JP2005058905A - Hollow fiber membrane type body liquid treating device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a body fluid treating device with a decreased disturbance in the flow of a liquid to be treated though hollow fiber membranes swellable by water are used, and, further, to provide a high performance hollow fiber membrane type body liquid treating device having such characteristics that it is excellent in performance of removing low molecular weight protein represented by a low molecular substance and β2-microglobulin, and also that the blood remaining after use is at a low level. <P>SOLUTION: The hollow fiber membrane type body fluid treating device is constituted in such a way that the inner diameters of hollow fiber membranes at a resin wrapping part and a resin non-wrapping part in their wet states are within specified ranges respectively in the use of hollow fiber membranes swellable by water and that the value (OD<SB>W2</SB>/OD<SB>W1</SB>) obtained when the outer diameter OD<SB>W2</SB>of the hollow fiber membrane at the resin non-wrapping part is divided by the outer diameter OD<SB>W1</SB>of the hollow fiber membrane at the resin wrapping part in the wet states is within a certain specified range. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a hollow fiber membrane type body fluid treatment apparatus used for hemodialysis, blood filtration, hemodiafiltration and the like. More specifically, while using a hollow fiber membrane that swells with water, it has excellent low molecular weight substance permeation performance and low molecular weight protein permeation performance, and also has the characteristics of low residual blood after use. The present invention relates to a blood type blood processing apparatus.

Cellulose hollow fiber membranes and various synthetic polymer membranes are widely used as hollow fiber membranes for blood treatment devices as hollow fiber membrane type body fluid treatment devices used for hemodialysis, blood filtration or hemodiafiltration. ing. A blood treatment apparatus for hemodialysis using cellulosic hollow fiber membranes, particularly saponified cellulose and regenerated cellulose hollow fiber membranes, has been used for over 30 years, has high reliability, and is widely used. Cellulose hollow fiber membranes for blood treatment devices generally have dimensions of about 160 μm to 200 μm in inner diameter and about several μm to several tens of μm in inner diameter. Cellulose, particularly saponified cellulose and regenerated cellulose hollow fibers The film swells when wet, and its inner diameter tends to increase to 180 μm to 220 μm and the film thickness increases to nearly 10 μm to 100 μm.
For a long time in hemodialysis therapy, it has been clarified that the accumulation of β2 microglobulin in the body of dialysis amyloidosis, including carpal trunk syndrome, has been revealed. ing.
In order to solve this problem, a hollow fiber membrane type blood treatment device using a hollow fiber membrane having higher permeation performance is required, and as a result, swelling of the hollow fiber membrane is required. Sex became higher.
When the hollow fiber membrane is embedded with a resin, the hollow fiber membrane is embedded in a dry state. When the hollow fiber membrane is wetted by a liquid to be treated such as blood, the hollow fiber membrane has a property of swelling as described above. Therefore, in the resin embedding portion, the resin swells in the outer diameter direction of the hollow fiber membrane. It is regulated and the inner diameter is reduced by the swelling of the membrane. On the other hand, since swelling is not regulated by the resin in the resin non-embedded portion, the film thickness, outer diameter, and inner diameter of the hollow fiber membrane are expanded to an equilibrium state.
In the hollow fiber membrane type blood treatment apparatus having such a configuration, a difference in the inner diameter of the hollow fiber membrane occurs between the resin embedding part and the non-resin embedding part, and the resin embedding is performed in the hollow fiber membrane of the blood introduction part. When blood flows from the part to the resin non-embedded part, the flux expands. Further, when blood flows from the resin non-embedded part to the resin embedded part in the blood outlet part, the flux is reduced. Because of these, blood flow disturbance is likely to occur, activation of blood components is caused, and residual blood in the blood processing apparatus using a hollow fiber membrane that swells with water increases. That is, it was one of the factors that increased the number of hollow fiber membranes in which blood remained when returning blood after blood treatment.

As described above, in a hollow fiber membrane type blood treatment apparatus using a hollow fiber membrane having a high permeation performance for efficiently removing β2 microglobulin, that is, a hollow fiber membrane having a higher swelling property as a result, It has been pointed out that residual blood further increases because the difference in dimensions of the hollow fiber membrane between the embedding part and the non-resin embedding part becomes more prominent.
In order to increase the permeability of low molecular weight proteins, various coagulation methods, hollow part forming agents, types of pore diameter retaining agents and the amount of adhesion are changed to increase the water content porosity and increase the average pore radius, for example, hemodialysis therapy Discloses a hollow fiber membrane-forming technique with high low molecular weight protein removal performance (Patent Document 1). In the invention described in Patent Document 1, in order to maintain a large pore diameter of the hollow fiber membrane, the amount of the pore diameter retaining agent must be increased, and as a result, the thickness of the hollow fiber membrane is increased. This hollow fiber membrane has the disadvantage that the film thickness is further increased when wet, leading to a decrease in the diffusion and permeation performance of low molecular weight substances. In addition, when the film thickness is thick, the film thickness further increases when wet, resulting in a large dimensional difference between the resin-embedded part and the non-resin-embedded part when wet. There was a problem.

Recently, in hemodialysis therapy, the following problem has occurred due to the pressure difference caused by the difference between the pressure distribution on the blood side called reverse filtration and the pressure distribution on the dialysate side. That is, endotoxin on the dialysate side flows into the blood side, induces inflammatory cytokines through the interleukin network, and exhibits various physiological activities. For example, concerns have been raised that cold-like symptoms such as fever and various dialysis complications are induced, and measures to make the dialysis solution endotoxin-free are required.
In order to prevent this reverse filtration phenomenon, a hollow fiber membrane having a gradient structure has been proposed. That is, a hollow fiber membrane having excellent biocompatibility has been developed that is excellent in the removal performance of high molecular weight substances in blood typified by β2 microglobulin and that suppresses the entry of endotoxin fragments from the dialysate into the patient. (Patent Document 2). However, since the hollow fiber membrane for blood treatment device described in Patent Document 2 has a hollow fiber membrane structure formed by a special coagulation method, the hollow fiber membrane swells greatly when wet, and residual blood of the blood treatment device is There was a big trend.
JP-A-2-135130 Japanese National Patent Publication No. 10-534087

  An object of the present invention is to solve the problems of the prior art and to provide the following body fluid treatment apparatus. That is, an object of the present invention is to provide a bodily fluid treatment apparatus that uses a hollow fiber membrane that swells with water and has little disturbance in the flow of the liquid to be treated. Furthermore, it is an object to provide a high-performance hollow fiber membrane type body fluid treatment device that is excellent in the removal performance of low molecular weight substances and low molecular weight proteins typified by β2 microglobulin and has low residual blood after use. And

