Note: Descriptions are shown in the official language in which they were submitted.
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1.
WO 97/34600 PCT/EP9710116T
Description
. Combination preparation, comprising 5-methyl-4'-trifluoromethyl-4-
isoxazolecarboxanilide and N-(4-trifluoromethylphenyl~2-cyano-3-
hydroxycrotonamide
The European Patent Application with the publication number 0 013 376
disclosed that 5-methyl-4'-trifluoromethyl-4-isoxazolecarboxanilide
(compound 1 ) has antifieumatic, antiinflammatory, antipyretic and
analgesic activity and can be employed against multiple sclerosis.
Pharmaceuticals which comprise the active compound 5-methyl-4'-
trifluoromethyl-4-isoxazolecarboxanilide are administered orally in doses of
from 25 mg to 150 mg.
The European Patent Application with the publication number 0 217 206
reports that N-(4-trifluoromethylphenylr2-cyano-3-hydroxycrotonamide
(compound 2) has immunomodulating properties and is suitable for treating
chronic graft-versus-host disease and autoimmune diseases, in particular
systemic lupus erythematosus. Pharmaceutical preparations which
comprise a compound 1 or compound 2 can be administered in a dose of
from 10 to 200 mg, preferably, however, of from 50 to 100 mg, in the case
of an injection solution in ampoule form (intravenous), in particular based
on compound 2 or a salt thereof, of from 1 to 30 mg, preferably of from 5 to
10 mg, and, in the case of rectal administration, of from 50 to 300 mg,
preferably of from 100 to 200 mg. However, the oral administration of 5 mg
or 10 mg of compound 1 or compound 2, in each case on its own, per kg
does not have any significant effect.
It has been found that a combination preparation, which comprises
compounds 1 and 2, exhibits surprisingly advantageous
immunosuppressive effects. The addition of small quantities of compound
2 to the main active component compound 1 results in a marked increase
in the activity of the combination preparation. Due to the magnitude of this
effect, the use of this combination can be extended to areas which hitherto
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remained closed to an immunosuppressive therapy using the individual
components. Furthermore, the reduction in the dose, without any
decreased activity, leads to greater safety in use. At the same time, it can
be assumed that a reduction in the dose in association with unchanged
activity will enable the therapy costs to be lowered substantially.
The invention relates, therefore, to a solid preparation which comprises
component 1 ) 5-methyl-4'-trifluoromethyl-4-isoxazolecarboxanilide,
component 2) N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide
and/or a physiologically tolerated salt of N-(4-trifluoromethylphenyl)-2-
cyano-3-hydroxycrotonamide and/or a stereoisomeric form of N-(4-
trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide and
3) a pharmaceutical excipient,
wherein the content of component 1 is from 2 to 20 mg and the content of
component 2) is from 0.3% to 50% of that of component 1 ).
The compounds 5-methyl-4'-trifluoromethyl-4-isoxazolecarboxanilide and
N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide can be
produced using known methods (EP 0 529 500). N-(4-
Trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide having the following
structural formula
0
NC-C-C- NH ~ ~ CFA
c
HO/ \CH3
is employed as such and/or a physiologically tolerated salt of N-(4-
trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide andlor a
stereoisomeric form of N-(4-trifluoromethylphenyl)-2-cyano-3-
hydroxycrotonamide in the preparation according to the present invention.
Examples of suitable physiologically tolerated salts of N-(4-
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trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide are alkali metal,
alkaline earth metal or ammonium salts, including those of physiologically
tolerated organic ammonium bases.
The novel solid preparation is suitable, for example, for treating
- acute immunological events, such as sepsis, allergy and graft-
versus-host reactions and host-versus-graft reactions
- autoimmune diseases, in particular rheumatoid arthritis, systemic
lupus erythrematosus and multiple sclerosis
- psoriasis, atopic dermatitis, asthma, urticaria, rhinitis and uveitis
- type II diabetes
- hepatic fibrosis, cystic fibrosis and colitis
- cancerous diseases, such as lung cancer, leukemia, ovarian cancer,
sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, lymph
node cancer, brain tumours, breast cancer, pancreatic cancer,
prostate cancer or skin cancer.
