JPH0659309B2 - Low specific gravity lipoprotein adsorption device - Google Patents

Description

TECHNICAL FIELD The present invention relates to a device for adsorbing and removing low-density lipoprotein from a body fluid such as blood or plasma by using an adsorbent.

It is considered that the increase of lipids in blood, especially low-density lipoprotein, is closely related to the cause or progression of arteriosclerosis, and as arteriosclerosis progresses, the severity of cardiovascular system such as myocardial infarction and cerebral infarction is increased. The chances of falling into serious symptoms are very high and the mortality rate is high. Therefore, by selectively adsorbing and removing low-density lipoproteins from body fluid components such as blood and plasma, it is expected that the above-mentioned diseases will be prevented from progressing, symptoms will be reduced, and healing will be accelerated. It had been.

(Prior art) The existing technology that can be used for the above purpose is adsorption by an adsorbent in which heparin is immobilized on agarose gel (Lupien, P-
J, et. al .: A new approach to the management
of familial hypercholesterolemia. Removal of
plasma-cholesterol based on the principle o
f affinity chromatography, Lancet, 2: 1261
~ 1264,1976. ), And glass powder or glass beads (Carlson, LA: Chromatographic se)
paration of serum lipoprotein on glass powde
r colums. Description of the method and so
me applications. Clin. Chim. Acta, 5: 528〜
538, 1960. ).

As a result of diligent studies to further enhance the low-density lipoprotein adsorbing ability of the low-density lipoprotein adsorbent, the present inventors have found that an adsorbent having a polyanion portion having a large number of negative charges in the molecule on the surface thereof has a low-density lipoprotein It has been found that it can adsorb proteins at a high rate and hardly adsorbs useful proteins such as high-density lipoprotein and albumin (Japanese Patent Application Nos. 58-80777 and 58-80778).

(Problems to be Solved by the Invention) A low-density lipoprotein having a polyanion portion on the surface is excellent in the absorptivity of the low-density lipoprotein, the selectivity for the high-density lipoprotein, albumin, etc. Since it has many negatively charged portions, it has a property of easily adsorbing a cationic inorganic electrolyte, especially a polyvalent cation such as calcium or magnesium. Therefore, treating the body fluid with the adsorbent is not preferable because the amount of the cationic inorganic electrolyte in the body fluid is reduced.

(Means for Solving the Problems) The inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, provided an inorganic electrolyte replenisher at a specific place in the circuit of the low-density lipoprotein adsorption device. Found that it is surprisingly easy to stably control the electrolyte concentration in body fluid without lowering the adsorption amount of low-density protein, and further, it is a liquid sending device for sending body fluid to a low-density lipoprotein adsorber. It was confirmed that the concentration of the electrolyte in the body fluid can be automatically and stably controlled by operating the inorganic electrolyte replenisher in conjunction with the above, and the present invention has been completed.

That is, the present invention is a low specific gravity lipoprotein adsorption that is located between the body fluid introducing part, the body fluid extracting part, the body fluid introducing part and the body fluid extracting part, and is filled with a low specific gravity lipoprotein adsorbent having a polyanion part on the surface. And a low specific gravity lipoprotein adsorber comprising a liquid feeder for sending a body fluid to the low specific gravity lipoprotein adsorber, wherein a low specific gravity lipoprotein adsorber is provided with an inorganic substance between a body fluid outlet and a body fluid outlet. A low specific gravity lipoprotein adsorption device characterized by being provided with an electrolyte replenisher,
Preferably, the low-density lipoprotein adsorbing device is provided so that the inorganic electrolyte replenisher operates in conjunction with the liquid feeder for sending the body fluid to the low-density lipoprotein adsorber.

