JPS63278503A - Filtering adsorption material and its usage - Google Patents

Abstract

PURPOSE:To produce filtering adsorption material having blood compatibility which can remove specified serum protein from blood without any damage of blood, by using hollow filament-like adsorption material having specified inside diameter and ratio of inside diameter to outside diameter for selective removal of serum protein. CONSTITUTION:Spinning dope such as dimethyl sulfoxide soln. of polysulfone is extruded through a double pipe nozzle with core fluid such as propylene glycol, etc., immersed in a coagulation fluid such as water, etc., after being run in the air, and subjected to heat treatment. Thereby, the hollow filament-like filtering adsorption material having 100-300mum inside diameter and ratio of inside diameter to outside diameter of 0.2-0.6 is produced. When blood is run along inside or outside of the filtering adsorption material, part of serum in blood is filtered and the targeted serum protein is removed by being adsorbed in the wall of the hollow filament.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a thick hollow fiber filter adsorbent having excellent T-filtration properties, adsorption properties and blood compatibility at the same time, and a method for using the same. More specifically, the present invention relates to a filtration adsorbent for removing specific plasma proteins from blood without damaging the blood, and a method for using the same.

[Prior art and its problems] In order to remove specific plasma proteins from blood by adsorption, conventionally, as an adsorbent, ■ granular activated carbon whose surface is coated with a material with relatively good blood compatibility (for example, O-orthots) has been used as an adsorbent. et al (0,0tubo
et al), Trans Actions American Society for Artificial Internal Organs (Trans.

Am, Soc, Artif', Inter
n, Organs, ) vol. 29, p. 480 (19
83)), and Activated carbon powder molded into a film using a polymeric material as a binder (for example, Kawanishi et al., Artificial Organs, 10).
Vol. 6, p. 1037 (19111) and PJ, Malchesky et al.
al), Artificial Organs (Artll
'1clal Organs, ), Volume 2, No. 4, 387
(1978)) is used.

In the adsorbent (2), the coating layer improves blood compatibility, but there is a problem in that the adsorption rate decreases. With the adsorbent (2), the contact area between the film surface and the blood is smaller than with the granular adsorbent, so it is thought that the blood compatibility is better. Similar to (2), the binder not only reduces the adsorption rate, but also reduces the proportion of activated carbon in the adsorbent, which increases the volume required to obtain a certain adsorption capacity, resulting in a large priming volume. There is a problem. Furthermore, as is common to (1) and (2), since the adsorption performance depends on the activated carbon, its properties are naturally limited, and there is a problem that components other than the target components may also be adsorbed.

Adsorbents that have the above-mentioned problems of low adsorption speed, that is, long time required for adsorption, large priming volume, and adsorption of components other than the target component, are particularly useful for the treatment of autoimmune diseases. Therefore, when applied to an extracorporeal circulation system, it imposes a burden on the patient, and does not satisfy the filtration characteristics necessary for this type of treatment.

If we focus only on adsorption properties, it is possible to select an adsorbent from a wide variety of materials that improves the above-mentioned problems, but most of these materials generally have a problem of poor blood compatibility (for example, Matsuyama et al. , Chemical Engineering, Volume 50, No. 10, 6
75 (1986)).

[Problems to be Solved by the Invention] An object of the present invention is to provide an adsorbent having novel filtration properties and a method for using the same, which solves the above-mentioned problems and satisfies blood compatibility and adsorption properties at the same time. The goal is to provide the following.

In other words, the present inventors believe that even with the above-mentioned material, if the contact area with blood is reduced and the degree of blood shear is increased at the contact surface, the adhesion of blood cell components will be reduced and the blood will not coagulate, thereby improving blood compatibility. We found that the adsorption can be improved, and that adsorption does not require diffusion flow, but can occur if the adsorption point and the adsorbed substance come into contact even during the process of convective flow (or Boiseuille flow), and we combined these findings. As a result, the present invention was completed.

