Note: Descriptions are shown in the official language in which they were submitted.
21 99642
"COMPOSITIONS CONTAINING AN ASSOCIATION OF ASPIRIN AND
AN ANTI-Xa OLIGOSACCHARIDE AND USE OF AN ANTI-Xa
OLIGOSACCHARIDE OPTIONALLY IN COM3INATION WITH ASPIRIN"
The subject of the present inventlon is the use
of synthetic oligosaccharides with factor Xa inhibiting
activity which act via antithrombin III, alone or in
combination with aspirin, in the treatment of
thromboembolic diseases which occur during or after a
percutaneous transluminal angioplasty (PTCA).
Pharmaceutical compositions containing the
combination of the active ingredients oligosaccharides
and aspirin are also part of the invention.
The active ingredients which constitute the
combination are present in the free state or in the
form of one of their pharmacologically acceptable
salts.
During the last decade, a wide interest has
been shown in the study of the role played by platelets
in the development of the thromboembolic diseases
associated with arteriosclerosis (myocardial infarc-
tion, angina, cerebral vascular accident, arterial
diseases of the lower limbs and the li~e). Moreover,
the well-established role of the blood coagulation
process in arterial thrombosis has allowed the
development of numerous medicaments which inhibit the
various coagulation enzymes. The discovery of the
essential role of thrombin and of factor Xa in the
thrombotic process has led to the use of anticoagulants
being proposed in the prevention and treatment of
arterial thrombosis.
Among the available anticoagulants, heparin is
the preferred medicament in the prevention and
treatment of thromboembollc diseases.
~eparin catalyses, especially via antithrombin
III (AT III), the inhibition of two enzymes which are
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la
involved in the blood coagulation cascade, namely
factor Xa and factor IIa (or thrombin). The relative
importance of these two activities in the overall
activity of heparin remains unknown. Low molecular
weight heparin (LMWH) preparations contain chains
formed of 4 to 30 monosaccharides which act like
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property of being more selective for factor Xa than
thrombin. Despite this different biological activity
profile, low molecular weight heparin has an
antithrombotic effect as has been demonstrated in
studies on animals and on patients suffering from
thromboembolic diseases or exhibiting risks of
formation of a thrombus (Hirsch J. et al, J. Thromb.
Hemost., 1987, Leuven, Belgium Leuven University Press,
325-348).
Unlike heparin and the LMWHs, some synthetic
oligosaccharides, especially those described in EP
84999, have the property of selectively inhibiting
factor Xa via antithrombin III but do not possess any
activity on thrombin.
lS These synthetic oligosaccharides corresponding
to the antithrombin binding domain (ABD) of heparin are
known and manifest an antithrombotic activity in venous
thrombosis. These compounds are described in EP 529715
and EP 621282
The efficacy of these oligosaccharides in the
treatment of thromboembolic diseases occurring during
or after percutaneous transluminal angioplasty was not
very likely because of their incapacity to inhibit
thrombin which is the mechanism involved in the
thromboses resulting from a PTCA.
Indeed, it has long been known in the
literature that thrombin plays a key role in arterial
thrombosis and this is again confirmed by recent
experiments (L. A. Harker, Blood, 1991, 77, 1006-
1012). Thrombin inhibitors therefore constitute aneffective means for preventing and combating this type
of thrombosis after PTCA.
It has been observed, by comparing the efficacy
of heparin with those of direct thrombin inhibitors (a
direct inhibitor is an inhibitor which inhibits
thrombin without requiring AT III as intermediate),
that the latter are a lot more effective than heparin
for preventing and treating arterial thrombosis
(Arteriosclerosis and thrombosis, 1992, 12, 879-885. J.
21 99642
Am. Coll. Cardiol., 1994, 23, 993-1003). The probable
reason for this lack of efficacy is that the heparin/AT
III complex cannot, for reasons to do with stearic
hindrance, inhibit thrombin in a platelet-rich thrombus
as is a platelet thrombus.
The weak heparin activity, compared to the
direct inhibitors, is therefore linked to its need to
use AT III.