The adsorbent targeted by the present invention is a low-density lipoprotein. More specifically, the adsorbent has a molecular weight of 2.2 × 10 ⁶
3.5 × 10 ⁶ , hydration density 1.003 to 1.034 (g / ml), levitation coefficient (1.063) 0 to 20 × 10 ^-13 cm ・ sec ^-1・ dyn
^-1 · g ^-1 , lipoproteins (SCANU, A.
M .: plasma lipoproteins: an introduction. "Th
e Biochemistry of Atherosclerosis ”ed. by SCA
NU A ≧ M. , 1979, p. 3 to 8).
Lipoprotein having a smaller specific gravity than this, that is, the levitation coefficient (1.063) is 20 × 10 ⁻¹³ cm · sec ⁻¹ . Lipoproteins larger than dyn ⁻¹ · g ⁻¹ may be adsorbed, but high specific gravity lipoproteins having high specific gravity are preferably not adsorbed.

The bodily fluid introduction part and the bodily fluid discharge part referred to in the present invention are used for the purpose of introducing or drawing out a bodily fluid, and a vinyl chloride tube, polyethylene tube, silicone tube or the like that is safe for the living body can be used. . Also,
A pump such as a blood pump used for ordinary hemodialysis can be used as the liquid feeder in the present invention, but it is possible to safely send a liquid to a living body without damaging blood, plasma and the like. Anything may be used as long as it is a thing.

The polyanion portion of the low-density lipoprotein adsorbent referred to in the present invention means a functional group having a molecular weight of 600 or more per molecule and a negative charge in one molecule, that is, a carboxyl group (COO
H, COO ^-), a sulfonic acid group ^{_{(SO 3 H, SO 3 -}} ) refers to a number or with a functional group exhibiting a negative charge in the plasma like. Exemplifying, vinyl-based synthetic polyanions such as polyacrylic acid, polyvinylsulfonic acid, polyvinylphosphoric acid, and polymethacrylic acid, polystyrenesulfonic acid, poly-α-methylstyrenesulfonic acid, styrene-based polyanions such as polystyrenephosphoric acid, and vinyl-based anions. Copolymers, for example, polyanions such as styrene-maleic acid copolymers, polyglutamic acid, synthetic peptide-based polyanions such as polyaspartic acid, polyU, synthetic nucleic acid-based polyanions such as polyA and polyA, polyphosphates, polyphosphates, alginic acid, Examples include polyanions such as heparin and dextran sulfate.

Among them, the polyanion obtained by synthesizing is
It is a natural product because it has excellent chemical stability, is easy to obtain stable against high pressure steam sterilization, γ-ray sterilization, ethylene oxide sterilization, etc., and the molecular weight can be adjusted relatively easily. Better and recommended. Further, in the case of a polyanion obtained by synthesis, a polyanion which hardly causes activation of complement as seen in natural polysaccharides is easily obtained, which is preferable. Furthermore, those that can be directly graft-polymerized to the carrier, such as vinyl anions,
A more preferable result is obtained in that the polyanion having a large molecular weight can be immobilized on the carrier with a high retention amount.

In addition, since the low specific gravity lipoprotein, which is the target substance for adsorption, is a huge lipoprotein having a diameter of about 200 Å, it is preferable that the structure of the polyanion part is a chain structure, and it is preferable that the polyanion part extends long from the surface of the adsorbent. preferable. The negative charge density in the polyanion portion is preferably at least 1 per 300 molecular weight. More preferably, the molecular weight is 2
It is preferably 1 or more per 00, and preferably 1 per unit of molecular weight 70 to 150. The molecular weight mentioned here includes the molecular weight of a functional group having a negative charge. When the molecular weight of the polyanion portion becomes small, the low specific gravity lipoprotein is not adsorbed so much, so that the molecular weight is at least 600. It is preferably 2,500 or more, more preferably 10,000 to 5,000,000.

The polyanion part has a large number of negatively charged functional groups,
By recognizing many points of the low-density lipoprotein, it is considered that the low-density lipoprotein binds with strong Coulomb force.