[Means for solving the problems] That is, the present invention has an inner diameter of 100 to 300 mm,
Hollow fiber-shaped filtration adsorbent for selective removal of plasma proteins with a ratio of inner diameter to outer diameter of 0.2 to 0.6 and an inner diameter of 100
~300p, and the ratio of the inner diameter to the outer diameter is 0.2~
At least one end of a hollow fiber-like filtration adsorbent for selective removal of plasma proteins having a molecular weight of 0.6 is placed in a container having an inlet and an inlet for blood or an outlet for plasma in the blood that has been filtered and adsorbed by the filtration adsorbent. A purifier and adsorbent for selectively removing plasma proteins, which is fixed to prevent direct mixing with plasma, and the inner surface of the filtration adsorbent is opened at the fixed end to serve as a passage for the plasma or blood. Concerning how to use.

[Function] When the hollow fiber-shaped filtration adsorbent for selectively removing plasma proteins of the present invention uses its inner or outer surface as a blood passageway, it t-filters a part of the plasma of the blood flowing therethrough, and at least One type of plasma protein is adsorbed and removed by the thick part of the hollow fiber.

In addition, in the method of using the filtration adsorbent of the present invention, blood flows at high speed on a surface with a small surface area, and plasma proteins, which are adsorbed components, are transported by convection flow to the vicinity of the adsorption point, instead of diffusion flow as in conventional methods. The substance is quickly transported, filtered and adsorbed. Moreover, since the entire hollow fiber serves as an adsorbent, all of the hollow fibers can be effectively used as a filtration adsorbent.

[Example] The hollow fiber filtration adsorbent of the present invention has an inner diameter of 100 to 300.
The ratio of the inner diameter to the outer diameter is 0.2 to 0.6 at f. Preferably, the inner diameter is 180 to 250 mm, and the ratio of the inner diameter to the outer diameter is 0.35 to 0.50.

If the inner diameter is less than approximately 180 us, if the inner surface of the hollow fiber is used as a blood passage, the inner diameter of the hollow fiber will be too small and the pressure loss of the blood will be large, causing destruction of blood cell components and hemolysis. Therefore, it is preferable to use the outer surface side of the hollow fiber as a blood passage. Also, the inner diameter is 10
If it is less than 0, the pressure loss of the filtered plasma will be large if the outer surface of the hollow fiber is used as a blood passage, and in order to achieve the required filtration rate, a large pressure must be applied to the blood. This is not desirable because it has to be done. Inner diameter is 180
In the case of ~300 km, the outer surface of the hollow fiber has a larger surface area than the inner surface, so the contact time with blood is longer.
Since a large amount of blood cell components may adhere or blood may coagulate, it is preferable to use the inner surface of the hollow fiber as a blood passage. However, if the inner diameter exceeds 300I, the priming volume will increase, which is not preferable.

Furthermore, if the ratio of the inner diameter to the outer diameter of the hollow fiber-like filter adsorbent of the present invention is less than 0.2, the pressure loss will increase because the passage for blood or filtered plasma on the inner surface is small. , problems such as destruction of blood components occur. On the other hand, 0
．． If it exceeds 6, the volume occupied by the thick part of the hollow fiber,
That is, a problem arises in that the volume of the adsorbent decreases and the priming volume increases. Therefore, the ratio of the inner diameter to the outer diameter is preferably in the range of 0.2 to 0.6.

The inner surface of the hollow fiber is often used as a blood passageway because the blood flow is uniform and there is little residual blood.
In that case, it is particularly preferable that the inner diameter is 180 to 250 ρ and the ratio of the outer diameter to the inner diameter is 0.35 to 0.50, since this provides a good balance among adsorption volume, pressure loss, contact area, and priming volume.

The effective length of the hollow fibers is determined by the required adsorption capacity, but it is preferably about 20 cm or less to avoid excessive pressure loss and priming volume.

Further, the material of the hollow fiber filter adsorbent of the present invention is preferably selected so as to have both blood compatibility and adsorption properties, and to satisfy the required filtration properties.

