JPH09164196A - Method to treat body fluid and instrument using this method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To effectively and practically remove the substances bonded to binding proteins like serum albumin, etc., from body fluids such as blood, plasma, etc., without leaking binding proteins. SOLUTION: It is possible to put fluids such as blood, plasma, etc., which contain substances bonded to proteins in contact with a liquid which is close in solubility parameter to the substances bonded to the proteins with a permselective membrane between them, i.e., to remove the substances bonded to the proteins using chemical potential by immobilizing purifying substances whose absolute value of the difference in solubility parameter from the substances bonded to the proteins is within 10(cal/cm<3> )<1/2> on the surface of the membrane which is in contact with fluids such as blood, plasma.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention is used for a method for purifying a body fluid for removing chemical substances such as endogenous metabolites and drugs bound to proteins such as serum albumin from the blood or plasma outside the body, and for purifying blood or plasma. The present invention relates to a body fluid purification device.

[0002]

BACKGROUND OF THE INVENTION Serum albumin plays a role in transporting it in the body and removing it from the body by binding with many chemical substances such as drugs. However, Engl. J. M
ed. , Vol. 285: 246-267, 1971,
Am. J. Med. , Vol. 62: 466-47
0,1977, J. Dial. , Vol. 4: 91-
As reported in 100, 1980, etc., it is known that the binding rate of chemical substances to serum albumin is reduced in patients with chronic renal failure. This decrease in the protein binding rate of the drug is due to the fact that endogenous metabolites are accumulated in the blood in patients with renal failure and thus competitively inhibit the binding of the drug to serum albumin. Serum albumin is hardly removed by conventional dialysis treatment or diafiltration treatment for patients with chronic renal failure, and thus endogenous metabolites bound to this serum albumin are not removed. Moreover, the endogenous metabolites that bind to serum albumin are disclosed in the magazine "Kidney Failure" Vol.
5: 97-101, 1993, reported to be a renal failure progression factor, and also Nephron Vol.
56: 241-245, 1990, Nikkei Vol. 3
1: 1151-1161,1989, it was said that it acts as a hematopoietic inhibitory factor.

Therefore, it has been desired to dissociate the above-mentioned endogenous metabolites from the binding protein such as serum albumin and remove them from the blood.

Endogenous metabolites that bind to proteins are
Hippuric acid, indoxyl sulfate, 2-hydroxyhippuric acid, 3
-(3-hydroxy) -3-hydroxypropanoic acid, 4
-Hydroxyphenylacetic acid, indole-3-acetic acid, 3
-Carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), 3-carboxy-4-methyl-5-pentyl-2-furanpropionic acid, 3-carboxy-4-methyl-5-ethyl- 2-furan propionic acid, 3-carboxy-5-propyl-2-furan propionic acid, bilirubin and the like can be mentioned. The binding state of these protein-binding substances with a protein is mainly a hydrophobic bond whose main binding force is the hydrophobic interaction between the hydrophobic region of the protein and the binding substance, and depending on the charge state, it may be ionic. Indicates the binding of.

The removal of these protein-binding substances can also be carried out by plasma exchange therapy in which plasma proteins such as serum albumin and immunoglobulin are separated from blood and replaced with human serum albumin preparations or fresh frozen plasma.
However, although plasma exchange therapy is applied to hyperlipidemia, rheumatism, etc., its application is limited because human serum albumin preparations and fresh frozen plasma are very valuable and expensive.

[0006] European Patent Publication No. 615780 discloses a method of removing a protein-binding substance by dialysis by dissolving a binding protein such as human serum albumin in a dialysate and circulating it. However, like plasmapheresis, human serum albumin and other binding proteins are either purified from precious human blood or synthesized by microorganisms or cultured cells using genetic recombination technology. It is very valuable and expensive. Therefore, it is not practical to use it by dissolving it in a dialysate used in a large amount.

[0007]

The object of the present invention is to efficiently and practically remove a protein-binding substance bound to a binding protein such as serum albumin from a body fluid such as blood or plasma without leaking the binding protein. It is to provide a method for treating body fluid that removes.