A compound which, on the one hand, acts itself
via AT III as intermediate, and, on the other hand,
does not inhibit thrombin would therefore be expected
to be ineffective in the treatment of arterial
thromboses after percutaneous transluminal angioplasty.
It has now been found, according to the present
invention, quite surprisingly, that a synthetic
oligosaccharide which is a selective inhibitor of
factor Xa acting via antithrombin III, may be used
alone or in combination with aspirin after PTCA in the
treatment of thromboembolic diseases of arterial
origin. Although it is now known that anti-factor Xa
pentasaccharides and aspirin act via two different
mechanisms of action, the combination or the
association of these active ingredients for use as
antithrombotics has never been studied.
Thus, according to one of its aspects, the
subject of the present invention is the use of a
synthetic oligosaccharide which is a selective
inhibitor of factor Xa acting via AT III, alone or in
combination with aspirin, for the preparation of
medicaments intended for preventing or treating
thromboembolic diseases occurring in a mammal which has
undergone a percutaneous transluminal angioplasty.
According to the invention, selective inhibitor
of factor Xa is understood to mean a compound capable
of selectively inhibiting factor Xa via antithrombin
III but not possessing a significant activity towards
thrombin.Preferably the selective inhibitor of factor
Xa has no activity towards thrombin.
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Advantageously, the said synthetic oligo-
saccharides are pentasaccharides, such as those
included in patents EP 84999 and US 5,378,829.
Particularly advantageous pentasaccharides are
especially:
methyl 0-(2-deoxy-2-sulphoamino-6-O-sulpho-a-D-gluco-
pyranosyl)-(1~4)-O-(~-D-glucopyranosyluronic acid)-
(1~4)-0-(2-deoxy-2-sulphoamino-3,6-di-O-sulpho-a-D-
glucopyranosyl)-(1~4)-0-(2-O-sulpho-a-L-idopyranosyl-
uronic acid)-(1~4)-2-deoxy-2-sulphoamino-6-O-sulpho-a-
D-glucopyranoside, in which the anion has the structure
(A)
HO ~ H ~ ~ O ~ OMe (A)
s6,- s'o,. so,. ~so,. s6,
and its pharmaceutically acceptable salts, especially
its decasodium salt, known by its code name SR 90107A
or ORG 31540, described in Chemical Synthesis to
Glycoaminoglycans, Supplement to Nature 1991, 350, 30-
33, deslgnated hereinafter "PS".
Methyl 0-(3,4-di-O-methyl-2,6-di-O-sulpho-a-D-
glucopyranosyl)-(1~4)-0-(3-O-methyl-2-O-sulpho-~-D-
glucopyranosyluronic acid)-(1~4)-0-(2,3,6-tri-O-
sulpho-a-D-glucopyranosyl-(1~4)-0-(3-O-methyl-2-O-
sulpho-a-L-idopyranosyluronic acid)-(1~4)-2,3,6-tri-O-
sulpho-a-D-glucopyranoside, in which the anion has the
structure (B)
MeO
so,- So~- SO~- 50,. So~
and its pharmaceutically acceptable salts, especially
its dodecasodium salt described in US 5,378,829;
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Methyl O-(2,3,4-tri-O-methyl-6-O-sulpho-a-D-glucopyran-
osyl)-(1~4)-0-(2,3-di-O-methyl-~-D-glucopyranosyluronic
acid)-(1~4)-O-(2,3,6-tri-O-sulpho-~-D-glucopyranosyl)-
(1~4)-0-(2,3-di-O-methyl-~-L-idopyranosyluronic acid)-
(1~4)-2,3,6-tri-O-sulpho-~-D-glucopyranoside, in which
the anion has the structure (C)
M ~ O ~ OM- (C)
So~. SO~- so,- 50,,
and its pharmaceutically acceptable salts, especially
its nonasodium salt, also described in US 5,378,829.
The use of the compound of formula (A),
preferably in decasodium salt form (PS) corresponds to
a preferred embodiment of the invention.