While using hollow fiber membranes that swell with water, the inventors have made the hollow fiber membrane inner diameters of the resin-embedded portion and the non-resin-embedded portion in a wet state within specific ranges, respectively, Surprisingly, the value (OD _w2 / OD _w1 ) obtained by dividing the outer diameter OD _w2 of the hollow fiber membrane of the resin non-embedded portion by the outer diameter OD _w1 of the hollow fiber membrane of the resin embedded portion is within a certain range. The flow resistance of the liquid to be treated at the introduction part and the outlet part of the liquid to be treated can be improved as much as possible. For example, when the liquid to be treated is blood, it has been found that residual blood in the hollow fiber membrane can be remarkably reduced, and the present invention has been achieved. did.
That is, this invention consists of the following structures.
(1) A large number of hollow fiber membranes swollen by water are collected and stored in an outer cylinder container having at least one set of treatment liquid inlet and treatment liquid outlet, and both ends of the hollow fiber bundle. Is a hollow fiber membrane type body fluid treatment apparatus provided with an inlet and an outlet of a liquid to be treated, which are adhesively fixed in a container with a resin with a hollow portion opened and liquid-tightly fixed to both ends of the hollow fiber bundle. There,
When the hollow fiber membrane outer diameter of the resin embedding part in the wet fiber membrane is OD _w1 and the hollow fiber membrane outer diameter of the resin non-embedded part is OD _w2 , the following formula (1) is satisfied. A hollow fiber membrane type bodily fluid treatment apparatus.
1.07 ≦ OD _w2 / OD _w1 ≦ 1.45 (1)
(2) The hollow fiber membrane has an inner diameter of 165 μm to 250 μm in the resin-embedded portion when the hollow fiber membrane is wetted with water, and the hollow fiber membrane has an inner diameter of 230 μm to 290 μm in the non-embedded resin portion. Hollow fiber membrane body fluid treatment device.
(3) The hollow fiber membrane type body fluid treatment device according to (1) or (2), wherein the liquid to be treated is blood.
(4) mass transfer coefficient of cytochrome C is a hollow fiber membrane type body fluid treatment device according to (3) is ^{1.0 × 10 -5 cm / sec~7.0 ×} 10 -5 cm / sec.
(5) The hollow fiber membrane type body fluid treatment device according to the water permeability ^{10ml / m 2 / mmHg~100ml / m} 2 / mmHg, the sieving coefficient of albumin is 0.06 or less (3) or (4).
(6) The hollow fiber membrane type body fluid treatment device according to any one of (1) to (5), wherein the following formula (2) is satisfied.
1.35 ≦ OD _w2 / OD _w1 ≦ 1.45 (2)
(7) The hollow fiber membrane type body fluid treatment device according to any one of (1) to (6), wherein the hollow fiber membrane is made of regenerated cellulose.
(8) The hollow according to any one of the above (1) to (7), wherein the hollow fiber membrane has a pore diameter satisfying the following formulas (3) to (7) and has at least one maximum portion inside the hollow fiber membrane: Yarn type body fluid treatment device.
10 ≦ D1 ≦ 300 (3)
0.6 ≦ (D2 / D1) ≦ 1.2 (4)
1.2 ≦ (D3 / D1) (5)
20 ≦ ρ1 ≦ 200 (6)
20 ≦ ρ2 ≦ 200 (7)
(Where D1 is the hole diameter (nm) of the inner surface of the hollow fiber membrane, D2 is the hole diameter (nm) of the outer surface of the hollow fiber membrane, D3 is the hole diameter (nm) inside the hollow fiber membrane, and ρ1 is the hole diameter of the inner wall layer of the hollow fiber membrane. (Increase rate (%), ρ2 represents the hole diameter decrease rate of the hollow fiber membrane outer wall layer)
(9) A hollow fiber membrane having a pore size satisfying the following formulas (3) to (7) and having at least one maximum portion inside the hollow fiber membrane, and the inner diameter when swollen with water is 230 μm ～290Myuemu, water permeability ^{10ml / m 2 / mmHg~100ml / m} 2 / mmHg, mass transfer coefficient of cytochrome C is ^{1.0 × 10 -5 cm / sec~7.0 ×} 10 -5 cm / sec, albumin A hollow fiber membrane which swells with water, characterized by having a sieving coefficient of 0.06 or less.
10 ≦ D1 ≦ 300 (3)
0.6 ≦ (D2 / D1) ≦ 1.2 (4)
1.2 ≦ (D3 / D1) (5)
20 ≦ ρ1 ≦ 200 (6)
20 ≦ ρ2 ≦ 200 (7)
(Where D1 is the hole diameter (nm) of the inner surface of the hollow fiber membrane, D2 is the hole diameter (nm) of the outer surface of the hollow fiber membrane, D3 is the hole diameter (nm) inside the hollow fiber membrane, and ρ1 is the hole diameter of the inner wall layer of the hollow fiber membrane. (Increase rate (%), ρ2 represents the hole diameter decrease rate of the hollow fiber membrane outer wall layer)

  The hollow fiber membrane type body fluid treatment apparatus of the present invention uses a hollow fiber membrane that swells with water, but, for example, when used for blood treatment, removes low molecular weight substances and low molecular weight proteins represented by β2 microglobulin. It is a high-performance hollow fiber membrane blood treatment device that has both excellent characteristics and low residual blood after use. The hollow fiber membrane-type blood treatment apparatus of the present invention can reduce the number of remaining hollow fiber membranes in appearance to 10 or less, and can be suitably used for hemodialysis, blood filtration, hemodiafiltration and the like. . It is also suitable for diffusion removal of low molecular weight substances such as urea nitrogen and creatinine and β2 microglobulin, and has excellent ability to remove high molecular weight substances other than β2 microglobulin. In addition, the loss of useful proteins such as albumin in blood treatment, particularly hemodialysis therapy, can be suppressed to an extent that does not cause a problem in practice.

Hereinafter, of the body fluid treatment device of the present invention, a blood treatment device will be specifically described as an example.
For the purpose of the blood processing apparatus, the water permeability, the transfer coefficient of the substance, and the sieve coefficient of the substance are required to be desired depending on the purpose.
Swelling with water as used in the present invention means that when a hollow fiber membrane in a dry state is wetted with water, the hollow fiber membrane sucks water into the film thickness portion, and the volume of the film thickness portion increases, and the external force increases accordingly. When no is added, it means that the inner diameter, film thickness, and outer diameter increase.
The wet, wet or wet state as used in the present invention refers to a state after the entire blood treatment apparatus is immersed in pure water at 37 ° C. for 1 hour or longer.

Patients who have traditionally received blood treatment due to chronic renal failure, etc. frequently have complications such as anemia, hypertension, pigmentation, and bone / joint disorders. It is strongly suggested that about 10,000 substances are involved. In particular, a blood processing apparatus capable of efficiently removing β2 microglobulin having a molecular weight of 11,800 is required, and a blood processing apparatus capable of minimizing leakage of albumin having a molecular weight of 66,000 which is a useful substance in blood. It is one of the required performance.
In the blood treatment apparatus of the present invention, in order to efficiently remove this β2 microglobulin, the water permeability of the hollow fiber membrane to be used needs to be at least 10 ml / m ² / mmHg or more. In order to more efficiently remove high molecular weight substances such as β2 microglobulin, it is preferably 12 ml / m ² / mmHg or more.
On the other hand, in order to keep leakage of albumin, which is a useful substance, to a minimum, the water permeability needs to be 100 ml / m ² / mmHg or less. In order to further reduce the leakage of albumin, the water permeability is preferably 60 ml / m ² / mmHg or less.
The water permeation performance here defined the permeation rate of water coming out from the inner surface side to the outer surface side when a pressure difference was made between the inner surface side and the outer surface side of the wet hollow fiber membrane and water was passed through the inner surface side. Is.

In the hollow fiber membrane used in the hollow fiber membrane type blood processing apparatus of the present invention, it requires the mass transfer coefficient of cytochrome C is ^{1.0 × 10 -5 cm / sec~7.0 ×} 10 -5 cm / sec is there. In the hollow fiber membrane used in the hollow fiber membrane blood treatment apparatus of the present invention, the mass transfer coefficient of cytochrome C is 1.0 × 10 ⁻⁵ cm / sec or more in order to efficiently remove β2 microglobulin. In order to minimize leakage of albumin, which is a useful substance, it is also necessary that the mass transfer coefficient of cytochrome C is 7.0 × 10 ⁻⁵ cm / sec or less.

