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Claims for Patent: 4,692,435

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Claims for Patent: 4,692,435

Title: Mucopolysaccharide composition having a regulatory action on coagulation, medicament containing same and process of preparation
Abstract:The invention pertains to a mucopolysaccharide fraction obtainable from heparin or from fractions including heparinic constituents of molecular weights from 2000 to 50,000, which has a Yin-Wessler titer which is high relative to the USP titer. It contains components whose molecular weights are less than 10,000, particularly oligosaccharides in the area of 2000-3000, comprising from 8 to 12, notably 10 monosaccharide units, among which glucosamine units whose primary positions are sulphated. The last mentioned oligosaccharides include one N-acetyl-glucosamine unit per two units of 2-O-sulphate iduronic acid and per two N-sulphate-glucosamine units, the other saccharide units being of a different nature and including distinct substituents.
Inventor(s): Lormeau; Jean-Claude (Maromme-la-Maine, FR), Goulay; Jean (Oissel, FR), Choay; Jean (Paris, FR)
Assignee: Choay, S.A. (Paris, FR)
Application Number:06/726,178
Patent Claims: 1. A process for obtaining heparinic mucopolysaccharides which have improved antithrombotic activity in vivo and inhibition of the Xa-factor (measured in terms of anti-Xa activity) more selective than that of heparin and a lower whole anticoagulation activity than heparin (measured in USP units), which mucopolysaccharides have a molecular weight in the range of about 2,000 to 10,000 daltons, a ratio of anti-Xa to USP titers of at least 3, which process comprises mixing heparin mucopolysaccharides having a molecular weight in the range of about 2,000 to 50,000 daltons in a 55.degree.-61.degree. GL aqueous-alcoholic medium, separating the liquid medium which contains mucopolysaccharides in solution and precipitating out the soluble mucopolysaccharides by alcoholic precipitation, said mucopolysaccharides having an increased ratio of anti-Xa titer to USP titer as compared to the starting heparin mucopolysaccharides.

2. The process of claim 1, which comprises recovering the alcohol-precipitated mucopolysaccharides, subjecting an aqueous solution of said mucopolysaccharides to gel-filtration and recovering the fraction, which fraction has a further increased anti-Xa titer to USP titer ratio as compared to that of the alcohol-precipitated mucopolysaccharides.

3. The process of claims 1 or 2, which comprises the further step of contacting the mucopolysaccharides which have increased anti-Xa titer with antithrombin III, selectively affixing thereon the mucopolysaccharides which have a higher Yin-Wessler activity than the mucopolysaccharides which are not affixed thereon and recovering the affixed mucopolysaccharides by elution, which mucopolysaccharides have further increased anti-Xa titer to USP titer ratio than the starting mucopolysaccharides.

4. A therapeutic method for controlling thrombosis and decreasing blood hypercoagulation and hemorrhaging risks in a patient which comprises administering to the patient in an antithrombotic effective amount, a composition which comprises a therapeutically acceptable carrier and heparinic mucopolysaccharide fractions having constituents of a molecular weight not in excess of about 10,000 daltons, which fractions have (1) a mixture of lower molecular weight fractions in the range of about 2,000 to about 4,000 daltons with higher molecular weight fractions of a molecular weight in the range of about 4,000 to about 10,000 daltons, (2) a Yin-Wessler of at least 40, and (3) a ratio of Yin-Wessler to USP titer in the range of 3 to 5, and the physiologically acceptable salts thereof, which mixture of fractions have improved antithrombotic activity in vivo which is higher than that of heparin and a whole anticoagulation activity lower than that of heparin, and said method controlling thrombosis by selectively inhibiting coagulation factor Xa while also having a whole anticoagulation effect which is slower and lower than that of heparin.

5. The method of claim 4 wherein the administration is by injection or infusion to the patient.

6. The method of claim 5 wherein the administration by injection is sub-cutaneous.

7. The method of claim 6 wherein the dosage administered sub-cutaneously is from about 1,000 to about 25,000 Yin-Wessler units per ml.

8. The method of claim 5 wherein the administration by injection is intravenous.

9. The method of claim 8 wherein the dosage administered discontinuously intravenously is from about 1,000 to about 25,000 Yin-Wessler units per ml per 25 hours.