[0008] Another object of the present invention is to efficiently and practically bind a protein-binding substance bound to a binding protein such as serum albumin to blood or plasma without leaking the binding protein such as serum albumin. Another object of the present invention is to provide a membrane-type body fluid treatment device that removes the body fluid from the body fluid.

[0009]

The present invention is achieved by the following method.

That is, in a body fluid containing a protein-binding substance bound to a binding protein, the absolute value of the difference between the protein-binding substance and the solubility parameter is 10 (cal / cm ³ ) ^{1/2 or} less via a permselective membrane. By contacting a purifying substance to promote dissociation of the binding protein and the protein binding substance and removing the protein binding substance from the body fluid through the permselective membrane.

In addition, the absolute value of the difference between the protein binding substance and the solubility parameter is 1 in the body fluid containing the protein binding substance bound to the binding protein via the permselective membrane.
A liquid containing a purifying substance within 0 (cal / cm ³ ) ^1/2 is contacted to promote dissociation of the binding protein and the protein binding substance, and the protein binding substance is removed from the body fluid through the permselective membrane. It depends. Also, a body fluid containing a protein-binding substance bound to a binding protein,
By contacting with a permselective membrane on which a purifying substance having an absolute value of a difference in solubility parameter with the protein-binding substance within 10 (cal / cm ³ ) ^1/2 is immobilized.

[0012] Further, the purifying substance is a non-protein which is medically acceptable.

The purifying substance is a fat-soluble vitamin or a surfactant.

[0014] Further, it is a body fluid treatment method in which the permselective membrane does not substantially permeate the binding protein.

Furthermore, regarding the sieving coefficient of the binding protein of the above-mentioned permselective membrane, using anticoagulated bovine blood, the magazine "High Performance Membrane for Hemodialysis Staff" (Tokyo Medical Co., 1990, p209-212).
The body fluid treatment method is 0.05 or less, more preferably 0.005, when measured according to.

A method for treating a body fluid, wherein the binding protein is serum albumin.

Another aspect of the present invention is achieved by the following device.

That is, it has a permselective membrane that does not substantially permeate a binding protein that binds a protein-binding substance, and has a first compartment and a second compartment separated by the permselective membrane, and the first compartment. Has an inlet and an outlet of a body fluid containing the binding protein bound to the protein-binding substance, and the absolute value of the difference in solubility parameter between the protein-binding substance and the second compartment is 10 (cal / cm ³ ) ^{1 / Two}
With a body fluid treatment device having a purifying substance within.

In addition, it has a permselective membrane that does not substantially permeate a binding protein that binds a protein-binding substance,
A first compartment and a second compartment separated by the permselective membrane, the first compartment having an inlet and an outlet for a body fluid containing a protein-binding substance, and at least the side surface of the first compartment of the permselective membrane. In the body fluid treatment device, a purification substance having an absolute value of the solubility parameter difference with the protein-binding substance of 10 (cal / cm ³ ) ^{1/2 or} less is immobilized.

Further, in the above body fluid treatment device, the purification substance is a medically acceptable non-protein.

Also, the purification substance is a fat-soluble vitamin or a surfactant.

Regarding the sieving coefficient of the binding protein of the above-mentioned permselective membrane, the anti-coagulated bovine blood was used and published in the magazine "High Performance Membrane for Hemodialysis Staff" (Tokyo Medical Co., 1990, p209-212). The body fluid treatment device has a value of 0.05 or less, and more preferably 0.005 or less when measured according to the above method.

A body fluid treatment device in which the binding protein is serum albumin.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION The body fluid treatment method and body fluid treatment apparatus of the present invention will be described below.

The substance to be removed according to the present invention is an endogenous metabolite that binds to a protein having a hydrophobic region such as serum albumin, hippuric acid, indoxyl sulfate, 2-hydroxyhippuric acid, 3- (3-hydroxy). -3-hydroxypropanoic acid, 4-hydroxyphenylacetic acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), 3-carboxy-4-methyl-5- Pentyl-2-furanpropionic acid, 3-carboxy-4-methyl-5-ethyl-2-
Furanpropionic acid, 3-carboxy-5-propyl-
Although it is a protein-binding substance such as 2-furanpropionic acid or bilirubin, a chemical substance having a benzene ring or a furan ring or a hydrophobic lipid may be applicable. Albumin and other binding proteins having a hydrophobic region bind these protein-binding substances mainly with a bond having a hydrophobic interaction between the hydrophobic region of the binding protein and the binding substance as the main binding force. , Depending on the charge state, it may be an ionic bond.

