JP2003210573A - Hollow fiber type blood-purifier, and manufacturing method for hollow fiber membrane - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hollow fiber type blood-purifier which can efficiently remove protein in a low-molecular weight region from blood without using a subsidiary liquid, and also, wherein an endotoxin from a dialysis liquid is prevented from invading. <P>SOLUTION: This hollow fiber type blood-purifier 1 is equipped with a bundle of hollow fiber membranes 2, a hollow fiber membrane case 3 which houses the bundle of the hollow fiber membranes 2, a bloods inlet 4 and a blood outlet 5 which are respectively provided on both end sections of the hollow fiber membrane case 3, a dialysis liquid inlet 6 which is provided on the blood outlet 5 side of the hollow fiber membrane case, and a dialysis liquid outlet 7 which is provided on the blood inlet 4 side of the hollow fiber membrane case 3. The hollow fiber type blood-purifier 1 is constituted in such a manner that the blood and the dialysis liquid are made to flow in the opposite directions through the hollow fiber membranes 2. In this case, a screening coefficient for a solute in the hollow fiber membranes 2 on the blood outlet 5 side is smaller than a screening coefficient for the solute in the hollow fiber membranes 2 on the blood inlet 4 side. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hollow fiber blood purifier, and more specifically, it is loaded with a hollow fiber membrane having different solute sieving coefficients on the blood inlet side and the blood outlet side, and is filled in blood. The present invention relates to a hollow fiber blood purifier that can remove unnecessary low molecular weight proteins contained therein and can prevent endotoxin from entering from a dialysate.

[0002]

2. Description of the Related Art Patients with chronic renal failure remove unnecessary substances such as waste products in the body by dialysis therapy several times a week. Recently, it has been found that proteins in low molecular weight regions such as β2 microglobulin also need to be removed by dialysis therapy. β2 microglobulin is a low molecular weight protein having a molecular weight of 11,800, and when it accumulates in the body, it becomes amyloid, which causes dialysis amyloidosis in which bone is destroyed by depositing in joints and the like. Therefore, attempts have been made to remove proteins with a molecular weight of tens of thousands that have not been removed in the past.

As a method for removing β2 microglobulin and the like, for example, there is a method of filtering blood while supplementing the blood with a replacement fluid. However, this method using a replacement fluid has a drawback that the cost of replacement fluid for blood is high.

It has been known that a dialysis membrane having improved water permeability in recent years causes a "back filtration phenomenon". The blood flowing in from the blood side inlet port of the dialyzer has a higher pressure than that on the dialysate side. Therefore, a filtering phenomenon occurs from the blood side toward the dialysate side. On the other hand, since a pressure loss occurs in the process of passing through the hollow fiber membrane and the blood pressure decreases, the pressure becomes lower near the blood side outlet port than on the dialysate side. Therefore, on the contrary, a back filtration phenomenon occurs from the dialysate side toward the blood side.

[0005]

By increasing the pore size of the hollow fiber membrane, that is, by increasing the sieving coefficient of the solute in the hollow fiber membrane, the water permeability is enhanced, and the above-mentioned filtration phenomenon is utilized to make a low molecular weight region. The protein can be efficiently permeated. However, on the other hand, if the sieving coefficient of the solute is increased over the entire hollow fiber membrane, the filtration from the dialysate side to the blood side increases due to the back filtration phenomenon at the blood side outlet, and it may be mixed in the dialysate. There is a problem that sexual endotoxin easily flows into the blood. Endotoxin is a kind of bacterial toxin that breaks down Gram-negative bacteria and liberates ribopolysaccharide, which is a constituent of the cell wall, to exert toxicity.

Therefore, the present invention is a hollow fiber type which can efficiently remove proteins in the low molecular weight region from blood without using a replacement fluid and does not allow endotoxin from infiltrating the dialysate. The purpose is to provide a blood purifier.

