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Claims for Patent: 4,486,420

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Claims for Patent: 4,486,420

Title: Mucopolysaccharide composition having a regulatory action on coagulation, medicament process for preparation and method of use
Abstract:The invention pertains to a mucopolysaccharide fraction obtainable from heparin or from fractions including heparinic constituents of molecular weights from 2,000 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 2,000-3,000, 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 2-0-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 C. (Maromme La Maine, FR), Choay; Jean (Paris, FR), Goulay, deceased; Jean (late of Oissel, FR), by Goulay, heir; Marie T. (St. Pierre de Varangeville, FR), by Goulay, heir; Marie A. (St. Pierre de Varangeville, FR), by Goulay, heir; Gerard (Saind Amand des Hautes Terres, FR)
Assignee: Choay, S.A. (Paris, FR)
Application Number:06/301,611
Patent Claims: 1. Heparinic mucopolysaccharide fractions which have improved antithrombotic activity in vivo (measured in terms of activity of anti-Xa per milligram), which are more selective with respect to anti-Xa activity than that of heparin and have a lower whole anticoagulation activity than heparin (measured in USP units per milligram), which heparinic mucopolysaccharide fractions have (1) a molecular weight in the range of about 2,000 to 10,000 daltons, (2) are soluble in water-alcohol having a titer of 55.degree.-61.degree. GL, (3) are insoluble in alcohol, (4) have a ratio of anti-Xa titer to USP titer of at least 3, wherein in said heparinic mucopolysaccharides, fractions comprise, (5) glucosamine units which are sulfated in the primary position, (6) one N-acetyl glucosamine unit for two 2-O-sulfate iduronic acid units and for two N-sulfate-glucosamine units, the carbon-13 NMR spectrum in H.sub.2 O (at a radiation of 20 MHz) having the following resonance signals (in the stated regions) indicating the presence of the stated atoms:

and the physiologically acceptable salts thereof.

2. The mucopolysaccharides of claim 1, which have a carbon-13 NMR spectrum as shown in FIG. 1a.

3. The mucopolysaccharides of claim 1, the carbon-13 NMR spectrum of which exhibits glucosamine units, the primary carbons in the 6-position being free of hydroxyl group and exhibiting resonance signals in the region corresponding to chemical displacements in the 100 ppm region (as shown by stars in FIG. 14).

4. The mucopolysaccharides of claim 2, wherein the carbon-13 NMR spectrum exhibits another resonance signal in the 75 ppm region.

5. The mucopolysaccharides of claim 4, which proton NMR spectrum exhibits resonance signals in the 4.8, 5.2 and 5.4 ppm regions,, which signals in the 4.8 and 5.2 ppm regions are weaker than that in the 5.4 ppm region.

6. The mucopolysaccharides of claims 3, wherein the carbon-13 NMR spectrum exhibits a supplementary signal in the 60 ppm region adjoining the G.sub.2 designated signal (as shown in FIGS. 14 and 15).

7. The mucopolysaccharides of claim 1, as shown by one of the NMR spectra of FIGS. 11, 12, 14 or 15.

8. The mucopolysaccharides of claim 1, which is selectively fixable on antithrombin III.

9. The mucopolysaccharides of claim 1, which have a USP titer of about 45 units per mg, an anti-Xa titer of about 160 units per mg and a ratio of anti-Xa titer to USP titer of about 3.55.

10. The mucopolysaccharides of claim 1, wherein the USP titer is less than about 10 units per mg and the anti-Xa titer is about 161 units per mg.

11. The mucopolysaccharides of claim 1, wherein the ratio of anti-Xa titer to USP titer is at least 6, and the anti-Xa titer is at least 300 units/mg.

12. The mucopolysaccharides of claim 11, wherein the ratio of anti-Xa titer to USP titer is at least 10.

13. The mucopolysaccharides of claim 12, wherein the ratio of anti-Xa titer to USP titer is at least 50.

14. The mucopolysaccharides of claim 11, wherein the ratio of anti-Xa titer to USP titer is at least 130.

15. The mucopolysaccharides of claim 11, wherein the anti-Xa titer is not less than about 50 units per mg.

16. The mucopolysaccharides of claim 11, wherein the ratio of anti-Xa titer to USP titer is higher than 18 and the anti-Xa titer is at least 900 units per mg.

17. The mucopolysaccharides of claim 13, wherein the ratio of anti-Xa titer to USP titer is higher than 65 and the anti-Xa titer is at least 1300 units per mg.

18. The mucopolysaccharides of claim 1, wherein the USP titer does not exceed about 13 units per mg, the anti-Xa titer is in the range of about 135 to about 160 units per mg, the ratio of anti-Xa units to USP units is in the range of 13 to 16 and the molecular range is from about 4,000 to about 8,000 daltons.

19. The mucopolysaccharides of claim 1, wherein the USP titer does not exceed about 6 units per mg, the anti-Xa titer is not less than about 44 units per mg, the ratio of anti-Xa to USP titers is over about 9 and the molecular weight is in the range of about 4,000 to 8,000 daltons.

20. The mucopolysaccharides of claim 1, wherein the salts are selected from the group consisting of sodium and calcium.

21. A therapeutic composition which comprises a therapeutically acceptable carrier and in an antithrombotic effective amount, the heparinic mucopolysaccharide fractions of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

22. The therapeutic composition of claim 21, which has an anti-Xa titer higher than about 100 units per mg.

23. The therapeutic composition of claim 21, which is a solution of the mucopolysaccharides in a concentration of about 1,000 to 100,000 Yin-Wessler units per ml.

24. The therapeutic composition of claim 23, which is a solution of the mucopolysaccharides in a concentration of about 5,000 to about 50,000 units per ml.

25. A therapeutic method for controlling thrombosis in a patient which comprises administering to the patient in a therapeutically antithrombotic effective amount, the composition of claims 21, 22, 23 or 24 and controlling thrombosis by selectively inhibiting the coagulation factor Xa.

26. The therapeutic method of claim 25 wherein the administration of the composition is by injection or infusion.

27. 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 being defined in claim 1.

28. The process of claim 27, which comprises recovering the alcohol-precipitated mucopolysaccharides, subjecting an aqueous solution of said mucopolysaccharides to gel-filtration and recovering the fraction which has a further increased anti-Xa titer to USP titer ratio as compared to that of the alcohol-precipitated mucopolysaccharides.

29. The process of claims 27 or 28, which comprises the further step of contacting the mucopolysaccharides which have increased anti-Xa titer with antithrombin III on a support, 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.
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