For protein-binding substances bound to these binding proteins contained in body fluids such as blood and plasma, the absolute value of the difference from the solubility parameter of the substance is 10 (ca).
It has been found that contact with a purifying substance having a solubility parameter within 1 / cm ³ ) ^1/2 through a permselective membrane causes transfer from the body fluid to the purifying substance layer.
Although the mechanism of removal of the protein-binding substance is not known exactly, the purifying substance comes into contact with the protein-binding substance bound to the binding protein in the pores of the permselective membrane, which causes a difference in chemical potential such as serum albumin. It dissociates from bound proteins and is removed from body fluids by purifying substances. Alternatively, the transfer of the protein-binding substance to the liquid containing the purifying substance progresses, the concentration of free protein-binding substance in the body fluid decreases, and the amount of the protein-binding substance bound to the binding protein decreases due to the adsorption equilibrium of the protein-binding substance. It is supposed to do.

At this time, the purification substance may be only the purification substance or a liquid in which the purification substance is suspended or dissolved.

It has also been found that the concentration of the binding substance in the body fluid is reduced by bringing the body fluid containing the protein-binding substance bound to the binding protein into contact with the selective permeation membrane having the purification substance immobilized thereon. It was

The solubility parameter is (ΔE ^v / V)
^The amount is defined as ^1/2 , where ΔE ^v is the molar evaporation energy of the solvent and V is the molar volume of the solvent. -△
E ^v is an energy change when a gas coagulates in a liquid, and −ΔE ^v / V corresponds to cohesive energy per unit volume of a solvent (liquid) and is called a cohesive energy density.

The purifying substance to be brought into contact with a body fluid such as blood or plasma by separating the permselective membrane is a liquid having a solubility parameter close to that of the protein-binding substance or a liquid containing a substance having a solubility parameter close to that of the protein-binding substance. is required. Further, the substance immobilized on the body fluid contacting surface of the permselective membrane must also have a solubility parameter close to that of the substance bound to the binding protein. For example, CMPF (solubility parameter estimated value 7.9 (ca
1 / cm ³ ) ^1/2 ) was removed by vitamin E (solubility parameter estimated value 7.9 (cal / c).
m ³ ) ^1/2 ), Pluronic P84 (solubility parameter estimated value 8.3 to 9.2 (cal / c)
m ³ ) ^1/2 ) and Pluronic P103 (solubility parameter estimated value 9.0 (cal / cm ³ ) ^1/2 ) are desirable. It is preferable that the absolute value of the difference from the solubility parameter of these purification substances is within 10 (cal / cm ³ ) ^1/2 .

When the above-mentioned purifying substance is a non-protein which is medically acceptable, human blood is not used for preparing the purifying substance, and cell culture technology or genetic engineering is not used. Do not use. Utilization of human blood is difficult for industrial mass production. In addition, production using cell culture technology and genetic engineering,
Expensive equipment is required for the process of mass production and the process of removing impurities. Therefore, the present invention, which can efficiently perform a protein-binding substance by using a non-protein, is practical.

Furthermore, since the purification substance is a fat-soluble vitamin or a surfactant, the protein binding substance can be effectively removed.

As a method for immobilizing the purifying substance on the body fluid contacting surface of the permselective membrane, there are methods such as a covalent bond and a bond by hydrophobic interaction. It should be free. When immobilizing vitamin E on a permselective membrane mainly composed of a hydrophobic polymer, a hexane solution of vitamin E is passed through the body fluid contact surface of the hollow fiber membrane and then the solvent is dried.

