METHOD FOR REMOVING CYTOKINES FROM BLOOD WITH SURFACE IMMOBILIZED POLYSACCHARIDES

• US 20110184377A1
• Filed: 12/01/2010
• Published: 07/28/2011
• Est. Priority Date: 12/01/2009
• Status: Active Grant

• Current Assignee: ExThera Medical Corporation
• Original Assignee: Exthera AB
• Inventors: Larm, Olle, MCCREA, Keith R., Adolfsson, Lars, WARD, Robert S.
• Granted Patent: US 8,758,286 B2
• Time in Patent Office: Days
• US Class Current: 604/500
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 31/722 Chitin, chitosan
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61M 1/3472 with treatment of the filtrate
• CPC Class Codes: A61M 1/3486 Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
• CPC Class Codes: A61M 1/3496 Plasmapheresis; Leucopheresis; Lymphopheresis A61M1/3472 takes precedence
• CPC Class Codes: A61M 1/36 Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
• CPC Class Codes: A61M 1/362 changing physical properties of target cells by binding them to added particles to facilitate their subsequent separation from other cells, e.g. immunoaffinity
• CPC Class Codes: A61M 1/3621 Extra-corporeal blood circuits single-needle circuits A61M1/30
• CPC Class Codes: A61M 1/3673 Anticoagulant coating, e.g. Heparin coating
• CPC Class Codes: A61M 1/3679 by absorption A61M1/3675 takes precedence
• CPC Class Codes: A61M 1/3687 Chemical treatment A61M1/3675 takes precedence
• CPC Class Codes: A61M 1/38 Removing constituents from donor blood and storing or returning remainder to body , e.g. for transfusion
• CPC Class Codes: A61M 2202/0057 retained by adsorption
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection

Abstract

The present invention is directed to a method for removing cytokines and/or pathogens from blood or blood serum (blood) by contacting the blood with a solid, essentially non micro-porous substrate which has been surface treated with heparin, heparan sulfate and/or other molecules or chemical groups (the adsorbent media or media) having a binding affinity for the cytokine or pathogen(s) to be removed (the adsorbates), and wherein the size of the interstitial channels within said media is balanced with the amount of media surface area and the surface concentration of binding sites on the media in order to provide adequate adsorptive capacity while also allowing relatively high flow rates of blood through the adsorbent media.

Claims

1. A method for removing at least one cytokine or pathogen from blood comprising:

causing a sample of blood or serum to flow over and past a high-surface-area solid substrate at a linear flow velocity of ≧

8 cm/min through the adsorption media, wherein the surface of said solid substrate comprises one or more polysaccharide adsorbents with a binding affinity for the cytokine or pathogen, wherein said substrate is sufficiently nonporous such that adsorbates in the blood do not need to pass through pores in said substrate or through an interposed barrier membrane prior to adsorption, separating them from said blood or serum, and wherein the size of interstitial channel spaces between individual portions of said substrate, and the amount of interstitial substrate surface area is such that the major fraction of cytokines or pathogens that bind to said adsorbent do so by convective transport to the surface-bound adsorbent.

2. The method according to claim 1, wherein said substrate comprises a packed column of non-porous rigid beads or particles, a column packed with a rigid reticulated foam, a column packed with a rigid monolithic bed of sintered beads or other sintered solid media with internal flow channels, a column packed with woven or non woven rigid fabric, a column packed with a rigid yarn or optionally hollow monofilament fibers, a spiral wound cartridge, or a combination of at least two members selected from the group consisting of beads, rigid reticulated foam, sintered beads, fabric, yarn and monofilament.

3. The method according to claim 1, wherein the solid substrate comprises polyethylene beads coated with one or more polysaccharides.

4. The method according to claim 3, wherein at least one of said polysaccharides is selected from the group consisting of heparin, heparan sulphate, hyaluronic acid, salicylic acid, carbohydrates with mannose sequences, and chitosan.

6. The method of any one of claims 1 and 5, wherein the linear flow velocity of blood or serum ranges from about 24 and 329 cm/minute through the adsorption media.

7. The method of claim 2, wherein the bead comprises a polymer of polyethylene.

8. The method of claim 7, wherein said beads have a diameter ranging from 100 and 450 microns.

9. The method of claim 8, wherein said beads have an average diameter of 0.3 mm.

10. The method of claim 9, wherein the beads are coated with 0.27-10 mg heparin per gram of bead.

11. The method of claim 10, wherein the bead is coated with 2±

0.5 mg heparin per gram of bead.

12. The method of claim 9, wherein the surface area concentration of heparin is between 1 and 37 μ

g/cm² of substrate.

13. The method of claim 12, wherein the bead is coated with 7.4±

0.5 μ

g heparin per square centimeter.

14. The method of claim 4, wherein the heparin has a mean molecular weight of about 8 kDa.

15. The method of claim 4, wherein the heparin is attached to the bead by covalent end-point attachment.

16. The method of any one of claims 1 and 5, wherein the cytokine is selected from the group consisting of IL-6, VCAM, TNF, GRO-α

, IL-8, and Rantes.