The novel solid preparation can also comprise combination packs or
compositions, in which the components are juxtaposed and can therefore
be administered simultaneously, separately or at graded time intervals to
one and the same human or animal body. According to the invention,
components 1 and 2 can also be present in juxtaposed, separate medicinal
forms, in particular when the spatial dimensions of the medicinal forms
make administration more difficult. This applies, in particular, to the oral
forms, since elderly patients often have an aversion to large tablets or
capsules. It is imperative that the separate, juxtaposed medicinal forms are
arranged so that they can be taken at the same time. In this context,
different forms, for example a tablet and a capsule, can also be present
alongside each other.
The invention furthermore relates to the use of a combination of
compounds 1 and 2 for preparing a pharmaceutical which exhibits a
hyperadditive increase in the immunosuppressive effect.
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The invention furthermore relates to a process for producing the novel
preparation, wherein compounds 1 and 2 and a pharmaceutical excipient
are processed into a pharmaceutical administration form.
The novel solid preparation can be present as a dosage unit in the form of
medicinal forms such as capsules (including microcapsules), tablets
(including coated tablets and pills) or suppositories, with it being possible,
when capsules are used, for the capsule material to exercise the function
of the excipient and the content to be present, for example, as a powder,
gel, emulsion, dispersion or solution. However, it is particularly
advantageous and simple to prepare oral (peroral~ formulations with the
two compounds 1 and 2, which formulations comprise the calculated
quantities of the active compounds together with each desired
pharmaceutical excipient. A corresponding formulation (suppository) for
rectal therapy can also be used. Transdermal administration in the form of
ointments, creams or oral administration of solutions which comprise the
novel preparation, is likewise possible.
In addition to the active compounds, ointments, pastes, creams and
powders can also comprise the customary excipients, for example animal
and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose
derivatives, polyethylene glycols, silicones, bentonites, talc, zinc oxide,
lactose, silicic acid, aluminum hydroxide, calcium silicate and polyamide
powders, or mixtures of these compounds.
The tablets, pills or granulate bodies can be prepared by customary
processes, such as compressing, dipping or fluidized bed processes or
boiler coating, and comprise excipients and other customary auxiliary
substances such as gelatin, agarose, starch (e.g. potato, corn or wheat
starch), cellulose, such as ethyl cellulose, silicon dioxide, various sugars,
such as lactose, magnesium carbonate and/or calcium phosphates. The
coating solution is normally composed of sugar and/or corn syrup and
usually also contains gelatin, gum arabic, polyvinylpyrrolidone, synthetic
cellulose esters, surface-active substances, plasticizers, pigments and
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similar additives corresponding to the state of the art. Any customary
flowance agent, lubricating agent or glidant, such as magnesium stearate
and mold lubricant can be used for producing the preparations.
Preferably, the preparations are in the form of casing/core tablets or
multilayer tablets, with compound 2 being located in the casing or in the
core or in a layer, while compound 1 is located in the core or in the casing
or in another layer. Compounds 1 and 2 can also be present in delayed
release form, or be adsorbed to release-delaying material or be enclosed
in the release-delaying material (for example material of this kind based on
cellulose or polystyrene resin, for example hydroxyethyl cellulose). Delayed
release of the active compounds can also be achieved by providing the
layer in question, or the compartment, with customary coatings which are
insoluble in gastric juice.
The dose to be used naturally depends on different factors, such as the
living subject (i.e. human or animal) to be treated, age, weight, general
state of health, the severity of the symptoms, the disease to be treated,
any accompanying diseases, (if present) the nature of the accompanying
treatment with other pharmaceuticals, or the frequency of the treatment. In
general, the doses are administered several times daily and preferably
from once to three times daily. In this context, the quantities of individual
active compound which are used are based on the recommended daily
dose of the particular individual active compound and should, in the
combination preparation, generally be from 10% to 100% of the
recommended daily dose, preferably from 20% to 80%, in particular 50%.