The body fluid treatment method of the present invention described above can remove protein-binding substances from blood collected in a blood collection container from a patient with renal failure or the like to enhance the binding ability of binding proteins such as serum albumin and purify them. In addition, the same effect can be obtained for general donated blood.

The permselective membrane used in the present invention is bound to protein with regenerated cellulose, cellulose derivative, polymethylmethacrylate, polyolefin, polysulfone, polyacrylonitrile, polyamide, polyimide, polyether nylon, silicone, polyester-based polymer alloy or the like. The substance is not particularly limited as long as it can pass through.

The body fluid treatment device of the present invention has a first compartment and a second compartment which are separated by a permselective membrane, and the first compartment has an inlet and an outlet for body fluid containing a binding protein bound to a protein-binding substance. . The second section may have a purification substance, and at this time, the second section may have an inlet and an outlet for the purification substance for circulating the purification substance. By circulating the purification substance, the removal amount and efficiency of the protein-binding substance can be improved. As a form of the body fluid treatment device of the present invention, a form of a conventional hollow fiber membrane type hemodialyzer can be adopted.

Further, another embodiment of the present invention has a first compartment and a second compartment separated by a permselective membrane, and the first compartment has an inlet and an outlet for a body fluid containing a protein-binding substance.
Further, the purifying substance is fixed to the surface of the permselective membrane on the first partition side. At this time, by providing an inlet and an outlet for a liquid such as a dialysate in the second compartment, it is possible to remove the protein-binding substance as well as the low molecular weight toxic substance by diffusion and / or filtration. As a form of the body fluid treatment device of the present invention, a form of a conventional hollow fiber membrane type hemodialyzer can be adopted. Regarding the sieving coefficient of the binding protein of the above-mentioned permselective membrane, using anticoagulated bovine blood, the magazine “High Performance Membrane for Hemodialysis Staff”
When measured according to (Tokyo Medical Co., 1990, p209-212), it is 0.05 or less, more preferably 0.00.
Since the body fluid treatment device has the number of 5 or less, the binding protein is not substantially leaked out, and thus the safety is high.

Since serum albumin is a major protein that binds a protein-binding substance, the sieving coefficient of serum albumin is 0.05 or less, more preferably 0.00.
By using a permselective membrane of 5 or less, serum albumin, which is an important component of body fluid, is not substantially leaked out.

The above-described body fluid treatment device of the present invention can be used to remove protein-binding substances from blood of patients with renal failure, etc. to enhance the binding ability of binding proteins such as serum albumin and purify them. Also, the same effect can be obtained by using it to purify general blood donated.

[0040]

According to the present invention, a liquid having a solubility parameter close to that of the harmful substance is disposed through the membrane in order to remove the harmful substance bound to the protein in the blood. Are removed. further,
By immobilizing a substance having a solubility parameter close to that of the harmful substance on the blood contact surface side of the membrane, the removal of the harmful substance is promoted by utilizing the chemical potential.

[0041]

Example 1 Polysulfone membrane (inner diameter 200 μm, thickness 4
(0 μm) A mini module having a membrane area of 100 cm ² was produced using about 350 pieces. The sieving coefficient of bovine serum albumin in this mini-module is 0.001 or less when measured according to the magazine “High Performance Membranes for Hemodialysis Staff” (Tokyo Medical Co., 1990, p209-212) using bovine blood. there were. After priming the mini-module with physiological saline, the inside of the hollow fiber was replaced with human plasma, and both ends of the blood side port were sealed. Pluronic P8
4 solutions (10g / dl physiological saline), Pluronic P1
03 module (10 g / dl physiological saline) and Vitamin E (stock solution) for 60 minutes,
The removal of CMPF was examined. HPL after plasma recovery
C (Column: Develosil PT C8-5, the mobile _{phase: H 2 0 / CH 3 CN} / TFA = 70/30/0.
CM at 08, flow rate: 1 ml / min, UV270 nm)
PF was quantified.