10. The of method of claim 4 wherein the administration is intramuscularly in a dosage of from about 1,000 to about 25,000 Yin-Wessler units per ml.

11. A therapeutic composition for controlling thrombosis and decreasing hemorrhaging and of blood hypercoagulation risks which comprises a therapeutically acceptable carrier and heparinic mucopolysaccharide fractions having constituents of a molecular weight not in excess of about 10,000 daltons, which fractions have (1) a mixture of lower molecular weight fractions in the range of about 2,000 to about 4,000 daltons with higher molecular weight fractions of a molecular weight in the range of about 4,000 to about 10,000 daltons, (2) a Yin-Wessler of at least 40, and (3) a ratio of Yin-Wessler to USP titer in the range of 3 to 5, and the physiologically acceptable salts thereof, which mixture of fractions have improved antithrombotic activity in vivo which is higher than that of heparin and a whole anticoagulation activity lower and slower than that of heparin.

12. The therapeutic composition of claim 11 which is a solution.

13. The therapeutic composition of claim 12 wherein the heparinic mucopolysaccharides fractions are in solution in a concentration of about 1,000 to 100,000 Yin-Wessler units per ml.

14. The therapeutic composition of claim 13 which is a solution of the mucopolysaccharides in a concentration of about 5,000 to about 50,000 Yin-Wessler units per ml.

15. The solution of claim 12 which is apyrogenic.

16. The solution of claim 15 which is sterile.

17. The composition of claim 11 wherein the pharmaceutically acceptable salt is a calcium salt.

18. Heparinic mucopolysaccharide fractions having constituents of a molecular weight not in excess of about 10,000 daltons, which fractions have (1) a mixture of lower molecular weight fractions in the range of about 2,000 to about 4,000 daltons with higher molecular weight fractions of a molecular weight in the range of about 4,000 to about 10,000 daltons, (2) a Yin-Wessler of at least 40, and (3) a ratio of Yin-Wessler to USP titer in the range of 3 to 5, which mixture of fractions have improved antithrombotic activity in vivo which is higher than that of heparin and a whole anticoagulation activity lower than that of heparin, and the physiologically acceptable salts thereof.

19. The heparinic mucopolysaccharide fractions of claim 18 wherein the lower molecular weight fractions are free of nucleic acids.

20. The heparinic mucopolysaccharides of claim 18 in which the lower molecular fractions have a USP titer less than about 10 units per mg.

21. The heparinic mucopolysaccharides of claim 18 wherein the molecular weight is not in excess of about 8,000 daltons.

22. The heparinic mucopolysaccharides of claim 18 which have a USP titer of about 45 units per mg, a Yin-Wessler titer of about 160 units/mg and a ratio of Yin-Wessler to USP titer of about 3.55.

23. The heparinic mucopolysaccharides of claim 18 in which fractions below 4,000 have a ratio of Yin-Wessler to USP titer which is at least 10.

24. The heparinic mucopolysaccharides of claim 18 in which fractions of about 4,000 have a ratio of Yin-Wessler to USP titer higher than 11, and the Yin-Wessler is at least 900 units per mg.

25. The heparinic mucopolysaccharides of claim 18 in which fractions have a Yin-Wessler to USP titer ratio higher than 60 and a Yin-Wessler of at least 1,300 units per mg.

26. The heparinic mucopolysaccharides of claim 18 wherein fractions above 4,000 have a USP titer not exceeding about 15 units per mg and a Yin-Wessler titer in the range of about 99 to about 160 units per mg.

27. The heparinic mucopolysaccharides of claim 26 wherein the fractions have a ratio of a Yin-Wessler to USP titer is in the range of about 13 to about 16.

28. The heparinic mucopolysaccharides of claim 18 wherein fractions have a USP titer that does not exceed about 6 units per mg, a Yin-Wessler titter not less than about 44 units per mg and the ratio of Yin-Wessler to USP titers if about at least 9.

29. The heparinic mucopolysaccharides of claim 18 having low molecular weight fractions with specific affinity for antithrombin III.

30. The heparinic mucopolysaccharides of claim 18 in which fractions have 8 to 12 monosaccharide units corresponding to a molecular weight ranging from about 2,500 to 3,800.

