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Details for Patent: 4,500,519

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Details for Patent: 4,500,519

Title: Mucopolysaccharides having biological properties, preparation and method of use
Abstract:Mucopolysaccharides biologically active and more specific than heparin, particularly with respect to the blood factor Xa. These mucopolysaccharides may be obtained by partial depolymerisation, under controlled conditions, of heparin, by the action of a chemical agent such as nitrous acid. The conditions implemented allow the preparation of mucopolysaccharides having a USP titer lower than that of the starting heparin and a Yin-Wessler titer at least equal to that of said heparin. These products may be used particularly as antithrombotic drugs.
Inventor(s): Lormeau; Jean-Claude (Maromme, FR), Petitou; Maurice (Paris, FR), Choay; Jean (Paris, FR)
Assignee: Choay S.A. (Paris, FR)
Filing Date:Nov 20, 1981
Application Number:06/323,567
Claims:1. A process for making mucopolysaccharide heparinic fractions which have the L-iduronosyl-2-O-sulfate-(1-alpha-4)-N-sulfo-D-glucosamine-6-O-sulfate disaccharide structural units of heparin with the O-sulfated iduronic component of heparin, which mucopolysaccharide heparinic fractions do not differ from heparin with respect to the unsulfated iduronic acid component and are further defined by having a terminal structure as follows ##STR6## wherein R.sub.1 is selected from the group consisting of aldehyde, alcohol or carboxylic acid and R.sub.2 is selected from the group consisting of hydrogen or --SO.sub.3, said mucopolysaccharides having a high and improved antithrombotic activity (as measured by anti-Xa activity determined by the Yin-Wessler test (YW)) as compared to heparin, and a YW/USP ratio of at least 2, which comprises the steps of partially depolymerizing heparinic chains having a molecular weight in the range of about 2,000 to about 50,000 daltons by contacting said heparinic chains with nitrous acid in an aqueous medium at a temperature in the range from about 0.degree. C. to about ambient temperature, discontinuing the depolymerization when the mucopolysaccharides has reached a molecular weight in the range of about 2,000 to about 8,000 daltons and separating the mucopolysaccharides having said terminal structure and which do not differ from heparin with respect to the amount of the unsulfated iduronic acid component.

2. The process of claim 1 wherein the depolymerization is carried out at a pH in the range of about 2 to 3.

3. The process of claim 1 wherein the depolymerization is stopped by adjusting the pH to a pH outside the depolymerization range.

4. The process of claim 3 wherein the depolymerization is stopped by adjusting the pH to an alkaline pH.

5. The process of claim 1 wherein the nitrous acid is generated in situ from a derivative selected from the group consisting of a salt or an ether salt.

6. The process of claim 5 wherein the salt is an alkaline earth salt.

7. The process of claim 6 wherein the alkaline salt is sodium nitrite.

8. The process of claim 5 wherein the nitrous acid is generated by the addition of an acid which has a physiologically acceptable anion.

9. The process of claim 8 wherein the acid is hydrochloric acid.

10. The process of claim 5 wherein the final concentration of heparin is from about 1 to about 10 g per 100 ml of reaction medium and the concentration of sodium nitrite is from about 0.02M to 0.1M.

11. The process of claim 10 wherein the concentration of heparin is about 2 g per 100 ml of reaction medium and the concentration of sodium nitrite is about 0.05M.

12. The process of claim 5 wherein the reaction is carried out at a temperature of from about 0.degree. C. to about 10.degree. C.

13. The process of claim 3 wherein the pH is increased to about 7.5.

14. The process of claim 4 wherein the pH is adjusted to an alkaline pH with an alkaline agent which is sodium hydroxide.

15. The process of claim 1 wherein alcohol is added in a proportion of about at least 5 volumes with respect to the volume of the reaction medium to separate the mucopolysaccharide fractions.

16. A process according to claim 1 which further comprises reducing the recovered polysaccharide fragments recovering polysaccharide fragments having terminal structures which are 2,5-anhydro-D-mannitol groups.

17. The process of claim 16 wherein the reducing agent is potassium borohydride.

18. A process according to claim 1 which further comprises oxidizing the recovered polysaccharide fragments recovering polysaccharide fragments having terminal structures which are 2,5-anhydro-D-mannonic acid groups and their pharmaceutically acceptable salts.