The decasodium salt of the compound of
structure (A) (PS), as representative compound for use
according to the present invention has been the subject
of a pilot clinical study in patients undergoing a
transluminal angioplasty of the coronaries. A single
dose of 12 mg of PS via the intravenous route and
500 mg of aspirin, via the intravenous route, was
administered to the patients. The results which were
obtained show the therapeutic value of the PS/aspirin
association in the prevention and treatment of acute
thromboses following a percutaneous transluminal
angioplasty.
To assess the antithrombotic activity 71
patients with stable angina (26), recent unstable
angina (11) or recent myocardial infarction (34) with
type A or B coronary lesions underwent PTCA with a
single 12 mg PS i.v. bolus injection and 500 mg i.v.
aspirin. Angiography was repeated 24 h after PTCA. The
endpoints were thrombus formation at PTCA sites and the
thrombolysis in myocardial infarction (TIMI) flow in
target vessel. ~eparin was not allowed before, during
and within 24 h after PTCA. Acute thrombotic closure at
dissected PTCA site occured in 1 patient and distal
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embolization of a thrombus containing plaque in
patient. Vessel patency was restored in both patients
with intracoronary alteplase. Stents were required in
ll patients (for dissection in 9, suboptimal result in
2) who were given 250 mg ticlopidine at the time of
implantation. Average minimal luminal diameter was 0.90
+ 0.50 mm before and 2.65 + 0.40 mm after PTCA
(reference diameter 2.95 _ 0.60 mm). At 24 h TIMI 3
flow without thrombus at PTCA site was observed in all
71 patients. No major bleeding occurred. Anti-Xa
activity peaked 10 min. after PS bolus (1.20 + 0.29 U
anti-Xa/ml) and was maintained on average at 0. a 7 +
0.14 U anti-Xa/ml 2 hours after PS administration. The
activated clothing time ACT remained unchanged.
Thrombin-antithrombin complexes levels (TAT) fell from
21.9 + 18.7 to 4.8 + 3.8 ug/l and prothrombin fragment
1+2 from 2.08 + 1.04 to 1.54 + 82 ng/ml 2 hours after
PS injection.
Thus the use according to the invention of an
oligosaccharide, alone or in combination with aspirin
is beneficial in relation to pathological states in
patients having undergone a percutaneous transluminal
angioplasty.
It will be noted that the use of the
oligosaccharide, alone or in association with aspirin
according to the invention, does not increase the
haemorrhagic risk.
For the treatment of the abovementioned
diseases, the oligosaccharide and the aspirin are
administered to mammals, including man, at daily doses
of the oligosaccharide or of the aspirin, respectively,
of 0.1 to 100 mg per kilo of bodyweight of the mammal
to be treated.
In a human being, the dose may vary for each of
the components from 1 to 1000 mg per day, according to
the age of the subject to be treated or the type of
treatment: prophylactic or curative. Preferably, the
pentasaccharide is administered at doses of between
0.30 mg and 30 mg per patient and per day.
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The aspirin may be formulated in a
pharmaceutical composition according to methods well
known to persons skilled in the art. The same applies
for the oligosaccharide.
The association of the oligosaccharide and the
aspirin may be formulated in pharmaceutical
compositions which may be used via the oral or
parenteral route, especially via the subcutaneous or
intravenous route, mixed with conventional
pharmaceutical exclpients.
These pharmaceutical compositions are
preferably provided in the form of dosage units
containing a predetermined quantity of active
ingredients, such as for example from 0.1 to 50 mg of
lS oligosaccharide or of aspirin, respectively, per dosage
unit.
When at least two active ingredients are
formulated in the same composition, it is necessary to
ensure the compatibility of the different active
substances. Thus the oligosaccharide is preferably used
in the form of an addition salt, for example the sodium
salt. Generally, indeed, the oligosaccharides in the
form of their addition salts with pharmaceutically
acceptable acids are not chemically incompatible with
aspirin.
