Adsorbent having differently modified surface areas, method for the production thereof and use of the same

• US 20040202783A1
• Filed: 09/12/2003
• Published: 10/14/2004
• Est. Priority Date: 09/14/2000
• Status: Active Grant

• Current Assignee: Fresenius Medical Care Deutschland GmbH (Fresenius Medical Care AG)
• Original Assignee: Fresenius Medical Care Deutschland GmbH (Fresenius Medical Care AG)
• Inventors: Schimmel, Martin, Metzger, Wolfgang, Baumann, Hanno, Hoffmann, Michael, Leinenbach, Hans-Peter, Horres, Roland, Kokott, Andreas, Gerner, Franz-Josef, Otto, Veit, Ruger, Walter, Mathar, Gunther
• Granted Patent: US 7,838,306 B2
• Time in Patent Office: Days
• US Class Current: 427/213.3
• CPC Class Codes: A61M 1/3679 by absorption A61M1/3675 takes precedence
• CPC Class Codes: B01J 20/30 Processes for preparing, regenerating, or reactivating
• CPC Class Codes: B01J 20/321 consisting of a polymer obtained by reactions involving only carbon to carbon unsaturated bonds
• CPC Class Codes: B01J 20/3212 consisting of a polymer obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
• CPC Class Codes: B01J 20/3219 involving a particular spacer or linking group, e.g. for attaching an active group
• CPC Class Codes: B01J 20/327 Polymers obtained by reactions involving only carbon to carbon unsaturated bonds
• CPC Class Codes: B01J 20/3272 Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
• CPC Class Codes: B01J 20/3282 Crosslinked polymers
• CPC Class Codes: B01J 20/3285 Coating or impregnation layers comprising different type of functional groups or interactions, e.g. different ligands in various parts of the sorbent, mixed mode, dual zone, bimodal, multimodal, ionic or hydrophobic, cationic or anionic, hydrophilic or hydrophobic

Abstract

An adsorbent for whole blood in the form of essentially spherical non-aggregated particles. The adsorbent comprises a porous carrier material having an average pore size of ≦1.5 μm, whereby a maximum of 50% of the pore volume may be in pores having a pore size of >1.5 μm, whereby the outer surfaces of the porous carrier material have at least one surface modification M₁ so that the outer surface essentially does not interact with blood cells, and the inner surfaces of the porous carrier material, e.g., the surfaces of the pores of the porous carrier material, have at least one surface modification M₂ which interacts with substances present in blood.

Claims

1. A method of producing an adsorbent, comprising the following steps:

providing a porous, particulate carrier material, which has modifiable binding sites on the outer and inner surfaces;

filling the pores of the carrier material with at least one medium which is liquid under the conditions of filling and is essentially not miscible, under the conditions of modification, with a solution by which binding sites on the surface of the carrier material can be modified essentially completely;

essentially completely modifying the binding sites on the outer surfaces of the carrier material to yield at least one surface modification M₁, and

optionally removing the medium from the pores, this medium being essentially not miscible, under the conditions of modification, with a solution by which binding sites on the outer surfaces of the carrier material can be modified essentially completely.

4. The method according to claims 1, 2 or 3,

whereby after the essentially complete modification of the binding sites on the outer surfaces of the carrier material to form at least one surface modification M₁, or after the step of removing the medium from the pores, the medium being essentially not miscible, under the conditions of the modification, with a solution by which binding sites on the outer surfaces of the carrier material can be modified essentially completely, or after removing the pore-forming medium from the pores, the binding sites on the inner surfaces of the carrier material are modified to form at least one surface modification M₂ using a solution that is not capable of modifying the surface modifications M₁.

5. The method according to one or more of claims 1 through 4,

whereby a water-based solution is used as the solution capable of modifying binding sites on the outer surfaces of the carrier material to yield at least one surface modification M₁.

6. The method according to one or more of claims 1 through 5,

whereby a hydrophobic medium is used as the pore-filling or pore-forming medium during a modification M₁ of the outer surfaces.

7. The method according to claim 6,

whereby the hydrophobic medium is at least one which is selected from the group consisting of linear and branched, cyclic or acyclic C₁- to C₂₀-alkanes, linear and branched cyclic or acyclic C₅- to C₂₀-alkanols, linear and branched, cyclic or acyclic C₂- to C₃₀-carboxylate esters and aromatic C₆- to C₂₀-hydrocarbon atoms.

