Hemocompatible adsorber for the dialysis of protein-bound uremic toxins

Abstract

A hemocompatible adsorber for separating protein-bound uremic toxins contained in the blood of a patient and having a molecular mass of <500 g/mol regarding their carrier proteins, to adsorb the uremic toxins during hemodialysis. The hemocompatible adsorber including a polymer based on a cyclic oligosaccharide or a derivative thereof which is disposed on a solid carrier component. A device for hemodiafiltration including an extracorporeal circuit for receiving blood to be purified and a hemodialyzer connected to the blood circulation of a patient, wherein a hemocompatible adsorber is provided for separating protein-bound uremic toxins contained in the blood of a patient and having a molecular mass of <500 g/mol regarding their carrier proteins. The hemocompatible adsorber, which is disposed on a solid carrier component in at least one layer on the blood side within the hemodialyzer, includes a polymer based on a cyclic oligosaccharide or a derivative thereof.

Claims

1. A hemodiafiltration apparatus comprising: an extracorporeal circuit for receiving blood to be purified; at least one of a hemodialyzer or hemofilter connected to the blood circulation of a patient; and a hemocompatible adsorber for separating protein-bound uremic toxins contained in the blood or blood plasma of the patient and having a molecular mass of <500 g/mol regarding their carrier proteins; wherein the hemocompatible adsorber, which is disposed on a solid carrier component in at least one layer on a blood side within the hemodialyzer or hemofilter, comprises a polymer based on a cyclic oligosaccharide or a derivative thereof, wherein the polymer is disposed on the solid carrier component using a layer by layer (LBL) technology, wherein the polymer for a first layer of the LBL technology is an anionic polyelectrolyte, wherein the polymer for a second layer disposed on the first layer is a cationic counterpart, and wherein the hemocompatible adsorber is integrated as the solid carrier component coated with the polymer in a blood cap of the hemodialyzer.

2. The hemodiafiltration apparatus according to claim 1, wherein the uremic toxins are selected from the group consisting of p-cresol, indoxyl sulfate, phenol, phenol derivatives, homocysteine, urofuranic acids, in particular 3-carboxy-4-methyl-5-propyl-2-furanopropionic acid, hippuric acid and p-hydroxyhippuric acid.

3. The hemodiafiltration apparatus according to claim 1, wherein the carrier protein is human albumin.

4. The hemodiafiltration apparatus according to claim 1, wherein the polymer based on cyclic oligosaccharides is selected from the group consisting of: polycyclodextrins, poly--cyclodextrins, poly(carboxymethyl--cyclodextrin) and poly(trimethylammonium--cyclodextrin) or their derivatives and cyclodextrins fused with epichlorohydrin.

5. The hemodiafiltration apparatus according to claim 1, wherein the solid carrier component is selected from the group consisting of: a preferably non-woven fabric material, a hollow fiber or flat membrane or other porous materials based on polyether sulfone [PES], polysulfone [PSU], polyether ether ketones [PEEK], polyphenylsulfone [PPSU], polyoxymethylene [POM], polyphenol, polyamides, in particular nylon, polystyrene, polyacrylate, polycarbonate or polymers containing acrylonitrile or a methylallylsulfonate salt or copolymers thereof.

6. The hemodiafiltration apparatus according to claim 1, wherein the solid carrier component is a porous material based on polyethersulfone [PES], polysulfone [PSU], polyether ether ketones [PEEK], polyphenylsulfone [PPSU], polyoxymethylene [POM], polyphenol, polyamides, in particular nylon, polystyrene, polyacrylate, polycarbonate or polymers containing acrylonitrile or a methylallylsulfonate salt or copolymers thereof.

7. The hemodiafiltration apparatus according to claim 1, wherein the anionic polyelectrolyte is poly(carboxymethyl--cyclodextrin).

8. The hemodiafiltration apparatus according to claim 1, wherein the cationic counterpart is polyethylene imine or poly(trimethylammonium-6-cyclodextrin).

9. A hemodiafiltration apparatus comprising: an extracorporeal circuit for receiving blood to be purified; at least one of a hemodialyzer or hemofilter connected to the blood circulation of a patient; and a hemocompatible adsorber for separating protein-bound uremic toxins contained in the blood or blood plasma of the patient and having a molecular mass of <500 g/mol regarding their carrier proteins; wherein the hemocompatible adsorber, which is disposed on a solid carrier component in at least one layer on a blood side within the hemodialyzer or hemofilter, comprises a polymer based on a cyclic oligosaccharide or a derivative thereof, wherein the polymer is disposed on the solid carrier component using a layer by layer (LBL) technology, wherein the polymer for a first layer of the LBL technology is an anionic polyelectrolyte, wherein the polymer for a second layer disposed on the first layer is a cationic counterpart, and wherein the hemocompatible adsorber is integrated into a pore system of hollow fiber membranes of the hemodialyzer.