31. The heparinic mucopolysaccharides of claim 18 wherein fractions have a molecular weight range of about 2,000 to about 8,000.

32. The heparinic mucopolysaccharide fractions of claim 19 which are soluble in an aqueous-alcoholic medium, and insoluble in pure alcohol.

33. A therapeutic composition which presents less risks than heparin of blood hypercoagulation and of a host hemorrhaging, which composition has improved antithrombotic activity (anti-X.sub.a activity) and improved selectivity with respect to anti-X.sub.a activity than heparin in vivo and a lower and slower anticoagulation activity than heparin, and which composition comprises a therapeutically acceptable carrier and an antithrombotic effective amount of heparinic mucopolysaccharide fractions having constituents of a molecular weight not in excess of about 10,000 daltons, which fractions have (1) a mixture of lower molecular weight fractions in the range of about 2,000 to about 4,000 daltons with higher molecular weight fractions of a molecular weight in the range of about 4,000 to about 10,000 daltons, (2) a Yin-Wessler of at least 40, and (3) a ratio of Yin-Wessler to USP titer in the range of 3 to 5, which mixture of fractions have improved antithrombotic activity in vivo which is higher than that of heparin and a whole anticoagulation activity lower than that of heparin, and the physiologically acceptable salts thereof.

34. The therapeutic composition of claim 33 in which the lower molecular fractions of the heparinic mucopolysaccharides have a USP titer less than about 10 units per mg.

35. The therapeutic composition of claim 33 in which the molecular weight of the heparinic mucopolysaccharides is not in excess of about 8,000 daltons.

36. The therapeutic composition of claim 33 in which the heparinic mucopolysaccharides have a USP titer of about 45 units per mg, a Yin-Wessler titer of about 160 units/mg and a ratio of Yin-Wessler to USP titer of about 3.55.

37. The therapeutic composition of claim 33 in which fractions of the heparinic mucopolysaccharides below 4,000 have a ratio of Yin-Wessler to USP titer which is at least 10.

38. The therapeutic composition of claim 33 in which heparinic mucopolysaccharides have fractions of about 4,000 which have a ratio of Yin-Wessler to USP titer higher than 11, and the Yin-Wessler is at least 900 units per mg.

39. The therapeutic composition of claim 33 in which fractions of the heparinic mucopolysaccharides have a Yin-Wessler to USP titer ratio higher than 60 and a Yin-Wessler of at least 1,300 units per mg.

40. The therapeutic composition of claim 33 wherein fractions of the heparinic mucopolysaccharides above 4,000 have a USP titer not exceeding about 15 units per mg and a Yin-Wessler titer in the range of about 99 to about 160 units per mg.

41. The therapeutic composition of claim 40 wherein the fractions of the heparinic mucopolysaccharides have a ratio of a Yin-Wessler to USP titer is in the range of about 13 to about 16.

42. The therapeutic composition of claim 33 wherein fractions of the heparinic mucopolysaccharides have a USP titer that does not exceed about 6 units per mg, a Yin-Wessler titer not less than about 44 units per mg and the ratio of Yin-Wessler to USP titers if about at least 9.

43. The therapeutic composition of claim 33 wherein the heparinic mucopolysaccharides have low molecular weight fractions with specific affinity for antithrombin III.

44. The therapeutic composition of claim 37 wherein fractions of the heparinic mucopolysaccharides have 8 to 12 monosaccharide units corresponding to a molecular weight ranging from about 2,500 to 3,800.

45. The therapeutic composition of claim 37 wherein fractions in the heparinic mucopolysaccharides have a molecular weight range of about 2,000 to about 8,000.

46. The therapeutic composition of claim 37 include the heparinic mucopolysaccharide fractions which are soluble in an aqueous-alcoholic medium, insoluble in pure alcohol.

47. The therapeutic method of claim 4 wherein the patient is exposed to risks of hypercoagulatability.

48. The therapeutic method of claim 4 wherein the heparinic mucopolysaccharides have a USP titer of about 45 units per mg, a Yin-Wessler titer of about 160 units/mg and a ratio of Yin-Wessler to USP titer of about 3.55.
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