JPH0626568B2 - Adsorption column for extracorporeal circulation therapy with improved storage stability - Google Patents

Description

TECHNICAL FIELD The present invention relates to an adsorption column for treating extracorporeal circulation with improved storage stability.

[Prior Art] Conventionally, an adsorption column for extracorporeal circulation treatment has been produced and used by filling an adsorbent having a sulfate ester group with water as a content liquid in the column.

For safety reasons, water is used as the content liquid because the produced adsorbent is usually steam sterilized, so that the adsorbent can be obtained in a wet state, and if water is used as the content liquid, it may be dried. This is because it is not necessary, and when it is used in an adsorption column for extracorporeal circulation treatment, water is always used as a content liquid before use.

The manufactured adsorption column for extracorporeal circulation treatment may be stored for about 1 year before it is used for a long time.
It is necessary to maintain the performance for at least one year.

[Problems to be Solved by the Invention] When an adsorption column for extracorporeal circulation treatment, which was produced by filling a column with an adsorbent having a sulfate ester group as a content liquid, was stored for a long period of time, a sulfate ester group or immobilized The sulfate ester group-containing compound is hydrolyzed or released. As the hydrolysis proceeds, a sulfuric acid compound is produced, and the hydrolysis is further accelerated. As a result, the amount of the sulfate ester group or the fixed sulfate ester group-containing compound is reduced, and the performance of the adsorption column for extracorporeal circulation treatment is reduced.

The present invention has been made to solve the above problems.

[Means for Solving Problems] The present invention provides an adsorbent having a sulfate ester group (excluding an adsorbent in which a sulfated polysaccharide is immobilized on a water-insoluble carrier) and a compound having a buffering effect in an amount of 0.001 to 10%. The present invention relates to an adsorption column for extracorporeal circulation treatment, which is filled with a content liquid containing pH 5 to 8.5 (% by weight, the same applies hereinafter).

[Examples] The adsorbent having a sulfate ester group in the present invention means (1) an adsorbent obtained by fixing a sulfate ester group-containing compound (excluding sulfated polysaccharides) to a water-insoluble carrier, (2) It refers to an adsorbent obtained by directly converting a hydroxyl group-containing water-insoluble carrier into a sulfuric acid ester, and (3) an adsorbent obtained by converting a hydroxyl group-containing water-soluble polymer into a sulfuric acid ester and then making it water-insoluble by a treatment such as crosslinking. , But is not limited to these.

Examples of the sulfate ester group-containing compound used in the adsorbent of the above (1) include sulfate ester of a hydroxyl group-containing compound such as alcohol, sugar and glycol (excluding sulfated polysaccharides). Further, a compound having a functional group that can be used for immobilization on a water-insoluble carrier is preferable. Such compounds include partially sulfated polyhydric alcohols, especially sulfated saccharides (excluding sulfated polysaccharides), which contain both sulfate ester groups and functional groups necessary for immobilization. It is particularly preferable because it has high biocompatibility and activity.

Examples of the water-insoluble carrier for immobilizing the sulfate ester group-containing compound (excluding sulfated polysaccharides) in the adsorbent of (1) above include, for example, agarose, dextran, and polyamine which are carriers usually used in affinity chromatography. Examples thereof include, but are not limited to, soft gels such as acrylamide, porous glass, inorganic porous materials such as porous silica, polymer gels made of synthetic polymers, and porous cellulose gels.

As the hydroxyl group-containing water-insoluble carrier used in the adsorbent of (2), agarose also used in the adsorbent of (1), a gel composed of a polysaccharide such as dextran, a polymer gel composed of a synthetic polymer compound, Formulas such as cross-linked polyvinyl alcohol, saponified ethylene-vinyl acetate copolymer and its cross-linked compounds Formulas such as polymer compounds having units represented by at least a part of the molecule, polyhydroxymethacrylate, copolymers containing hydroxymethacrylate, etc. Using a polymer compound having a unit represented by, a hydroxyl-containing polyunsaturated compound such as pentaerythritol dimethacrylate or glycerin dimethacrylate, or a compound having an oxirane ring such as epichlorohydrin or butanediol diglycidyl ether as a crosslinking agent Examples thereof include gels made of polymer compounds having a hydroxyl group introduced therein, porous cellulose gels, and the like, but are not limited thereto.