[0007]

Means for solving the above-mentioned problems are as follows: a bundle of hollow fiber membranes, a hollow fiber membrane case accommodating the bundle of hollow fiber membranes, and both ends of the hollow fiber membrane case. Blood inlet and blood outlet provided respectively, dialysate inlet provided on the blood outlet side of the hollow fiber membrane case, dialysate flow provided on the blood inlet side of the hollow fiber membrane case A hollow fiber blood purifier having an outlet and countercurrently flowing blood and dialysate through a hollow fiber membrane, wherein the sieving coefficient of the solute in the hollow fiber membrane on the blood outlet side is the blood inlet. A hollow fiber type blood purifier characterized by being smaller than the sieving coefficient of the solute in the hollow fiber membrane on the side, and the solute is albumin, and the sieving coefficient of albumin in the hollow fiber membrane on the blood outlet side. (SC2) is the hollow fiber on the blood inlet side Sieving coefficient of albumin in the (S
Smaller than C1) and SC2 is less than 0.5,
Furthermore, a hollow fiber type blood purifier characterized in that the sieving coefficient of the solute in the hollow fiber membrane is continuously reduced in the longitudinal direction from the blood inlet side of the hollow fiber membrane to the blood outlet side. Still another means is a method for producing a hollow fiber membrane in which the sieving coefficient of the solute on one end side is small and the sieving coefficient of the solute on the other end side is large, and a membrane forming stock solution containing a hydrophobic polymer resin and an organic solvent is used. A core liquid containing a good solvent having a high solubility for the hydrophobic polymer resin and a poor solvent having a low solubility for the hydrophobic polymer resin, which is discharged together with the core liquid into a coagulating liquid from a double-tube spinneret. A method for producing a hollow fiber membrane, characterized in that the mixing ratio of a good solvent and a poor solvent is changed at the time of discharging the production stock solution.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION A hollow fiber blood purifier according to the present invention will be described with reference to FIG. The hollow fiber blood purifier of the present invention is
The hollow fiber membrane is similar to the conventional hollow fiber blood purifier except that the sieving coefficient of the solute in the hollow fiber membrane changes in the longitudinal direction of the hollow fiber membrane.

The hollow fiber blood purifier 1 comprises a bundle of hollow fiber membranes 2 and a hollow fiber membrane case 3 for containing the bundle of hollow fiber membranes 2.
A blood side inlet port 4 provided at both ends of the hollow fiber membrane case, a blood side outlet port 5, and a dialysate provided at the blood side outlet port 5 side of the hollow fiber membrane case 3. Inflow port 6 and dialysate outflow port 7 provided at the blood side inlet port 4 side of the case side surface of the hollow fiber membrane case 3.
With.

Blood that has flowed in from the blood side inlet port 4 flows through the hollow of the hollow fiber membrane 2 in the direction of the solid line arrow from right to left in FIG. 1 and is discharged from the blood side outlet port 5. on the other hand,
The dialysate flowing from the dialysate inlet 6 flows in the space 10 formed by the outer peripheral surfaces of the hollow fiber membranes and the inner peripheral surface of the hollow fiber membrane case 3 in the direction of the dotted arrow from left to right in FIG. It is discharged from the dialysate outlet 7. Thus, it has a structure in which blood and dialysate flow countercurrently.

In the first region 8 from the blood side inlet port 4 of the hollow fiber type blood purifier 1 to the intermediate point, the inflow pressure of the blood flowing through the hollow of the hollow fiber membrane 2 is the space 1
It becomes larger than the inflow pressure of the dialysate flowing through the inside of zero.
Therefore, in this region 8, not only the transfer of waste products from the blood to the dialysate due to the diffusion phenomenon but also the transfer of the low molecular weight protein from the blood to the dialysate due to the filtration phenomenon occurs.

