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Claims for Patent: 5,389,618

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Claims for Patent: 5,389,618

Title: 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.
Inventor(s): Debrie; Roger (Rieux, FR)
Assignee: Rhone-Poulenc Rorer S.A. (Antony, FR)
Application Number:08/092,577
Patent Claims: 1. A heterogeneous intimate admixture of sulfated heparinic polysaccharides, such sulfated polysaccharides having a weight average molecular weight less than that of heparin and said admixture consisting essentially of

from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons

from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, and

from 60-86% of polysaccharide chains having a molecular weight of between 2,000 and 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

said admixture (i) exhibiting a bioavailability and antithrombotic activity greater than heparin and (ii) having an average molecular weight of between approximately 3,500 and 5,500 daltons.

2. The heterogeneous polysaccharide admixture as defined by claim 1, comprising less than 2% of dermatan sulfate.

3. The heterogeneous polysaccharide admixture as defined by claim 1, such sulfated polysaccharides comprising a 2-O-sulfo-4-enopyranosuronic endgroup.

4. The heterogeneous polysaccharide admixture as defined by claim 1, exhibiting an anti-Xa activity of about 90 IU.

5. The heterogeneous polysaccharide admixture as defined by claim 1, comprising sulfated polysaccharides of porcine heparin origin.

6. The heterogeneous polysaccharide admixture as defined by claim 1, comprising polysaccharides of bovine heparin origin.

7. A process for the preparation of the heterogeneous polysaccharide admixture as defined by claim 1, comprising (a) salifying a heparin with a long-chain quaternary ammonium salt in an aqueous medium, (b) esterifying the salt thus produced to a degree of esterification ranging from 9.5% to 14%, and then (c) depolymerizing such ester having a degree of esterification ranging from 9.5% to 14%.

8. The process as defined by claim 7, comprising (b) esterifying said salt in a chlorinated organic solvent, in the presence of a chlorine compound.

9. The process as defined by claim 8, said chlorinated organic solvent comprising chloroform or methylene chloride and said chlorine compound comprising benzyl chloride.

10. The process as defined by claim 8, said esterification step (b) comprising mixing 1 part by weight of said heparin salt with about 1 part by volume of said chlorine compound in from 3 to 5 parts by volume of said chlorinated organic solvent at a temperature ranging from 25.degree. C. to 45.degree. C.

11. The process as defined by claim 10, said temperature ranging from 30.degree. to 40.degree. C.

12. The process as defined by claim 7, said depolymerization step (c) comprising treating said ester with a strong base in aqueous solution.

13. The process as defined by claim 12, wherein said strong base and said ester are present in a weight ratio which ranges from 0.05 to 0.2.

14. The process as defined by claim 13, said ratio ranging from 0.08 to 0.15.

15. The process as defined by claim 12, wherein water in said aqueous solution and said ester are present in a weight ratio which ranges from 15 to 30.

16. The process as defined by claim 12, wherein said depolymerization is carried out at a temperature adjusted to a value ranging from 50.degree. to 70.degree. C. and said depolymerization is carded out therein for from 30 minutes to 3 hours.

17. The process as defined by claim 16, said temperature being adjusted to a value ranging from 55.degree. to 65.degree. C. and said depolymerization being carried out for from 1 to 2 hours.

18. The process as defined by claim 7, comprising (a) salifying the heparin with a benzethonium salt.

19. The process as defined by claim 18, said benzethonium salt comprising benzethonium chloride.

20. The process as defined by claim 7, the partial ester prepared in step (b) comprising an aromatic ester.

21. The process as defined by claim 7, the partial ester prepared in step (b) comprising a sodium salt thereof.

22. The process as defined by claim 7, said starting material heparin having been precipitated from an alcohol.

23. The heterogeneous intimate admixture of sulfated heparinic polysaccharides produced by the process as defined by claim 7.

24. A method for the prevention of thrombotic episodes in a human patient, comprising administering to a human in need of such prevention, a therapeutically effective amount of the heterogeneous polysaccharide admixture as defined by claim 1.

25. A method for the prevention of venous thromboses in a postoperative human patient, comprising administering to such patient a therapeutically effective amount of the heterogeneous polysaccharide admixture as defined by claim 1.

26. The method as defined by claim 24, such human suffering risk of myocardial infarction.

27. A therapeutic composition of matter useful for the prevention of thrombotic episodes in a human, comprising the heterogeneous polysaccharide admixture as defined by claim 1 and a therapeutically acceptable carrier or diluent therefor.

28. The heterogeneous polysaccharide admixture as defined by claim 1, exhibiting an anti-Xa activity of about 100 IU.

29. A method for the treatment of thrombotic episodes in a human, comprising administering to a human in need of such treatment, a therapeutically effective amount of the heterogeneous polysaccharide admixture as defined by claim 1.

30. A therapeutic composition of matter useful for the treatment of thrombotic episodes in a human, comprising the heterogeneous polysaccharide admixture as defined by claim 1 and a therapeutically acceptable carrier or diluent therefor.

31. A heterogenous intimate admixture of sulfated heparinic polysaccharides, such sulfated polysaccharides having a weight average molecular weight less than that of heparin and said admixture comprising:

from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons,

from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, and

from 60% to 86% of polysaccharide chains having a molecular weight of between 2,000 and 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,

said admixture (i) exhibiting a bioavailability and antithrombotic activity greater than heparin, (ii) having an average molecular weight of between approximately 3,500 and 5,500 daltons, and (iii) including less than 2% of dermatan sulfate.

32. A heterogeneous intimate admixture of sulfated heparinic polysaccharides, such sulfated polysaccharides having a weight average molecular weight less than that of heparin and said admixture consisting essentially of:

from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons,

from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, and

from 60% to 86% of polysaccharide chains having a molecular weight of between 2,000 and 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,

said admixture (i) exhibiting a bioavailability and antithrombotic activity greater than heparin and (ii) having an average molecular weight of between approximately 3,500 and 5,500 daltons, said admixture being prepared by a process comprising the steps of:

(a) salifying a heparin with a long-chain quaternary ammonium salt in an aqueous medium,

(b) esterifying the salt thus produced to a degree of esterification ranging from 9.5% to 14%, and

(c) depolymerizing such ester having a degree of esterification ranging from 9.5% to 14%.
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