Among the water-insoluble carrier used in the adsorbent of (1) and (2), a sufficient body fluid flow rate can be obtained, a hard gel is preferable because it is less likely to cause clogging, and a porous cellulose gel is particularly preferable. i) The mechanical strength is relatively high, and since it is tough, it is less likely to be broken or generate fine powder by an operation such as stirring, and when packed in a column, it is compacted even if body fluid is flown at a high flow rate, Since it does not clog, it is possible to flow at a high flow rate, and the pore structure is not easily changed by high-pressure steam sterilization, etc. (ii) Since the gel is composed of cellulose, it is hydrophilic and has a sulfate ester group. There are a large number of hydroxyl groups that can be used for binding of contained compounds and conversion to sulfate ester groups, and less non-specific adsorption. (Iii) Since the pore volume is relatively high, the strength is relatively high.
It has advantages such as high adsorption capacity comparable to that of soft gels and (iv) higher safety than synthetic polymer gels, etc., and retains sulfate ester group-containing compounds in the porous cellulose gel. Alternatively, or by directly converting the porous cellulose gel into a sulfuric acid ester, an adsorbent capable of selectively adsorbing and removing harmful components at a high flow rate can be obtained. The adsorbent using a porous cellulose gel is described in detail in Japanese Patent Application No. 58-68116 and Japanese Patent Application No. 59-231012.

Next, as a typical example of the hydroxyl group-containing water-soluble polymer used in the adsorbent of the above (3), polyvinyl alcohol, ethylene-polymer compounds obtained by saponification of ethylene-vinyl acetate copolymer having a low ethylene content, etc. However, the present invention is not limited to these.

In the present invention, the adsorbent (1) is produced by immobilizing a sulfate ester group-containing compound (excluding sulfated polysaccharides) on a water-insoluble carrier, and various known immobilization methods are known. Any method can be used. That is, a physical method, an ionic bond method, a covalent bond method and the like can be mentioned. Since it is important that the immobilized sulfate ester group-containing compound is difficult to be eliminated, a covalent bond method with a strong bond is preferable, and it is preferable to prevent the elimination even if other methods are used. If necessary, a spacer may be introduced between the water-insoluble carrier and the sulfate ester group-containing compound.

As a method for the esterification with sulfuric acid in the steps (2) and (3) for producing the adsorbent, various known methods using chlorosulfonic acid, sulfuric acid and the like can be used.

The method of cross-linking the hydroxyl group-containing water-soluble polymer compound that has been sulfated in the production step of the adsorbent of (3), various known methods such as a method using a crosslinking agent, a method by irradiation with ultraviolet rays or β Can be used.

In the present invention, the adsorbent for extracorporeal circulation treatment thus produced is usually sterilized by a steam sterilization method in an aqueous solvent at 121 ° C. for about 20 minutes, and a compound having a buffering effect of 0.001 to 10 is added. %, Preferably 0.01 to 2%, and a content liquid having a pH of 5 to 8.5 is filled in a predetermined column to manufacture the column for extracorporeal circulation treatment of the present invention.

The aqueous solvent for steam sterilization is usually water, but the compound having a buffering effect used in the present invention is about 0.001 to 10%,
A liquid which can be used as a content liquid having a pH of 5 to 8.5, which preferably contains about 0.01 to 2%, may be used as the aqueous solvent. It is preferable to use a liquid that can be used as the content liquid as an aqueous solvent for steam sterilization because the performance deterioration due to the pH change generated during steam sterilization is reduced. Further, an aqueous solvent can be used as it is as a content liquid.

Examples of the compound having a buffer action are safe for human body, such as citric acid, phosphoric acid, acetic acid, boric acid, tartaric acid, carbonic acid, maleic acid, glycine, etc., or their sodium salts, potassium salts, calcium salts, etc. Those are preferable, and these may be used alone or in combination of two or more kinds.

The amount of the compound having a buffering effect in the content liquid is
If it is less than 0.001%, the pH of the content liquid cannot be maintained in the range of 5 to 8.5 for a long period of time.
If it exceeds%, the washing performed for using the adsorption column for extracorporeal circulation treatment may take a long time, or a compound having a buffer action may be precipitated during storage.

When the pH of the content liquid is less than 5, the adsorption activity of the adsorbent is remarkably reduced when stored for a long time, and the desorption due to hydrolysis of the sulfate ester group or the fixed sulfate ester group-containing compound is remarkable. To become. Further, even if the pH exceeds 8.5, the same phenomenon as when the pH is less than 5 occurs, and the adsorbent performance deteriorates in both cases.

