EA000048B1 - Compositions containing an association of aspirin and an anti-xa oligosaccharide and use of anti-xa oligosaccharide optionally in combination with aspirin - Google Patents

Abstract

The invention relates to the use of a synthetic oligosaccharide which is a selective inhibitor of factor Xa acting via antithrombin III, alone or in association 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. The subject of the invention is moreover pharmaceutical compositions for the treatment or prophylaxy of thromboembolic diseases occurring 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 with one or more pharmaceutically acceptable excipients.

Description

The present invention relates to the use of synthetic oligosaccharides with factor Xa inhibitory activity, which act through antithrombin III, alone or in combination with aspirin, in the treatment of thromboembolic diseases that occur during or after transcutaneous intraluminal angioplasty (PTCA).

Pharmaceutical compositions containing a combination of oligosaccharides and aspirin as active ingredients is also an object of the present invention.

The active ingredients that make up the combination are present in a free state or in the form of one of their pharmacologically acceptable salts.

During the last decade, much attention has been paid to the role that platelets play in the development of thromboembolic diseases associated with arteriosclerosis (myocardial infarction, angina pectoris, stroke, lower limb arterial disease, etc.). Moreover, the well-studied role of the process of blood coagulation in arterial thrombosis has allowed the development of a number of drugs that inhibit various coagulating enzymes. The discovery of the significant role of thrombin and X-factor in thrombotic processes led to the use of anticoagulants proposed for the prevention and treatment of arterial thrombosis.

Among the anticoagulants used, heparin is the preferred drug for the prevention and treatment of thromboembolic diseases.

Heparin catalyzes, especially through antithrombin III (AT III), the inhibition of two enzymes, which include the blood coagulation cascade, that is, factor Xa and factor Pa (or thrombin). The relative importance of these two activities in the total heparin activity remains unknown. Low molecular weight heparin preparations (LMWH) contain chains of 4-30 monosaccharides that act like heparin on X-factor and on thrombin, but which are more selective for X-factor than for thrombin. Despite this difference in biological activity, low molecular weight heparin has an antithrombotic effect, as shown in animal studies and patients suffering from thromboembolic diseases or at risk of thrombus formation (Hirsch J. et al., J. Thromb. Hemost. , 1987, Leuven, Belgium Leuven University Press, 325-348).

In contrast to heparin and low molecular weight heparins, some synthetic oligosaccharides, for example, described in EP 84999, have the property of selectively inhibiting X-factor through antithrombin III, but do not have any activity against thrombin.

These synthetic oligosaccharides corresponding to the antithrombine binding domain (ABD) of heparin are known and exhibit antithrombotic activity in venous thrombosis. These compounds are described in EP 529715 and EP 621282.

The effectiveness of these oligosaccharides in the treatment of thromboembolic diseases occurring during or after percutaneous intraluminal angioplasty was unlikely due to their inability to inhibit thrombin, which is a mechanism involved in thrombosis resulting from PTCA.

Indeed, it has long been known from 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 are thus effective in preventing and treating this type of thrombosis after PTCA.

When comparing the effectiveness of heparin with the effectiveness of direct inhibitors of thrombin (a direct inhibitor of thrombin is an inhibitor that inhibits thrombin without using AT III as an intermediate), the latter are found to be more effective than heparin in preventing and treating arterial thrombosis (Arteriosclerosis and thrombosis, 1992, 12, 879885. J. Am. Coll. Cardiol., 1994, 23, 993-1003). A possible reason for this lack of effectiveness is that the heparin / AT III complex cannot inhibit thrombin in a thrombus enriched with platelets, which are a platelet thrombus due to steric hindrance.

The weak activity of heparin in comparison with direct inhibitors, therefore, is due to the need to use AT

Iii.

A compound that, on the one hand, acts on its own through AT III as an intermediate and, on the other hand, does not inhibit thrombin, as would be expected, should be ineffective in the treatment of arterial thrombosis after transcutaneous intraluminal angioplasty.

Quite unexpectedly, it was found that a synthetic oligosaccharide, which is a selective inhibitor of factor Xa, acting through antithrombin III, can be used alone or in combination with aspirin for the treatment of thromboembolic diseases of arterial origin after PTCA.

Although it is now known that pentasaccharides with activity against factor Xa and aspirin act by two different mechanisms, the use of a combination or combination of these active ingredients as an antithrombotic agent has never been studied.

Thus, an object of the invention is the use of a synthetic oligosaccharide, which is a selective inhibitor of factor Xa, acting through AT III alone or in combination with aspirin, to produce drugs intended to prevent or treat thromboembolic diseases occurring in a mammal that has undergone transcutaneous intraluminal angioplasty.