Regarding blood compatibility, in addition to the adhesion of blood cell components, blood coagulation and hemolysis, the ability to activate complement components is also an important factor (for example, Detection, Chemical Engineering, Vol. 50, No. 10, 675 (See page 198B).

Hydrophobic materials, such as polystyrene, polymethyl methacrylate, polybutyl-methacrylate, polylauryl methacrylate, polyethylene terephthalate, polybutylene terephthalate, polyolefinic polymers, etc., and materials with cation exchange ability, such as sulfonic acid groups, sulfate ester groups, carboxyl groups It is known that materials having cation exchange groups such as cation exchange groups have a low ability to activate complement.

It is generally known that hydrophobic adsorbents have greater adsorption characteristics for proteins than hydrophilic adsorbents. For example, it is known that proteins are hardly adsorbed to extremely hydrophilic materials such as cellulose and polyvinyl alcohol, but are well adsorbed to hydrophobic materials such as polystyrene. In addition, materials with intermediate properties between hydrophilicity and hydrophobicity, such as polyacrylonitrile, polysulfone, cellulose acetate, cellulose propionate, cellulose butyrate, polyamide, and random copolymers consisting of hydrophobic monomers and hydrophilic heptamers are also used. Coalescence or block copolymers exhibit selective adsorption properties for specific proteins.

Therefore, by combining these characteristics,
It is possible to select a material that has good blood compatibility and also has selective adsorption properties for specific plasma proteins.

Furthermore, since the i-filtration adsorbent of the present invention has ultra-i filtration characteristics, for example, it can be made into an asymmetric structure having a so-called skin layer on the surface to adjust the t-filtration fraction molecular weight from several thousand to several hundred blade daltons. Can be done.

However, in the present invention, the filtration molecular weight is preferably 10,000 Daltons or more because the filtration rate decreases if the molecular weight is less than several thousand Daltons.

The filtration adsorbent of the present invention can be produced using the above-mentioned materials using various known hollow fiber membrane manufacturing methods. For example, a solution of the material, that is, a spinning dope, is extruded from the annular part of a double tubular nozzle, and a coagulated liquid of this spinning dope is extruded from an inner nozzle hole, and the coagulated liquid of this spinning dope is pushed out through the air for an appropriate distance, and then allowed to enter the external coagulated liquid. Roll it up later. The fibers are then heat treated or soaked in a hydrophilic treatment agent such as propylene glycol or glycerin, dried, and replaced with hollow fibers.

The inner diameter of the hollow fiber is mainly adjusted by the flow rate of the core liquid and the spinning speed. The inner thickness is mainly adjusted by the flow rate of the spinning solution and the spinning speed.

The internal, external and cross-sectional structure of the hollow fibers can be varied in various ways. In general, if a core liquid with strong coagulation effect is used, the inner pores will become smaller.

Similarly, the use of an external coagulant with a strong coagulant effect reduces the pores on the outer surface. Therefore, by changing the coagulation effect, the molecular weight cut-off on the inner or outer surface can be adjusted from a few thousand to a few hundred edge daltons.

Further, the cross-sectional structure can be changed by various known methods. For example, a solution of the above-mentioned material dissolved in a good solvent will generally yield an asymmetric structure containing macrovoids, while a solution dissolved in a poor solvent will yield a uniform network or spongy structure.

Furthermore, if the concentration of the material in the spinning dope is varied greatly, the cross section will become denser overall. In this way the adsorption capacity can be varied.

In the method of using the filtration adsorbent of the present invention, first, at least one end of the filtration adsorbent of the present invention is connected to the r
When the inner surface of the filtration adsorbent is used as a passage, the plasma in the blood that has been filtered and adsorbed by the filtration adsorbent is passed through a container having an outlet, or the blood to be filtered is passed through the outer surface of the filtration adsorption object. In this case, the blood and the plasma are fixed in a container having an inlet and an outlet for the blood so that they do not mix directly.