In the blood processing apparatus of the present invention, in order to minimize leakage of albumin due to the sieving effect in blood processing therapy, it is necessary that the sieving coefficient of albumin of the hollow fiber membrane to be used is 0.06 or less. A blood processing apparatus using a hollow fiber membrane in which the sieving coefficient of albumin exceeds 0.06 is not preferable because albumin leaks to a degree that cannot be ignored in a single blood processing therapy.
Here, the sieving coefficient of albumin refers to a pressure difference between the inner surface and the outer surface of a wet hollow fiber membrane using bovine albumin having a molecular weight of 66,000 as a reagent, and bovine albumin physiological saline solution on the inner surface side. The bobain albumin concentration on the inner surface side of the hollow fiber membrane and the outer surface side of the hollow fiber membrane was measured and calculated.
Sieve coefficient = bobain albumin concentration in filtrate / bobain albumin concentration in original solution

The configuration of the hollow fiber membrane blood processing apparatus of the present invention will be described with reference to FIG. For example, a large number of the hollow fiber membranes 20 are converged substantially in parallel, and the hollow fiber membranes are accommodated in an outer tube container 10 having a fluid inlet 12 and an outlet 13, and both ends of the bundle are made of urethane, epoxy, silicon, or the like. After embedding and bonding using resin 50, the hollow fiber is separated by separating the inner space 20A of the hollow fiber and the space 30 formed between the outer side of the hollow fiber and the outer tube container, and then cutting both ends of the bonded portion. It can be manufactured by opening the inner space of the membrane to the atmosphere and fixing the blood inlet 31 and the outlet 41 to the respective ends of the membrane in a liquid-tight manner.
Of the hollow fiber membrane, a portion embedded in the resin is a resin embedding portion 51, and a portion not embedded in the resin is a resin non-embedding portion 20B.

In the present invention, the inner diameter of the resin-embedded hollow fiber membrane when wetted with water needs to be in the range of 165 μm to 250 μm. If the inner diameter of the hollow fiber membrane in the resin-embedded portion is less than 165 μm, the blood flow resistance becomes high, so that residual blood is likely to occur, and if it exceeds 250 μm, the inner diameter of the hollow fiber membrane in the non-resin-embedded portion is further increased. The permeability (clearance) of the molecular weight substance is lowered, which is not preferable. The inner diameter of the resin-embedded hollow fiber membrane when wetted with water is more preferably 185 μm to 230 μm.
Furthermore, in the present invention, the inner diameter of the resin non-embedded hollow fiber membrane when wetted with water needs to be in the range of 230 μm to 290 μm. If the inner diameter of the hollow fiber membrane in the resin non-embedded portion is less than 230 μm, the hollow fiber membrane is longer than that in the resin embedded portion, so that even with this inner diameter, blood flow resistance increases and residual blood is likely to occur, and 290 μm. If it exceeds 1, the permeability (clearance) of the low molecular weight substance is lowered, which is not preferable. The inner diameter of the resin non-embedded hollow fiber membrane when wetted with water is more preferably 250 μm to 270 μm.

In the hollow fiber membrane-type blood treatment apparatus of the present invention, when the hollow fiber outer diameter of the resin embedding part is OD _w1 and the hollow fiber outer diameter of the non-resin embedding part is OD _w2 when the hollow fiber membrane is wet. It is necessary to satisfy the following formula (1).

1.07 ≦ OD _w2 / OD _w1 ≦ 1.45 (1)
The smaller the value of OD _w2 / OD _w1 , the larger the flux when blood flows from the resin-embedded part to the non-resin-embedded part in the blood introduction part, and the resin wrapping from the resin non-embedded part in the blood outlet part The shrinkage of the flux when blood flows into the buried portion is reduced and the blood flow is less likely to be disturbed, but the inner diameter range of the resin-embedded hollow fiber of the hollow fiber membrane used in the present invention, the resin non-embedded portion It was found that if the OD _w2 / OD _w1 is 1.45 or less in addition to the inner diameter range of the hollow fiber, the residual blood can be sufficiently reduced.
In the region where OD _w2 / OD _w1 exceeds 1.45, the expansion of the flux when blood flows from the resin embedding part to the resin non-embedding part in the blood introduction part, and the resin non-embedding part in the blood outlet part This is not preferable because the reduction of the flux when blood flows from the resin to the resin-embedded portion becomes large, blood flow disturbance is likely to occur, and residual blood increases.
On the other hand, when OD _w2 / OD _w1 is smaller than 1.07, the water permeability is lowered and the mass transfer coefficient of cytochrome C is decreased. Therefore, OD _w2 / OD _w1 needs to be 1.07 or more. More preferably, it is 1.25 or more, and it is desirable that it is 1.35 or more.
Such a hollow fiber membrane can be produced by controlling the amount of the hollow agent with respect to the inner diameter, and controlling the amount of spinning solution calculated according to the inner diameter, spinning speed, polymer concentration and the like. In order to prevent the hollow fiber from being broken, it is necessary to increase the film thickness, but in order to improve the permeation performance, it is necessary to decrease the film thickness, and this is adjusted according to the application. Moreover, in order to make a film thickness small, it may implement | achieve by reducing the amount of pore diameter retainers.

  Examples of the hollow fiber membrane used in the hollow fiber membrane type blood treatment apparatus of the present invention include hollow fiber membranes of various materials, and a cellulose-based hollow fiber membrane is preferable. Examples of the cellulose-based hollow fiber membrane used in the present invention include cellulose acetate membranes such as cellulose diacetate membranes and cellulose triacetate membranes, saponified cellulose membranes, and regenerated cellulose membranes. Furthermore, the surface of hollow fiber membranes of saponified cellulose and regenerated cellulose Are hollow fiber membranes modified with aliphatic, aromatic carboxylic acid, aliphatic, aromatic amino acid, aliphatic, aromatic alcohol, aliphatic, aromatic amino alcohol and the like. As a treatment for modifying the surface of the hollow fiber membrane, a known method (for example, JP-A-3-4924) can be used.

Furthermore, recently, in blood treatment membranes, in order to more efficiently remove β2 microglobulin, there is a tendency to increase the pore diameter. With the increase in permeation performance of hollow fiber membranes, Substances are easily permeated from the outer surface of the hollow fiber membrane to the inner wall surface of the hollow fiber membrane. For example, in hemodialysis, there is a problem that endotoxin fragments enter the blood from the dialysate side, and a hollow fiber membrane blood treatment apparatus that can eliminate this problem is preferred. As the hollow fiber membrane used for this, a hollow fiber membrane having a pore diameter D1 on the inner surface of the hollow fiber membrane and a pore diameter D2 on the outer wall surface of the hollow fiber membrane that is smaller than the pore diameter D3 inside the hollow fiber membrane and having the above-mentioned membrane performance is preferable. . That is, the hollow fiber membrane having such a structure has a pore diameter satisfying the following formulas (3) to (7), and the pore diameter of the hollow fiber membrane is from the inner wall surface of the hollow fiber membrane to the inside of the hollow fiber membrane. Examples of the hollow fiber membrane include a hollow fiber membrane that continuously increases and decreases continuously from the inside of the hollow fiber membrane toward the surface of the outer wall of the hollow fiber membrane and has at least one maximum portion inside the hollow fiber membrane.
10 ≦ D1 ≦ 300 (3)
0.6 ≦ (D2 / D1) ≦ 1.2 (4)
1.2 ≦ (D3 / D1) (5)
20 ≦ ρ1 ≦ 200 (6)
20 ≦ ρ2 ≦ 200 (7)
Here, D1 is the hole diameter (nm) of the hollow fiber membrane inner wall surface, D2 is the hole diameter (nm) of the hollow fiber membrane outer wall surface, D3 is the hole diameter (nm) inside the hollow fiber membrane, and ρ1 is the hollow fiber membrane inner wall layer hole diameter increase. The rate (%) and ρ2 represent the hollow fiber membrane outer wall layer pore diameter reduction rate (%).
When the pore diameter D1 on the inner wall surface of the hollow fiber membrane exceeds 300 nm, the high molecular weight protein easily enters the hollow fiber membrane, and when it is less than 10 nm, the removal performance of the high molecular weight substance represented by β2 microglobulin is insufficient. become. A more preferable pore size is 20 nm or more and 100 nm or less.