According to the invention, a selective factor Xa inhibitor is understood to mean a compound capable of selectively inhibiting factor Xa through antithrombin III, but not possessing significant activity against thrombin. Preferably, the selective inhibitor of factor Xa has no activity against thrombin.

Said synthetic oligosaccharides are predominantly pentasaccharides known from EP 84999 and US Pat. No. 5,378,829.

The most preferred pentasaccharides are:

methyl O- (2-deoxy-2-sulfamino-6-Osulfo-a-O-glucopyranosyl) - (1 ^ 4) -O- (v-Pglucopyranosyluronic acid) - (1 ^ 4) -O- (2deoxy-2 -sulfamino-3,6-di-O-sulfo-α-D glucopyranosyl) - (1 ^ 4) -O- (2-O-sulfo-α-Lidopyranosyluronic acid) - (1 ^ 4) -2deoxy-2-sulfamino -6-O-sulfo-α-D-glucopyranoside, in which the anion has the structure of formula (A) (see the end of the description), and its pharmaceutically acceptable salts, especially the decanodium salt, codenamed SR 90107A or ORG 31540, which described in Chemical Synthesis to Glycoaminoglycans, Supplement to Nature 1991, 350, 30-33, and hereinafter referred to as PS;

methyl O- (3,4-di-O-methyl-2,6-di-O-sulfoa-E-glucopyranosyl) - (1 ^ 4) -O- (3 -O-methyl-2-Osulfo-β - D-glucopyranosyluronic acid) (1 ^ 4) -O- (2,3,6-tri-O-sulfo-α-D-glucopyranosyl) - (1 ^ 4) -O- (3-O-methyl-2- O-sulfo-α-Lidopyranosyluronic acid) - (1 ^ 4) -2,3,6tri-O-sulfo-α-D-glucopyranoside, in which the anion has the structure of formula (B) (see the end of the description), and its pharmaceutically acceptable salts, especially dodecanate salt, described in US patent No. 5378829;

methyl O - (2,3,4 -tri-O-methyl-6 -O-sulfo-αD-glucopyranosyl) - (1 ^ 4) -O- (2,3-di-O-methylv ^ -glucopyranosyluronic acid) - (1 ^ 4) O- (2,3,6-tri-O-sulfo-α-D-glucopyranosyl) (1 ^ 4) -O- (2,3-di-O-methyl-α-L- idopyranosyluronic acid) - (1 ^ 4) -2,3,6-tri-O-sulfo-αD-glucopyranoside, in which the anion has the structure of formula (C) (see the end of the description), and its pharmaceutically acceptable salts, especially non-sodium salt described in US patent No. 5378829.

The use of a compound of formula (A), preferably in the form of a decanodium salt (PS), is in accordance with a preferred embodiment of the present invention.

The decanate salt of the compound of structure (A) (PS), as a typical compound for use according to the present invention, was the object of experimental clinical trials in patients who underwent reconstruction of coronary vessels through the lumens. Patients were administered a single dose of 1 2 mg PS intravenously and 500 mg of aspirin also intravenously. The results show the therapeutic value of a PS / aspirin combination in the prevention and treatment of acute thrombosis following transcutaneous intraluminal angioplasty.

To assess the antithrombotic activity, 71 patients with stable angina pectoris (26), recent unstable angina pectoris (11) or acute myocardial infarction (34) with pathological coronary changes of type A or B are subjected to PTCA using intravenous injection of a single dose dose of 12 mg. PS and 500 mg of aspirin intravenously. Angiography is repeated 24 hours after PTCA. The end points are the formation of blood clots in the areas of PTCA and thrombolysis (thrombus dissolution) in myocardial infarction (T1M1) in the target vessel. Heparin should not be used before, during, and within 24 hours after PTCA. Acute thrombotic closure of the area opened in PTCA was observed in one patient, and peripheral (distal) embolization of blood clots containing platelets, also in one patient. The open state of the vessels was restored in both patients with intracoronary changes. For 11 patients, stents (devices for lumen reconstruction) were required (for dissection - for 9 patients, results below optimal were obtained in the case of 2 patients), they were given 250 mg of ticlopidine during implantation. The mean minimum lumen diameter was 0.90 ± 0.50 mm before and 2.65 ± 0.40 mm after PTCA (reference diameter 2.95 ± 0.60 mm). After 24 h of T1M1, 3 streams without thrombi were observed at the RTA site in each of 71 patients. There is a lack of heavy bleeding. Anti-Xa activity drops 10 minutes after the administration of a loading dose of PS (1.20 ± 0.29 units of anti-Xa / ml) and remains at an average level of 0.87 ± 0.14 units. anti-Xa / ml 2 h after the introduction of PS. ACT activated clotting time remains unchanged. The concentrations of the thrombin-antithrombin (TAT) complexes decrease from 21.9 ± 18.7 to 4.8 ± 3.8 μg / l, and the 1 + 2 fragments of prothrombin from 2.08 ± 1.04 to 1.54 ± 0 , 82 ng / ml 2 h after PS administration.