[0042]

Comparative Example 1 The same mini-module as in Example 1 was primed with physiological saline, and then the inside of the hollow fiber was replaced with human plasma, and both ends of the blood side port were sealed. Physiological saline and human serum albumin solution (3 g / dl physiological saline)
The mini-module was immersed in the solution of 60 minutes for 60 minutes to collect plasma, and then HPLC (column: Develosil PT C
8-5, mobile _{phase: H 2 0 / CH 3 CN} / TFA = 70 /
30 / 0.08, flow rate: 1 ml / min, UV270n
Quantification of CMPF was performed in m).

[0043]

[Test Example 1] Table 1 shows the results of Example 1 and Comparative Example 1.

The rate of decrease in concentration was obtained by measuring the plasma CMPF concentration Cpre before immersion and the plasma CMPF concentration Cpo after immersion.
It was calculated from equation (1) using st.

[0045]

[Equation 1]

[0046]

[Table 1]

In Example 1 and Comparative Example 1, almost no decrease in protein concentration was observed. As seen in Example 1, according to the present invention, the decrease rate of the concentration of CMPF was increased by about 4 to 12% as compared with the human serum albumin of Comparative Example 1, and the CMPF removal performance was remarkably improved. Further, since the physiological saline solution of Comparative Example 1 did not remove CMPF at all, the present invention enabled efficient removal of CMPF from blood.

[0048]

Example 2 Polysulfone membrane (inner diameter 200 μm, film thickness 4
(0 μm) About 1000 pieces were used to make a minidialyzer with a membrane area of 590 cm ² . The sieving coefficient of bovine serum albumin in this mini-module is 0.001 or less when measured according to the magazine “High Performance Membranes for Hemodialysis Staff” (Tokyo Medical Co., 1990, p209-212) using bovine blood. there were. After priming the mini dialyzer with physiological saline, the outside of the hollow fiber bundle was filled with Pluronic P84 solution (10 g / dl physiological saline) and vitamin E (stock solution). Plasma was introduced into the mini dialyzer from the plasma storage tank in which plasma was stored, and after replacing the inside of the circulation circuit with plasma, 50 ml of plasma was flowed at 18 ml / min.
Circulated in. Samples were taken from pooled plasma before and after circulation over time. HPLC with sampled plasma
(Column: Develosil PT C8-5, the mobile _{phase: H 2 0 / CH 3 CN} / TFA = 70/30 / 0.0
8. Flow rate: 1 ml / min, UV270 nm) was analyzed to examine the removal of CMPF.

[0049]

[Comparative Example 2] As in Example 2, after priming the mini dialyzer with physiological saline, the hollow fiber bundle was filled with physiological saline and a human serum albumin solution (3 g / dl physiological saline). . Plasma was introduced into the minidialyzer from the plasma storage tank in which plasma was stored, and after replacing the inside of the circulation circuit with plasma, 50 ml of plasma was circulated at a flow rate of 18 ml / min. Samples were taken from pooled plasma before and after circulation over time. HPLC (column: De) using the collected plasma
velosil PT C8-5, the mobile _phase: H 2 0 / C
H ₃ CN / TFA = 70/30 / 0.08, flow rate: 1 m
l / min, UV270nm) for analysis and CMPF
Was examined.

[0050]

Test Example 2 The results of Example 2 and Comparative Example 2 are shown in Table 2.

The clearance C _L is (2) of the way of the log and circulation time of the ratio t of the plasma CMPF concentration C _B at time t _(t) and CMPF concentration C _B of the plasma prior to the circulation ₍₀₎ It was calculated from the slope by the method of least squares.

[0052]

(Equation 2)

[0053]

[Table 2]

As can be seen in Example 2, according to the present invention, CM
The PF clearance was increased more than about twice as much as the human serum albumin of Comparative Example 2, and the CMPF removal performance was remarkably improved. Moreover, CMPF was not removed at all in the physiological saline system. In clinical practice, blood flow is 200m
The clearance is 40 ml / min or more, which is very practical because it increases to 1 / min and the membrane area also increases.