Among the functional groups that show a negative charge, carboxyl groups (COOH,
COO ^-) is give particularly favorable results. Sulfonic acid group (SO
₃ H, SO ₃ ^- for) is a weak acid as compared to, small adsorptivity for useful proteins such as albumin. In addition, blood coagulation proteins are less adsorbed, and activation is less likely to occur. further,
It is also difficult to adsorb complement system proteins.

Among the above polyanion moieties, polycarboxylic acids such as polyacrylic acid and polymethacrylic acid are particularly stable and can be recommended.

The density of the negative charges is in the range of 1 μed to 1 meq per 1 ml of the adsorbent, which has good adsorption performance for low density lipoprotein, good adsorption selectivity, and little influence on coagulation fibrinolysis system and complement system. When the negative charge density is lower than 1 μeq / ml, the adsorption capacity of low-density lipoprotein is less than the practical performance, and when it exceeds 1 meq, non-selective adsorption increases, which adversely affects the coagulation fibrinolysis system and the complement system. A more preferable range is 5 μeq / ml to 70
0 μeq / ml, more preferably 10 μeq / ml to 50
It is 0 μeq / ml.

The negative charge density can be measured according to the usual ion exchange capacity measuring method for cation exchange resins.

The method for producing the low-density lipoprotein adsorbent referred to in the present invention includes, for example, a method of activating a carrier and covalently bonding a polyanion, a method of graft-polymerizing an anion monomer on the carrier to form a graft chain of a polyanion, and the like. To be

The carrier may be either a hydrophilic carrier or a hydrophobic carrier as long as it can immobilize the polyanion. However, when a hydrophobic carrier is used, nonspecific adsorption of albumin to the carrier sometimes occurs. Gives good results.

The shape of the insoluble carrier may be any known shape such as a particle shape, a fiber shape, a hollow fiber shape, a film shape, etc., but in view of the amount of polyanion retained and the handleability as an adsorbent, a particle shape or a fiber shape is preferable. preferable.

As the carrier, any material may be used as long as it can fix the polyanion. Carriers that can be used include cellulose gels, dextran gels, agarose gels, vinyl polymer gels, polyacrylamide gels,
Organic or inorganic porous materials such as polyhydroxyethyl methacrylate-based gel, porous glass, and silica can be used, and all the materials for the carrier used in ordinary affinity chromatography can be used, but the substance to be adsorbed Low specific gravity lipoprotein is 200 ~ 300Å in diameter,
Since the molecular weight is as large as 2.2 × 10 ^{6 to} 3.5 × 10 ⁶ , the adsorption efficiency is higher when the exclusion limit molecular weight of the carrier is 2.2 million or more and the diameter of the pore is 200 Å or more.

Among the above-mentioned carriers, the carrier composed of a cross-linked copolymer having a vinyl alcohol unit as a main constituent component has a small interaction with a solute such as protein in plasma due to its hydrophilicity, and minimizes nonspecific adsorption. Lower. Further, it has extremely excellent properties such as not interacting with the complement system and coagulation system in plasma. Also in terms of physical properties, it exhibits an excellent pore size distribution, has heat resistance, enables heat sterilization, and has excellent physical and mechanical strength, which is a characteristic of synthetic polymers.
Even when used as a carrier for an adsorbent for whole blood, it has very excellent properties such as minimal interaction with blood cell components and minimal formation of thrombus, non-specific adhesion of blood cell components, residual blood, etc. .

A cross-linked polymer having a vinyl alcohol unit as a main constituent can be synthesized by polymerizing a monomer having a hydroxyl group or introducing a hydroxyl group by a chemical reaction of the polymer. Both can be used in combination. A radical polymerization method can be used as the polymerization method. The cross-linking agent may be introduced by copolymerization at the time of polymerization, or may be introduced by a chemical reaction of the polymer (between the polymers, between the polymer and the cross-linking agent),
You may use both together.

As an example, it can be produced by copolymerization of a vinyl monomer and a vinyl or allyl crosslinking agent. Examples of vinyl monomers in this case include vinyl esters of carboxylic acids such as vinyl acetate and vinyl propionate, and vinyl ethers such as methyl vinyl ether and ethyl vinyl ether.