Thus, according to the present invention, the use of oligosaccharide, alone or in combination with aspirin, has a curative effect on the pathological conditions of patients who undergo transcutaneous intraluminal angioplasty.

It should be noted that the use of oligosaccharide, alone or in combination with aspirin, in accordance with the present invention, does not increase the hemarrhagic risk.

For the treatment of the above diseases, oligosaccharides and aspirin are administered to mammals, including humans, at daily doses of oligosaccharide or aspirin, respectively, from 0.1 to 1 mg per kg of body weight of the mammal in need of treatment.

In the case of a person, the dose may vary for each component from 1 to 1,000 mg per day, depending on the age of the patient being treated, or the type of treatment: prevention or treatment. Preferably, pentasaccharide is administered to one patient in doses of between 0.30 and 30 mg per day.

Aspirin can be formulated as a pharmaceutical composition in accordance with known methods that are well known to those skilled in the art. Similar formulations are used for oligosaccharide.

The combination of oligosaccharide and aspirin, together with conventional pharmaceutically acceptable carriers, may be pharmaceutical compositions suitable for oral or parenteral and, especially, subcutaneous or intravenous administration.

These pharmaceutical compositions are preferably obtained in the form of dosing units containing a certain amount of active ingredients, for example, from 0.1 to 50 mg of oligosaccharide or aspirin, respectively, per one dose.

When at least two active ingredients are administered in one composition, it is necessary to ensure the compatibility of the various active compounds. Thus, the oligosaccharide is preferably used in the form of an additive salt, for example, a sodium salt. Oligosaccharides in the form of their additive salts with pharmaceutically acceptable acids are usually chemically incompatible with aspirin.

Thus, an object of the present invention is also a pharmaceutical composition for the treatment or prevention of thromboembolic diseases of a mammal that has undergone percutaneous intraluminal angioplasty. The composition contains as an active ingredient a combination of an effective amount of at least one synthetic oligosaccharide, which is a selective inhibitor of factor Xa, acting through antithrombin III, and an effective amount of aspirin, possibly in a mixture with one or more pharmaceutically acceptable carriers.

These compositions are prepared in such a way that they can be administered through the gastrointestinal tract or parenterally.

The pharmaceutical compositions according to the invention are advantageously represented by various forms, such as, for example, solutions for injection and oral administration, sugar-coated tablets, simple tablets or gelatin capsules. Injection solutions are preferred pharmaceutical forms.

In the pharmaceutical compositions according to the invention, for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal administration, for mucosal administration, for local and rectal administration in animals and humans, the active ingredient can be administered in single forms and as a mixture with conventional pharmaceutical carriers. Suitable unit forms are oral forms such as tablets, gelatin capsules, powders, granules, microgranules and oral solutions or suspensions, forms for sublingual and oral administration, forms for subcutaneous administration, intramuscular, intravenous, intranasal or intraocular administration, as well as forms for rectal use.

When solid compositions are obtained in the form of tablets, the main active ingredient is mixed with a pharmaceutical binder such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. Tablets can be coated with sucrose or other suitable materials, or tablets can be processed so that they have a prolonged action or delayed activity, constantly releasing a certain amount of the active ingredient.

Preparations in gelatin capsules are obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

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 sweetening agents and flavoring agents.

For rectal administration, suppositories are used, which are prepared with binding agents melting at rectal temperature, such as coconut oil or polyethylene glycols.

For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions are used which contain pharmaceutically acceptable dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.

For administration via mucosal active ingredients may be formulated in the presence of a promoter such as a bile salt, a hydrophilic promoter such as, for example, gidropropiltsellyuloza, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, pectins, starches, gelatin, casein, acrylic acids, acrylic esters and their copolymers, vinyl polymers or copolymers, vinyl alcohols, alkoxy polymers, polyethylene oxide polymers, polyethers or x mixture.

The active ingredients can be formulated in the form of microcapsules, possibly with one or more carriers or additives.

The active ingredients can also be obtained in the form of a complex with a cyclodextrin, for example, with a-, β- or γ-cyclodextrin, 2-hydroxypropyl-in-cyclodextrin or methyl β-cyclodextrin.

