Note: Descriptions are shown in the official language in which they were submitted.
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PREPARATIONS OF NON-STEROIDAL ANALGESICS
The present invention relates to analgesic preparations obtained by extrusion
of
a melt, said preparations comprising a non-steroidal analgesic with
antipyretic
and anti-inflammatory effect and a mixture:
a) 40-99.5% by weight of a homopolymer of N-vinylpyrrolidone
with a Fikentscher K value of 30,
b) 0.25-59.75% by weight of water-soluble N-vinylpyrrolidone
copolymers, and
c) 0.25-10% by weight of one or more physiologically acceptable
salts of sodium or potassium,
where the stated amounts are based on the total of components a),
b) and c), and subsequent shaping.
The invention furthermore relates to a process for producing such
preparations.
Rapid release of the active ingredient is crucially important
particularly with analgesics in order to achieve a rapid onset of
the pain-relieving effect.
In the case of active ingredients which have low solubility in
water, like the organic acids which have analgesic activity,
rapid release of adequate doses is often not simple to achieve
(cf. Deutsche Apotheker Zeitung, No. 32,-page 54).
EP-A 607 467 proposes promoting rapid release of ibuprofen by
adding basic salts which are applied in the form of aqueous sol-
utions during the pelleting process to the active ingredient
which has been premixed with an ancillary substance. The pellets
are subsequently compressed to tablets in a conventional way.
This procedure is, however, relatively complicated and therefore
economically unfavorable.
Recent investigations have shown that rapid release of ibuprofen
can be achieved by using the corresponding lysine salts
(G. Geisslinger et al., Drug. Invest. SC4), 238-242, 1993).
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It is furthermore known that drug forms can be produced in a very
economic manner by extruding polymer melts which contain active
ingredients, with subsequent continuous shaping.
EP-B 240 904 describes such a process for producing solid pharma-
ceutical forms by extruding polymer melts which contain active
ingredients, the polymers used being homo- or copolymers of
N-vinylpyrrolidone.
However, the basic problem in such a process is that the matrix-
forming polymers on the one hand are sufficiently thermoplastic
at the processing temperatures, or become processable by addition
of a plasticizer, but on the other hand lead to drug forms which
are stable under the usual storage conditions and with which no cold flow
occurs.
This problem is all the more difficult to solve when the inten-
tion is to produce rapid release drug forms. Normally suitable
for this purpose are, in particular, relatively low molecular
weight polymers which rapidly dissolve in digestive fluids. How-
ever, it is precisely these which are prone to cold flow of the
finished drug forms. High molecular weight polymers normally do
not give rapid release and can scarcely be extruded without a
plasticizer because the glass transition temperature (DIN 52324)
is considerably higher.
An additional problem arises when transparent drug forms are to
be produced by melt extrusion.
It is an object of the present invention to find transparent,
rapid release preparations of non-steroidal analgesics which can
be produced in a simple manner by melt extrusion with subsequent
shaping and have a long shelf life.
We have found that this object is achieved by the preparations
defined at the outset.
Suitable active ingredients according to the invention are non-
steroidal analgesics with antipyretic and antiinflammatory
effect, as also employed for symptomatic antirheumatic therapy.
Accordingly, suitable active ingredients are derivatives of sali-
cylic acid, such as acetylsalicylic acid, and derivatives of
other organic acids and pyrazole derivatives and, where they
exist, their physiologically tolerated salts. Thus, suitable
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active ingredients are aryl acetic acid derivatives, such as diclofenac,
tolmetin or
zomepirac, also arylpropionic acid derivatives, such as ibuprofen, with both
enantiomerically pure S(+)-ibuprofen and a racemate enriched with this
enantiomer being embraced, as well as D,L-Iysine salts of ibuprofen, naproxen,
fenoprofen, flurbiprofen or ketoprofen, or else indole- and
indeneacetic acid derivatives such as indomethacin or sulindac.
Examples of suitable pyrazole derivatives are phenazone, amino-
phenazone, metamizole, propyphenazone, phenylbutazone or oxy-
phenbutazone.
