NON-ANTICOAGULANT SULFATED OR SULFONATED POLYSACCHARIDES

• US 20130209444A1
• Filed: 01/30/2013
• Published: 08/15/2013
• Est. Priority Date: 01/30/2012
• Status: Abandoned Application

• Current Assignee: Baxalta GmbH (Shire plc), Baxalta Incorporated (Shire plc)
• Original Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Inventors: Dockal, Michael, Scheiflinger, Fritz, Knappe, Sabine, Till, Susanne, Hai, Ton, Sanders, Paul, Jiang, Cong, Dande, Prasad
• Application Number:
  US13/754,575
• Publication Number:
  US 20130209444A1
• Time in Patent Office: Days
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 31/724 Cyclodextrins
• CPC Class Codes: A61K 31/737 Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate A61K31/727 takes precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07H 5/10 to sulfur
• CPC Class Codes: C08B 37/0012 Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

Abstract

The present invention provides non-anticoagulant sulfated or sulfonated polysaccharides (NASPs), which accelerate the blood clotting process. Also provided are pharmaceutical formulations comprising a NASP of the invention in conjunction with a pharmaceutically acceptable excipient and, in various embodiments, these formulations are unit dosage formulations. The invention provides a NASP formulation, which is orally bioavailable. Also provided are methods for utilizing the compounds and formulations of the invention to promote blood clotting in vivo as therapeutic and prophylactic agents and in vitro as an aid to studies of the blood clotting process.

Claims

1. A composition comprising a therapeutically effective amount of a composition comprising a non-anticoagulant sulfated or sulfonated polysaccharide (NASP), wherein the sulfated or sulfonated polysaccharide is a member selected from α

-cyclodextrin, β

-cyclodextrin, melezitose, stachyose, raffinose, maltotriose, maltotetraose, maltopentaose, cellotriose, cellotetraose, cellopentaose, xylan, icodextrin, and 6-carboxylcodextrin; and

a pharmaceutically acceptable excipient.

2. The composition according to claim 1, wherein said composition is a unit dosage formulation for use in a method for treating a subject in need of enhanced blood coagulation comprising administering a therapeutically effective amount of a composition comprising a non-anticoagulant sulfated or sulfonated polysaccharide (NASP) to the subject wherein the sulfated or sulfonated polysaccharide is a member selected from α

-cyclodextrin, β

-cyclodextrin, melezitose, stachyose, raffinose, maltotriose, maltotetraose, maltopentaose, cellotriose, cellotetraose, cellopentaose, xylan, icodextrin, and 6-carboxylcodextrin, the unit dosage formulation comprising the NASP in an amount from about 0.5 mg to about 1000 mg.

3. The unit dosage formulation according to claim 2 wherein the NASP is in an amount sufficient to provide a dosage from about 0.01 mg/kg to about 100 mg/kg.

4. The unit dosage formulation according to claim 2, wherein the NASP is in an amount sufficient to enhance blood coagulation in a subject to whom the unit dosage formulation is administered.

5. The unit dosage formulation according to claim 2, wherein the unit dosage formulation is an oral unit dosage formulation.

6. A method for treating a subject in need of enhanced blood coagulation comprising administering a therapeutically effective amount of a composition according to claim 1.

7. The method according to claim 6, wherein the NASP is administered at a dosage of about 0.01 mg/kg to about 100 mg/kg.

8. The method according to claim 6, wherein the NASP is administered as a unit dosage formulation.

9. The method according to claim 6, wherein the NASP is administered orally.

10. The method according to claim 6, wherein the subject has a bleeding disorder selected from the group consisting of a chronic or acute bleeding disorder, a congenital coagulation disorder caused by a blood Factor deficiency, and an acquired coagulation disorder.

11. The method according to claim 6, wherein the blood factor deficiency is a deficiency of one or more factors selected from the group consisting of Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, prothrombin, fibrinogen, and von Willebrand Factor.