Thus, according to another of its aspects, the
subject of the invention is a pharmaceutical
composition for the treatment or prophylaxy of
thromboembolic diseases in a mammal which has undergone
a percutaneous transluminal angioplasty, comprising the
association of an effective quantity of at least one
synthetic oligosaccharide, which is a selective
inhibitor of factor Xa acting via antithrombin III, and
of an effective quantity of aspirin, optionally mixed
3s with one or more pharmaceutically acceptable
excipients.
These compositions are produced so as to be
administrable via the digestive or parenteral route.
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The pharmaceutical compositions of the
invention are advantageously presented in various
forms, such as for example injectable or oral
solutions, sugar-coated tablets, plain tablets or
gelatin capsules. The injectable solutions are the
preferred pharmaceutical forms.
In the pharmaceutical compositions of the
present invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, transdermal, transmucosal,
local or rectal administration, the active ingredient
may be administered in unit forms for administration,
mixed with conventional pharmaceutical carriers, to
animals and to human beings. The appropriate unit forms
for administration comprise the oral forms such as
tablets, gelatin capsules, powders, granules,
microgranules and oral solutions or suspensions, the
forms for sublingual and oral administration, the forms
for subcutaneous, intramuscular, intravenous,
intranasal or intraocular administration and the forms
for rectal administration.
When a solid composition in tablet form is
prepared, the principal active ingredient is mixed with
a pharmaceutical vehicle such as gelatin, starch,
lactose, magnesium stearate, talc, gum arabic and the
like. The tablets may be coated with sucrose or other
appropriate materials or they may be treated so that
they have a prolonged or delayed activity and
continuously release a predetermined quantity of active
ingredient.
A preparation in gelatin capsules is obtained
by mixing the active ingredient with a diluent and by
pouring the mixture obtained into soft or hard gelatin
capsules.
The water-dispersible powders or granules may
contain the active ingredient mixed with dispersing
agents or wetting agents, or suspending agents, such as
polyvinylpyrrolidone, as well as with sweeteners or
flavour correctors.
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For a rectal administration, suppositories are
used which are prepared with binders which melt at the
rectal temperature, for example cocoa butter or
polyethylene glycols.
s For a parenteral, intranasal or intraocular
administration aqueous suspensions, isotonic saline
solutions and sterile and injectable solutions are used
which contain dispersing agents and/or wetting agents
which are pharmacologically acceptable, for example
propylene glycol or butylene glycol.
For a transmucosal administration, the active
ingredients may be formulated in the presence of a
promoter such as a bile salt, a hydrophilic polymer
such as for example hydropropyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
ethyl cellulose, carboxymethyl cellulose, dextran,
polyvinylpyrrolidone, pectins, starches, gelatin,
casein, acrylic acids, acrylic esters and copolymers
thereof, vinyl polymers or copolymers, vinyl alcohols,
alkoxy polymers, polyethylene oxide polymers,
polyethers or a mixture thereof.
The active ingredients may also be formulated
in the form of microcapsules, optionally with one or
more carriers or additives.
The active ingredients may also be provided in
the form of a complex with a cyclodextrin, for example
a- ~- or ~-cyclodextrin, 2-hydroxypropyl-~-cyclodextrin,
or methyl-~-cyclodextrin.
One of the active ingredients, for example the
oligosaccharide, may also be released by a balloon
containing it or by an endovascular stent introduced
into the blood vessels. The pharmacological efficacy of
the active ingredient is thus not affected.
According to a preferred embodiment of the
3s invention, the pharmaceutical compositions comprise the
association of aspirin and the compound of formula (A)
preferably in the form of its decasodium salt.
Preferably still, the oligosaccharide is
administered via the intravenous or subcutaneous route.
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The pharmaceutical compositions of the
invention contain, preferably, from 5 to 30 mg of an
oligosaccharide which is a selective inhibitor of
factor Xa and 200 to 800 mg of aspirin, better still
from 8 to 20 mg of the said oligosaccharide and from
400 to 600 mg of aspirin, for example 12 mg of the said
oligosaccharide and 500 mg of aspirin.