In the second region 9 extending from the intermediate point to the blood side outlet port 5 of the hollow fiber blood purifier 1, the inflow pressure of the blood flowing through the hollow of the hollow fiber membrane 2 decreases due to the pressure loss. Therefore, it becomes smaller than the inflow pressure of the dialysate flowing through the space 10. Therefore, in this region 9, the solute is transferred from the dialysate to the blood due to the back filtration phenomenon.

The hollow fiber membrane 2 has a large solute sieving coefficient in the first region 8 and a small solute sieving coefficient in the second region 9.

When the sieving coefficient of albumin in the first area 8 on the blood inlet side is SC1 and the sieving coefficient of albumin in the second area 9 on the blood outlet side is SC2, SC1> SC2 and SC2 <0.5 is preferable. More preferably, SC1> 0.8. The sieving coefficient is an index representing the solute permeability of the filtration membrane and can be represented by SC. The closer the SC value is to 1, the better the transparency is, and the closer the SC value is to 0, the worse the transparency is. Blood inlet concentration is Cb
i, the blood outlet concentration is Cbo, and the filtrate concentration is Cf, for example,

[Equation 1] SC = 2 × Cf / (Cbi + Cbo) Can be shown as

The sieving coefficient of the solute in the first region 8 may be the same in the entire region 8 or the sieving coefficient of the solute may be smaller in the region 8 as it gets closer to the blood outlet. You may change it. The same applies to the solute sieving coefficient in the second region 9. When the solute sieving coefficient changes in the regions 8 and 9, the solute sieving coefficients SC1 and SC2 are the average solute sieving coefficient in the first region 8 and the average solute sieving in the second region 9, respectively. Becomes the sieving coefficient.

In the filtering phenomenon in the first region 8,
Since the solute sieving coefficient of the hollow fiber membrane 2 is large, proteins in the low molecular weight region can be efficiently moved. In particular, β2 microglobulin that causes dialysis amyloidosis can be efficiently removed.

The protein in the low molecular weight region includes a protein having a lower molecular weight than serum albumin having a molecular weight of 69000 contained in blood.

Further, in the back-filtration phenomenon in the second region 9, since the solute sieving coefficient of the hollow fiber membrane 2 is small, even when fragmented endotoxin is mixed in the dialysate, it penetrates into the blood. It gets harder.

The hollow fiber membrane 2 in the present invention can be made of hydrophilic polymer and hydrophobic polymer as membrane materials. Among them, hydrophobic polymers are preferable because they have endotoxin adsorption ability.

Examples of the hydrophobic polymer that can be used in the present invention include polysulfone resin, polyether sulfone resin, and polyarylate resin. These may be used alone or in combination.

In order to impart hydrophilicity to the hollow fiber membrane 2 of the present invention, a hydrophilic polymer such as polyvinylpyrrolidone may be attached and held on the hydrophobic polymer membrane. By imparting hydrophilicity to the membrane surface, it is possible to reduce the adsorption of plasma proteins that cause thrombus.

The spinning of the hollow fiber membrane 2 is almost the same as the known method. That is, a hydrophobic polymer resin such as a polyester resin and a polysulfone resin is dissolved in an organic solvent such as N-methylpyrrolidone. Next, this membrane-forming stock solution is discharged together with the core solution into the coagulating solution using a double-tube spinning spinneret, and is spun into a hollow fiber to obtain a porous membrane. By changing the spinning conditions, the solute sieving coefficient in the longitudinal direction of the hollow fiber membrane, that is, the pore size of the membrane can be changed. The spinning conditions to be changed include, for example, the discharge rate of the film-forming stock solution into the coagulating solution and the composition of the core solution. Among them, it is preferable to change the composition of the core liquid because it is easy to operate and the sieving coefficient of the solute of the hollow fiber membrane can be changed at intervals of several tens of centimeters.

Although the core liquid can be used as water alone, a mixed solvent of a good solvent having a high solubility for the polymer resin as a raw material of the hollow fiber membrane and a poor solvent having a low solubility for the polymer resin can be used. It can be used as a core liquid. For example, a mixed solvent using N-methylpyrrolidone as a good solvent and water as a poor solvent is preferable as the core liquid because both solvents are mixed without separation.

