Process for the quantitative selective removal or preparative isolation of tumour necrosis factor (TNF) or/and lipopolysaccharides (LPS) from aqueous liquids

• US 5,403,917 A
• Filed: 10/06/1993
• Issued: 04/04/1995
• Est. Priority Date: 10/12/1992
• Status: Expired due to Term

• Current Assignee: B Braun Melsungen AG (B. Braun Holding GmbH & Co. KG)
• Original Assignee: B Braun Melsungen AG (B. Braun Holding GmbH & Co. KG)
• Inventors: von der Haar, Friedrich, Siedel, Dietrich, Boos, Karl-Siegfried
• Primary Examiner(s): Russel, Jeffrey E.
• Assistant Examiner(s): Gromet, Nancy J.
• Application Number:
  US08/132,316
• Time in Patent Office: 545 Days
• Field of Search: 424/85.1, 530/351, 530/382, 530/412, 530/415, 530/416, 530/417, 536/55.1, 536/123, 604/4, 604/5, 604/6, 436/86
• US Class Current: 530/351
• CPC Class Codes: A61M 1/3486 Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
• CPC Class Codes: B01D 15/08 Selective adsorption, e.g. chromatography
• CPC Class Codes: C07K 14/525 Tumour necrosis factor [TNF]

Abstract

For the quantitative selective removal or/and preparative isolation of tumour necrosis factor (TNF) or/and lipopolysaccharides from aqueous liquids, in particular blood, plasma or serum, the aqueous liquid is passed over an adsorption material which consists of a porous supporting material to which functional groups made of synthetic or/and semisynthetic or/and natural polyanion chains and namely in a linear or branched form, are covalently bound and if desired, the molecules chromatographically separated in this way are eluted from the adsorption material using a saline solution. A device according to the present invention for the extracorporeal removal of tumour necrosis factor and/or lipopolysaccharides (LPS) from aqueous liquids, in particular blood, plasma or serum, consists of a cylindrical housing which is filled with an adsorption material which consists of a porous supporting material to which functional groups made of synthetic or/and semisynthetic or/and natural polyanion chains and namely in a linear or branched form, are covalently bound and is provided with covers at its front ends which each have a central inlet and outlet.

Claims

1. A process for the selective removal of tumor necrosis factor (TNF) and/or lipopolysaccharides (LPS) from a patient'"'"'s body fluids by extracorporeal perfusion, comprising the steps of:

a) passing a body fluid over an adsorption material, and

b) then returning said body fluid to said patient,

wherein said adsorption material comprises a porous supporting material covalently bound to linear or branched functional groups selected from the group consisting of biological polycarboxylic acids and polysulfonic acids.

2. The process according to claim 1, wherein said body fluid is selected from the group consisting of blood, plasma and serum.

3. The process according to claim 1, wherein said porous supporting material has an average pore diameter less than 30 nm.

4. The process according to claim 1, wherein said porous supporting material has a molecular exclusion limit for globular proteins of less than 10⁶ daltons.

5. The process according to claim 4, wherein said molecular exclusion limit is less than 2×

10⁴ daltons.

6. A process for the isolation of tumor necrosis factor (TNF) and/or lipopolysaccharides (LPS) from a patient'"'"'s body fluids by extracorporeal perfusion, comprising the steps of:

a) passing a body fluid over an adsorption material,

b) then returning said body fluid to said patient, and

c) eluting any TNF and/or LPS from said adsorption material using a 0.5 to 2.0 molar sodium chloride solution,

wherein said adsorption material comprises a porous supporting material covalently bound to linear or branched functional groups selected from the group consisting of synthetic polyanion chains, semisynthetic polyanion chains and natural polyanion chains.

7. A process for the selective removal of tumor necrosis factor (TNF) and/or lipopolysaccharides (LPS) from a patient'"'"'s body fluids by extracorporeal perfusion, comprising the steps of:

a) passing a body fluid through a plasma fractionation filter, wherein said plasma fractionation filter is impermeable to fibrinogen and LDL,

b) then passing said body fluid over an adsorption material, and

c) then returning said body fluid to said patient,

wherein said adsorption material comprises a porous supporting material covalently bound to linear or branched functional groups selected from the group consisting of synthetic polyanion chains, semisynthetic polyanion chains and natural polyanion chains.