Then, opening the inner surface of the filtration adsorbent at the fixed end,
The plasma proteins in the blood are filtered by a method in which the blood to be filtered is passed through the blood, or when the blood to be filtered is passed through the outer surface of the filtration adsorbent, the plasma in the blood that has been subjected to filtration and adsorption is passed through. In order to do this, a filtration adsorbent is used.

The method of using the hollow fiber i-filtration adsorbent of the present invention is similar to known membrane filtration devices for plasma separation and membrane filtration type artificial kidneys. However, in the method of using the filtration adsorbent of the present invention,
The filtered plasma has already adsorbed and removed pathogenic substances such as specific plasma proteins such as β-2-micropropurine, Pence-Jones protein, and other special antibodies that cause autoimmune diseases. This can then be recombined with blood and returned to the human body instead of being discarded, as in traditional plasmapheresis therapy. Therefore, there is no need for fluid replacement, and a simpler circuit can be achieved.

The present invention will be explained in more detail below based on Examples, but the present invention is not limited to these Examples.

Example 1 Polysulfone (manufactured by Union Carbide ■, P-3500
) was dissolved in dimethyl sulfoxide at 110℃, and at 80℃, the core diameter was 150 mm and the inner diameter was 2 mm.
6 g per minute was extruded from a double tubular nozzle with a diameter of 50 ttrn and an outer diameter of 400 m, and at the same time, 1 g of propylene glycol at 40°C was extruded as a core liquid per minute, and after traveling 15 cm in air, it was introduced into water at 60°C. It was wound up at a speed of 30 m/min. The hollow fibers were thoroughly washed with hot water at 97°C and then air-dried at 40°C overnight.

When the cross section, inner surface, and outer surface of this hollow fiber were observed using a scanning electron microscope (manufactured by Hitachi, Ltd., X-650), the inner diameter and outer diameter were 200 IJm and 430 IJm, respectively, and the ratio of the inner diameter to the outer diameter was 0. It was .47. On the inner side,
Although no pores were observed even at 20,000 times magnification, many pores with a diameter of 0.2 mm or less were observed on the outer surface. The cross section had a substantially uniform network structure with a mesh size of approximately 0.6.

These 40 hollow fibers were placed in a Pyrex glass T-tube with an inner diameter of 4 mm and an outer diameter of 61 mm, and both ends of the hollow fibers were fixed with urethane resin, and then both ends were cut at the portion fixed with urethane resin. The inner surface of the hollow fiber was opened. The effective length of the hollow fiber was approximately 1OC1. The circuit was constructed so that it ran from the inner surface to the outer surface of the hollow fiber.
After flowing for 10 minutes at a flow rate of 1 cc/min for 10 minutes, physiological saline was replaced by flowing at a flow rate of 1 cc/min for 30 minutes.

Next, ACD (acid-cltra) is used as an anticoagulant.
Add 3 cc of tedextrose solution and 30 cc of fresh human blood kept at 36° C. to flow ice every minute on the inner surface of the hollow fiber, and filter 0.15 ccF per minute on the outer surface of the hollow fiber for 3 hours to collect the filtered plasma and the hollow fiber. A circulation test was performed by mixing the blood that had passed through the thread outside the hollow fiber. The average value of the filtration pressure at this time was 70 aml/g. During this period, regular sampling was performed to detect albumin (molecular weight 6364) in the blood.
Dalton) and the concentration of zozyme (molecular weight 14,500 Daltons) was analyzed. After the circulation test, the plasma was centrifuged and the presence or absence of hemolysis was observed.

Finally, deposits on the inner surface of the hollow fibers were observed as shown below.

After completing the circulation test, add 1 cc of physiological saline per minute to the blood flow path.
After running it for 20 minutes, take out the hollow fiber and add glutaraldehyde to fix the deposits on the inner surface of the hollow fiber.
A ratio of 1 volume part of a phosphate buffer solution with a pH of 7.2 to 9 parts by volume of a 5% aqueous solution was prepared, and after soaking in the solution stored at 4°C overnight, the hollow fibers were taken out and placed in the solution at 4°C. in phosphate buffer. Next, add this hollow fiber to 50% by volume.
, 70% by volume, 90% by volume, and 100% by volume in ethanol aqueous solutions for 1 hour each, and then dried using a critical point dryer (manufactured by Hitachi, Ltd., ICP-2). Observation was made using a microscope.