When the pore diameter D2 on the surface of the outer wall of the hollow fiber membrane is relatively small (0.6> (D2 / D1)), the removal performance of the high molecular weight substance represented by β2 microglobulin becomes insufficient. Conversely, if it is relatively large (1.2 <(D2 / D1)), endotoxin fragments enter the hollow fiber membrane from the dialysate due to the sieving effect, and as a result, endotoxin fragments in the blood during various blood treatment therapies. It becomes easy to invade.
The pore diameter D3 inside the hollow fiber membrane is preferably 1.2 ≦ (D3 / D1). When (D3 / D1) is less than 1.2, the porosity inside the hollow fiber membrane becomes small, and the removal performance of β2 microglobulin becomes insufficient.

The hollow fiber membrane inner wall layer pore diameter increase rate (ρ1) and hollow fiber membrane outer wall layer pore diameter decrease rate (ρ2) referred to in the present invention are the hollow fiber membrane inner wall surface and inner wall, respectively, when the hollow fiber film thickness portion is equally divided into 10 parts. The hole diameter increase rate between the surface and 3/10 of the hollow fiber film thickness and the hole diameter decrease rate between the hollow fiber film outer wall surface and 3/10 of the hollow fiber film thickness, which are defined by the following equations . However, D _X1 represents a hole diameter at a thickness of 3/10 from the inner surface of the hollow fiber membrane, and D _X2 represents a hole diameter at a thickness of 3/10 from the outer wall surface of the hollow fiber membrane.
ρ1 = {(D _X1 −D1) / D1} × 100
ρ2 = {(D _X2 −D2) / D2} × 100
When ρ1 and ρ2 are each less than 20%, the hollow fiber membrane inner wall surface and the inner wall surface are between 3/10 of the hollow fiber film thickness and the hollow fiber membrane outer wall surface and the outer wall surface are 3/10 of the hollow fiber film thickness. The permeation resistance of the high molecular weight substance between them increases, and the removal performance of the high molecular weight substance becomes insufficient. On the other hand, if ρ1 exceeds 200%, the permeation resistance when a substance permeates from the blood becomes too small, and even a high molecular weight protein tends to enter the hollow fiber membrane. When ρ2 exceeds 200%, the permeation resistance when a substance permeates from the dialysate becomes small, and endotoxin fragments easily enter. For this reason, in the present invention, ρ1 and ρ2 are preferably in the range of 20% to 200%.
A hollow fiber membrane having a pore structure having at least one maximum portion inside the hollow fiber membrane as described above has excellent removal performance of high molecular weight substances in hemodialysis therapy, which is the most common blood treatment therapy. The endotoxin fragment can be prevented from entering the blood from the dialysate while maintaining the pH, which is preferable in the hollow fiber membrane blood processing apparatus of the present invention.

The method for producing the hollow fiber membrane of the present invention will be described taking cellulose as an example.
The hollow fiber membrane used in the hollow fiber membrane-type blood treatment apparatus of the present invention discharges a spinning solution comprising a polymer and a polymer solvent from an outer spinning outlet of a double annular spinneret and a hollow part forming agent from an inner spinning outlet. It can be adjusted by a production method characterized in that coagulation is carried out sequentially in one or more coagulation baths made of a solution having a faster coagulation rate than water by discharging and spinning.
The hollow portion forming agent is non-solidified with respect to air, nitrogen, carbon dioxide, argon, oxygen, so-called freon gas such as tetrafluoromethane, hexafluoroethane, and octafluoropropane, other halogen gas, or spinning solution. It is a liquid exhibiting a property or microcoagulability. Such a liquid is appropriately selected depending on the type of spinning solution. For example, a solution containing at least one selected from polyols such as parkren, trichrene, trichlorofluoroethane, methanol, ethanol, propane, polyethylene glycol, or a mixed solution thereof is preferably used.

As the cellulose spinning solution, a cellulose solution in which cellulose is dissolved in a solvent capable of dissolving cellulose can be used. The cellulose concentration in the cellulose spinning solution is preferably 4 to 12% by weight. When the cellulose concentration is less than 4% by weight, the mechanical strength of the hollow fiber-shaped molded product before forming the resulting hollow fiber membrane is not sufficient, and a hollow fiber membrane having the required characteristics cannot be formed. When the cellulose concentration exceeds 12% by weight, the solubility of the spinning solution is lowered, and the viscosity of the spinning solution is increased, so that it is difficult to dissolve in the spinning solution and the permeation performance of the obtained hollow fiber membrane is also lowered. The cellulose spinning solution is prepared by a known method. The cellulose spinning solution is discharged from the double spinneret together with the hollow portion forming agent and passed through a non-solidifying atmosphere. The discharged spinning solution and the hollow part forming agent are led to one or a plurality of coagulation baths. When a plurality of coagulation baths are provided, a bath for washing with water may be provided between the coagulation baths. For the coagulation bath, a solution containing an acid, alkali or neutral salt solution is usually used. Among these, ammonium sulfate, ammonium chloride, calcium chloride, sodium chloride, hydrochloric acid, acetic acid, sulfuric acid, and caustic soda are preferable, and ammonium sulfate, sulfuric acid, and caustic soda are particularly preferable. The solution types in the first, second and subsequent coagulation baths may be the same or different. The coagulation bath may be one stage or two stages, but a multistage coagulation bath can be used if necessary.
The coagulated hollow fiber membrane is refined or washed with an aqueous solution of water and inorganic salts, and then retained with pores formed by coagulation, so that a known membrane pore size retaining agent such as glycerin or polyethylene glycol is applied, and thereafter And dried under known conditions.

In the hollow fiber membrane type blood treatment apparatus according to the present invention, a plurality of hollow fiber membranes are accommodated in a plastic container in a bundled form, and both ends of the bundle are resin embedding agents such as silicon, urethane, and epoxy. The bundle is fixed at both ends to form a module, which is used as a blood treatment apparatus typified by hemodialysis, hemofiltration or hemodiafiltration, and particularly preferred is hemodialysis.
As the resin embedding agent, a urethane-based resin is preferable from the viewpoint of foreign matters eluted from the resin during assembly, washing, and sterilization, and from the viewpoint of adhesive strength with the hollow fiber membrane. After that, it is cured by a known method, the resin embedding part is cut with a sharp metal to open the hollow fiber membrane, and the headers with blood introduction / extraction ports are fixed to both ends of the container, and filled with distilled water for injection. After that, it is sealed and packaged in a sterilization bag, and subjected to irradiation sterilization treatment to obtain a hollow fiber membrane blood treatment apparatus.

Next, the present invention will be described with reference to examples and comparative examples. The numerical values described in the examples and comparative examples were measured according to the following procedure.
[Measurement of hollow fiber membrane dimensions]
Lightly wrap dozens of wet hollow fiber membranes taken out by disassembling the blood treatment device with a nonwoven fabric, etc., set on a copper plate with small holes, cut the hollow fiber membrane with a razor, and at least of the hollow fiber membranes One end was opened. The hollow fiber membrane inner diameter and film thickness dimension on the cut surface were observed and measured with a digital HD microscope VH7000 (manufactured by Keyence Corporation). The dimensions of the dried hollow fiber membrane were similarly observed and measured.