The sterilized adsorption column for extracorporeal circulation treatment of the present invention produced in this manner is used as an adsorption column for ordinary extracorporeal circulation treatment, such as extracorporeal circulation treatment performed by passing blood, plasma, etc. through the adsorption column. It can be used without any limitation.

Next, the adsorption column for extracorporeal circulation treatment of the present invention will be described based on Examples.

Production Example 1 CK gel A-3 as a porous cellulose gel (excluding limit molecular weight 50,000,000, particle size 45 to 105 μm, manufactured by Chitso Corporation) 10
ml was taken and dried in ethanol by critical point drying. The dried gel was suspended in 10 ml of well dehydrated pyridine and cooled with ice. To this, 2 ml of chlorosulfonic acid was added dropwise with stirring, and after completion of the addition, stirring was continued for 10 minutes. After the reaction
After neutralizing with 20% caustic soda, the gel was separated by filtration, washed with pyridine and then with water to obtain CK gel A-3 (hereinafter referred to as A) in which a sulfuric acid residue was introduced at 0.05 mmol / ml on the surface.

Production Example 2 Method described in Examples of JP-A-58-12656,
That is, a uniform mixed liquid comprising 100 g of vinyl acetate, 24.1 g of triallyl isocyanurate, 124 g of ethyl acetate, 124 g of heptane, 3.1 g of polyvinyl acetate (polymerization degree 500) and 3.1 g of 2,2′-azobisisobutyronitrile, Polyvinyl alcohol 1% by weight, sodium dihydrogen phosphate-2
Hydrate 0.05% by weight and disodium phosphate dodecahydrate
400 ml of water in which 1.5% by weight was dissolved was placed in a flask and sufficiently stirred, and then heated and stirred at 56.5 ° C. for 18 hours and further at 75 ° C. for 5 hours to carry out suspension polymerization to obtain a granular copolymer.
After filtration, washing with water, and extraction with acetone, a solvent consisting of 46.5 g of caustic soda and methanol 2 was added.
Take 10 ml of porous water-insoluble hard gel (exclude molecular weight about 1.8 million, average particle size 150 μm) containing vinyl alcohol unit as the main constituent obtained by transesterification of copolymer at 40 ℃ for 18 hours. , Dried in acetone by the critical point drying method. The dried gel obtained was dehydrated well, N, N-
After suspending in 10 ml of dimethylformamide and cooling with ice, 1 ml of chlorosulfonic acid was added dropwise thereto with stirring.
Stirring was continued for a minute. After completion of the reaction, neutralize with 10% caustic soda aqueous solution, filter the gel and wash thoroughly with water to make porous water-insoluble hard gel with sulfuric acid residue 0.8 mmol / ml introduced on the surface (hereinafter referred to as B). I got it.

Examples 1-3 and Comparative Examples 1-2 Gels (adsorbents) 10 shown in Table 1 obtained in Production Examples 1-2.
g (wet weight) was placed in a hard glass flask, 10 ml of the content liquid shown in Table 1 was added, and the container was sealed and placed in a thermostat at 40 ° C. for 2 months.

For each adsorbent, the pH of the content liquid before and after standing, the amount of eluate in the content solution after standing, and the amount of ligand immobilized on the carrier before and after standing were measured. The results are shown in Table 1.

[Advantages of the Invention] The adsorption column for extracorporeal circulation treatment of the present invention has a small amount of ligand desorption and the amount of eluate even when stored for 2 months under the condition of 40 ° C, which is more severe than ordinary storage conditions. It retains good quality as an adsorption column.

Claims (3)

[Claims] 1. An adsorbent having a sulfate ester group (provided that
(Excluding adsorbents in which sulfated polysaccharides are immobilized on a water-insoluble carrier)
And an adsorbent column for extracorporeal circulation treatment, which has improved storage stability, and is filled with a content liquid having a pH of 5 to 8.5 containing 0.001 to 10% by weight of a compound having a buffer action. 2. The content of the compound having a buffering effect is 0.
The adsorption column for extracorporeal circulation treatment according to claim 1, which contains 01 to 2% by weight. 3. The compound according to claim 1, wherein the compound having a buffering action is at least one kind of citric acid, phosphoric acid, acetic acid, boric acid, tartaric acid, carbonic acid, maleic acid, glycine or salts thereof. An adsorption column for extracorporeal circulation treatment according to the item.