JPH0595999A - Adsorption body for contrast medium - Google Patents

Abstract

PURPOSE:To provide an adsorption body which selectively adsorb and remove a contrast medium in blood. CONSTITUTION:The title adsorption body is an adsorption body for a contrast medium consisting of a water-insoluble porous body with a cationic group on its surface. 1 is an adsorption device wherein an adsorption body layer 9 is filled and held between filters 3 and 3' and blood enters the adsorption device 1 from an inlet 5 and flows out of an outlet 7. In this instance, the contrast medium in the blood is adsorbed and removed by the adsorption body layer 9.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an adsorbent for a contrast agent that selectively adsorbs a contrast agent used for imaging a blood vessel.

[0002]

2. Description of the Related Art In recent years, a method of angiography using a contrast medium has been clinically used as a means for early detection of abnormalities in blood vessels and organs. Although this angiography with a contrast agent is very useful clinically, it is also known that there are side effects due to the contrast agent. For example, skin, cutaneous appendage disorders, cardiovascular disorders, respiratory disorders, or urinary disorders.

Particularly, when a contrast medium is used in patients with renal dysfunction such as renal failure, the side effects are particularly serious because they are not rapidly excreted from the body. Therefore, a technique for selectively removing a contrast agent from blood to prevent side effects is strongly desired.

Existing techniques that can be used for this purpose include plasma exchange and plasma filtration. Plasma exchange is a method in which plasma, which is a filtered component thereof, is separated from blood containing a contrast agent by a hollow fiber membrane, plasma containing the contrast agent is discarded, and frozen fresh plasma or albumin solution is replenished.

However, in this method, albumin, immunoglobulin, which is a useful component in blood, together with a contrast agent,
Blood coagulation proteins, complement components, and hormones are discarded at the same time, and because the supplementary liquid, frozen fresh plasma or albumin, is of biological origin, infection with an infectious disease is likely to occur, and raw material plasma is available. However, there are various problems such as difficulty in manufacturing and high price.

[0006] Plasma filtration is a method of filtering and discarding all molecules smaller than a contrast agent from blood, and replenishing with electrolyte. This method requires less material to be discarded than plasmapheresis. However, it has the disadvantage that useful components in the blood that are smaller than the contrast agent are discarded, and because the pore size distribution of the plasma filtration membrane is not constant, there is also a large loss of protein that is greater than the contrast agent, which results in low loss. There are some problems, such as sometimes falling into protein plasma.

[0007]

As described above, the conventional techniques cannot avoid the removal of useful components in blood, and it has been impossible to selectively remove only the contrast agent in blood.
An object of the present invention is to provide a technique for selectively removing a contrast agent in blood, which is less likely to remove useful substances such as albumin and immunoglobulin, and is an adsorption capable of selectively adsorbing and removing the contrast agent. To provide the body.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies in accordance with the above-mentioned object, and as a result, a water-insoluble porous material having a cationic group on the surface has an astonishingly high efficiency and selective imaging. The inventors have found that the agent can be adsorbed and have completed the present invention.

That is, the gist of the present invention is an adsorbent for a contrast agent, which comprises a water-insoluble porous material having a cationic group with an ion exchange dose of 0.1 meq (milliequivalent) or more per 1 ml of the adsorbent. (Hereinafter simply referred to as the present adsorbent).

The contrast agent targeted by the present adsorbent is used for intravascular administration and has a molecular weight of 10,000 or less, more preferably 10 or less.
0 or more and 2000 or less, and 1 molecule or more in 1 molecule, 1
It is a contrast agent containing iodine of 0 molecule or less. At this time, the content of iodine is preferably 40% or more and 80% or less by weight.

Specific examples include monomers such as amidotrizoic acid, iotalamic acid, iodoamide and metrizoic acid, dimers such as ioxaglic acid, iodoxamic acid, adipiodone and iotroxic acid, and a benzene nucleus or pyridine in the molecule. Some have a nuclear structure. Among these, particularly ionic contrast agents are mentioned as more preferable examples. This adsorbent is characterized by having a cationic group on the surface.

The ion exchange capacity of the adsorbent is 1 m of the adsorbent.
0.1 meq (milliequivalent) or more per 1 (hereinafter simply referred to as 0.
1 meq / ml). If the ion exchange capacity is smaller than this, the adsorbing ability of the contrast agent is extremely lowered, and the practical ability as an adsorbent of the blood contrast agent is poor. On the other hand, if the ion exchange capacity is too large, the non-selective adsorption tends to increase although the adsorption capacity of the contrast agent is high, which is a problem. The preferred ion exchange capacity is
0.1 meq / ml to 50 meq / ml, more preferable range is 0.5 meq / ml to 10 meq / m
The range is l.