19. The process of claim 18 wherein the oxidizing agent is potassium permanganate.

20. Mucopolysaccharide heparinic fractions which have the L-iduronosyl-2-O-sulfate-(1-alpha-4)-N-sulfo-D-glucosamine-6-O-sulfate disaccharide structural units of heparin with the O-sulfated iduronic component of heparin, which mucopolysaccharide heparinic fractions do not differ from heparin with respect to the unsulfated iduronic acid component and are further defined by having a terminal structure as follows ##STR7## wherein R.sub.1 is selected from the groups consisting of an alcohol and a carboxylic acid and R.sub.2 is selected from the group consisting of hydrogen or --SO.sub.3, which fractions have a molecular weight in the range of about 2,000 to 8,000 daltons and the physiologically acceptable salts thereof.

21. The mucopolysaccharide heparinic fractions of claim 20 wherein fractions have R.sub.2 which is --SO.sub.3 and R.sub.1 is selected from the specified groups.

22. The mucopolysaccharide haparinic fractions of claim 21 wherein fractions have R.sub.2 which is --SO.sub.3 and R.sub.1 is an aldehyde radical.

23. The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have R.sub.2 which is --SO.sub.3 and R.sub.1 is --CH.sub.2 OH.

24. The mucopolysaccharide heparinic fractions of claim 21 wherein R.sub.1 is --CH.sub.2 OH and R.sub.2 is --SO.sub.3.

25. The mucopolysaccharide heparinic fractions of claim 20 wherein the molecular weight is in the range of about 3,000 to about 5,000 daltons.

26. The mucopolysaccharide heparinic fractions of claim 20 which is soluble in a water-ethanol medium having a titer of 55.degree.-61.degree. GL.

27. The mucopolysaccharide heparinic fractions of claim 20 which have a Yin-Wessler titer higher than that of heparin and of at least 200 IU/mg and a Yin-Wessler to USP titer ratio of at least 10.

28. The mucopolysaccharide heparinic fractions of claim 20 wherein the Yin-Wessler titer is at least 250 IU/mg and the ratio of YW to USP titer is about 22.

29. The mucopolysaccharide heparinic fractions of claim 21 which is soluble in a water-ethanol medium having a titer of 55.degree.-61.degree. GL.

30. The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have the terminal structure, 2,5-anhydro-D-mannose.

31. The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have the terminal structure, 2,5-anhydro-D-mannitol.

32. The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have the terminal structure, 2,5-anhydro-D-mannonic acid.

33. The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have a Yin-Wessler activity from about 200 IU/mg to about 270 IU/mg.

34. Partially depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannose terminal structure and a --SO.sub.3 primary alcohol function in the 6-position, which products have a Yin-Wessler activity from about 200 IU/mg to about 270 IU/mg.

35. The partially depolymerized heparin products of claim 34 which have a YW/USP ratio in the range of about 10 to about 22.

36. Partially depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannitol terminal structure and a --SO.sub.3 primary alcohol function in the 6-position, which products have a Yin-Wessler activity from about 200 IU/mg to about 270 IU/mg.

37. Partially depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannoic acid terminal structure and a --SO.sub.3 primary alcohol function in the 6-position, which products have a Yin-Wessler activity from about 200 IU/mg to about 270 IU/mg.

38. The mucopolysaccharide heparinic fractions of claims 34, 36, or 37 which is soluble in a water-ethanol medium having a titer of 55.degree.-61.degree. GL.

39. A biological composition which has antithrombotic activity higher than that of heparin (as measured by the Yin-Wessler test) which has increased selective inhibition of the Xa factor in vitro and in vivo, which composition comprises a therapeutically acceptable carrier and in a therapeutically effective amount, a mucopolysaccharide of claims 20, 21, 22, 23, 24, 25, 26, 27, 28 29, 30, 31, 32, 33, 34, 35, 36, 37 or 41.

40. A therapeutic method for controlling thrombosis in a patient which comprises administering to said patient a biological composition of claim 39 and controlling thrombosis by inhibiting coagulation factor Xa.

41. The mucopolysaccharide heparinic fractions of claim 20 which have a ratio of anti-Xa to USP titers of at least 6.

42. The mucopolysaccharide fractions of claim 20 which have an anti-Xa titer of over about 22 units/mg and a ratio of titers of anti-Xa to USP of at least 3.
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