The solute sieving coefficient of the hollow fiber membrane can be changed by changing the mixing ratio of the core liquid, for example, the mixing ratio of water and N-methylpyrrolidone (hereinafter referred to as NMP). In the case of a mixed solution of water and NMP,
The larger the NMP mixing ratio in the core liquid, the larger the sieving coefficient of the obtained hollow fiber membrane. The change of the mixing ratio of the core fluid is to change the solute sieving coefficient of the hollow fiber membrane at intervals of several tens of centimeters by providing a device for varying the NMP concentration in the core fluid in the hollow fiber membrane spinning device. Is possible.

The hollow fiber membrane of the present invention may be a uniform membrane having a constant pore size in the cross-sectional direction or a non-uniform membrane having different pore sizes in the cross-sectional direction.

[0026]

EXAMPLES Example 1 7.5 parts of polyarylate as a hydrophobic polymer, 7.5 parts of polyether sulfone and 85 parts of NMP as an organic solvent were mixed to prepare a stock solution for film formation. As a coagulating liquid, a mixed solution of 30 parts of water and 70 parts of NMP was used. A mixed solution of water and NMP was used as the core liquid. The membrane-forming stock solution was discharged together with the core solution into the coagulating solution from the double-tube spinneret to spin the hollow fiber membrane. The mixing ratio of the core liquid during spinning of the hollow fiber membrane was periodically changed from 51 parts NMP 49 parts water (lower limit value) to 47 parts NMP 53 parts water (upper limit value).

(Example 2) When the hollow fiber membrane was spun, the mixing ratio of the core liquid was 50.5 parts of water to 49.5 parts of NMP to 4 parts of water.
A hollow fiber membrane was obtained in the same manner as in Example 1 except that it was periodically varied between 4.5 parts NMP55.5 parts.

Comparative Example A hollow fiber membrane was obtained in the same manner as in Example 1 except that the mixing ratio of the core liquid during spinning of the hollow fiber membrane was kept constant at 47 parts of water and 53 parts of NMP.

(Measurement of sieving coefficient) The sieving coefficients on the blood inlet side and the blood outlet side of the hollow fiber membrane were determined as follows. The hollow fiber membranes produced in Example 1, Example 2 and Comparative Example and cut into module lengths were further cut into half lengths from the center to produce mini-modules. Bovine serum albumin (molecular weight 690
00) was made to flow in and water was made to flow out to the dialysate side, and the sieving coefficient ALBSC for albumin was measured. ALBSC on the blood outlet side is SC2, and ALBSC on the blood inlet side
Was designated as SC1. Among the hollow fiber membranes cut in half, the sieving coefficient of the mini-module using the hollow fiber membrane part produced when the core fluid is on the lower limit side is the sieving coefficient on the blood outlet side, and the core fluid is the upper limit value. The sieving coefficient of the mini-module using the hollow fiber membrane portion that was created on the side is the sieving coefficient on the blood inlet side.

(Measurement of the amount of permeation of endotoxin and β2 microglobulin) A module was formed by using the hollow fiber membranes produced in Example 1, Example 2 and Comparative Example and cut to the module length. In Examples 1 and 2, the blood side inlet was provided on the side of the hollow fiber membrane having a large sieving coefficient for albumin, and the blood side outlet was provided on the side of the hollow fiber membrane having a small sieving coefficient for albumin. On the dialysate side, a dialysate containing 2000 EU / l of endotoxin (ET) was circulated at a flow rate of 500 ml / min. On the other hand, bovine blood containing 30 mg / l of β2 microglobulin (β2MG) was circulated on the blood side at a flow rate of 200 ml / min. E
In order to evaluate the amount of T penetrating into blood, sample A2 is sampled at the blood outlet side and sample A1 is sampled at the blood inlet side, and the ET concentration of each sample is measured to obtain sample A2 and sample A1. Was calculated, and the difference in concentration was defined as the ET permeation amount. In order to evaluate the permeation amount of β2MG into the dialysate, sample B2 was sampled at the dialysate outlet side and sample B1 was sampled at the dialysate inlet side, and the β2MG concentration of each sample was measured to obtain sample B2. The concentration difference from the sample B1 was calculated, and the concentration difference was defined as the β2MG transmission amount.

