Then the still ductile product strings or tapes
are shaped into tablets or other forms of administration, such as
suppositories or granules, With the aid of suitable tools. For
example, the extruded melt can be compressed into shapes
complementary to the desired form of administration by means of a
cal.endering method with counter-rotating shaping rollers. To this
end, depressions complementary to the shape of the desired tablet
or suppository are provided in one or both shaping rollers. In
accordance with another known variation, a tape, which has
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depressions or openings in the desired tablet or suppository
shape, is passed between smooth cal'endering rollers.
Single- or twin-screw extrudezs are customarily employed as
extruders. A method for producing solid pharmaceutical
S dispersions is described in European Patent EP-B 0 580 860, in
Which a twin-screw extruder having kneading disks is employed.
The employment of mufti-screw extruders in the course of the
production of pharmaceutical compositions is ment~.oned in European
Patent Application LP-A 0 729 748. Hut actually this document
only deals With train-screw extruders v~rith kneading disks.
Extruders with more than two screws are not described either in
EP-H 0 580 860 or in EP-A 0 729 748.
8owever, such twin-screw extruders have the disadvantage
that spot-like occurring temperature peaks and large shear
stresses act on the material to be plasticized in the area of the
kneading disks. This poses a problem, particularly for the
extrusion of melts containing active ingredient, since many
active ingredients are extremely sensitive to heat. Moreover,
only those polymeric binders and additives which are insensitive
to increased temperatures and high shear stresses can be used in
conventional twin-screw extruders with kneading disks. These
disadvantages greatly limit the range of substances which are
customarily employed in tablet making by means of melt extrusion.
It is therefore the object of the present invention to
provide a method for producing solid forms of adartinistratian by
means of melt extrusion, which makes it possible to plasticize the
original substances of the extrudable mixture, i.e. the polymeric
binders and the active pharmaceutical compositions in particular,
in a gentle manner, in particular without the appearance of high
shear and temperature stresses, and to mix them.
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This object is attained by the method in accordance with
the attached main claim. In accordance with the invention, for
the production of solid forms of administration by means of melt
extrusion it is proposed to mix a polymeric binder, at least one
active pharmaceutical composition, and possibly further additives
in a planetary roller extruder, to melt them and to subsequently
extrude them in the shape of a continuous ductile production
string.
Surprisingly it was found that, when employing a planetary
roller extruder, it is possible to also work sensitive polymQrs,
materials and additives into a solid form of administration.
Planetary roller extruders are known per se and for example
are produced in Germany by ~ntex Rust & Mitschke GmbH of Mochwn.
Planetary roller extruders are continuous screw kneaders,
IS whose kneading element is embodied in the manner of a planetary
rolling mill. The same as conventional single- and twin-screw
extruders, planetary roller extruders also have a material inlet,
which is followed by a plastification and homogenization zone. A
cooling zone for cooling the heated material mixture to the
~0 extrusion temperature is customarily arranged upstream of the
outlet nozzle. The plastification and homogenization zone has a
central spindle, which typically is notched at less than X50.
Several planetary spindles mesh with this central spindle and, in
turn, engage a cylindrical bushing with teeth on the interior.
25 When the central spindle is driven, the planetary spindles freely
rotate in a rolling-off process between the bushing and the
central spindle. They are not seated and swim in the material to
be extruded during the operation. To the extent that the teeth
are in engagement with the central spindle, or the interior teeth
30 0~ the bushing, each planetary spindle represents a sort of a
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propeller-pump. The material to be plasticized is typically
pushed axially into the plastification and homogenization zone of
the planetary roller extruder and i.s very extensively rolled out
between the rotating planetary spindles and the central spindle,
on the one hand, or the bushing with interior teeth on the other
hand.
The material to be plasticized which reaches the gap
clearance between the teeth is repeatedly subjected tv a short
term spot-shaped rolling stress but, because of the roll-off
movement of the planetary spindles on the central spindle, is
immediately relaxed again and released. The material absorbs the
required plastification heat in a very short time because of this
thin film rolling and is intensely mixed and kneaded and
homogenized in the process.
Planetary roller extruders arQ customarily of very short
construction because of their considerably higher efficiency in
respect to single- and twin-screw extruders, so that the dwell
times of the material to be extruded in the plastification and
homogenization zone are also very short.
