Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events

Abstract

Heterogeneous intimate admixtures of sulfated heparinic polysaccharides, well suited for the prophylaxis / treatment of acute thrombotic episodes in a human patient, comprise immixture of sulfated polysaccharides having a weight average molecular weight less than that of heparin and which include from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons and from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, the ratio between the weight average molecular weight and the number average molecular weight thereof ranging from 1.3 to 1.6.

Description

[0001]This application is a continuation, of application Ser. No. 07 / 721,315, filed Jun. 26, 1991, now abandoned.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to novel mixtures of low molecular weight (LMW) polysaccharides and, more especially, to novel mixtures of LMW heparinic polysaccharides will adopted for the prevention of venous thromboses.[0004]2. Description of the Prior Art[0005]The heparins are biologically active agents of the glycosaminoglycan family, extracted from natural sources, and have valuable anticoagulant and antithrombotic properties. In particular, they are useful in the treatment of postoperative venous thromboses. However, in their native state, the heparins present a number of disadvantages which limit the extent of their effective use. Indeed, the marked anticoagulant activity of the heparins can cause hemorrhaging, and their sensitivity to certain serum factors such as pf4 mandates the administration of rel...

AI Technical Summary

Benefits of technology

[0016]In addition, in humans, the mixtures of the invention display excellent bioavailability, as measured by the anti-Xa activity. Thus, this value is approximately 30 <?delete-start id="DEL-S-00001" date="20050614" ?>IU<?delete-end id="DEL-S-00001" ?> <?insert-start id="INS-S-00001" date="20050614" ?>% for heparin, but is approximately 90 <?delete-start id="DEL-S-00002" date="20050614" ?>IU<?delete-end id="DEL-S-00002" ?> <?insert-start id="INS-S-00002" date="20050614" ?>% for the mixtures of the invention. This too is desirable in that it permits the doses administered to be reduced and the therapeutic potential to be improved.

[0018]Another characteristic of the mixtures according to the invention is their low clearance compared with other products and with mature heparin. As a result of their chemical structure, their molecular weight or their sulfate content, these mixtures effectively display a particular pronounced resistance to degradation (desulfation, hydrolysis) and to elimination, which further enhances their therapeutic availability.

[0020]Too, these preparations also exhibit a reduced sensitivity to serum factors, which enhances their duration of action in vivo and permits them to be used in low doses.

Problems solved by technology

However, in their native state, the heparins present a number of disadvantages which limit the extent of their effective use.

Indeed, the marked anticoagulant activity of the heparins can cause hemorrhaging, and their sensitivity to certain serum factors such as pf4 mandates the administration of relatively large doses thereof.

However, one of the principal difficulties associated with the heparins is that they are very heterogeneous products.

Therefore, it is difficult to assess the contribution of each of the species to the activity of heparin, to determine the behavior of these species during depolymerization and, finally, to control the structure of such species and their respective proportions in the final products.

For these reasons, it has not to date been possible to resolve completely satisfactorily the difficulties indicated above.

In particular, the processes described in the prior art, and especially in EP 40,144, do not permit the production of mixtures possessing the requisite pharmacological properties for improved therapeutic applications, namely, a sufficiently long plasma half-life, a fairly high absorption rate, a high bioavailability or, alternatively, a low clearance.

Nonetheless, these final mixtures continue to elicit a residual hemorrhagic effect, or too low an antithrombotic response.

This is reflected in the above publication, where the authors conclude, “We do not know what combination of the properties of heparin is optimal.