The appropriate therapy with the novel combinations consequently
comprises, for example, the administration of one, two or 3 individual
doses of the preparation composed of
1 ) 5-methyl-4'-trifluoromethyl-4-isoxazolecarboxanilide in a quantity of
from 2 to 20 mg, 2 to 19.9 mg, 4.5 to 19.5 mg, 4.85 to 19 mg, 5 to
18 mg, 5 to 15 mg, 5 to 10 mg, 5 to 9.9 mg, 5 to 9.7 or 5 to 9.0 mg
and
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2) N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide in a
quantity of from 0.3% to 50%, preferably of from 0.5% to 20%, in
particular of from 0.8% to 15%, particularly preferably of from 1 % to
10%, very particularly preferably of from 1 % to 5°l0; in each case
based on the content of 5-methyl-4'-trifluoromethyl-4-
isoxazolecarboxanilide, and
3) a pharmaceutically tolerated excipient.
The percentage values (%) of compounds 1 and 2 refer in each case to
percent by weight.
The quantities of the active components naturally depend on the number of
individual doses and also on the disease to be treated. The individual dose
can also be composed of several dosage units which are administered
simultaneously.
Example 1
Pharmacological tests
Adjuvant-induced arthritis, modification in accordance with Perper
(Proc. Soc. exp. Biol. Med. 137, 506 (1971 ))
Male rats of a Lewis strain (Moeliegard, Denmark) having a body weight of
from 160 to 210 g are used as the experimental animals. On the 1 st day,
the animals are injected subcutaneously, into the tail root, with complete
Freund's adjutant containing a suspension of Mycobacterium butyricum in
heavy paraffin oil (Difc~; 6 mg/kg in paraffin oil; Merck). Compounds 1 and
2 are suspended in carbcxyr~;ethyl cellulose (1% in water) and this
suspension is administered orally. The compounds are administered once
daily from the 1 st to the 12th day of the experiment. The paw volume and
the arthritis index are determined on the 18th day.
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The severity of the disorder is determined by measuring the volumes of
both hind paws. The measurement is carried out by the water
. displacement method, using a 2060 plethysmometer (Rhema-
Labortechnik, Hofheim, Germany). In addition, the arthritis index is
determined on the 18th day after injection.
Determination of the arthritis index:
1. Ears 0.5 point for each ear on which redness appears and
nodules are formed
2. Nose 1 point for connective tissue swelling
3. Tail 1 point for the emergence of nodules
4. Front paws 0.5 point for each paw in which at least one
inflammation appears on a joint
5. Hind paws 1 point for slight inflammation (swelling)
2 points for a medium-strength inflammation
3 points for a massive inflammatory reaction
Animals forming a control group are only given the solvent (1 °/a
carboxymethyl cellulose in water). 6 animals are used for each dose and in
the control group. A reduction in the increase in paw volume and a
decrease in the arthritis index, as compared with the untreated control
group, are used as the criteria for an effect having been achieved.
Table 1 shows the results. The total quantity of compounds 1 and 2 is
constant in each of the different experiments.
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Table 1
Compound 1 Compound 2 Decrease in Decrease
in
paw volume arthritis
index
(mg/kg of rat)(mg/kg of rat)(%) (%)
0 74 58
9.9 0.1 93 66
9.7 0.3 94 71
9.0 1.0 95 66
5 0 10% increase 12% increase
4.85 0.15 10 5
4.5 0.5 46 35
Both at 5 mg/kg and at 10 mg/kg of rat live weight, the effect of the novel
preparation is markedly intensified by increasing quantities of compound 2.
Therefore, small additional quantities of compound 2 lead to a marked
intensification of the effect of the novel preparation.