Examples of the cationic group include ammonium group, sulfonium group and phosphonium group. Among these, a particularly preferred example is a tertiary or quaternary ammonium group.

As the shape of the present adsorbent, any of spherical shape, granular shape, thread shape, hollow fiber shape, flat membrane shape and the like can be effectively used.
From the aspect of circulation of body fluid during circulation of body fluid, spherical or granular is most preferably used. A spherical or granular average particle size of 10 to 2500 μm is easy to use, but 25
To 1000 μm, more preferably 5
It is 0 to 600 μm.

The present adsorbent needs to be a porous material from the viewpoint that the adsorption surface area of the contrast agent can be made large and the practical adsorption ability can be obtained. The exclusion limit molecular weight (protein) of the porous body may be at least the molecular weight of the contrast agent to be adsorbed. Specifically, 5 × 10 ² to 1 × 10
A range of ⁷ is preferred. More preferably, it is 2 × 10 ³ to 1 × 10 ⁵ .

The pore distribution of the pore pair can be obtained from the mercury intrusion curve by the mercury intrusion method (for example, Catalyst Engineering Course-4, Catalyst Measurement Method, The Catalysis Society of Japan, Jijijinshokan, 69-73). It is preferable that there are many pores having a pore diameter of 0.1 nm or more, and it is preferable that the pores are gathered in the range of 0.1 nm to 5000 nm. More preferably, it is in the range of 1 nm to 2000 nm.

Further, since the adsorbent of the present invention is used for removing the contrast agent mixed in body fluids, especially blood, it is necessary that the adsorbent is a hard water-insoluble porous body insoluble in blood.

The water-insoluble porous material having a cationic functional group referred to in the present adsorbent has a cationic functional group of 0.1 meq / m.
As long as it is a porous body capable of holding 1 or more, regardless of whether it is an inorganic compound or an organic compound, an organic polymer is preferable because it has little eluate in warm water and the pores of the porous body can be controlled more easily and precisely. .. Examples thereof include polymers and copolymers of vinyl compounds such as polypropylene, polystyrene, polymethacrylate ester, polyacrylate ester, polyacrylic acid and polyvinyl alcohol, polyamide compounds such as nylon 6 and 66, polyethylene terephthalate. Examples thereof include polyester compounds. The material of the porous body used in the present invention has a cationic functional group of 0.1 meq.
It is sufficient to introduce at least / ml and is not limited to the above examples.

Among the examples, vinyl compound polymers and copolymers are more preferably used because of the ease of polymerization, the control of pores, and the ease of introduction of cationic functional groups. Examples thereof include styrene, P-methylstin, styrene compound polymers such as P-ethylstyrene, and methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, and other (meth) acrylates.
Examples thereof include polymers of acrylic acid ester compounds and copolymers of the above compounds with vinyl compounds such as divinylbenzene, methacrylonitrile, vinylpyrrolidone, ethylene glycol and methyl acrylate.
These are particularly preferably used as the material used for the adsorbent of the present invention.

The present adsorbent is produced by bulk polymerization, solution polymerization,
It can be carried out by a generally known method such as suspension polymerization and emulsion polymerization, and a commercially available monomer is purchased, and an additive, a polymerization initiator and a solvent for dissolving the monomer are used together with each polymer. It is manufactured according to a known manufacturing method.

For example, in the case of a styrene-divinylbenzene copolymer, by stirring under the coexistence of styrene, ethylbenzene, divinylbenzene and toluene, octanol and AIBN (azobisisobutyronitrile), a spherical shape of about 50 to 1000 μm is obtained. It is possible to make porous particles. Also, particles having various particle diameters and pore diameters can be produced by radical polymerization in a suspension polymerization system.

In the adsorbent of the present invention, the water-insoluble porous body may be subjected to a surface treatment for controlling the adhesion of platelets in order to improve the affinity with blood. This can be achieved, for example, by providing a coating layer of a low-adhesive platelet material on the surface of the water-insoluble porous material having a cationic functional group that comes into contact with blood cells.

As the platelet low-adhesion material, a polymer material having a hydroxy group such as hydroxyethyl methacrylate and hydroxyethyl acrylate, vinylamine,
Copolymers of a monomer having a basic nitrogen-containing functional group such as dimethylaminoethyl (meth) acrylate and a polymerizable monomer having no basic nitrogen-containing functional group, segmented polyurethane, segmented polyester, etc. Examples of the block copolymer, a graft copolymer such as a copolymer of a monomer having a polyethylene oxide chain and another polymerized monomer, and the like.

