Note: Descriptions are shown in the official language in which they were submitted.
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HOECHSTAKTIENGESELLSCHAFT HOE 96/F 073 Dr. Th/we
Description
Solid pharmaceutical preparation, comprising 5-methylisoxazole-
4-carboxylic acid (4-trifluoromethyl)anilide
European Patent Application, publication number 0 013 376 A2, discloses
that 5-methylisoxazole4-carboxylic acid (4-trifluoromethyl)anilide
(compound 1) has antirheumatic, antiinflammatory, antipyretic and
analgesic activity and can be employed against multiple sclerosis.
Pharmaceuticals comprising the active compound 5-methylisoxazole-
15 4-carboxylic acid (4-trifluoromethyl)anilide are administered orally in doses of 5mgto 150mg.
European Patent Application, publication number 0 217 206 A2, discloses
that N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide (compound
20 2) has immunomodulating properties and is suitable as a pharmaceutical
against chronic graft-versus-host diseases and against autoimmune
disorders, in particular systemic lupus erythematosus. Pharmaceuticals
comprising the active compound N-(4-trifluoromethylphenyl)-2-cyano-
3-hydroxycrotonamide are administered in doses from 50 mg to 200 mg.
It has now been found that the production of solid pharmaceutical
preparations, comprising compound 1, for example in tablet form, leads
during storage to the formation of 6% to 9% of compound 2, the
percentage data relating to compound 1. Compound 2 is formed here from
30 compound 1 during storage. Pharmaceutical preparations containing 6 to
9% contamination by other active compounds are not adequate for modern
therapy, as they make difficult an accurately dosed, constant, controlled
administration of the compound 1.
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The invention aims, by modification of the production process, at making
available a pharmaceutical preparation comprising compound 1 in which
substantially less compound 2 is formed during storage.
The object is achieved by the production of the pharmaceutical preparation
comprising compound 1 being carried out in an essentially anhydrous
manner.
The invention therefore relates to a solid pharmaceutical preparation
comprising 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide
and a pharmaceutically tolerable excipient, which comprises compressing
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide and the
pharmaceutically tolerable excipient in an essentially anhydrous manner to
give a solid pharmaceutical preparation.
The preparation of 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)-
anilide is carried out according to EP 0 013 376. The pharmaceutically
tolerable excipient employed can be, for example, lactose, corn starch,
polyvinylpyrrolidone, highly disperse silica, cellulose, polyethylene glycol,
polyglycol or magnesium stearate.
After 6 months' storage at 40~C and 75% humidity in air, the solid
pharmaceutical preparations according to the invention have an N-(4-tri-
fluoromethylphenyl)-2-cyano-3-hydroxycrotonamide content of 1.0 to 4.5%,
as a rule of 1.5% to 4%, in particular of 1.5% to 3.5%; in each case based
on the content of the compound 1, which is set at 100%.
The expression "solid pharmaceutical preparation" means preparations
such as tablets, capsules, powders, suppositories or granules. The
expression "in an essentially anhydrous manner" means that dry active
compound and dry auxiliaries are employed and no additional water is
employed in the production of the pharmaceutical preparation.
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The content of 5-methylisoxazole-4-carboxylic acid (4-trifluoro-
methyl)anilide in a solid pharmaceutical preparation is 2 mg to 250 mg,
preferably 5 mg to 150 mg, in particular 10 mg to 50 mg7 particularly
preferably 10 mg to 20 mg.
The production of the pharmaceutical preparation according to the
invention is carried out, for example, by direct tableting, dry granulation
and tableting or by production of granules by melt solidification and
subsequent tableting. In direct tableting, the binding between the powder
10 particles is effected by the use of high mechanical pressures
(Pharmazeutische Technologie [Pharmaceutical Technology], Bauer,
Fromming, Fuhrer, 3rd Edition, Georg Thieme Verlag Stuttgart, New York
(1991 ) pages 292 - 307). The melt solidification granules are produced
either by melting and shock-freezing, by pouring out and comminuting or
15 by spray solidification in spray towers (Pharmazeutische Technologie,
page 295). In dry granulation, the bindings between the powder particles to
be granulated are effected by the use of high mechanical pressures. This
can be achieved both using tablet presses, relatively large tablets or
briquettes resulting as intermediates, and using compacting rolls, which
20 yield scales. The scales or briquettes obtained are then comminuted using
counter-rotating toothed rolls and/or put through sieves (Pharmazeutische
Technologie, page 295). For example, the compound 1 and one or more of
the pharmaceutically tolerable excipients are mixed without addition of
water. The dry auxiliaries such as binders, flow agents, glidants and
25 lubricants are then added and the mixture is compressed to give solid
tablets.