8. The method according to claim 7,

whereby the pore-forming medium is a mixture of at least two components selected from linear, branched or cyclic alcohols having 5 to 14 carbon atoms and esters of monocarboxylic or dicarboxylic acids having 2 to 10 carbon atoms, which are esterified with monohydric or polyhydric alcohols having 1 to 6 carbon atoms.

2. A method of producing an adsorbent, comprising the following steps:

producing a porous, particulate carrier material having modifiable binding sites on the outer and inner surfaces, by suspension polymerization, whereby a hydrophobic phase made up of at least one monomer, at least one crosslinking agent, a pore-forming medium and a polymerization initiator is dispersed in a continuous phase made up of water and at least one protective colloid, and the monomers and crosslinking agents present in the hydrophobic phase are polymerized, whereby the pores of the resulting porous, particulate carrier material are filled with the pore-forming medium,

essentially complete modification of the modifiable binding sites on the outer surfaces of the carrier material particles to form at least one surface modification M₁, and

optionally removing the pore-forming medium from the pores.

10. The method according to claim 2 or 3,

whereby the monomer contained in the hydrophobic phase is a monomer containing epoxy groups or a mixture of a monomer containing epoxy groups and at least one additional monomer.

11. The method according to claim 10,

whereby the monomer containing epoxy groups is a (meth)acrylic acid monomer containing epoxy groups.

12. The method according to claim 11,

whereby the (meth)acrylic acid monomer containing epoxy groups is glycidyl (meth)acrylate.

13. The method according to one or more of claims 2, 3 and 10 through 12,

whereby the crosslinking agent is a monomer having at least two polymerizable groups.

14. The method according to claim 13,

whereby the monomer having at least two polymerizable groups is a monomer based on (meth)acrylic acid.

15. The method according to claim 14,

whereby the monomer having at least two polymerizable groups is ethylene glycol di(meth)acrylate.

16. The method according to one or more of claims 2, 3 and 10 through 15,

whereby the polymerization initiator is selected from the group of azo compounds, peroxides and redox initiators.

17. The method according to claim 16,

whereby the polymerization initiator is azobisisobutyronitrile or dibenzoyl peroxide.

18. The method according to one of claims 3 and 10 through 17,

whereby the water-soluble monomer is a monofunctional vinyl compound.

19. The method according to one of claims 3 and 10 through 18,

whereby the water-soluble monomer has one or more polar groups.

20. The method according to one of claims 3 and 10 through 19,

whereby the water-soluble monomer is selected from the group comprising hydroxyalkyl methacrylates, aminoalkyl methacrylates, N-vinyl-2-pyrrolidone, acrylonitrile and methacrylonitrile, acrylic and methacrylic acid, allyl alcohol, allylamine, 3-allyloxy-1,2-propanediol, (ethylene glycol)_n-vinylmethyl ether, where n=1 to 10, N-methylolacrylamide, 2-acrylamido-2-methylpropanesulfonic acid and salts of vinylbenzenesulfonic acid and vinylsulfonic acid, as well as combinations thereof.

21. The method according to one of claims 3 and 10 through 20,

whereby the proportion of water-soluble monomer is 2 percent by weight to 80 percent by weight based on the total starting monomer weight of the porous carrier material.

3. A method of producing an adsorbent, comprising the following steps:

producing a porous, particulate carrier material which has modifiable binding sites on the outer and inner surfaces, by suspension polymerization, whereby a hydrophobic phase made up of at least one monomer, at least one crosslinking agent, a pore-forming medium and a polymerization initiator is dispersed in a continuous phase made up of water, at least one protective colloid and at least one water-soluble monomer that is essentially insoluble in the hydrophobic phase, whereby the monomers and crosslinking agents present in the hydrophobic phase are polymerized, forming a porous core, and the at least one water-soluble monomer in the phase boundary between the hydrophobic and continuous phase is polymerized to form at least one surface modification M₁, whereby at least one part of the polymer chains being formed from the water-soluble monomer is bonded covalently to the porous core thus formed, and

optionally removing the pore-forming medium from the pores.