[0055]

[Example 3] A minidialyzer similar to that in Example 2 was prepared and
% Vitamin E / hexane solution was poured into the hollow fiber membrane of the minidialyzer and then dried to immobilize vitamin E on the inner surface of the hollow fiber membrane. After priming this mini dialyzer with physiological saline, the inside of the hollow fiber was replaced with human plasma, and both ends of the blood side port were sealed. Isopropyl myristate (IPM), human serum albumin (HSA) solution (3 g / dl saline) and vitamin E (Vi
E) (stock solution) was filled. Plasma is collected after 60 minutes, and H
PLC (Column: Develosil PT C8-
5, mobile _{phase: H 2 0 / CH 3 CN} / TFA = 70/30
/0.08, flow rate: 1 ml / min, UV270 nm)
Then, the removal of CMPF was examined.

[0056]

Comparative Example 3 A minidialyzer similar to that in Example 2 was produced.
After priming this mini dialyzer with physiological saline, the inside of the hollow fiber was replaced with human plasma, and both ends of the blood side port were sealed. Isopropyl myristate (IPM) and human serum albumin (HSA) solution (3 g
/ Dl saline) and Vitamin E (ViE) (stock solution). Plasma was collected after 60 minutes and analyzed by HPLC
(Column: Develosil PT C8-5, the mobile _{phase: H 2 0 / CH 3 CN} / TFA = 70/30 / 0.0
8, flow rate: 1 ml / min, UV270 nm), and the removal of CMPF was examined.

[0057]

[Test Example 3] Table 3 shows the results of Example 3 and Comparative Example 3.

[0058]

[Table 3]

In Example 1 and Comparative Example 1, almost no decrease in protein concentration was observed. As seen in Example 3, according to the present invention, the reduction rate of the CMPF concentration was increased by about 1.5 to 9 times as compared with the untreated film of Comparative Example 3, and the CMPF removal performance was remarkably improved.

[0060]

INDUSTRIAL APPLICABILITY As described above, the present invention provides a body fluid containing a binding protein bound with a protein binding substance,
The absolute value of the difference between the protein-binding substance and the solubility parameter is 10 (cal / cm ³ ) through the permselective membrane.
A body fluid treatment method for contacting a purifying substance within ^1/2 to promote dissociation of the binding protein and the protein binding substance, and removing the protein binding substance from the body fluid through the permselective membrane, or binding the protein binding substance The absolute value of the difference between the protein binding substance and the solubility parameter is 10 in the body fluid containing the bound protein through the permselective membrane.
A body fluid in which a liquid containing a purifying substance within (cal / cm ³ ) ^1/2 is contacted to promote dissociation of the binding protein and the protein binding substance, and the protein binding substance is removed from the body fluid through the permselective membrane. A treatment method, or a body fluid containing a binding protein bound with a protein-binding substance,
Since the absolute value of the difference in the solubility parameter from the protein-binding substance is within 10 (cal / cm ³ ) ^1/2, it is a body fluid treatment method of contacting with a permselective membrane having a purified substance immobilized thereon. Since it is possible to remove protein-binding substances that could not be removed with blood from blood, the protein-binding substances are removed from blood collected in blood collection containers from patients with renal failure, and the binding ability of binding proteins such as serum albumin is increased and purified. can do. In addition, the same effect can be obtained for general donated blood.

Further, since the purification substance is a non-protein which is medically acceptable, it can be easily mass-produced and the protein-binding substance can be efficiently and practically used.

Further, since the purification substance is a fat-soluble vitamin or a surfactant, it is highly effective and practical.

Another aspect of the present invention has a permselective membrane that is substantially impermeable to a binding protein that binds a protein-binding substance, and has a first compartment and a second compartment that are separated by the permselective membrane. , The first compartment has an inlet and an outlet of a body fluid containing a binding protein bound to a protein-binding substance, and the second compartment has an absolute value of a difference in solubility parameter from the protein-binding substance of 10 (cal / cm ^3). )
A body fluid treatment device having a purification substance within ^1/2 , or
It has a permselective membrane that does not substantially permeate a binding protein that binds a protein-binding substance, and has a first compartment and a second compartment that are separated by the permselective membrane, and the first compartment is a protein-binding substance. It has an inlet and an outlet for a body fluid containing bound binding protein, and the absolute value of the difference in solubility parameter with the protein-binding substance is at least 10 (cal / cm ³ ) at least on the side surface of the first compartment of the permselective membrane.
^Since it is a body fluid treatment device in which purification substances within ^1/2 are immobilized, protein-binding substances that could not be removed by conventional dialysis methods can be removed from the blood, so it can be used as a blood collection container from renal failure patients. Not only can it be used to remove protein-binding substances from the collected blood and enhance the binding ability of binding proteins such as serum albumin, and can also be used in a method of purifying the blood of patients with renal failure by extracorporeal circulation. .