Tf required, the plastiaiaed and homogenized material is
grasped by a downstream-connected short discharge screw and can be
extruded through breaker plates or other nozzles. However, the
extruder can also be operated without die plates and w~.thout a
pressure buildup.
The plastification and homogenization zone of the extruder
is customarily heatable. To this end, heating or cooling means,
for example, aan be conducted through the housing ~aeket of the
extruder surrounding the bushing.
The planetary roller extruder is particularly
advantageously constructed in a module-like manner from individual
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sections, wherein the layout of the rollers and the temperature
profile can be separately optimized for each section.
The planetary roller extruder is distinguished by easy
self-cleaning properties, which is particularly advantageous when
producing pharmaceuticals.
The pressureless chambers existing between the zoller units
assure sufficient degassing of the material to be plasticized.
In spite of the short-term temperature and shear stresses,
it is possible by means of the method of the invention to achieve
the optimum homogenization of the material in the shortest time.
This has shown itself to be advantageous ra~hen producing solids
solutions, since it becomes possible to achieve a molecularly
dispersed distribution of the active ingredient in the matrix
without the use of solvents and high temperatures.
On the average, with the method of the invention, i.e. the
employment of a planetary roller extruder, the temperatures needed
for plasticizing and homogenizing the pharmaceutical mixture are
approximately 20°C lower than the temperatures required by the
conventional extrusion methods, i.e. when using a twin-screar
extruder.
A planetary roller extruder having a central spindle and
three to eight planetary spindles is advantageously used.
The use of a planetary roller extruder having six planetary
spindles is particularly preferred. It is possible by means of
this arrangement to mix and plasticize the mixture to be extruded
particularly effectively without excessive temperature and shear
stresses of the material occurring.
The planetary roller extruder does not require kneading
disks because of the good ~.ntermi_xing aad plastification of the
pharmaceutical mixture. The above described disadvantages
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occurring, fvr example, when twin-screw extruders with kneading
disks are employed, are avoided with the method in accordance with
the invention.
The dwell time of the pharmaceutical mixture in the
planetary roller extruder is short and preferably is approximately
0.5 to 2 minutes, depending on the number of revolutions of the
central spindle and the length of the roller element.
Since in accordance with the method of the invention the
material to be plasticized is not subjected to te~nnperatuxe and
shear stresses lasting over a long time, a planetary roller
extruder is particularly suitable for extruding materials which
contain heat- or shear-sensitive substances, which can be active
iaaterial, excipients or added materials here.
Therefore the use of a planetary roller extruder for
extruding a heat-sensitive pharmaceutical mixture is al~o an
object of the invention.
Within the scope of the present invention, the term "form
of administration" should be understood in its broadest possible
sense. It is tied neither to any definite shape nor to a definite
application. It therefore includes, for example, tablets for
peroral application, suppositories for rectal application,
granules, or even larger shapes, such as cubes, blocks (cuboids)
or cylindrical shapes. The method ~,n accordance with the
invention is suitab7.e for producing any arbitrary forms of '
administration, which are finding use, fox example, as
medicaments, plant treatment agents, feeds and foodstuffs, as well
as for the release of scents and essential oiler.
All materials having a pharmaceutical effect and the least
possible side effects are understood to be active pharmaceutical
agents, provided that they do not decompose under the processing
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conditions. The amounts of effective agent per unit of dosage and
the concentration can vary within wide limits, depending on their
effectiveness and speed of release. The only condition here is
that they are sufficient for obtaining the desired effects. The
concentration of active agents in respect to the total weight of
the form of administration therefore can lie in the range between
0 and 90, preferably between 0.1 and 60. In the present
connection, the term active ingredient also includes any arbitrary
combinations of active ingredients. For example, vitamins are
also active ingredients in the sense of the invention. Preferred
active ingredients are ibuprofen (in the form of racemates,
enantiomers or enriched enantiomers), ketoprofen, flurbiprofen,
acetylsalicylic avid, verpamil, paraeetamol, nifedipin and
catopriJ. .
Hut the method in accordance with the invention is
particularly suitable for heat-sensitive substances such as, for
example, enzymes, peptides, vitamins, hormones, insulin, plant
extracts, dihydropyridine derivatives, antibiotics, for example
makrolyte ox zytostatic agents. The method in accordance with the
invention is also particularly suited for the extrusion of plant
extracts and other natural active ingredients.