9. A method of producing an adsorbent, comprising the steps

preparing a porous, particulate carrier material which has modifiable binding sites on the outer surfaces and the inner surfaces,

essentially completely modifying the binding sites on the outer surfaces of the carrier material to form at least one surface modification M₁ by means of a reaction which is triggered by radiation that essentially does not penetrate through the carrier material, and

if necessary, essentially completely modifying the binding sites on the inner surfaces of the carrier material to form at least one surface modification M₂ by means of a reaction that is not capable of modifying the surface modifications M₁.

22. An adsorbent for whole blood in the form of essentially spherical, nonaggregated particles, comprising a porous carrier material having an average pore size of ≦

1.5 μ

m, whereby a maximum of 50% of the pore volume may be in the form of pores having a pore size of >

1.5 μ

m , whereby the outer surfaces of the porous carrier material have at least one surface modification M₁, so that the outer surface essentially does not interact with blood cells, and the inner surfaces of the porous carrier material, i.e., the surfaces of the pores of the porous carrier material, have at least one surface modification M₂ which interacts with substances contained in blood.

23. The adsorbent according to claim 22,

whereby the particles of the adsorbent have a particle size of 50 to 500 μ

m.

24. The adsorbent according to claim 22 or 23,

whereby the inner surface of the porous carrier material is surface-modified by amination.

25. The adsorbent according to one or more of claims 22 through 24,

whereby the outer surface is modified by covalent bonding of at least one group M₁ to bonding sites on the outer surface and/or the inner surface is modified by covalent bonding of at least one group M₂ to bonding sites on the inner surface.

26. The adsorbent according to one or more of claims 22 through 25,

whereby the at least one group M₁ is at least one poly(carboxylic acid), albumin, heparin, heparan sulfate and/or polymyxin.

27. The adsorbent according to one or more of claims 22 through 26,

whereby the at least one group M₁ is selected from polyacrylic acid and/or heparin.

28. The adsorbent according to one or more of claims 22 through 27,

whereby the at least one group M₂ is an immunoadsorber.

29. The adsorbent according to one or more of claims 22 through 28,

whereby the at least one group M₂ is selected from the group consisting of complement factor C1q, peptides, antibodies such as monoclonal or polyclonal anti-fibrinogen or anti-fibrin antibodies and antigens such as synthetic A/B blood group antigens.

30. The adsorbent according to one or more of claims 22 to 29,

whereby the carrier material is a copolymer derived from (meth)acrylate esters and/or amides.

31. The adsorbent according to claim 30,

whereby the copolymer derived from (meth)acrylate esters and/or amides has epoxy groups.

32. The adsorbent according to claim 30 or 31,

whereby the copolymer is a random statistic copolymer formed by polymerization of ethylene glycol di(meth)acrylate and glycidyl (meth)acrylate and/or allylglycidyl ether.

33. The adsorbent according to claim 30 or 31,

whereby the copolymer is a crosslinked random statistic copolymer produced by polymerization of the monomer units

(A) (meth)acrylamide in an amount of 10 to 30 percent by weight,

(B) N,N′

-methylene-bis(meth)acrylamide in an amount of 30 to 80 percent by weight, and

(C) allylglycidyl ether and/or glycidyl (meth)acrylate in an amount of 10 to 20 percent by weight, each based on the total weight of the monomer units.

34. The adsorbent according to one or more of claims 30 through 33,

whereby the copolymer was produced by suspension polymerization.

35. A use of the adsorbent according to one or more of claims 22 through 34 for separating biomolecules and/or pathogenic substances from whole blood.

36. The use according to claim 35,

whereby the biomolecules to be separated are immunoglobulins, fibrinogens and/or immune complexes.

37. The use of an adsorbent according to one or more of claims 22 through 34 for producing an adsorber comprising a housing and an adsorbent situated therein for separating biomolecules and/or pathogenic substances from whole blood.

38. The use according to claim 37,

whereby the adsorber has a volume of 10 ml to 1250 ml.

39. The use according to claim 37 or 38,

whereby the adsorber has an inlet area on the head end and an outlet area at the bottom of the housing.

40. The use according to one or more of claims 37 to 39,

whereby the adsorber has a filter in its outlet area.

41. The use according to claim 40, whereby the filter is a particle filter.

42. The use according to one or more of claims 37 through 41,

whereby a screen with a mesh of at least 25 μ

m is situated at the bottom of the housing.

43. The use according to one or more of claims 37 through 42,

whereby a screen with a mesh of at least 40 μ

m is situated at the bottom of the housing.