12. The method according to claim 6, wherein the cause of the need for enhanced blood coagulation is prior administration of an anticoagulant, surgery or other invasive procedure.

13. The method according to claim 6, further comprising administering an agent selected from the group consisting of a procoagulant, an activator of the intrinsic coagulation pathway, an activator of the extrinsic coagulation pathway, and a second NASP.

14. The method according to claim 13, wherein the agent is selected from the group consisting of tissue factor, Factor II, Factor V, Factor Va, Factor VII, Factor VIIa, Factor VIII, Factor VIIIa, Factor X, Factor Xa, Factor IX, Factor IXa, Factor XI, Factor XIa, Factor XII, Factor XIIa, Factor XIII, prekallikrein, kallikrein, and HMWK, and von Willebrand Factor.

15. The method according to claim 12, wherein the anticoagulant is selected from the group consisting of heparin, a coumarin derivative, such as warfarin or dicumarol, tissue factor pathway inhibitor (TFPI), antithrombin III, lupus anticoagulant, nematode anticoagulant peptide (NAPc2), active-site blocked Factor VIIa (Factor VIIai), Factor IXa inhibitors, Factor Xa inhibitors, including fondaparinux, idraparinux, DX-9065a, and razaxaban (DPC906), inhibitors of Factors Va and VIIIa, including activated protein C (APC) and soluble thrombomodulin, thrombin inhibitors, including hirudin, bivalirudin, argatroban, ximclagatran, and an antibody that binds a coagulation factor.

16. The method according to claim 12, wherein the anticoagulant is an antibody that binds a coagulation factor selected from the group consisting of Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XIII, Factor II, Factor XI, Factor XII, von Willebrand Factor, prekallikrein, and HMWK.

17. A method of inhibiting Tissue Factor Pathway Inhibitor (TFPI) activity in a subject, the method comprising administering an amount of a composition according to claim 1 sufficient to inhibit the TFPI to the subject, wherein the NASP is a member selected from α

-cyclodextrin, β

-cyclodextrin, melezitose, stachyose, raffinose, maltotriose, maltotetraose, maitopentaose, cellotriose, cellotetraose, ceilopentaose, xylan, icodextrin, and 6-carboxylcodextrin thereby inhibiting TFPI.

19. The composition according to claim 1, further comprising:

one or more factors selected from the group consisting of Factor XI, Factor XII, prekallikrein, HMWK, Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XIII, Factor II, and von Willebrand Factor, tissue factor, Factor VIIa, Factor Va, Factor Xa, Factor IXa, Factor XIa, Factor XIIa, and Factor VIIIa.

18. A method of inhibiting Tissue Factor Pathway Inhibitor (TFPI) activity in a biological sample, the method comprising combining the biological sample with a sufficient amount of a non-anticoagulant sulfated or sulfonated polysaccharide (NASP) to inhibit the TFPI activity, wherein the NASP is a member selected from α

-cyciodextrin, β

-cyclodextrin, melezitose, stachyose, raffinose, maltotriose, maltotetraose, maltopentaose, cellotriose, cellotetraose, cellopentaose, xylan, icodextrin and 6-carboxylcodextrin.

20. A method of measuring acceleration of blood clotting by a non-anticoagulant sulfated or sulfonated polysaccharide (NASP) in a biological sample, wherein the NASP is a member selected from α

-cyclodextrin, β

-cyclodextrin, melezitose, stachyose, raffinose, maltotriose, maltotetraose, maltopentaose, cellotriose, cellotetraose, cellopentaose, xylan, icodextrin and 6-carboxylcodextrin, the method comprising;

a) combining the biological sample with a composition comprising the NASP; and

b) measuring the clotting time of the biological sample, c) comparing the clotting time of the biological sample to the clotting time of a corresponding biological sample not exposed to the NASP, wherein a decrease in the clotting time of the biological sample exposed to the NASP is indicative of a NASP that accelerates the clotting time.