[Adhesion rate of pore diameter retaining agent]
About 5 g of a sample to be measured of the hollow fiber membrane is taken and then accurately weighed to obtain the “initial yarn weight”. The sample is accurately added with 300 ml of pure water, stoppered, and shaken with a shaker for 5 minutes to remove the adhering pore diameter retaining agent, for example, PEG400 (Macrogor 400). The amount of pore size retaining agent is determined by measuring the concentration of Macrogol 400 from a differential refractometer and a standard solution using an aqueous solution after shaking the sample to be measured, and estimating the amount of pore size retaining agent from the amount of pure water and the concentration. Only the sample is taken out from the aqueous solution, dried at 105 ° C. for 12 hours or more with a dryer, and the yarn weight of the dried sample is measured to obtain “the yarn weight after drying”.
From the following formula, the pore size retention agent adhesion rate of the sample is calculated.
Sample pore diameter retention agent adhesion rate (%) = “amount of pore diameter retention agent” / “weight of thread after drying” × 100

[Measurement of water permeability]
After priming the blood treatment device with 1 L or more of water on both the blood side and the dialysate side, the transmembrane pressure difference (TMP) at 37 ° C. ± 0.5 ° C. with a blood side flow rate of 200 ml / min and a dialysis side flow rate of 500 ml / min. ) Measure the water permeability at 200 mmHg. The membrane area of the blood treatment apparatus was 1.5 m ² . The water permeation performance is calculated from the filtrate flow rate, TMP, and membrane area.
Permeability (ml / m ² / mmHg) = filtrate flow rate (ml / min) × 60 ÷ membrane area (m ² ) ÷ TMP (mmHg)

[Measurement of mass transfer coefficient of cytochrome C]
As a working solution, a physiological saline solution having a molecular weight of 12,400 cytochrome C having a concentration of 0.2 g / L is prepared. As a measurement sample, a mini-module with 100 hollow fiber membranes in a wet state, which is obtained by disassembling and removing the same type of blood processing apparatus as used for measuring the water permeability, is used. The minimodule is placed in a pot filled with physiological saline and adjusted to 37 ° C. ± 0.5 ° C. Similarly, the physiological saline solution of cytochrome C having a concentration of 0.2 g / L is adjusted to 37 ° C. ± 0.5 ° C. and circulated for 60 minutes at a flow rate of 3.0 ml / min. The concentration of the solution after the circulation is measured with a spectrophotometer at a measurement wavelength of 409 nm using physiological saline as a blank. Using a spectrophotometer, the physiological saline, the concentration on the outer surface of the hollow fiber membrane (C ^Dt ), the concentration on the inner surface of the hollow fiber membrane (C ^Bt ), and the concentration of the original solution (C ^B0 ) are colorimetrically measured for absorbance. .
The mass transfer coefficient is calculated using the following formula. In this calculation formula, the volume of the mini module is significantly smaller than the volume of the pot. Therefore, it is assumed that the inlet concentration and the outlet concentration on the inner surface of the hollow fiber membrane hardly change after passing the mini module once. It has led.
Pm = 2 · C ^Dt · V ^D / A · (C ^B0 + C ^Bt −C ^D0 −C ^Dt ) · Δt
Pm: Mass transfer coefficient (cm / sec)
C ^B0 : Absorbance on the inner surface side of the hollow fiber membrane before the start of measurement C ^Bt : Absorbance on the inner surface side of the hollow fiber membrane after the end of measurement C ^D0 : Absorbance on the outer surface side of the hollow fiber membrane before the start of measurement C ^Dt : Hollow after the end of measurement Absorbance on the outer surface side of the thread membrane A: membrane area (cm ² )
V ^D : Volume of pot (container contacting outer surface of hollow fiber membrane) = 265 (cm ³ )
Δt: Collection time = 60 (minutes)

[Measurement of aqueous urea clearance]
As a working solution, urea having a molecular weight of 60 is prepared as an aqueous solution having a concentration of 1 g / L. As the measurement sample, the same type of blood processing apparatus as that used for measuring the water permeability is used. This blood processing apparatus is put in a container filled with water and left to reach a temperature of 37 ° C. ± 0.5 ° C., and then a filtrate flow rate = 0 (with a blood side flow rate of 200 ml / min and a dialysis side flow rate of 500 ml / min). ml / min / m ² ). The urea concentration of the solution after the circulation was measured using a refractometer with blood treatment device blood inlet side concentration ( ^CBI ) (mg / dl), blood treatment device blood outlet side concentration ( ^CBO ) (mg / dl), and water blank. Measure as Using this concentration and blood treatment apparatus blood inlet side flow rate (Q ^BI ) (ml / min), the clearance is calculated using the following equation.
CL = (C ^BI −C ^B0 ) · Q ^BI / C ^BI
CL: Clearance of blood treatment device C ^BI : Blood treatment device blood inlet side concentration (mg / dl)
C ^BO : Blood treatment apparatus blood outlet side concentration (mg / dl)
Q ^BI : Blood treatment apparatus blood inlet side flow rate (ml / min)
The urea clearance is preferably 175 ml / min or more in a 1.5 m ² blood treatment apparatus, and the upper limit is 200 ml / min. The urea clearance is more preferably 178 ml / min or more. In the case of blood processing apparatuses having different membrane areas, the urea clearance of a 1.5 m ² blood processing apparatus can be obtained and compared in terms of membrane area by a normal method.

[Measurement of bovine plasma ultrafiltration rate (UFR)]
A CPD solution was used as an anticoagulant for 5 L of bovine blood having a total protein concentration of 7.2 g / dL at the time of collection. The composition and concentration of the CPD solution are: Trisodium citrate dihydrate 29.97 g / L, glucose 23.13 g / L, citric acid monohydrate 3.58 g / L, sodium dihydrogen phosphate dihydrate It adjusted with 0.614L of distilled water for injection so that it might become 2.51 g / L. The bovine whole blood prepared with the CPD solution is centrifuged, and then bovine plasma obtained by filtering the suspended matter through a net is used. As the measurement sample, the same type of blood processing apparatus as that used for measuring the water permeability is used. The bovine plasma was measured at a blood side solution temperature and a dialysis side solution temperature of 37 ° C. ± 1.0 ° C., and the bovine plasma UFR was measured. The bovine plasma UFR is calculated using the following formula.
Bovine plasma system UFR = 60 × Q _F / TMP
TMP = (P _BI + P _BO ) / 2−P _F −Δπ
UFR: Ultrafiltration rate (ml / m ² / mmHg)
TMP: Pressure difference between hollow fiber membranes (mmHg)
P _BI : Blood side inlet pressure (mmHg)
P _BO : Blood side outlet pressure (mmHg)
P _F : Filter side pressure (mmHg)
Δπ: Colloid osmotic pressure (about 22 mmHg)

[Measurement of bovine plasma clearance]
The bovine plasma used for the measurement of the bovine plasma system UFR is used. The total protein concentration, CPD solution composition and concentration, and measurement conditions of bovine plasma are the same as those of bovine plasma UFR. The β2 microglobulin concentration was adjusted to 1 mg / L. As the measurement sample, the same type of blood processing apparatus as that used for measuring the water permeability is used. The β2 microglobulin concentration at the blood side inlet and the blood side outlet is obtained by using a LX2200 manufactured by Eiken Chemical Co., Ltd., and transmitting light using a wavelength 660 nm LED as a light source for a reaction product that forms an aggregate by an antigen-antibody reaction of polystyrene latex particles. The β2 microglobulin concentration was measured by the latex nephelometry using the standard solution as a blank by the photometric method. The formula for calculating the bovine plasma clearance is calculated using the following formula.
_{CL = (Q BI · C BI} -Q BO · C BO) / C BI
CL: Bovine plasma clearance (ml / min)
Q _BI : Blood side inlet flow rate (ml / min)
Q _BO : Blood side outlet flow rate (ml / min)
C _BI : Blood side inlet solute concentration (mg / L)
C _BO : blood side outlet solute concentration (mg / L)

[Measurement of bovine plasma sieving coefficient]
The bovine plasma used for the measurement of the bovine plasma system UFR is used. The total protein concentration, CPD solution composition and concentration, and measurement conditions of bovine plasma are the same as those of bovine plasma UFR. As the measurement sample, the same type of blood processing apparatus as that used for measuring the water permeability is used. The filtrate flow rate was 10 ml / min, and the filtrate after 60 to 65 minutes was collected and used. The β2 microglobulin concentration at the blood side inlet and the blood side outlet was measured using the LX2200 manufactured by Eiken Chemical Co., Ltd. in the same manner as the measurement of bovine plasma system clearance. Regarding the albumin concentration, an antigen-antibody reaction was performed using albumin as an antigen to form an aggregate, and the albumin concentration was measured from the standard solution concentration using a turbidimeter. The bovine plasma sieving coefficient is calculated using the following formula.
SC = 2 · C _F / (C _BI + C _BO )
SC: Bovine plasma sieving coefficient (-)
C _F : filtrate side solute concentration (mg / L)
C _BI : Blood side inlet solute concentration (mg / L)
C _BO : blood side outlet solute concentration (mg / L)

[Evaluation of residual blood]
As the measurement sample, the same type of blood processing apparatus as that used for measuring the water permeability is used. The hollow fiber membrane blood treatment apparatus was comparatively evaluated for its residual blood properties under the following conditions. After each blood treatment apparatus was washed with 2.0 L of physiological saline, fresh beef blood (41% hematocrit, total protein concentration 7.2 g / dL, heparin addition amount 3000 IU / L) was added to the pressure difference between the hollow fiber membranes. The filtrate was circulated for 3 hours while returning to blood under the conditions of 100 mmHg and blood flow rate of 200 ml / min. 2.0 L of blood was used per blood processing device. Thereafter, blood return operation was performed with 200 ml of physiological saline. After the blood return operation, the number of residual blood hollow fiber membranes and the header portion of the appearance were disassembled, and the state of the cut surface of the hollow fiber membrane fixed resin embedded portion was visually observed, and judged by the presence or absence of blood clots.