Examples of the cross-linking agent include allyl compounds such as triallyl isocyanurate and triallyl cyanurate, di (meth) acrylates such as ethylene glycol dimethacrylate and diethylene glycol dimethacrylate, butanediol divinyl ether, diethylene glycol divinyl ether, and tetravinyl. Polyvinyl ethers such as glyoxal, polyallyl ethers such as diarylidene pentaerythritol and tetraallyloxyethane, and glycidyl acrylates such as glycidyl methacrylate can be used. Moreover, what copolymerized the other comonomer can also be used as needed.

In the case of a vinyl copolymer, triallyl isocyanurate crosslinking of polyvinyl alcohol obtained by copolymerizing a vinyl ester of a carboxylic acid and a vinyl compound having an isocyanurate ring (allyl compound) and hydrolyzing the copolymer The body provides a particularly good carrier in terms of strength and chemical stability.

As a method for fixing the polyanion on the surface of the insoluble carrier, any known method such as covalent bond, ionic bond, physical adsorption, embedding or precipitation insolubilization on the polymer surface can be used, but the elution property of the immobilized compound Considering from the above, it is preferable to use by fixing and insolubilizing by covalent bond. Therefore, the immobilized enzyme, a known method for activating a carrier used in affinity chromatography, a method for binding with a ligand, and a graft polymerization method using a carrier or an activated carrier as a trunk polymer and a polyanion as a branch are used. be able to.

Examples of the activation method include a cyanogen halide method, an epichlorohydrin method, a bisepoxide method, a halogenated triazine method, a bromoacetyl bromide method, an ethyl chloroformate method, and a 1,1′-carbonyldiimidazole method. . The activation method of the present invention is not limited to the above examples, as long as it can perform a substitution and / or addition reaction with a nucleophilic reactive group having an active hydrogen such as an amino group, a hydroxyl group, a carboxyl group and a thiol group of a ligand. However, considering chemical stability, thermal stability, etc., the method using an epoxide is preferable, and the epichlorohydrin method is particularly recommended.

Further, regarding the carrier having a silanol group such as silica type and glass type, various silanes such as γ-glycidoxypropyltrimethoxysilane, γ-aminopropyltriethoxysilane, γ-mercaptopropyltrimethoxysilane, and vinyltrichlorosilane. A coupling agent is preferably used.

Examples of the graft polymerization method include a method utilizing a chain transfer reaction, a method utilizing a reaction such as dehydrogenation and dehalogenation by radiation and ultraviolet rays, a method utilizing a peroxide formation, a hydroxyl group, Supports with reducing groups such as thiols, aldehydes, amines, cerium salts,
A method of graft-polymerizing an anionic monomer using an iron salt as an initiator is simple and recommended. The graft polymerization system is preferably used because it can fix a polyanion having a relatively large molecular weight to the inside of the carrier.

It does not matter if two or more polyanions are bound to the carrier.

The method for activating the carrier and then binding the polyanion as the method for producing the low-density lipoprotein adsorbent has been described above, but the method is not limited to this.

The low-density lipoprotein adsorber is one in which the above-mentioned low-density lipoprotein adsorbent is filled and held in a container having a body fluid outlet.

In FIG. 1, reference numeral 1 represents an example of a low-density lipoprotein adsorber containing a low-density lipoprotein adsorbent,
A cap with a body fluid inlet is screwed into one end opening of the cylinder 2 via a packing 4 with a filter 3 inside, and a packing 4 with a filter 3 ′ inside is fitted into the other end opening of the cylinder 2. A cap 8 having a body fluid outlet 7 is screwed into the container to form a container, and a low specific gravity lipoprotein adsorbent is filled and held in the gap between the filters 3 and 3'to form an adsorbent layer 9. It will be.