The method in accordance with the invention is particularly
suited for producing solid forms of administrat~.on containing
those polymers which, because of their high molecular weight or
thermolability, are subject to decomposit~.on phenomena in the
course of extrusion in twin-screw extruders, for example oxidative
degradation, depolymerization, molecular weight loss, elimination
of side groups, or which enter into chemical reactions with other
components of the formulation.
In the total mixture of all components, the polymeric
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binder must soften or melt in the range between 50 and 250°C,
preferably 60 to 180°C, and particularly preferred in the range
between 80 to 150°C. Therefore the glass transition temperature
of the mixture must lie below 200°C., preferably below 150°C,
and
particularly preferred below I30°C. If required, it will be
reduced by conventional, pharmacologically acceptable plasticizing
excipients. Suitable polymeric binders are described in WO
97/15291, for example.
The following are preferably employed as polymeric binders
for the melt extrusion of active pharmaceutical agents: polymers
or copolymers of N-vinyl pyrrolidone, eudragit types (acrylic
resins) or celluloses. Particularly preferred here are: polyvinyl
pyrrolidone (PVP), copolymers of Nwinyl pyrrolidone and vinyl
esters, such as vinyl acetate, poly(hydroxyalkylacrylates),
I5 poly(hydroxyalkylm~ahacrylates), polyaerylates, polymethacrylates,
alkyl celluloses or hydroxyalkyl celluloses.
Besides the polymeric binder and the active ingredient(s),
the extrndable mixture can also contain customary additives, for
example plasticizers, lubricants, solvents, dyestuffs,
stabilizers, or wetting, preservative, blasting, adsorption,
unmolding and expanding agents. Also, customary galenic
excipients, fox example extenders or fillers, can be contained in
it. Suitable additives and galenic excipients are described in WO
97115291, for example.
The typical structure of a planetary roller extruder is
shown in a sectional. representation in the attached drawing.
Following its plasti.fication and homogenization area, the
Planetary roller extruder ZO has a heatable, essentially
cylindrical housing jacket 11, on whose interior wall a bushing 12
is arranged, out of whose interior surface a helical groove 12a
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has been cut. A driveable central spindle 13 i~ rotatably seated
centered is the interior of the bushing 12 and is surrounded by
several freely rotating planetary spindles 14. Each planetary
spindle 14 meshes with its helical outer surface 14a r~rith the
helical outer surface 13a of the central spindle 13, as well as
with the interior spiral 12a of the bushing 12. The bushing 12 is
arranged, fixed against relative rotation, in the housing of the
planetary roller extruder 10. A thrust ring, not visible in the
sectional representation of the attached drawing figure, for the
rotating planetary spindles 14 is arranged at the extruder end.
Example 1:
Production of a Solids Solution of Ibuprofen in a Matrix of
Kollidon 90 F, Using a planetary Roller Extruder
30 wt.-% of ibuprofen were extruded together with 69.5 wt.-
Z5 % of Kollidon 90 F of a k value of 90, and with 0.5 wt.-% of
Aerosil 200 in a planetary roller extruder.
The planetary roller extruder had a central spindle of a
diameter of 43 ~, which was surrounded by six planetary spindles
each of a diameter of 20 mat and of a length of 398 mm each.
Extrusion was performed at a number of revolutions of 40 rpm and
with a throughput of 5kg/h.
Plasticizing and homogenizing took place at a maximum
temperature in the extruder of 150°C.
Following extrusion, the k value of Kollidon was 85.
Comparison Example 1:
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Production of a Solids Solution of Ibuprofen in a Matrix of
Kollidon 90 F, Using a Twin-Screw Extruder
30 art,.-% of ibuprofen were extruded together with 69.5 wt,-
% of Kollidon 90 F of a k value of 90, and with 0.5 wt.-% of
S Aerosil 200 in a ZSK twin-screw extruder of the Werner &
Pfleiderer company at a number of revolutions of 100 rpm and a
throughput of 2 kg/h.
A maximum temperature in the extzuder of 190°C was required
for satisfactory plasticizing and homogenizing.
ZO Following extrusion, the k value of Kollidon was only
approximately 70.
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