8. The process according to claim 7, wherein said porous supporting material has an average pore diameter of at least 30 nm.

9. The process according to claim 7, wherein said synthetic polyanion chains, semisynthetic polyanion chains and natural polyanion chains have an average molecular weight of 600 to 10⁶ daltons.

10. The process according to claim 9, wherein said average molecular weight is between 5×

10³ to 5×

10⁵ daltons.

11. The process according to claim 7, wherein said natural polyanion chains are sulfated polysaccharides.

12. The process according to claim 7, wherein said synthetic polyanion chains and said semisynthetic polyanion chains are selected from the group consisting of a) polymers and copolymers of acrylic acid, methacrylic acid, vinyl sulfonic acid, and maleic acid, b) acrylic acid derivatives and methacrylic derivatives having the formula H₂ C═

CR₁ --CO--R₂, in which the substituent R₁ is hydrogen or a methyl group and R₂ is an amidically or esterically linked linear or branch-chained aliphatic sulfonic acid, carboxylic acid or phosphoric acid group, c) styrene sulfonic acid, d) anethole sulfonic acid, e) styrene phosphoric acid, f) glutamic acid, g) aspartic acid, h) adenosine-3'"'"',5'"'"'-diphosphate, and i) guanosine-3'"'"',5'"'"'-diphosphate.

13. The process according to claim 7, wherein said porous supporting material is selected from the group consisting of porous glass, porous silica gel, silica gel coated with organic polymers or copolymers, cross-linked carbohydrates, organic polymers and organic copolymers.

14. The process according to claim 13, wherein said porous supporting material is cellulose and said functional group is dextran sulfate.

15. A method for the determination of the concentration of tumor necrosis factor in a body fluid, comprising the steps of:

a) passing a body fluid over an adsorption material,

b) eluting any TNF from said adsorption material using a 0.5 to 2.0 molar sodium chloride solution, and

c) determining the concentration of any tumor necrosis factor eluted from said adsorption material as an indication of the concentration of tumor necrosis factor in said body fluid,

wherein said adsorption material comprises a porous supporting material covalently bound to linear or branched functional groups selected from the group consisting of synthetic polyanion chains, semisynthetic polyanion chains and natural polyanion chains.

16. Device for the extracorporeal removal of tumor necrosis factor (TNF) and lipopolysaccharides (LPS) from body fluids, comprising a plasma fractionation filter which is impermeable to fibrinogen and LDL;

in combination with a cylindrical housing with covers at both ends, wherein said covers have a central inlet and outlet and wherein said cylindrical housing is filled with an adsorption material comprising a porous supporting material covalently bound to linear or branched functional groups selected from the group consisting of synthetic polyanion chains, semisynthetic polyanion chains and natural polyanion chains.

17. Device according to claim 16, wherein said cylindrical housing has a diameter of 3 to 20 cm and a length of 1 to 40 cm.

18. Device according to claim 17, wherein said cylindrical housing has a diameter of 5 to 10 cm and a length of 5 to 20 cm.

19. Device according to claim 16, wherein said cylindrical housing is composed of glass or plastic.

20. Device according to claim 16, further comprising sieves in the covers to eliminate particles, wherein said sieves have a pore size of 10 to 200 μ

m.

21. Device according to claim 20, wherein said sieves have a pore size of 20 to 100 μ

m.

22. Device according to claim 16, wherein said cylindrical housing is part of a closed circuit in which said body fluid is circulated by means of a pump.

23. A method for the extracorporeal removal of tumor necrosis factor and lipopolysaccharides from body fluids, comprising:

a) passing a body fluid through a device unit comprising two cylindrical housings, each with covers at both ends, wherein said covers have a central inlet and outlet and wherein said cylindrical housings are filled with an adsorption material comprising a porous supporting material covalently bound to linear or branched functional groups selected from the group consisting of biological polycarboxylic acids and polysulfonic acids,

b) alternately perfusing the two cylindrical housings of the device unit with the body fluid to be treated, and

c) rinsing the cylindrical housing which is not being perfused and which is saturated with tumor necrosis factor (TNF) and/or lipopolysaccharides (LPS) with a regeneration solution to elute bound tumor necrosis factor (TNF) and/or lipopolysaccharides (LPS).

24. The method according to claim 23, wherein said regeneration solution is a 0.5 to 2.0 molar sodium chloride solution.