Anion exchange materials and processes

Details Anion exchange materials and processes Anion exchange materials and processes

1999-07-26

2002-08-13

Cintins, Ivars (Department: 1724)

Liquid purification or separation

Processes

Ion exchange or selective sorption

C210S683000, C521S028000, C521S031000, C521S032000, C521S033000

Reexamination Certificate

active

06432314

ABSTRACT:

The present invention relates to anion exchange separation processes and novel polymers for use in such processes. It relates especially to processes in which anionic components such as anticoagulants are removed from blood.
In WO-A-93/01221 we describe various polymers and their use to coat surfaces to improve their biocompatibility. The polymers include zwitterionic groups and pendant groups which are capable of providing stable surface binding of the polymer to underlying substrate surfaces. The binding may be by provision of pendant hydrophobic groups which physisorb onto hydrophobic substrates, by counterionic attraction between pendant ionic groups on the polymer and oppositely charged groups at the substrate surface, by providing covalent attachment between coreactive pendant groups on the polymer and groups at the substrate surface or by crosslinking the polymer after coating. Post coating crosslinking may also be used to improve the stability of a polymer which is physisorbed, covalently bonded or counterionically bonded to the surface. The polymers have good hemocompatibility as indicated by the low platelet adhesion values reported in that specification.
It has also been shown that zwitterionic groups at substrate surfaces, for instance of contact lenses, show lower rates of deposition of proteins and lipids from biological liquids such as tear film. In WO-A-92/07885, reduced levels of protein deposition are described for contact lenses formed from a hydrogel of a crosslinked copolymer of copolymerisable zwitterionic monomer and non ionic comonomer.
In WO-A-93/21970 it is disclosed that microorganisms, especially bacteria, adhere to surfaces having pendant phosphoryl choline groups less than to similar surfaces without such groups present.
Another way of reducing the thrombogenicity of surfaces has involved attachment or adsorption of anti-thrombogenic active compounds to substrate surfaces. For instance heparin may be attached through covalent or counterionic bonding to surfaces. In U.S. Pat. No. 3,634,123 the binding of heparin to a surface was increased by incorporation of cationic surfactant. A related process is described in EP-A-0350161, in which a surface is first coated with a cationic surfactant and subsequently with heparin. In EP-A-0086187 the surface is first coated with a cationic polymer and subsequently with heparin. In JP-A-53/137268 a cross-linked acrylic copolymer of a cationic monomer and a polyethyleneglycol monomer is blended with polyurethane and made into tubing which can be coated with heparin. In EP-A-0086186 heparin is attached to an underlying surface through a covalent bond via the end carbohydrate unit. In U.S. Pat. No. 5,342,621, a complex of heparin with phosphatidyl choline and admixed with a polymer of caprolactone or L-lactic acid (both of which have no overall charge) and subsequently used to coat medical devices.
Generally patients who are undergoing complex operations requiring that their blood be directed through extra corporeal circuitry, require administration of heparin into the circulation to prevent the blood clotting. Subsequently the heparin has to be neutralised or removed from the blood stream. In order to remove heparin from the circulation without administering a further active compound to neutralise the heparin, it has been suggested to immobilise protamine, a cationic polypeptide used to neutralise heparin, at the surfaces of a filter used in an extra corporeal blood circuit, to scavenge heparin from a patient who has been systemically heparinised.
In J. Chromatography A (1996) 722, 87-96 and Int. Symp. Chromatog. 35
th
Anniv. Res. Group Liq. Chrom. Jpn 1995, 593-597, Yang et al describe ion exchange stationary phases for HPLC. The materials were based on silica to which organic groups including secondary amine groups were attached which in turn were partially derivatised to zwitterionic groups.
In a new ion exchange process according to the invention a substrate has at its surface zwitterionic pendant groups and cationic pendant groups having anionic counterions and is contacted with an aqueous solution having suspended or dissolved therein an anionically charged compound, whereby the anionic compound is ion exchanged with the counterions.
The process is of particular value for treatment of blood, especially for scavenging clotting inhibitors, for instance anionic mucopolysaccharides. The anionically charged mucopolysaccharide may be heparin or a similar is anti-thrombogenic compound such as hirudin or chondroitin sulphate, or may be alginate or hyaluronic acid. The provision of zwitterionic groups seems to minimise adsorption of other components from blood or biological fluids contacted with the substrate surface, thereby preventing fouling of the surface which may prevent ion exchange taking place. In the process of the invention the zwitterionic group, hereinafter referred to as a group X, preferably has a permanent cation, that is a quaternary ammonium or phosphonium or a tertiary sulphonium group. The cationic group at the surface, similarly, is preferably permanently cationic and thus not pH sensitive. The cationic group is preferably a group N
+
R
5
3
, P
+
R
5
3
or S
+
R
5
2
in which the groups R
5
are the same or different and are each C
1-4
-alkyl or aryl (preferably phenyl) or two of the groups R
5
together with the heteroatom to which they are attached from a saturated or unsaturated heterocyclic ring containing from 5 to 7 atoms, preferably the cationic group is N
+
R
5
3
in which each R
5
is C
1-4
-alkyl, preferably methyl.
It is preferred for the anion of the zwitterion to be a phosphate or a phosphonate group, usually a phosphate ester and is most preferably a phosphate diester and thus having a single negative charge.
Most preferably X is a group of formula
in which the moieties X
1
and X
2
, which are the same or different, are —O—, —S—, —NH— or a valence bond, preferably —O—, and W
+
is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which is preferably a C
1-12
-alkylene group.
Preferably W contains as cationic group an ammonium group, more preferably a quaternary ammonium group.
The group W
+
may for example be a group of formula —W
1
—N
+
R
23
3
, —W
1
—P
+
R
23a
3
, —W
1
—S
+
R
23a
2
or —W
1
—Het
+
in which:
W
1
is alkylene of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl, alkylene aryl, aryl alkylene, or alkylene aryl alkylene, disubstituted cycloalkyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, which group W
1
optionally contains one or more fluorine substituents and/or one or more functional groups; and either
the groups R
23
are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenyl or two of the groups R
23
together with the nitrogen atom to which they are attached form a heterocyclic ring containing from 5 to 7 atoms or the three groups R
23
together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R
23
is substituted by a hydrophilic functional group, and the groups R
23a
are the same or different and each is R
23
or a group OR
23
, where R
23
is as defined above; or
Het is an aromatic nitrogen-, phosphorus- or sulphur-, preferably nitrogen-, containing ring, for example pyridine.
Preferably W
1
is a straight-chain alkylene group, most preferably 1,2-ethylene.
Preferred groups X of the formula VI are groups of formula VA.
The groups of formula (VA) are:
where the groups R
12
are the same or different and each is hydrogen or C
1-4
alkyl, and e is from 1 to 6, preferably 2 to 4.
Preferably the groups R
12
are the same. It is also preferable that at least one of the groups R
12
is methyl, and more preferable that the groups R
12
are a

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