The compound 1 can further be mixed with lactose, microcrystalline
cellulose and Macrogol 6000 (polyethylene glycol) in a high-speed mixer,
30 the material being heated by friction and forming granules. The cooled
granules are passed through a screen of 1.2 mm mesh width and dusted
with magnesium stearate. The granules are then compressed to give
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tablets.
The solid pharmaceutical preparations according to the invention differ
from tablets which have been produced by moist granulation by a differing
5 release behavior of the active compound. The solid pharmaceutical
preparation according to the invention shows a release of 70% to 85% of
the active compound after 15 minutes, preferably of 76% to 80% and, after
30 minutes, of 85% to 95%, preferably of 88% to 92%.
10 Tablets which have been prepared by the moist granulation method show
a release of 87% to 92% of the active compound after 15 minutes, and,
after 30 minutes, a release of 93% to 98%.
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Example 1
Direct tableting
The following are needed for one tablet:
10.0 mg of 5-methylisoxazole-4-carboxylic acid (4-trifluoro-
methyl)anilide (I)
78.0 mg of lactose (Il); (Meggle Milchindustrie GmbH &
Co. KG, Wasserburg)
50.0 mg of corn starch(lll); (Cerestar Benelux B. V., Sas van
Gent, Netherlands)
100.5 mg of highly disperse silica (IV); (Degussa AG,
Rheinfelden)
7.5 mg of crosslinked poly(1-vinyl-2-pyrrolidone) (V);
(BASF, Ludwigshafen) and
0.5 mg of magnesium stearate (Vl); (Otto Balocher
GmbH, Munich)
The components I to lll are mixed for 5 minutes in a paddle mixer. The
components IV to Vl are then added and mixed for a further 60 seconds
(ready-to-press mixture). The ready-to-press mixture is compressed to give
20 tablets having a final weight of 146.5 mg each.
After 6 months' storage at 40~C with an air humidity of 75%, the tablets
have a content of the compound 2 of 1.5%, based on the content of the
compound 1.
Example 2
Spray granulation
The following are needed for 1 tablet:
10.0 mg of 5-methylisoxazole-4-carboxylic acid (4-trifluoro-
methyl)anilide (I)
78.0 mg of lactose (Il)
50.0 mg of corn starch (Ill)
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3.5 mg of poly(1-vinyl-2-pyrrolidone) K25 (IV); (BASF,
Ludwigshafen)
0.5 mg of highly disperse silica (V)
7.5 mg of crosslinked poly(1-vinyl-2-pyrrolidone) (Vl)
0.5 mg of magnesium stearate (Vll)
The components I to lll are mixed for 5 minutes in a tumble mixer. Poly(1-
vinyl-2-pyrrolidone) is dissolved in water (5 to 7.5 percent strength solution)
and sprayed onto the mixed components I to lll in a spray tower at an
10 incoming air temperature of approximately 60~C and an outgoing air
temperature of approximately 21~C. The product is then dried. The spray
granules obtained are transferred to a mixer and mixed for 60 seconds with
the components V to Vll. The ready-to-press mixture is processed as in
Example 1 to give tablets having a final weight of 150 mg.
After 6 months' storage at 40~C at an air humidity of 75%, the tablets have
a content of the compound 2 of 8.3%, based on the compound 1.
Example 3
20 Release of compound 1 from tablets
1 tablet each according to Examples 1 and 2 is added to 100 ml of water
each. After 15 minutes and after 30 minutes, the amount of compound 1 in
the supernatant is determined. Table 1 shows the results.
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Table 1:
Tablet according to Release after Release after
15 minutes 30 minutes
Example 2 92 % + 3.1 % 98 % + 1.1 %
Example 1 77 % + 1.0 % 88 % +1.1 %