The adsorbent of the present invention is generally used by being filled and held in a container having a body fluid outlet. FIG. 1 shows an example of an adsorber filled with the present adsorbent. In FIG. 1, the adsorber 1 has a cap 6 having a body fluid introducing port 5 screwed into one end opening of the cylinder 2 via a packing 4 having a filter 3 inside, and the adsorber 1 is fitted into the other end opening of the cylinder 2. ,
A container is formed by screwing a cap 8 having a bodily fluid outlet 7 through a packing 4 ′ with a filter 3 ′ inside to form a container, and a space between the filters 3 and 3 ′ is filled with and held by an adsorbent for adsorption. The body layer 9 is formed.

The adsorbent layer 9 may be filled with the present adsorbent alone, or may be mixed or laminated with another adsorbent. The capacity of the adsorbent layer 9 is 10 to 10 when used for extracorporeal circulation.
About 500 ml is suitable.

When the adsorber of the present invention is used for extracorporeal circulation, there are roughly the following two methods. One is to separate the blood taken out from the body into a plasma component and a blood cell component by using a centrifugal separator or a membrane plasma separator, and after passing the plasma component through the adsorber to purify the blood component, The other is a method of purifying the blood taken out of the body by directly passing through the adsorber. Regarding the passage rate of blood or plasma, since the adsorption capacity of this adsorbent is very high, it is possible to make the particle size of this adsorbent coarse and to reduce the packing degree, so that the shape of the adsorbent layer A high passing speed can be given regardless of how. Therefore, a large amount of body fluid can be treated.

The method for passing a body fluid through the adsorbent of the present invention has an effect on the adsorption effect, whether continuous or intermittent, depending on the clinical need or the situation of equipment. Absent.

[0028]

The adsorbent for contrast of the present invention has the ability to selectively adsorb the contrast agent in the body fluid, so that there is a risk of adsorbing the protein component in blood useful for treatment. There is no. Further, since it is a hard, water-insoluble porous material that is insoluble in blood, there is no risk that the adsorbent will elute into blood even when used for treatment, and therefore there is no risk of side effects due to the use of the adsorbent.

Furthermore, since it has the ability to adsorb the contrast agent in the body fluid at a high rate, an extremely small adsorber can be realized, and the blood of the patient can be drawn out of the body even when it is used by incorporating it in the extracorporeal circulation circuit. The amount can be kept to a minimum.

The adsorbent of the present invention can be used by incorporating it into a known extracorporeal circulation circuit, and is effective in a treatment for surely suppressing side effects associated with administration of a contrast agent into blood. Further, the adsorbent of the present invention can be used not only as an extracorporeal circulation treatment as described above but also as an affinity adsorbent for separating and purifying a contrast agent.

[0031]

EXAMPLES As an adsorbent, a styrene / divinylbenzene copolymer (Dowex 1 × 2, Dow.Dow) having a quaternary amino group on the surface and an ion exchange capacity of 1.4 meq / ml was used.
Chemical Co., Ltd.) was used. A test solution was prepared by preparing a contrast agent (Hexabrix 320, manufactured by Eiken Chemical Co., Ltd., containing 53.330 g of ioxaglic acid in 100 ml of the present contrast agent) so that the concentration of ioxagric acid was 1.7%. 1 ml of the styrene / divinylbenzene copolymer was added to 6 ml of the test solution, and the mixture was shaken at 37 ° C. for 2 hours to adsorb ioxaglic acid. Then, the styrene / divinylbenzene copolymer was precipitated to obtain a supernatant. The concentration of the contrast agent in the supernatant was measured by absorbance at a wavelength of 244 nm, and the ioxaglic acid concentration was determined from a separately measured standard solution.

As a result of the adsorption experiment, the concentration of the original solution was 1.7%, while that after the adsorption was 0.23%. That is, 86.6% of ioxaglic acid in the test solution could be adsorbed.

[0033]

[Comparative Example] As an adsorbent, a methylmethacrylate / divinylbenzene copolymer having no cationic group on the surface (80:20 wt%, Ambersep, manufactured by Organo)
It carried out like Example except having used. The original liquid concentration was 1.7%, and the concentration after adsorption was 1.1%. That is, only 35.3% of ioxaglic acid in the test solution could be adsorbed, and there was no sufficient adsorption capacity for clinical use.

[Brief description of drawings]

FIG. 1 is a schematic sectional view showing an example of an adsorber using a contrast medium adsorbent of the present invention.

[Explanation of symbols]

 1 Adsorber 2 Cylinder 3,3 'Filter 4,4' Packing 5 Body fluid inlet 6 Cap 7 Body fluid outlet 8 Cap 9 Adsorbent layer

Claims (1)

[Claims] 1. An adsorbent for a contrast agent, which comprises a water-insoluble porous material having a cationic group on the surface.