[Measurement of pore diameter in cross section of hollow fiber membrane in the film thickness direction]
A hollow fiber membrane piece is sequentially immersed in 30%, 50%, 70%, 80%, 90%, 95%, each aqueous ethanol solution and 100% ethanol solution at 25 ° C. for 30 minutes, respectively. The water inside is replaced with ethanol. Next, the film piece is embedded in an epoxy resin and cured under conditions of 60 ° C. and 24 hours. Thereafter, a section having a cross-sectional portion in the film thickness direction (radial direction) having a thickness of about 70 nm was prepared from the hollow fiber membrane piece, and this section was subjected to a condition of 40 ° C. for 15 minutes in a 0.2% aqueous lead citrate solution. Stain with
A transmission electron microscope (TEM) photograph of the cross section is obtained from the obtained slice. The above TEM photograph corresponding to the entire cross-section from the hollow fiber membrane inner wall surface to the hollow fiber membrane outer wall surface in the film thickness direction of the hollow fiber membrane is divided into 10 cross-sectional parts on the photograph, and each obtained cross-sectional part Then, the hole distribution analysis of the hollow fiber membrane by the image analysis processing device (Asahi Kasei Co., Ltd. IP-1000) is performed, and the circle equivalent radius (radius of the perfect circle equal to the area of the hole) of the hole in each cross section is obtained. The average value is defined as the pore diameter. In the present invention, the hole diameter of the cross-sectional portion closest to the inner wall surface of the hollow fiber membrane having the cross section equally divided into 10 is D1, and the hole diameter of the cross-sectional portion closest to the outer surface of the hollow fiber membrane wall is D2.

A cupra-ammonium rayon spinning solution having a cellulose concentration of 8%, prepared by a known method as a spinning solution, and tetrafluoromethane (gas at normal temperature and normal pressure) as a hollow portion forming agent from a double spinneret, respectively, 11.7 ml / The solution was discharged at a rate of 4.3 ml / min., And dropped in the air by 35 cm, and then solidified with an aqueous 11% caustic soda solution at 38 ° C. and led to a net conveyor in the refining process. On the net conveyor where no forced mechanical tension is applied to the hollow fiber membrane filamentous body, hot water, dilute sulfuric acid aqueous solution and hot water are refined in the order of shower method, and then separated from the net conveyor to give a membrane pore size retainer. After applying polyethylene glycol 400 (“Macrogol 400” listed in Japanese Pharmacopoeia) at a concentration of 18% aqueous solution using an apparatus, a tunnel dryer at 175 ° C. was run, wound up at a speed of 90 m / min, and hollow It was set as a yarn film, and then bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 13.0% per cellulose. This hollow fiber membrane bundle is stored in a plastic container by a known method, and a urethane treatment (main agent, curing agent) manufactured by Nippon Polyurethane Co., Ltd. is used to assemble a blood treatment device having an effective membrane area of 1.5 m ² and after washing with water. And sterilized by irradiation. The residual blood property of the blood processing apparatus was evaluated, and the permeation performance of the water system and the bovine plasma system was measured with the same type of blood processing apparatus as the blood processing apparatus. In addition, the hollow fiber membrane was taken out by disassembling the same type of blood processing apparatus, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2.

A cupra-ammonium rayon solution with a cellulose concentration of 5.45% prepared by a known method as a spinning solution and tetrafluoromethane (gas at normal temperature and normal pressure) as a hollow portion forming agent are each 18.2 ml from a double spinneret. After discharging at a rate of 23 cm by weight in the air, it was solidified with an aqueous 11% sodium hydroxide solution at 45 ° C. and led to a net conveyor in the refining process. In the same manner as in Example 1, after refining the shower method in the order of warm water, dilute sulfuric acid aqueous solution, and warm water on the net conveyor, it was separated from the net conveyor and polyethylene glycol 400 by the membrane pore size retaining agent applying device (listed in the Japanese Pharmacopoeia) After application of “Macrogol 400” at a concentration of 16% aqueous solution, a tunnel-type dryer at 180 ° C. was run, wound up at a speed of 85 m / min to form a hollow fiber membrane, and then bundled .
The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 12.0% per cellulose. The hollow fiber membrane bundle was assembled with a blood treatment device in the same manner as in Example 1, the residual blood property was evaluated, and the permeation performance of the water system and the bovine plasma system was measured with the same type of blood treatment device as the blood treatment device. . In addition, the same type of blood processing apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2.

  A cupra ammonium rayon solution with a cellulose concentration of 5.45% prepared by a known method as a spinning solution and tetrafluoromethane (gas at normal temperature and normal pressure) as a hollow portion forming agent from a double spinneret 19.7 ml each. After being discharged at a rate of 23 cm by weight in the air, it was solidified in the same manner as in Example 1 and led onto a net conveyor in the refining process. This hollow fiber membrane filament was refined in the order of warm water, dilute sulfuric acid aqueous solution, and hot water in the order of hot water, dilute sulfuric acid solution and hot water in the same manner as in Example 1, and then separated from the net conveyor, and then polyethylene glycol by a membrane pore size retaining agent applying device. After application of 400 at a 16% aqueous solution concentration, a tunnel-type dryer at 180 ° C. was run, wound up at a speed of 90 m / min to form a hollow fiber membrane, and then bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 9.7% per cellulose. Using this hollow fiber membrane bundle, a blood treatment apparatus was assembled in the same manner as in Example 1 to measure residual blood properties. The permeation performance of the water system and the bovine plasma system was measured with the same type of blood processing apparatus as the blood processing apparatus. In addition, the same type of blood processing apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2.

  A cupra ammonium rayon solution with a cellulose concentration of 5.45% prepared by a known method as a spinning solution and tetrafluoromethane (gas at normal temperature and normal pressure) as a hollow portion forming agent from a double spinneret 17.0 ml each. After discharging at a rate of 28.5 cm in the air by dropping at a rate of 3.4 ml / min / min, it traveled 0.8 m in a coagulation bath made of 7.0% sulfuric acid aqueous solution and kept at 45 ° C. Stage coagulation was performed. Subsequently, immediately after washing with water, the second stage solidification was performed by running 1.3 m in an aqueous solution of 11% sodium hydroxide at 50 ° C. The obtained hollow fiber membrane was guided onto a net conveyor. After refining this hollow fiber membrane in the same manner as in Example 1, it was pulled away from the net conveyor and applied with a membrane pore size retaining agent application device in a concentration of 24% aqueous solution of polyethylene glycol 400 (“Macrogol 400” published in Japanese Pharmacopoeia). Then, the tunnel type dryer at 180 ° C. was run and wound at a speed of 80 m / min to obtain a hollow fiber membrane, which was then bundled. The amount of polyethylene glycol 400 attached to the hollow fiber membrane thus obtained was 16.7% per cellulose. A blood treatment apparatus was assembled on the hollow fiber membrane bundle in the same manner as in Example 1, and residual blood properties were measured. The permeation performance of the water system and the bovine plasma system was measured with the same type of blood processing apparatus as the blood processing apparatus. In addition, the same type of blood processing apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2.