Preferred active ingredients are ibuprofen, acetylsalicylic acid
and ketoprofen, sulindac, indomethacin, flurbiprofen.
It is also possible to employ mixtures of active ingredients.
Also suitable are mixtures of the analgesics with caffeine or
codeine.
The preparations according to the invention comprise as component
a) a homopolymer of N-vinylpyrrolidone with a Fikentscher K value
of 30. this homopolymer is readily water-soluble, "water-soluble" meaning that
at
least 0.5 g, preferably at least 2 g, of the polymer dissolves, possibly as
colloidal
solution, in 100 g of water at 20 C. Preparation of the homopolymer is
generally
known.
Suitable as component b) are water-soluble copolymers of N-vinyl-
pyrrolidone. Particularly suitable copolymers are those with
vinyl acetate in amounts of 10-50%, particularly preferably those
obtained by copolymerizing 60% by weight of N-vinylpyrrolidone
and 40% by weight of vinyl acetate.
Suitable as component c) are physiologically tolerated sodium
and/or potassium salts, also in the form of their hydrates, for
example sodium acetate, potassium acetate, sodium carbonate,
potassium carbonate, sodium bicarbonate, potassium hydroxide, sodium
chloride or potassium chloride, sodium citrate, with sodium acetate being
preferred, particularly preferably as sodium acetate trihydrate.
The ratios of the amounts of components a), b) and c) are chosen according to
the invention so that the preparations comprise a mixture of:
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a) 40-99.5% by weight, preferably 45-95% by weight, of compo-
nent a),
b) 0.25-59.75% by weight, preferably 0.5-50% by weight, of com-
ponent b), and
c) 0.25-10% by weight, preferably 0.5-7% by weight, of compo-
nent c),
where the stated amounts are based on the total of a), b) and c).
Very particularly preferred drug forms comprise, besides the med-
icinal substance, a mixture of
a) 60-85% by weight of component a)
b) 5-35% by weight of component b)
C) 0.5-5% by weight of component c).
The proportionate amount of the total of components a), b) and c)
in the drug form is preferably from 60 to 85% by weight. Accord-
ingly, the drug forms preferably comprise 15 to 40% by weight of
one or more active ingredients.
The drug forms may additionally comprise 0 to 5% by weight of
other conventional ancillary substances in the usual amounts.
The mixing of the active ingredient or ingredients with the poly-
meric binders and, where appropriate, pharmaceutical additives
can take place before or after the melting of the polymeric
binder by conventional processes. Mixing in an extruder is pre-
ferred, preferably a twin screw extruder or a single screw
extruder with mixing compartment.
The melts contain no solvent. This means that no water and no or-
ganic solvent is added.
Production takes place by extrusion at from 50 to 180 C, prefera-
bly 60 to 150 C with subsequent shaping of the still plastic
extrudate, eg. by shaping to tablets, for example as disclosed in
EP-A 240 906 by passing the extrudate between two rolls which are
driven in opposite directions and have mutually opposite depress-
ions on the surface of the rolls, whose design determines the
shape of the tablets. Cold cutting is also suitable.
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A hot-cut process is preferred. This entails the extrudates being
cut immediately after emerging from the die arrangement on the
extruder by, for example, rotating knives or another suitable
arrangement, expediently into pieces whose length is approxi-
5 mately equal to the diameter of the extrudate. The pellets which
have been cut off cool in the stream of air or gas to such an
extent that the surface is tack-free even before contact with
other pellets or a vessel wall but, on the other hand, the
pellets are still sufficiently plastic for them to acquire a
spherical shape by collisions, eg. with the wall of a downstream
cyclone. This results, in a simple manner, in substantially
spherical or lenticular pellets with diameters of from 0.5 to 4,
preferably 0.8 to 2 mm. The preferred smaller pellets are
primarily suitable for packing capsules, but can also
subsequently be compressed to tablets with the addition of other
ancillary substances.
The solid drug forms can also be provided with a conventional
coating to improve the appearance and/or the taste (sugar-coated
tablet).
The preparations according to the invention of non-steroidal
analgesics with antipyretic and antiinflammatory effect are
transparent, stable on storage and show rapid release. "Rapid
release" means that the release of the active ingredient is at
least 70% after 30 min, measured by the USP XXII paddle method.
