The present invention relates to a lipoprotein adsorbent for use in extracorporeal circulation treatment in order to remove harmful lipoproteins in blood, especially low density lipoproteins (hereinafter referred to as "LDL") and very low density lipoproteins (hereinafter referred to as "VLDL"), from blood, plasma or serum by selectively adsorbing the lipoproteins and a process for preparing thereof.
It has been known that LDL and VLDL among lipoproteins present in blood, contain a large amount of cholesterol and cause arteriosclerosis. In hypercholesterolemia such as familial hyperlipemia LDL shows several times higher values than those observed in normal conditions and causes coronary arteriosclerosis.
Although regimen or medication with probucol or cholestyramine have been employed for treatment of hypercholesterolemia such as familial hyperlipemia, they show only limited effect and have a fear of unfavorable side effects. Hitherto, familial hyperlipemia, in particular, can be effectively treated only by the so called plasma exchange therapy, where the plasma in the body of the patient is separated and exchanged with normal plasma or replacing fluid containing albumin. As is well known, however, the plasma exchange therapy has various defects, i.e.
(1) it needs to employ expensive fresh plasma or plasma fractions,
(2) it removes not only harmful components but also effective ones, and
(3) it has a danger to lead to infection by hepatitis viruses and the like.
A method for removing harmful components in blood by using a membrance has been adopted in order to overcome the above-mentioned defects. However, the method still has defects. For example, it does not have a sufficient selectivity and needs to supplement a part of proteins in plasma which are removed concurrently with the removal of harmful components.
Also, for the same purpose, a method using an immune adsorbent, in which an antibody is immobilized, has been employed. Though selectivity in the method is almost satisfactory, there exist many problems such as difficulty for obtaining the antibody, a high price of the antibody, difficulty for sterilizing adsorbent and poor stability of the adsorbent when preserving.
Furthermore, there has been adopted an adsorbent based on the principle of the affinity chromatography, wherein a compound having an affinity for harmful components (such compound is hereinafter referred to as "ligand") is immobilized. The adsorbent has a good selectivity and the ligand employed is not too expensive. However, it is required to lower the cost in order to use in extracorporeal circulation treatment in large quantities. Since the adsorbent based on the principle of the affinity chromatography has a carrier made of a soft gel such as agarose, it provides a poor flow rate of body fluids and frequently produces cloggings.
At a small cost, there has been known a lipoprotein adsorbent (by Maaskant, N. et al.) which is obtained by cross-linking polyvinyl sulfate (ester of polyvinyl alcohol and sulfuric acid) in an aqueous solution by applying .gamma. ray, which makes the resultant insoluble in water. However, in the method, where a porous gel which is made water-insoluble by cross-linking a water-soluble polymer previously converted to sulfate is obtained, the amount of the sulfuric acid residue decreases to a great extent as the cross-linking reaction proceeds and a solvent which can be employed in the cross-linking reaction is substantially restricted to water due to hydrophile property of the sulfuric acid residue in the polymer converted to sulfate, which results in a great restriction on the method of cross-linking which can be employed. Furthermore, there is a problem such as great difficulty in beads formation.
The adsorbent used in hemoperfusion or plasma perfusion therapy employing extracorporeal circulation (so-called plasmapheresis) is required to have enough mechanical strength (pressure durability) so that it can provide a large flow rate. The gel prepared as mentioned above, however, contains a polymer having an essentially high degree of hydrophile property and thus it cannot be a hard gel even though a water-insoluble gel is formed by the cross-linking and the like, which results in the gel being improper for use in extracorporeal circulation to cause consolidation.
The object of the present invention is to provide a safe and low-cost adsorbent for use in extracorporeal circulation treatment, which can selectively remove LDL and VLDL, by preparing a water-insoluble porous hard gel, followed by direct sulfation.