The adsorbent layer 9 may be filled with the low-density lipoprotein adsorbent alone, or may be mixed or laminated with another adsorbent. As another adsorbent, for example, activated carbon having a wide adsorption capacity can be used. As a result, a broader clinical effect due to the synergistic effect of the adsorbent can be expected. The volume of the adsorbent layer 9 is 5 when used for extracorporeal circulation.
About 0 to 400 ml is suitable.

When the apparatus of the present invention equipped with this low specific gravity lipoprotein adsorber is used for extracorporeal circulation, there are roughly two methods described below.
One is to separate the blood taken out from the body into a plasma component and a blood cell component by using a centrifuge or a membrane-type plasma separator, and then pass the plasma component through the device for purification and It is a method of returning it to the body together with the components, and the other is a method of passing blood taken out of the body directly to the device for purification.

As a method for passing the bodily fluid, it may be continuously passed or may be used intermittently depending on the clinical need or the condition of the equipment.

The low specific gravity lipoprotein adsorbing device of the present invention is configured, for example, as shown in FIG.

In the figure, 10 is a body fluid inlet, 11 is a body fluid outlet, 12 is a low-density lipoprotein adsorber, 13 is a liquid feeder, and 14 is an inorganic electrolyte replenisher.

Hereinafter, a method for adsorbing and removing low-density lipoprotein from plasma using the low-density lipoprotein adsorption device of the present invention will be described as an example.

First, the plasma is sent to the low-density lipoprotein adsorber 12 by the liquid feeder 13 through the body fluid introducing unit 10. Here, for the liquid feeder 13, a pump similar to a blood pump used for normal artificial dialysis can be used. The low-density lipoprotein is removed from the plasma sent to the low-density lipoprotein adsorber 12, and polyvalent cations such as calcium and magnesium are adsorbed and removed.

Next, the plasma from which the low-density lipoprotein and polyvalent cations have been removed is sent to the inorganic electrolyte replenisher 14 where it is replenished with inorganic electrolytes containing polyvalent cations such as calcium and magnesium. After the electrolyte balance is returned to normal, the electrolyte is discharged from the body fluid discharge unit 11. As described above, in the low-density lipoprotein adsorbing device of the present invention, the body fluid can be treated in a state where the adsorption capacity of the low-density lipoprotein is kept high, and the electrolyte concentration is corrected downstream from the low-density lipoprotein adsorber. Because it is possible, it is always safe to control to a constant electrolyte concentration.

Next, there is a method of controlling the electrolyte balance by using an inorganic electrolyte replenisher, but the electrolyte concentration in body fluid shows a stable value unless there is a special disease. Since the degree of adsorption can be known in advance, even if the electrolyte concentration of the body fluid after passing through the low-density lipoprotein adsorbent is not measured, if the amount of body fluid that has passed through the adsorbent is known, it can be met. By supplying a large amount of polyvalent cations, it becomes possible to restore the electrolyte concentration of the body fluid to a normal value. The most suitable control method for doing this automatically is to link the liquid feeder for sending body fluid to the low-density lipoprotein adsorber and the inorganic electrolyte replenisher, and adjust the volume of body fluid that has passed through the adsorber. It is to supplement the amount of inorganic electrolyte. That is, when a certain amount of body fluid has passed through the low-density lipoprotein adsorber, a predetermined amount of cationic electrolyte is replenished.

An example of a device for achieving this is shown in FIGS.

FIG. 3 shows a liquid feeder 13 for feeding body fluid and an inorganic electrolyte replenisher 14 which are interlocked by a control device 15. As the liquid feeder 13, a vinyl tube is used as a roller to squeeze blood. Pump, inorganic electrolyte replenisher 1
An injection pump using a syringe can be used as 4, and the control device 15 controls the injection speed of the replenisher 14 in association with the speed of the liquid supply of the liquid supply device 13 when the liquid supply speed of the liquid supply device 13 changes. To control. The control method may be intermittent injection of the inorganic electrolyte, but it is preferable to perform the injection continuously or in proportion to the speed of the liquid feeder.