Surprisingly, despite use of a relatively high molecular weight
polymer, even drug forms weighing as much as 1000 mg show rapid
release. The advantage of large tablets is that they can also be
used as pastilles without being swallowed. Elderly patients or
patients with dysphagia often find difficulty in swallowing
larger tablets so that rapid release pastilles have great advan-
tages.
It is surprising that it is possible to find a mixture of compo-
nents a and b for every size of the form (1000, 850 or 650 mg
bolus) which achieves a maximum release which is distinctly
greater than the release from mixtures of different composition,
or especially of the individual polymers alone.
The release rate also exceeds that of solid solutions produced by
a solvent process as described in the literature (M. Najib,
M. Suleilman, A. Malakh, 32 (1986) 229-236.)
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Examples
The compositions indicated in each of the examples were premixed
and introduced into the feed section of a twin screw extruder
5(Werner & Pfleiderer, ZSK 30). The melt extrusion took place with
a product throughput of 3 to 4 kg/h. The temperatures in the
individual zones (sections) of the extruder, and the temperature
of the heated die strip, are indicated for each of the tests.
Tablets weighing 1000, 850 or 650 mg were produced from the extru-
date by the calendering process described in EP-B 240 906.
Extrusion conditions:
Section 1: 430C
Section 2: 570C
Section 3: 1200C
Section 4: 1000C
Section 5: 1000C
Head: 1000C
Die: 1000C
Calender temperature: 180C
The release of active ingredient was measured by the USP XXII
paddle method. This in vitro test method is used to determine the
rate of dissolution of articles, eg. tablets, containing active
ingredients.
For this purpose 900 ml of a phosphate buffer with a pH of 7.2
were equilibrated at 370C in a 1 1 round-bottom vessel. An
appropriate amount of drug form was weighed in. The release of
active ingredient from the tablets was determined in this USP
XXII no-change test by UV spectroscopy after 30 min in each case
with a paddle speed of 150 rpm.
40
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Example 1
Tablet weight 850 mg
Composition:
Ibuprofen 26.0% by weight
Kollidon(D K 301) 56.5% by weight
KollidonOO VA 642) 15.0% by weight
Na acetate x 3 H20 2.0% by weight
Fine-particle silica 0.5% by weight
Release after 30 min: 88.0% by weight
Example 2
Tablet weight 650 mg
Composition:
Ibuprofen 33.0% by weight
Kollidon(D K 30 44.2% by weight
KollidonOO VA 64 20.0% by weight
Na acetate x 3 H20 2.0% by weight
Fine-particle silica 0.8% by weight
Release after 30 min: 90.0% by weight
1) PVP homopolymer, Fikentscher K value 30
2) Copolymer, obtained from 60% by weight of N-vinylpyrrolidone
and 40% by weight of vinyl acetate, K value 30.
Example 3
Tablet weight 850 mg
Composition:
Ibuprofen 23.5% by weight
Kollidon0 K 30 59.0% by weight
Kollidon VA 64 15.0% by weight
Na acetate x 3 H20 2.0% by weight
Fine-particle silica 0.5% by weight
The bioavailability in dogs was determined:
6 dogs, single administration of 1 tablet per animal
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Crossover study with 1-week washout
The active ingredient contents in the plasma were determined by
HPLC with UV-detection.
For comparison, a commercial product containing 342 mg of ibu-
profen D,L-lysinate (equivalent to 200 mg of ibuprofen) was admi-
nistered under the same conditions.
The results are listed in the table.
Table: Pharmacokinetics in dogs
Plasma level [ g/ml] x 103
Time [h] Tablet of Ex. 3 Ibuprofen lysinate
0.25 14.98 6.37
0.5 35.12 13.45
0.75 42.19 25.83
1.0 51.06 35.27
1.5 55.16 46.07
2.0 49.13 47.82
2.5 43.23 40.65
3.0 38.12 39.66
4.0 34.63 32.42
6.0 23.49 35.72
8.0 14.40 14.46
24.0 0.71 0.90
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