Further, since the purification substance is a non-protein which is medically acceptable, it can be easily mass-produced and the protein-binding substance can be efficiently and practically used.

Further, since the purification substance is a fat-soluble vitamin or a surfactant, it is highly effective and practical.

[0066]

Claims (15)

[Claims] 1. The absolute value of the difference between the protein binding substance and the solubility parameter is 10 in a body fluid containing the protein binding substance bound to the binding protein via a permselective membrane.
(Cal / cm ³ ) contact with a purifying substance within ^1/2 ,
A method for treating a body fluid, which promotes dissociation of the binding protein and the protein-binding substance and removes the protein-binding substance from the body fluid through the permselective membrane. 2. The method for treating body fluid according to claim 1, wherein the purification substance is a non-protein which is medically acceptable. 3. The body fluid treatment method according to claim 2, wherein the purification substance is a fat-soluble vitamin or a surfactant. 4. The absolute value of the difference between the protein binding substance and the solubility parameter is 10 in a body fluid containing the protein binding substance bound to the binding protein via a permselective membrane.
Contacting a liquid containing a purification substance within (cal / cm ³ ) ^1/2 to promote dissociation of the binding protein and the protein binding substance, and removing the protein binding substance from the body fluid through the permselective membrane. A method for treating body fluid, comprising: 5. The method for treating body fluid according to claim 4, wherein the purification substance is a non-protein which is medically acceptable. 6. The body fluid treatment method according to claim 5, wherein the purifying substance is a fat-soluble vitamin or a surfactant. 7. The absolute value of the difference in solubility parameter between a body fluid containing a protein-binding substance bound to a binding protein and the protein-binding substance is 10 (cal / cm ³ ).
^A method for treating body fluid, which comprises contacting with a permselective membrane on which purification substances within ^1/2 are fixed. 8. The method for treating body fluid according to claim 7, wherein the purification substance is a non-protein which is medically acceptable. 9. The body fluid treatment method according to claim 8, wherein the purification substance is a fat-soluble vitamin or a surfactant. 10. A first permeable compartment having a permselective membrane that is substantially impermeable to a binding protein that binds to a protein-binding substance, and having a first compartment and a second compartment separated by the permselective membrane. Has an inlet and an outlet for a body fluid containing the protein-binding substance bound to the binding protein, and the absolute value of the difference in solubility parameter between the second compartment and the protein-binding substance is 10 (cal / cm ³ ) ^{1 /} A membrane-type body fluid treatment device having a purification substance of ^{2 or} less. 11. The method according to claim 10, wherein the purifying substance is a medically acceptable non-protein.
The membrane type body fluid treatment device according to the item. 12. The purifying substance according to claim 11, wherein the purifying substance is a fat-soluble vitamin or a surfactant.
The membrane type body fluid treatment device according to the item. 13. A first permeable compartment having a permselective membrane that is substantially impermeable to a binding protein that binds a protein-binding substance, and having a first compartment and a second compartment separated by the permselective membrane. Has an inlet and an outlet for a body fluid containing the protein-binding substance bound to the binding protein, and the absolute value of the difference in solubility parameter with the protein-binding substance is at least 10 on the side surface of the first compartment of the permselective membrane.
A membrane-type body fluid treatment device, wherein purification substances within (cal / cm ³ ) ^1/2 are immobilized. 14. The purifying substance according to claim 13, wherein the purifying substance is a medically acceptable non-protein.
The membrane type body fluid treatment device according to the item. 15. The purifying substance according to claim 14, wherein the purifying substance is a fat-soluble vitamin or a surfactant.
The membrane type body fluid treatment device according to the item.