PHARMACEUTICAL COMPOSITIONS CONTAINING DILTIAZEM AND ALFUZOSIN

COMPOSES PHARMACEUTIQUES CONTENANT DU DILTIAZEM ET DE L'ALFUZOSIN

English Abstract

ABSTRACT:

The invention provides a pharmaceutical composition
which may be used for treating cardiovascular diseases, eg
hypertension and angina. The composition comprises a
synergistic mixture of diltiazem and alfuzosin, both of
which are known compounds. The composition preferably
contains 25 to 160 mg of diltiazem and 0.1 to 10 mg
alfuzosin per unit dose.

Claims

Claims:

1. A pharmaceutical composition which comprises the
combination of diltiazem and alfuzosin.

2. A pharmaceutical composition according to claim 1,
which contains from 25 to 160 mg of diltiazem and from 0.1
to 10 mg of alfuzosin, by unit dose.

3. A pharmaceutical composition according to claim 1 or 2
which also includes a pharmaceutically acceptable
excipient.

Description

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Pharmaceutical compositions containing diltiazem and
alfuzosin.

The present invention relates to pharmaceutical compositions
containing alfuzosin plus diltiazem which may be used for
tresting cardiovascular diseases, more particularly
hypertension of any origin and angina.

Diltiazem of the forrnula
OCH3




.: ~ N- ~ ~ CH~


CH N \

is known for its antianginal and antihypertensive
properties.

Alfuzosin of the formula
CH3

CH30 ~ ~ N ~ ~

CH3û ~ N 0
~H2




has also an antihypertensive actlvity.

The applicant stated that, surprisingly, a synergestic
effect exists between the antihypertensive properties of the

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two compounds when they are combined.
The pharmaceutical compositions of the invention were
subjected to a series of pharmacological experiments which
demonstrate their valuable properties in the cardiovascular
field.

The following tests have been used :

1~ 1. Intravenous test
SHR rats, over 5 months, are anesthetized with sodium
pentobarbital (60 mg/kg i.v.) and prepared so that the blood
pressure is measured from a cannulated carotid artery.
The products to be tested are administered by intravenous
route via the femoral vein.
ln ug/kg/mn of diltiazem or of the solvent are infused by
intravenous route (the solvent is distilled water containing
o .ns ~ of ~aCl), dlJring 45 mn.
1û mn later, alfuzosin is injected (2 ug/kg/mn during 5 mn).
2~ The maximal cllsnges of the blood pressure after injection of
diltiazem, alfuzos;n or of their association are measured.

Diltiazem alone produces a sustained decrease of blood
pressure of 12.6 + 2,1 mmHg (n=15).
With alfuzosin alone the decrease of blood pressure is of
19.7 + 4,7 mmHg (n=6) at the end of the administration, and
of 4.2 + 1,5 mmHg, 15 mn later.

With the association diltiazem/alfuzosin the decrease of
blood pressure is of 58.4 + 7,8 mmHg (n=7) at the end of the
administration of alfuzosin, and still of 48.7 + 8,7 mmHg,
15 mn later.

2. _al test
Male vigile SHR rats, aged of more than 5 months, are used
in the oral test.
Their arterial blood pressure and cardiac frequency are
measured, continuously, from a catheterized tail artery
When the arterial blood pressure is stabilized (after 2 h
about), the animals receive, by oral route, in a volume of

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5 ml/kg, either 1 mg/kg of alfuzosin, either 12.5 mg/kg of
diltiazem, either placebo (distilled water + n,2 ~ of Tween
80), either the association diltiazem/alfuzosin.

The oral administration of 12.5 mg/kg of diltiazem has no
significant influence on the arterial hlood pressure or on
the cardiac frequenCy of the rat.
Alfuzosin (1 mg/kg p.o.) decreases slightly the arterial
blood pressure (-22 + 4 mmHg after 30 mn ; the initial blood
1~ pressure being 186 + 4 mmHg ; n=9).1 h after the treatment,
the parameter is recovered to the initial value.

The association alfuzosin/diltiazem provokes a decrease of
the arterial blood pressure.
lS The hypotensive activity of the association is maximal 15 mn
after the treatment (-96 + 4 mmHg ; initial pressure = 195 +5
mmHg ; n = 11).
1 h after the treatment the decrease is still equal to 70
of the maximu~n.
4 h after the treatment the decrease is still equal to 30
of the maximum.

The cardiac frequency is not significantly modified by each
of the compound or by the association.


These results show that there exists a synergism between the
antihypertensive effects of diltiazem and alfuzosin.
The pharmaceutical compositions of the invention may contain
from 25 to 160 mg of diltiazem and from 0.1 to 10 mg of
alfuzosin, per unit dose.
They may be presented in any suitable form for the oral or
parenteral administration in association with any suitable
excipient.
The daily dosage is such that 25 to 320 mg of diltiazem and
0.2 to 20 mg of alfuzosin are administered.