Note: Descriptions are shown in the official language in which they were submitted.
~ss~
- 1 -
The invent;on relates to a new act;ve compound
comb;nation ~ith an antihypertensive and antianginal
action, which contains dihydropyridines (component A),
some of which are known, and certain ~-blockers ~compon-
ent B), and which has a long duration of action and agood tolerance.
It is already known that comb;nations of var;ous
~-blockers with various calcium antagonists can be used
in the treatment of circulatory diseases, in particular
1n hypertension and coronary diseases~ However, from the
action mechanis~s of calcium antagonists and of ~-
blockers, a higher risk in comparison with monotherapy
can be deduced in respect of possible undesirable side
effects. For e)~ample, V.S. Wayne et al., in Australia
N.Z.JOMed. 1Z, ~o. 4, 285 - 289 (1982), report serious
side effects of a combination of the calcium antagonist
verapamil and the ~-blockers metoprolol and pindolol.
M~D. Winniford et al. (Zirkulation 66, No. 4 Part 2, page
120 (1982) Dallas USA) also report possible serious side
2û effects in connection ~ith the treatment of 13 angina
patients with a combination of the ~-blocker propanolol
and the calcium antagonist verapamil. In contrast, the
calcium antagonists selected accord;ng to the invention
from the 1,4-dihydropyridine group are distinguished by a
clearly better tolerance in this respect; if suitable
~ -blockers are chosen as combination partners, the
benefit/risk ratio is further optimised.
The present invention relates to a new antihyper-
tensive and antianginal combination product containing a
combination of a dihydropyridine with an unsymmetric
ester grouping (component A), of the general formula I
Le A 22 709
31 2SS5~6
- 2 -
4 ~ (I)
R 00 ~ COOR2
ll ~
~' N ~R1
in which
R1 and R5 are identical or different and repre-
sent methyl, hydroxymethyl or cyano,
R2 and R4 are always different from one another
and represent alkyl ~ith 1 to 10 carbon atoms,
which i~ optionally substituted by alkoxy with 1
to 4 carbon atoms, fluorine, chlorine or N-methyl-
benzylamino, and
R3 represents 1 or 2 identical or different
substituents fro~ the group comprising ni~ro,
chlorine and trifluoromethyl, or represents the
radical =N-O-N=
and a ~-blocker without a local anaesthetic action, in a
weight ratio of 0.1 to 10 parts by we;ght of co~ponent A
and 10 to 200 parts by weight of component B.
The invention preferably relates to an antihyper-
tensive and antianginal combination product which con-
tains the dihydropyridine isobutyl ~ethyl 1,4-dihYdro-
2,6-dimethyl-4-(2-nitrophenyl)-pyridin~-3,5-dicarboxylatP (nisol-
dip;ne) or the ~ihydropyridine 3-methyl 5-ethyl Z,6-di-
methyl-4-(3'-nitrophenyl~-1,4-dihydropyridine-305-dicar-
boxylate tnitrendipine) as component A and a~ -blocker
from the group ~comprising atenolol, sotalol, timolol or5 nadolol as component B.
The two dihydropyridines and their action on the
blood pressure ~and their coronary action are known (com-
pare DOS ~German Published Spec;fication) 2,117,571;
British Patent 1,358,951; DOS tGerman Published Specifi-
cation) 2,549,568; and British Patent 1,516,793). TheirLe A 22 709
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:l~S5i~96
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use as combination partners w;th the ~-blockers mentioned
is new.
The~ -blockers ~hich can be used according to the
invention and halve no local anaesthetic action are also
known (compare Llloth et al., J. Med. Chem. 9, 8$ ~1966),
and U.S. Patents 3,663~607, 3,836,671, 3,619,370,
3,655,663, 3,657,237 and 3,9~5,267).
Their use as combination partners w;th the un-
symmetric dihydropyridines mentioned is new.
The g -bLockers mentiorled according to the inven-
tion are selected from the large group of knownf~-
blockers. In the prior art, there are numerous indica-
tions that combînations o~ ~-blockers with many calcium
antagonists have the risk of undesirable side effects and
can thus be used to only a limited degree for therapy of
coronary and circulatory diseases. Knowledge of the
mechanisms of the automaticity in cardiac pacemaker
tissue and of the influences of calcium antagonists and
~-blockers on these shows that, for example in animals
treated with ~-blockers, the spontaneous excitation of
the cardiac pacemaker tissue may be lost if relatively
high doses of calcium antagonists are s;multaneously
administered.