FIG. 4 shows that both the liquid feeder 13 and the inorganic electrolyte replenisher 14 are carried out by one roller pump. The vinyl tube of the liquid feeder 13 for feeding body fluid is thick and the vinyl tube of the cationic electrolyte replenisher is large. It is possible to control the difference in the flow rate by making it thin.

By using the device as described above, the electrolyte concentration is automatically corrected, which is very convenient.

(Effect of the invention) By using the low-density lipoprotein adsorbing device of the present invention, while maintaining a high low-density lipoprotein adsorption capacity of the low-density lipoprotein adsorbent, the calcium adsorbed by the adsorbent, It became possible to return the concentration of polyvalent cations such as magnesium to the normal value, and the control thereof was also very simple. In addition, the use of an automated device has made it possible to more stably and easily control the body fluid electrolyte concentration.

(Example) An adsorption experiment of low-density lipoprotein was conducted using the apparatus shown in FIG.

A soft vinyl chloride tube is used for the body fluid introduction part and body fluid discharge part, a soft vinyl chloride tube is used as a liquid pump for sending body fluid with a roller-shaped blood pump, and a syringe is used as an inorganic electrolyte replenisher. The information pump was used.

The low specific gravity lipoprotein adsorber has an inner diameter of 1.4 cm, a length of 6.5 cm, and an internal volume of 10 ml.
Was used.

The low-density lipoprotein adsorbent was produced by the method described below.

Vinyl acetate 1000g, triallyl isocyanurate 4
14 g, ethyl acetate 1000 g, heptane 1000 g,
Polyvinyl acetate (polymerization degree 500) 70g and 2,2'-
A homogeneous mixture of 36 g of azobisisobutyronitrile and water containing 1% by weight of polyvinyl alcohol, 0.05% by weight of sodium dihydrogen phosphate dihydrate and 1.5% by weight of disodium hydrogen phosphate dodecahydrate. 4 and 4 were placed in a flask, and after sufficiently stirring, at 65 ° C. for 18 hours, and further 7
Suspension polymerization was performed by heating and stirring at 5 ° C for 5 hours to obtain a granular copolymer. During the polymerization, the stirring speed was controlled so that the particle size was smaller. After filtration, washing with water, and extraction with acetone, transesterification of the copolymer was carried out at 40 ° C. for 18 hours in a solution consisting of 465 g of sodium hydroxide and 20 of methanol. The average particle size of the obtained particles is 40 μm.
It was.

This gel was packed in a stainless steel column having an inner diameter of 7.5 mm and a length of 120 cm, and an aqueous solution of dextran or polyethylene glycol having various molecular weights and albumin, immunoglobulin G, immunoglobulin M, β-lipoprotein, tobacco, mosaic, When the phosphate buffered saline solutions of the viruses were measured, they were eluted in descending order of molecular weight. The exclusion limit molecular weight of dextran is about 5 × 10 ⁶ ,
The exclusion limit molecular weight of the protein was about 2 × 10 ⁷ .
In addition, when a solution of human-γ-globulin and human-albumin was run using an aqueous solution containing 0.3M sodium chloride and 0.1M sodium phosphate as a solvent, the recovery was almost 100%, and the gel was nonspecific. Adsorption was very low. Flow rate of all samples is 1ml / mi
n.

Next, 150 g of the transesterified, thoroughly washed with water and dried gel was suspended in a solution of 1800 ml of dimethyl sulfoxide and 1200 ml of epichlorohydrin, and 150 ml of 50% aqueous sodium hydroxide solution was added to
The reaction is carried out at 0 ° C for 5 hours with stirring. After completion of the reaction, the mixture was passed through a glass filter, washed with dimethyl sulfoxide (3) and then with water (20) to obtain an epoxy group-bonded gel.