  The spinning solution and the hollow part forming agent were discharged at a rate of 16.9 ml / min and 3.2 ml / min, respectively, dropped in the air by 28.5 cm by their own weight, and then composed of an 8.5% aqueous sulfuric acid solution at 45 ° C. The first stage solidification was carried out by running 0.8 m in the maintained coagulation bath. Subsequently, immediately after washing with water, the second solidification was performed by running 1.3 m in an aqueous 11% sodium hydroxide solution at 55 ° C. The obtained hollow fiber membrane was guided onto a net conveyor in the refining process. This hollow fiber membrane filament was refined on a net conveyor in the same manner as in Example 1, and then separated from the net conveyor, and polyethylene glycol 400 (“Macrogol 400” listed in the Japanese Pharmacopoeia) using a membrane pore diameter retaining agent applying device. After application at a concentration of 25% aqueous solution, a tunnel-type dryer at 180 ° C. was run, wound up at a speed of 85 m / min to obtain a hollow fiber membrane, and then bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 18.7% per cellulose. This hollow fiber membrane bundle was assembled with a blood treatment apparatus in the same manner as in Example 1, and the residual blood property was measured. The permeation performance of the water system and the bovine plasma system was measured with the same type of blood processing apparatus as the blood processing apparatus. In addition, the same type of blood processing apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2.

12. A cupra ammonium cellulose rayon spinning solution having a cellulose concentration of 8% prepared by a known method as a spinning solution and trichlorotrifluoroethane (liquid at room temperature and normal pressure) as a hollow part forming agent from a double spinneret, respectively. After discharging at a rate of 6 ml / min and 5.10 ml / min and dropping in the air by 15 cm by weight, it was solidified with a 20% aqueous solution of ammonium sulfate at 28 ° C. and led to a net conveyor in the refining process. After refining the hollow fiber membrane filamentous membrane on the net conveyor in the same manner as in Example 1, it was pulled away from the net conveyor, and after application with glycerin (85% aqueous solution concentration) by a membrane pore diameter retaining agent application device, After running a tunnel dryer at 155 ° C., it was wound up at a speed of 100 m / min to form a hollow fiber membrane, and then bundled. The hollow fiber membrane thus obtained had a glycerin adhesion of 10.6% per cellulose. This hollow fiber membrane bundle is housed in a blood treatment device container by a known method, and a urethane treatment (main agent, curing agent) manufactured by Nippon Polyurethane Co., Ltd. is used to assemble a blood treatment device having an effective membrane area of 1.5 m ² , After washing and assembling, γ-ray sterilization was performed. The residual blood property of the blood processing apparatus was evaluated. The permeation performance of the water system and the bovine plasma system was measured with the same type of blood processing apparatus as the blood processing apparatus. In addition, the same type of blood processing apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2.

  A cupra ammonium cellulose rayon spinning solution having a cellulose concentration of 5.45%, prepared by a known method as a spinning solution, and octafluoropropane (gas at normal temperature and normal pressure) as a hollow portion forming agent from a double spinneret, respectively. The solution was discharged at a rate of 0.4 ml / min and 3.85 ml / min, and dropped in the air by 23 cm, and then solidified with an aqueous 11% sodium hydroxide solution at 45 ° C. and led to a net conveyor in the refining process. After refining this hollow fiber membrane in the same manner as in Example 1, it was pulled away from the net conveyor, and a 16% aqueous solution concentration of polyethylene glycol 400 (“Macrogol 400” listed in the Japanese Pharmacopoeia) by a membrane pore size retaining agent applying device. After running the tunnel-type dryer at 180 ° C., the film was wound up at a speed of 85 m / min to form a hollow fiber membrane, which was then bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 10.5% per cellulose. A blood treatment apparatus was assembled on this hollow fiber membrane bundle in the same manner as in Example 1, and residual blood properties were measured. The permeation performance of the water system and the bovine plasma system was measured with the same type of blood processing apparatus as the blood processing apparatus. In addition, the same type of blood processing apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2.

  The spinning solution and the hollow part forming agent were discharged at a rate of 15.2 ml / min and 3.3 ml / min, respectively, dropped in the air by 28.5 cm by weight, and then composed of a 7.0% sulfuric acid aqueous solution at 40 ° C. The first stage solidification was carried out by running 0.8 m in the maintained coagulation bath. Subsequently, immediately after washing with water, the second solidification was performed by running 1.3 m in an aqueous 11% sodium hydroxide solution at 55 ° C. The obtained hollow fiber membrane was guided onto a net conveyor in the refining process in the same manner as in Example 1. The hollow fiber membrane filaments were refined on the net conveyor in the same manner as in Example 1 and then separated from the net conveyor, and then polyethylene glycol 400 (“Macrogol 400” listed in the Japanese Pharmacopoeia) using a membrane pore diameter retaining agent application device. After applying at a concentration of 25% aqueous solution, a tunnel-type dryer at 180 ° C. was run, wound at a speed of 85 m / min to obtain a hollow fiber membrane, and then bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 19.4% per cellulose. A blood treatment apparatus was assembled on the hollow fiber membrane bundle in the same manner as in Example 1, and residual blood properties were measured. The permeation performance of the water system and the bovine plasma system was measured with the same type of blood processing apparatus as the blood processing apparatus. In addition, the same type of blood processing apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2.

  A cupra ammonium rayon solution having a cellulose concentration of 8% prepared by a known method as a spinning solution and tetrafluoromethane (gas at normal temperature and normal pressure) as a hollow portion forming agent from a double spinneret at 11.7 ml / min. After discharging at a rate of 4.4 ml / min and dropping in the air by 33 cm by weight, it was solidified with an aqueous solution of 11% caustic soda at 38 ° C. and refined by the net conveyor method in the same manner as in Example 1 and then the net. Pulled away from the conveyor, passed through a tunnel dryer at 160 ° C. after application of polyethylene glycol 400 at a concentration of 18% aqueous solution by a membrane pore size retention agent application device, wound up at a speed of 110 m / min, and hollow fiber membrane After that, this was bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 13.5% per cellulose. A blood treatment apparatus was assembled from the hollow fiber membrane bundle in the same manner as in Example 1, and the residual blood property was measured. Further, the permeation performance of the water system and the bovine plasma system was measured using the same type of blood processing apparatus as the blood processing apparatus. Furthermore, the same kind of blood treatment apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2. In Example 9, the permeation performance as a blood treatment apparatus was good, but there were 20 hollow fiber membranes remaining.

  16.7 ml each of a cupra ammonium rayon solution having a cellulose concentration of 5.45% prepared by a known method as a spinning solution and tetrafluoromethane (gas at normal temperature and normal pressure) as a hollow portion forming agent from a double spinneret. / Min, discharged at a rate of 2.8 ml / min, dropped by 23 cm by weight in the air, solidified with an aqueous 11% sodium hydroxide solution at 45 ° C., and refined by the net conveyor method in the same manner as in Example 1. Later, it was pulled away from the net conveyor, passed through a tunnel dryer at 170 ° C. after being applied with a 20% aqueous concentration of polyethylene glycol 400 by a membrane pore size retaining agent application device, wound up at a speed of 100 m / min, and hollow A yarn membrane was obtained and then bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 17.1% per cellulose. A blood treatment apparatus was assembled on the hollow fiber membrane bundle in the same manner as in Example 1, and the residual blood property was measured. Further, the permeation performance of the water system and the bovine plasma system was measured using the same type of blood processing apparatus as the blood processing apparatus. Furthermore, the same kind of blood treatment apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2. In Example 10, the permeation performance as a blood treatment apparatus was good, but there were 30 hollow fiber membranes remaining in the blood.