It could not be predicted that a combination of
selected~Y-blockers without a local anaesthetic or sodium
antagonistic action with the calc;um antagonists selected
according to the invention from the 1,4-dihydropyridine
group shows such an advantageous action and is particu-
larly distinguished by a good tolerance.
It is therefore decidedly surprising that the
combinations according to the invention of selected
calc;um antagonists with selected ~-blockers without a
local anaesthetic (sodium antagonistic) action have a
considerably better tolerance, cou~led with an advantage-
ous antihypertensive and antianginal action, than combina-
tions with other ~-blockers which have a local anaesthetic
~e A Z2 709
12S~S~
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or sodium antagonistic action.
This applies all the more so since all the known
electrophysiological investigations suggest that the
sodium system plays no part in the automaticity of ~he
pacemaker cells in the heart ~compare, for example,
Brown, H.F., Physiol~ Rev. 62:505-530 (1982)).
In the combination according to the invention,
1 part by weight of component A is advantageously brought
together with 1 to 10, in particular 2 to 6, parts by
weight of component B. The daily dose of the comb;nation
according to the invention advantageously contains 1 to
100 mg, preferably 2 to 50 mg and ;n particular 5 to 30
mg, of component A and 1 to Z00 mg, preferably 10 to 100
mg and ;n part;cular 30 to 80 mg, of component B.
The combination product according to the inven-
tion is preferably used as a solid formulation, for
example in the form of tablets, pills, dragees, granules,
powders, capsules or sachets~
The galenical formulations can be prepared in a
known manner using known auxiliaries and excipients and,
if appropriate, with the addition of other suitable
active compounds, such as saluretics, in particular the
active compounds mefruside or muzolimine.
Those combination products in ~hich the active
compound of component A is employed in a sustained
release formulation, such as, for example, in the form
of active compound crystals with a specific surface area
of 0.5 to 4 m~/g, are to be particularly singled OUtr
Another possibility for component A ;s the use of a di-
hydropyridine which is in crystalline form to the extent
of 60 to 100% and in amorphous form to the extent of 0
to 40%, for exarnple as a co-precipitate with polyvinyl-
pyrrolidone tPVP), methylcellulose, hydroxypropylcellu-
lose or hydroxypropylmethylcellulose.
By using a mixture of amorphous dihydropyridine
and crystalline dihydropyridine, the advantage of a rapid
Le A 22 709
~2S5596
onset of action is combined with the advantage of a long
duration of action.
The combination according to the invention is very
well tolerated. Rats which had been beta-blocked by pre-
treatment with propranolol show the occurence of ECG-
abnormalties (loss of artrial excitation) after intravenous
infusion of a cummulative dose of nitrendipine of 2,5 mg/kg
(infusion rate: 300 ~g/kg/min). Rats which have been b~ta-
blocked by pretreatment with sotalo, tolerate a five-times
higher dose of rlitrendipine which is 12,2 mg/kg. If the
rats were beta-blocked by pretreatment with atenolol a
dosis of 6,8 mg/kg of nitrendipine was tolerated.
Besides the unexpectedly good tolerance of the
combination according to the invention, which leads to a
clear reduction in risk to the patient to be treated, the
administration of the fixed combination according to the
invention facilitates handling by the patient (improved
patient compliance).
Other advantages of the combination according
to the invention are to be seen in the fact that, in
the case of serious circulatory diseases, i~ par-
ticular severe hypertension or coronar.~ heart disease,
~hen therapy with monoproducts is no longer successful,
the combination product according to the invention can
be conveniently and reLiably used. Even if the
handling abiLity of the patient is limited, ;ntake of
both active compounds in the combined form in the
correct dosage is ensured and can be controlled more
easily by the treating physician.
The following formulation examples are intended
to illustrate the subject of the invention.
Example 1
20 mg of nitrendipine, consisting of 15 ~9 of
m;crocrystalline active compound ~ith a specific crystal
surface area of about 3 m2/g and 5 mg of nitrendipine
co-precipitate with PVP, are mixed toget~er with 53 mg
of crystalline atenolol, 370 mg of microcrystalline
cellulose, 85 rng of lactose and 7 mg of magnesium stear-
ate and the mixture is pressed to tablets.
Le A 22 709
, .