[0031]

[Table 1]

In the blood purifier of the comparative example, which has a large sieving coefficient in the longitudinal direction of the hollow fiber membrane, that is, a large pore size, β2MG could be removed, but endotoxin flowed into the blood. Occurred. It should be noted that if the pore size is made smaller overall in the longitudinal direction of the hollow fiber membrane, the inflow of endotoxin into the blood can be blocked, but β2MG cannot be removed.

In the blood purifier of Example 1 in which only the pore size on the blood outlet side of the hollow fiber membrane, in which the inflow of endotoxin is dominant, is reduced, the inflow of endotoxin into the blood can be prevented and β2MG Removal was achieved. However, the removal efficiency of β2MG was lower than that of the comparative example.

In the blood purifier of Example 2 in which the pore size is improved on both the blood outlet side and the blood inlet side as compared with Example 1, the inflow of endotoxin into the blood can be prevented and β2MG is high. Removal efficiency was achieved.

[0035]

INDUSTRIAL APPLICABILITY The present invention uses a hollow fiber membrane in which the sieving coefficient of solute in the hollow fiber membrane on the blood inlet side is increased while the sieving coefficient of solute in the hollow fiber membrane on the blood outlet side is decreased. Thus, it is possible to efficiently remove proteins in the low molecular weight region from the blood without using a replacement fluid, and to provide a hollow fiber blood purifier that does not allow endotoxin to enter from the dialysate. it can.

[Brief description of drawings]

FIG. 1 is a diagram showing an outline of a hollow fiber blood purifier of the present invention.

[Explanation of symbols]

1 Hollow fiber blood purifier 2 Hollow fiber membrane 3 Hollow fiber membrane case 4 Blood side inlet port 5 Blood side outlet port 6 Dialysate side inlet 7 Dialysate side outlet 8 First area 9 Second area 10 spaces

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Claims (4)

[Claims] 1. A bundle of hollow fiber membranes, a hollow fiber membrane case accommodating the bundle of hollow fiber membranes, a blood inlet and a blood outlet provided at both ends of the hollow fiber membrane case, respectively. A hollow fiber type blood purifier comprising a dialysate inlet provided on the blood outlet side of a hollow fiber membrane case and a dialysate outlet provided on the blood inlet side of the hollow fiber membrane case. The hollow fiber blood purifier is characterized in that the sieving coefficient of the solute in the hollow fiber membrane on the blood outlet side is smaller than the sieving coefficient of the solute in the hollow fiber membrane on the blood inlet side. 2. The solute is albumin, and the sieving coefficient of albumin (S
C2) is smaller than the sieving coefficient (SC1) of albumin in the hollow fiber membrane on the blood inlet side, and SC2 is less than 0.5. vessel. 3. The sieving coefficient of the solute in the hollow fiber membrane continuously decreases from the blood inflow side of the hollow fiber membrane toward the blood outflow side. The hollow fiber blood purifier described. 4. A method for producing a hollow fiber membrane having a small sieving coefficient of a solute on one end side and a large sieving coefficient of a solute on the other end side, wherein a membrane-forming stock solution containing a hydrophobic polymer resin and an organic solvent is prepared.
A good core liquid containing a good solvent having a high solubility for the hydrophobic polymer resin and a poor solvent having a low solubility for the hydrophobic polymer resin, which is discharged together with the core liquid from the double-tube spinneret into the coagulation liquid. A method for producing a hollow fiber membrane, characterized in that the mixing ratio of the solvent and the poor solvent is changed at the time of discharging the production stock solution.