One of the active ingredients, for example an oligosaccharide, can also be released from the balloon in which it is contained, or with the help of an intravascular stent injected into blood vessels. The pharmacological efficacy of the active ingredient does not change.

In accordance with a preferred embodiment of the invention, the pharmaceutical compositions comprise a combination of aspirin and a compound of formula (A), preferably in the form of a decanodium salt.

Intravenous or subcutaneous administration of the oligosaccharide is also preferred.

The pharmaceutical compositions according to the invention preferably contain from 5 to 30 mg of oligosaccharide, which is a selective inhibitor of factor Xa, and from 200 to 800 mg of aspirin, more preferably from 8 to 20 mg of the indicated oligosaccharide and from 400 to 600 mg of aspirin, for example 12 mg of the indicated oligosaccharide and 500 mg of aspirin.

Claims (13)

CLAIM 1. The use of a synthetic oligosaccharide, which is a selective factor Xa inhibitor, acting through antithrombin III in combination with aspirin to produce drugs intended for the prevention or treatment of thromboembolic diseases occurring in a mammal undergoing percutaneous intraluminal angioplasty. 2. The use according to claim 1, characterized in that the oligosaccharide is methyl O (2-deoxy-2-sulfamino-6-O-sulfo-a-O-glucopyranosyl) - (1 ^ 4) -0- (β - D-glucopyranosyluronic acid) - (1 ^ 4) -O- (2-deoxy-2sulfamino-3.6-di-O-sulfo-aX-glucopyranosyl) - (1 ^ 4) -O- (2-O-sulfo-a L-idopyranosyluronic acid) - (1 ^ 4) -2-deoxy-2-sulfamino-6-O-sulfo-a ^ -glucopyranoside, in which the anion has the structure of formula (A) (see end of description), or one from its pharmaceutically acceptable salts. 3. The use according to claim 2, characterized in that the oligosaccharide is a decanatrium salt. 4. A pharmaceutical composition for the treatment and prevention of thromboembolic diseases of a mammal undergoing percutaneous intraluminal angioplasty. 5. The composition according to claim 4, characterized in that it contains from 5 to 30 mg of the indicated oligosaccharide and from 200 to 800 mg of aspirin. 6. The composition according to claims 4 and 5, characterized in that it contains from 8 to 20 mg of the indicated oligosaccharide and from 400 to 600 mg of aspirin. 7. The composition according to any one of claims 4 to 6, characterized in that the oligosaccharide is methyl O- (2-deoxy-2-sulfamino-6-Osulfo-a ^ -glucopyranosyl) - (1 ^ 4) -O- ( c ^ glucopyranosyluronic acid) - (1 ^ 4) -O- (2deoxy-2-sulfamino-3,6-di-O-sulfo-a ^ glucopyranosyl) - (1 ^ 4) -O- (2-O-sulfo -a-bidopyranosyluronic acid) - (1 ^ 4) -2deoxy-2-sulfamino-6-O-sulfo-aX-glucopyranoside in which the anion has the structure of formula (A) (see end of description), or one of its pharmaceutically acceptable salts. 8. The composition according to claim 7, characterized in that the oligosaccharide is a decanatrium salt. 9. A method of treating or preventing thromboembolic diseases of a mammal undergoing percutaneous intraluminal angioplasty, comprising administering to said mammal an effective amount of at least one synthetic oligosaccharide, which is a selective factor Xa inhibitor acting through antithrombin III, in combination with aspirin. 1 0. The method according to claim 9, characterized in that the oligosaccharide is methyl O- (2deoxy-2-sulfamino-6-O-sulfo-aX-glucopyranosyl) - (1 ^ 4) -O- (β-glucopyranosyluronic acid ) - (1 ^ 4) -O- (2-deoxy-2-sulfamino-3,6-di-O-sulfo-a-D-gluco pyranosyl) (1 ^ 4) -O- (2-O-sulfo -a-b-idopyranosyluronic acid) - (1 ^ 4) -2-deoxy-2-sulfamino-6O-sulfo-a-O-glucopyranoside in which the anion has the structure of formula (A) (see end of description), or one of its pharmaceutically acceptable salts. 11. The method according to p. 10, characterized in that the oligosaccharide is a decanatrium salt. 12. The method according to any one of paragraphs. 9-11, characterized in that from 0.1 to 100 mg of oligosaccharide and from 0.1 to 100 mg of aspirin per kilogram of body weight are administered per day to a mammal in need of treatment. 13. The method according to any one of paragraphs. 9-12, characterized in that the oligosaccharide with aspirin is administered intravenously or subcutaneously.