23. The method according to claim 1, wherein said method for removing a cytokine or pathogen is conducted in combination with at least one other extracorporeal treatment of said blood.

24. The method according to claim 23, wherein said at least one other extracorporeal treatment comprises at least one member selected from the group consisting of cardiopulmonary bypass (CPB), hemodialysis, and oxygenation

5. A method for removing at least one cytokine or pathogen from blood comprising:

causing a sample of blood to flow in contact with rigid polyethylene beads in a container at a linear flow velocity of ≧

8 cm/min, wherein the surface of said beads comprises one or more polysaccharide adsorbents with a binding affinity for the cytokine or pathogen, wherein said beads are sufficiently rigid such that blood does not pass through pores in said substrate, and wherein the size of the interstitial channel spaces between individual ones of said beads and the amount of interstitial surface area of said beads is such that when said blood is in flow contact with said substrate at a linear flow velocity of ≧

8 cm/min, said cytokine or pathogen binds to said one or more polysaccharide adsorbents to separate from said blood and the flow transport of said blood past said substrate is by convection transport more than Brownian diffusion transport method.

17. A method of treating a disease in a mammal in need of such treatment, comprising:

a) bringing a sample of blood from a mammal into flow contact with a solid substrate comprising with rigid polyethylene beads in a container at a linear flow velocity of at least about 24 cm/min, wherein the surface of said beads comprises one or more polysaccharide adsorbents with a binding affinity for the cytokine or pathogen, wherein said beads are sufficiently rigid such that blood does not pass through pores in said substrate, and wherein the size of the interstitial channel spaces between individual ones of said beads and the amount of interstitial surface area of said beads is such that when said blood is in flow contact with said substrate at a linear flow velocity of at least about 24 cm/min, said cytokine or pathogen binds to said one or more polysaccharide adsorbents to separate from said blood and the flow transport of said blood past said substrate is by convection transport more than Brownian diffusion transport method;

b) separating the blood from the solid substrate; and

c) administering said blood to a mammal.

18. The method according to claim 17, wherein at least one of said polysaccharides is selected from the group consisting of heparin, heparan sulphate, hyaluronic acid, salicylic acid, carbohydrates with mannose sequences, and chitosan.

19. The method according to claim 17, wherein the disease is sepsis.

20. The method according to claim 17, wherein the disease is an autoimmune disorder such as IBD or Chron'"'"'s disease.

21. The method according to claim 17, wherein the medical condition is a severe burn.

22. The method according to claim 17, wherein the blood is taken from and returned to the same mammal.

25. A device for removing at least one cytokine or pathogen from blood which comprises a solid substrate in a container, said solid substrate having one or more polysaccharide adsorbents on the surface thereof with a binding affinity for the cytokine or pathogen, wherein said substrate is sufficiently rigid such that blood does not pass through pores in said substrate, and wherein the size of the interstitial channel spaces between individual portions of said substrate and the amount of interstitial substrate surface area is such that when blood is in flow contact with said substrate at a linear flow velocity through said device of at least about 24 cm/min, said cytokine or pathogen binds to said one or more polysaccharide adsorbents to separate from said blood and the flow transport of said blood past said substrate is by convection transport more than Brownian diffusion transport.

27. The device according to claim 25, wherein at least one of said polysaccharides is selected from the group consisting of heparin, heparan sulphate, hyaluronic acid, salicylic acid, carbohydrates with mannose sequences, and chitosan.

28. The device of claim 25, wherein the linear flow velocity is between about 24 and 328 cm/minute.

29. The device of claim 28, wherein the bead comprises a polymer of polyethylene.

30. The device of claim 25, wherein said beads have a diameter ranging from 100 and 450 microns.

31. The device of claim 30, wherein said beads have an average diameter of 0.3 mm.

32. The device according to claim 25, wherein said beads are coated with 0.5-10 mg heparin per gram of bead.

33. The device of claim 32, wherein said beads are coated with 2±

0.5 mg heparin per gram of bead.

34. The device according to claim 25, wherein the heparin has a mean molecular weight of about 8 kDa.

35. The device according to claim 25, wherein the heparin is attached to the bead by covalent end-point attachment.

26. A device for removing at least one cytokine or pathogen from blood which comprises a plurality of rigid polyethylene beads in a container, wherein the surface of said beads comprises one or more polysaccharide adsorbents with a binding affinity for the cytokine or pathogen, wherein said beads are sufficiently rigid such that blood does not pass through pores in said substrate, and wherein the size of the interstitial channel spaces between individual ones of said beads and the amount of interstitial surface area of said beads is such that when said blood is in flow contact with said substrate at a linear flow velocity of at least about 24 cm/min, said cytokine or pathogen binds to said one or more polysaccharide adsorbents to separate from said blood and the flow transport of said blood past said substrate is by convection transport more than Brownian diffusion transport method.