~S~;~6
Example 2
20 mg of nitrendipine, consisting of S mg of
microcrystalline active compound with a specific crystal
surface area of about 3 m2/g and 15 mg of nitrendipine
co-precipitate with PVP, are mixed together with 25 mg
of crystalline atenolol, 150 mg of microcrYstalline
cellulose, 110 mg of maize starch, 30 mg of crospovidone
and 5 mg of magnesium stearate and the mixture is pressed
to tablets.
~xample 3
30 mg of nitrendipine, consisting of 10 mg of
microcrystalline active compound with a specific crystal
surface area of about 3 m2/g and 20 mg of nitrendipine
co-precipitate with PVP, are mixed ~ith 60 mg of crystal-
line timolol, 200 mg of microcrystalline ceLlulose~
150 mg of maize starch, 35 mg of crospovidone and S mg
of magnesium stearate and the mixture is pressed to tab-
lets.
Example 4 (only for n;trendipine)
50 mg of nitrendipine as a microcrystalline
active compound with a specific crystal surface area of
about 3.5 m2/g are mixed with 10û mg of crystalline
timolol, 50 mg of microcrystalline cellulose, 70 mg of
maize starch, 26 mg of lactose, 20 mg of PVP, 2 mg of
sodium lauryl-sulphate and 2 mg of magnesium stearate and
the mixture is pressed to tablets.
Fxample 5
10 mg of nitrendipine as a microcrystalline
active compound with a specific crystal surface area of
about 3 m2/g are mixed with 50 mg of crystalline
sotalol, 27.5 mg of maize starch, 20 mg of microcrystal-
line cellulose, 16 mg of calcium hydrogen phosphate,
5 mg of PVP~ 1 mg of polysorbate and 0.5 mg of magnesium
stearate and the mixture is pressed to tablets.
Example 6
20 mg of nitrendipine as a microcrystalline
active compound ~ith a specific crystal surface area of
about 3 m2/g are mixed with 30 mg of crystalline
nadolol, 28.5 mg of maize starch, 25 mg of microcrystal
line cellulose, 20 mg of magnesium carbonate, 5 mg of
PVP, 1 rg of sodium lauryl-sulphate and 0.5 mg of mag-
nesium stearate and the mixture is pressed to tablets.
Le A 2~ 709
1~5~59~
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Example 7
- Z0 mg of nisoldipine as a microcrystalline active
compound with a specific crystal surface area of about
2~5 m2/g are mixed with 120 mg of crystalline atenolol,
80 mg of microcrystalline cellulose, 66 mg of maize
starch, 40 mg of lactose, 10 mg of PVP, 2 mg of sodium
lauryl-sulphate and Z mg of magnesium stearate and the
mixture is pressed to tablets~
Example 8
10 mg of nitrendipine as a microcrystalline
active compound ~ith a specific crystal surface area of
about 2.5 m2/g are mixed with 60 mg of crystalline
sotalol, 40 mg of microcrystalline cellulose, 33 mg of
maize starch, 20 mg of lactose, 5 mg of PVP, 1 mg of
sodium lauryl-sulphate and 1 mg of magnesium stearate and
the mixture is pressed to tablets.
Example 9
5 mg of nitrendipine as a microcrystalline active
compound with a specific crystal surface area of about 3
m2/g are mixed with 40 mg of crystalline nadolol,
30 mg of microcrystall;ne cellulose, 29 mg of maize
starch, 20 mg of magnesium carbonate, 5 mg of PVP, 0.5 mg
of polysorbate and 0.5 mg of magnesium stearate and the
mixture is pressed to tablets.
Example ~0
1 mg of n;trendipine as a microcrystalline active
compound ~ith a specific crystal surface area of about
2.5 m2/g are mixed with 70 mg of crystalline timolol,
20 mg of microcrystalline cellulose~ 15 mg of calc;um
hydrogen phosphate, 8 mg of maize starch, 0.5 mg of
sod;um lauryl-sulphate and 0.5 mg of magnesium stearate
and the mixture is pressed to tablets.
Example 11 (only for nisoldipine)
0.5 mg of nisoldipine as a microcrystalline
active compound ~ith a specific crystal surface area of
about 3.5 m2/g are mixed with 25 mg of crystalline
Le A 22 709
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atenolol, 20 mg of cellulose powder, 1D mg of lactose,
19.7 mg of ma;ze starch, 4 mg of PVP~ 0O5 mg of sodium
lauryl-sulphate and 0.3 mg of magnes;um stearate and the
mixture is pressed to tablets.
Le A 22 7D9