The amount of epoxy groups bound in the gel was 0.11 mmol per ml. Using the epoxy group-bonded gel, polyacrylic acid (weight average molecular weight 9 × 10 ⁴ , manufactured by Aldrich Co., USA)
Was bound as a ligand to prepare an adsorbent.

4.5 g of polyacrylic acid was made up to 500 ml with distilled water and used as a ligand solution. 100 ml of the epoxy group-bonding gel was added to this ligand solution, and the ligand-binding reaction was carried out at 50 ° C. for 16 hours while shaking.

After that, it is thoroughly washed with water, sucked and dehydrated, and then immersed in 0.1N sodium hydroxide solution for 30 minutes to make polyacrylic acid into a sodium form, and then washed with a sufficient amount of water.
It was used as a low-density lipoprotein adsorbent.

The adsorption experiment was performed using plasma from patients with familial hypercholesterolemia.

First, the inside of the plasma flow circuit and the low-density lipoprotein adsorber was primed with physiological saline, and then the patient plasma was flowed from the body fluid introduction part at a flow rate of 0.67 ml / min by a liquid pump (blood pump). Introduced. At the same time, calcium and magnesium were replenished with a replenisher (infusion pump). Concentration of calcium and magnesium is 5Eq / each
, 2.3 g / dl to prepare a mixed solution. The flow rate of the information pump was 1.67 μl / min. Discard the first 10 ml discharged from the body fluid discharge part, and then plasma 1
When 00 ml was sampled, calcium concentration, magnesium concentration and total cholesterol concentration were measured and compared with the plasma concentration before the adsorption experiment, the calcium concentration was 5.0 meq /
Is 4.9 meq /, magnesium concentration is 2.3 mg / dl is 2.4
While stable control was possible at mg / dl, the total cholesterol concentration was significantly reduced from 420 mg / dl to 160 mg / dl.

Comparative Example Using the same low specific gravity lipoprotein adsorber as in Example 1, except that calcium and magnesium were not supplemented,
An adsorption experiment was conducted in the same manner as in Example 1. As a result, the calcium concentration of 5.0 meq / was 0.2 meq /, and the magnesium concentration of 2.3 mg / dl was 0.1 mg / dl. However, the total cholesterol concentration is 420 mg
/ Dl was greatly reduced to 158 mg / dl, and it could be adsorbed well.

[Brief description of drawings]

FIG. 1 is a schematic diagram showing an example of a low-density lipoprotein adsorber,
FIG. 2 is a schematic diagram showing an example of the low-density lipoprotein adsorption device of the present invention, and FIGS. 3 and 4 are schematic diagrams showing an example of automation of the low-density lipoprotein adsorption device of the present invention. 1 ... Low specific gravity lipoprotein adsorber 2 ... Cylinder, 3,3 '... Filter 4 ... Packing 5 ... Body fluid inlet 6,8 ... Cap, 7 ... Bodily fluid outlet 9 ... Adsorbent Layer, 10 ... Body fluid introduction section 11 ... Body fluid discharge section, 12 ... Low specific gravity lipoprotein adsorber, 13 ... Liquid feeder 14 ... Replenisher, 15 ... Control device

Claims (2)

[Claims] 1. A low-density lipoprotein adsorber which is located between a body-fluid inlet, a body-fluid outlet, and between a body-fluid inlet and a body-fluid outlet and is filled with a low-density lipoprotein adsorbent having a polyanion portion on its surface. And a low specific gravity lipoprotein adsorber comprising a liquid feeder for sending a body fluid to the low specific gravity lipoprotein adsorber, wherein an inorganic electrolyte is provided between the body fluid outlet and the body fluid outlet of the low specific gravity lipoprotein adsorber. An apparatus for adsorbing low-density lipoprotein, characterized in that a replenisher for the same is provided. 2. The low specific gravity lipo according to claim 1, wherein the inorganic electrolyte replenisher is provided so as to operate in conjunction with a liquid feeder for sending a body fluid to the low specific gravity lipoprotein adsorber. Protein adsorption device.