The measurement results are described below.

The color of the centrifuged plasma remained unchanged before and after circulation, and no hemolysis was observed.

After circulation, no deposits were observed on the inner surface of the hollow space, whereas with conventional adsorbents, a large amount of blood cell components and fibrin formation were always observed.

The concentration of lysozyme decreased over time, dropping to 20% of the initial value after 3 hours, but the concentration of albumin remained unchanged. This result shows that the inner diameter is 5 cm with 7 liquid outlets.
Using a device in which 8,000 hollow fibers were placed in a cylindrical container with an effective length of 1ocI, approximately 6 g of blood was flowed at 200 cc/min on the inner surface of the hollow fibers, and plasma was pumped at 30 cc/min. If the lysozyme is then recirculated and recombined with the blood, lysozyme can be reduced to 20% of its initial concentration after 3 hours with little damage to the blood and without decreasing albumin. means.

Example 2 Polyacrylonitrile (manufactured by Masu Nippon Exlan) was mixed with propylene glycol and dimethyl sulfoxide (32:68).
Weight ratio) Dissolve in a mixed solution at 110°C to a concentration of 20%, extrude 6g per minute from the same nozzle as in Example 1 at 80°C, and at the same time add a 60% aqueous solution of dimethyl sulfoxide as a core liquid at 40"C per minute. 1g was extruded.Next, 15c was extruded in the air.
* After driving, enter water at 80℃, 15a+
It was wound at a speed of /min. The hollow fibers were thoroughly washed with warm water at 70°C, immersed in a 30% aqueous propylene glycol solution for one day and night, and then air-dried at 40°C for one day and night.

Separately, this hollow fiber was soaked in methanol for a day and night, dried under vacuum, and observed with a scanning electron microscope. The inner and outer diameters were 260 la and 820 am, respectively, and the ratio of the inner diameter to the outer diameter was 0.42. No pores were observed on the inner surface even under 20,000x magnification, but many pores with a diameter of 0.4ρ or less were observed on the outer surface. There were several macrovoids with diameters of 30 to 40 mm in the cross section, but the rest had a nearly uniform spongy structure, and the cell size was approximately 0.2 to 0.5 mm.
It was ρ.

A circuit was constructed in the same manner as in Example 1 using the aforementioned 20 hollow fibers containing propylene glycol.

A blood circulation test was conducted in the same manner as in Example 1 except that the 30% by volume ethanol aqueous solution was not flowed. The average value of the filtration pressure at this time was 90 ts ts II g. The results were the same as in Example 1.

Example 3 Polystyrene with an average molecular weight of 180,000 Daltons was mixed with propylene glycol and N-methyl-2-pyrrolidone in a ratio of 33:8.
7 (Weight ratio) Dissolve 20% in the mixed liquid, extrude 6g/min from the same nozzle as in Example 1 at 80°C, and add N as the core liquid at the same time.
-An 80% aqueous solution of methyl-2-pyrrolidone was extruded at 1 g per minute at 40°C. Next, it was run in air for 15 ells, then entered into 50°C warm water, and wound up at a speed of 30*/min. After washing this hollow fiber thoroughly with warm water at 80℃,
It was air-dried at 40°C for a day and a night.

Separately, this hollow fiber was observed using a scanning electron microscope. inner diameter,
The outer diameters are 190 am and 430 ρ, respectively, and the ratio of the inner diameter to the outer diameter is 0. ．． It was 44. Although no pores were observed on the inner surface even under 20,000x magnification, many pores with a diameter of 0.3ρ or less were observed on the outer surface. The cross section showed a nearly uniform spongy structure, and the cell size was approximately 0.5 to 1 cell.