  A cupra ammonium rayon solution with a cellulose concentration of 5.45% prepared by a known method as a spinning solution and tetrafluoromethane (gas at normal temperature and normal pressure) as a hollow portion forming agent from a double spinneret 21.3 ml each. / Min, discharged at a rate of 5.3 ml / min, dropped in the air by 23 cm by weight, solidified with an aqueous 11% sodium hydroxide solution at 45 ° C., and refined by the net conveyor method in the same manner as in Example 1. Later, it was pulled away from the net conveyor, passed through a 20% aqueous solution of polyethylene glycol 400 using a membrane pore size retaining device, run through a tunnel dryer at 180 ° C., wound up at a speed of 90 m / min, and hollow A yarn membrane was obtained and then bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 12.2% per cellulose. A blood treatment apparatus was assembled on the hollow fiber membrane bundle in the same manner as in Example 1, and the residual blood property was measured. Further, the permeation performance of the water system and the bovine plasma system was measured using the same type of blood processing apparatus as the blood processing apparatus. Furthermore, the same kind of blood treatment apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2. In Example 11, the number of remaining hollow fiber membranes as a blood treatment apparatus was a good result, but the aqueous urea clearance was low.

Comparative Example 1

  A cupra ammonium rayon spinning solution having a cellulose concentration of 5.45% and a hollow portion forming agent prepared by a known method as a spinning solution were discharged at a rate of 17.5 ml / min and 2.9 ml / min, respectively, After dropping by its own weight of 28.5 cm, the solidification of the first stage was performed by running 0.77 m in a coagulation bath made of 7.0% sulfuric acid aqueous solution and kept at 50 ° C. Subsequently, immediately after washing with water, it was run for 1.0 m in an aqueous solution of 11% caustic soda at 60 ° C. and solidified in the second stage. After refining by the net conveyor method as in Example 1, it was separated from the net conveyor. After passing a 20% aqueous solution concentration of polyethylene glycol 400, a tunnel type dryer at 175 ° C. was run, and then wound up at a speed of 100 m / min to obtain a hollow fiber membrane, which was then bundled. The amount of polyethylene glycol 400 adhered to the hollow fiber membrane thus obtained was 18.6% per cellulose. A blood treatment apparatus was assembled on the hollow fiber membrane bundle in the same manner as in Example 1, and the residual blood property was measured. The permeation performance of the water system and the bovine plasma system was measured with the same type of blood processing apparatus as the blood processing apparatus. In addition, the same type of blood processing apparatus was disassembled and the hollow fiber membrane was taken out, and the hollow fiber membrane inner diameter and film thickness of the resin embedding part when wet, and the hollow fiber membrane inner diameter and film thickness of the resin non-embedded part were measured. . The measurement results are shown in Tables 1 and 2. In Comparative Example 1, the permeation performance as a blood treatment apparatus was good, but the number of remaining hollow fiber membranes was as high as 100.

  The hollow fiber membrane type body fluid treatment apparatus of the present invention is excellent in the removal performance of low molecular weight substances and low molecular weight proteins typified by β2 microglobulin while using a hollow fiber membrane that swells with water, and residual blood after use. It is possible to provide a high-performance hollow fiber membrane-type body fluid treatment apparatus that has a few characteristics. As a result, it can be suitably used for hollow fiber membrane blood treatment such as hemodialysis, hemofiltration or hemodiafiltration.

It is explanatory drawing which showed the structure of the hollow fiber membrane type blood processing apparatus of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Outer cylinder container 12 Fluid inlet 13 Fluid outlet 20 Hollow fiber membrane 20A Hollow fiber inner space 20B Resin non-embedding part 30 Space formed between hollow fiber outer side and outer cylinder container 31 Blood inlet 41 Blood Outlet 50 Resin 51 Resin embedding part

Claims (9)

A plurality of hollow fiber membranes swollen by water are collected and stored in an outer cylinder container having at least one set of treatment liquid inlet and treatment liquid outlet, and both ends of the hollow fiber bundle are hollow portions. A hollow fiber membrane-type body fluid treatment apparatus comprising an inlet and an outlet for a liquid to be treated, which are adhesively fixed in a container with a resin in an open state and are liquid-tightly fixed to both ends of the hollow fiber bundle. ,
When the hollow fiber membrane outer diameter of the resin embedding part in the wet fiber membrane is OD _w1 and the hollow fiber membrane outer diameter of the resin non-embedded part is OD _w2 , the following formula (1) is satisfied. A hollow fiber membrane type bodily fluid treatment apparatus.
1.07 ≦ OD _w2 / OD _w1 ≦ 1.45 (1)   2. The hollow fiber membrane according to claim 1, wherein the hollow fiber membrane has an inner diameter of 165 μm to 250 μm in the resin-embedded portion when the hollow fiber membrane is wet with water, and an inner diameter of the hollow fiber membrane of the resin non-embedded portion is 230 μm to 290 μm. Mold body fluid treatment device.   The hollow fiber membrane type body fluid treatment apparatus according to claim 1 or 2, wherein the liquid to be treated is blood. The hollow fiber membrane type body fluid treatment device according to claim 3, wherein the mass transfer coefficient of cytochrome C is 1.0 x 10 ^-5 cm / sec to 7.0 x 10 ^-5 cm / sec. Water permeability hollow fiber membrane type body fluid treatment device according to claim 3 or ^{4 10ml / m 2 / mmHg~100ml /} m 2 / mmHg, the sieving coefficient of albumin is 0.06 or less. The hollow fiber membrane type body fluid treatment device according to any one of claims 1 to 5, wherein the following formula (2) is satisfied.
1.35 ≦ OD _w2 / OD _w1 ≦ 1.45 (2)   The hollow fiber membrane type body fluid treatment apparatus according to any one of claims 1 to 6, wherein the hollow fiber membrane is made of regenerated cellulose. The hollow fiber membrane body fluid treatment according to any one of claims 1 to 7, wherein the hollow fiber membrane has a pore diameter satisfying the following formulas (3) to (7), and has at least one pore diameter maximum portion inside the hollow fiber membrane. apparatus.
10 ≦ D1 ≦ 300 (3)
0.6 ≦ (D2 / D1) ≦ 1.2 (4)
1.2 ≦ (D3 / D1) (5)
20 ≦ ρ1 ≦ 200 (6)
20 ≦ ρ2 ≦ 200 (7)
(Where D1 is the hole diameter (nm) of the inner surface of the hollow fiber membrane, D2 is the hole diameter (nm) of the outer surface of the hollow fiber membrane, D3 is the hole diameter (nm) inside the hollow fiber membrane, and ρ1 is the hole diameter of the inner wall layer of the hollow fiber membrane. (Increase rate (%), ρ2 represents the hole diameter decrease rate of the hollow fiber membrane outer wall layer) A hollow fiber membrane having a pore diameter satisfying the following formulas (3) to (7) and having at least one pore diameter maximum portion inside the hollow fiber membrane, and the inner diameter when swollen with water is 230 μm to 290 μm , water permeability ^{10ml / m 2 / mmHg~100ml / m} 2 / mmHg, mass transfer coefficient of cytochrome C is ^{1.0 × 10 -5 cm / sec~7.0 ×} 10 -5 cm / sec, sieve albumin A hollow fiber membrane which swells with water, characterized by having a coefficient of 0.06 or less.
10 ≦ D1 ≦ 300 (3)
0.6 ≦ (D2 / D1) ≦ 1.2 (4)
1.2 ≦ (D3 / D1) (5)
20 ≦ ρ1 ≦ 200 (6)
20 ≦ ρ2 ≦ 200 (7)
(Where D1 is the hole diameter (nm) of the inner surface of the hollow fiber membrane, D2 is the hole diameter (nm) of the outer surface of the hollow fiber membrane, D3 is the hole diameter (nm) inside the hollow fiber membrane, and ρ1 is the hole diameter of the inner wall layer of the hollow fiber membrane. (Increase rate (%), ρ2 represents the hole diameter decrease rate of the hollow fiber membrane outer wall layer)