10. The hemodiafiltration apparatus according to claim 9, wherein the anionic polyelectrolyte is poly(carboxymethyl--cyclodextrin).

11. The hemodiafiltration apparatus according to claim 9, wherein the cationic counterpart is polyethylene imine or poly(trimethylammonium-6-cyclodextrin).

12. The hemodiafiltration apparatus according to claim 9, wherein the uremic toxins are selected from the group consisting of p-cresol, indoxyl sulfate, phenol, phenol derivatives, homocysteine, urofuranic acids, in particular 3-carboxy-4-methyl-5-propyl-2-furanopropionic acid, hippuric acid and p-hydroxyhippuric acid.

13. The hemodiafiltration apparatus according to claim 9, wherein the carrier protein is human albumin.

14. The hemodiafiltration apparatus according to claim 9, wherein the polymer based on cyclic oligosaccharides is selected from the group consisting of: polycyclodextrins, poly--cyclodextrins, poly(carboxymethyl--cyclodextrin) and poly(trimethylammonium--cyclodextrin) or their derivatives and cyclodextrins fused with epichlorohydrin.

15. The hemodiafiltration apparatus according to claim 9, wherein the solid carrier component is selected from the group consisting of: a preferably non-woven fabric material, a hollow fiber or flat membrane or other porous materials based on polyether sulfone [PES], polysulfone [PSU], polyether ether ketones [PEEK], polyphenylsulfone [PPSU], polyoxymethylene [POM], polyphenol, polyamides, in particular nylon, polystyrene, polyacrylate, polycarbonate or polymers containing acrylonitrile or a methylallylsulfonate salt or copolymers thereof.

16. The hemodiafiltration apparatus according to claim 9, wherein the solid carrier component is a porous material based on polyethersulfone [PES], polysulfone [PSU], polyether ether ketones [PEEK], polyphenylsulfone [PPSU], polyoxymethylene [POM], polyphenol, polyamides, in particular nylon, polystyrene, polyacrylate, polycarbonate or polymers containing acrylonitrile or a methylallylsulfonate salt or copolymers thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is best understood from the following detailed description when read in connection with the accompanying drawings. Included in the drawings are the following figures:

(2) FIG. 1 illustrates a small additional blood volume for series connection of a separate cartridge to a dialyzer.

(3) FIG. 2 illustrates that no additional blood volume for series connection of a separate cartridge to a dialyze is required if it is used in the blood caps of the dialyzer.

(4) FIG. 3 illustrates no additional blood volume for series connection of a separate cartridge to a dialyze is required if it is used on the entire surface of the hollow fiber membrane.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(5) Either a small additional blood volume is required for series connection of a separate cartridge to a dialyzer (FIG. 1) or no additional blood volume is required if it is used in the blood caps of the dialyzer (FIG. 2) or on the entire surface of the hollow fiber membrane (FIG. 3). Furthermore, the adsorber does without a diffusion-inhibiting protective layer, as the material itself is suitable for direct blood contact.

(6) In principle, the innovative adsorber can be used for any dialysis treatment, since toxins <500 g/mol that are difficult to dialyze and place a heavy burden on every patient can be effectively removed. It can be integrated in the desired quantity into a hemodialysis system without affecting the function, i.e. ideally on a non-woven fabric in the blood caps (FIG. 2) without high pressure loss.

(7) Cyclodextrins are known and accepted in the pharmaceutical industry and are used as excipients in the manufacture of drugs (injections, tablets and ointments) to dissolve water-insoluble drugs and thus make them biologically available.

(8) Due to the chemical properties of modified poly-(cyclodextrin), a 15 to 200-fold increase in the adsorption rate of hydrophobic toxins in aqueous systems can be achieved with suitable preparation as compared to activated carbon [23, 27].

(9) Furthermore, no vital minerals, amino acids or vitamins are removed from the blood.

(10) This invention therefore describes a new adsorber for the effective removal of protein-bound blood toxins up to 500 g/mol as a support for conventional hemodialysis. It is based on modified cyclodextrin and can be integrated into any part of a hemodialysis system using LbL technology.