Construct a circuit in the same manner as in Example 1 using the hollow fibers described above,
A blood circulation test was conducted in the same manner as in Example 1. The average value of the filtration pressure at this time was 120-10 g. The results were almost the same as in Example 1, except that a small amount of blood cell components believed to be white blood cells and platelets were observed adhering to the inner surface of the hollow fiber.

Example 4 The same hollow fiber as in Example 1 was used, except that 0.2% lysozyme was dissolved in physiological saline whose pH was adjusted to 7.4 by adding phosphate buffer, and 38 cc of this solution was used instead of blood. A similar circulation test was conducted for 90 minutes.

The filtration pressure remained constant at 40 mm and 11 g during the test, and lysozyme decreased over time. After 90 minutes, the concentration of lysozyme was 0.
It dropped to 11. This means that 7 g of lylisozyme was adsorbed per 100 cc of adsorption volume.

Reference Example 1 A commercially available adsorbent made of styrene-divinylbenzene copolymer with a particle size of approximately 100 to 400 particles was used with an inner diameter of 7.
A column was prepared by filling a container made of 111% Pyrex glass with a length of 70 mm and a polyester net with a mesh size of approximately 70 Ja and a polyethylene blood inlet/outlet attached at both ends.

Physiological saline was flowed through this column at a rate of 2.7 cc per minute for 10 minutes, and then 80 cc of fresh human blood to which 8 cc of ACD solution was added as an anticoagulant was circulated at a rate of 2.7 cc per minute. Immediately after the start of circulation, the blood pressure at the column inlet gradually rises, and after about 15 minutes it rises suddenly, and after 30 minutes it reaches 20
Since the weight exceeded 0 mm and 11 g, circulation was discontinued.

When the presence or absence of hemolysis before and after circulation was observed in the same manner as in Example 1, the plasma after circulation was clearly colored red, indicating hemolysis.

After circulation, remove the adsorbent from the column and add 100% physiological saline.
cc and separated using a stainless steel sieve with a JIS mesh size of 74. This washing with saline was repeated again.

The deposits on the surface of this adsorbent were fixed with glutaraldehyde in the same manner as in Example 1, and then observed under an electron microscope. As a result, a fibrin network was formed so large that the surface of the adsorbent was not visible, and it was observed that a large number of red blood cells and white blood cells were embedded in the network.

[Effects of the Invention] The adsorbent for selective removal of plasma proteins of the present invention has excellent blood compatibility compared to conventional adsorbents, and has excellent adsorption properties such as a high adsorption rate and adsorption of only target components. It has the revolutionary effect of satisfying the required filtration characteristics and having a small priming volume.

Furthermore, when the method of using the filtration adsorbent of the present invention is applied to an extracorporeal circulation system for treatment, it has the effect of significantly reducing the burden on the patient.

Claims (1)

[Scope of Claims] 1. A hollow fiber-shaped filtration adsorbent for selectively removing plasma proteins, having an inner diameter of 100 to 300 μm and a ratio of inner diameter to outer diameter of 0.2 to 0.6. 2. The filtration adsorbent according to claim 1, which has an inner diameter of 180 to 250 μm and a ratio of the inner diameter to the outer diameter of 0.35 to 0.50. 3. The filtration adsorbent according to claim 1 or 2, which has a filtration cutoff molecular weight of 10,000 Daltons or more. 4 At least one end of a hollow fiber-shaped filtration adsorbent for selectively removing plasma proteins having an inner diameter of 100 to 300 μm and a ratio of the inner diameter to the outer diameter of 0.2 to 0.6 is connected to the blood inlet/outlet or the filtration adsorbent. The plasma in the blood, which has been subjected to filtration and adsorption treatment, is fixed in a container having an outlet so that the blood and the plasma do not mix directly, and the inner surface of the filtration and adsorption body is opened at the fixed end to collect the plasma or the plasma. A method of using a filtration adsorbent for selectively removing plasma proteins, which is characterized in that it is used as a passageway for blood. 5. A method of using the filtration adsorbent according to claim 4, wherein the filtration molecular weight is 10,000 Daltons or more.