JPH02135130A - Hollow fiber membrane made of regenerated cellulose - Google Patents

Abstract

PURPOSE:To control the loss of useful protein by forming a hollow fiber membrane made of regenerated cellulose and having a hollow part piercing through the membrane in the axial direction of the fiber and also having a specified water-contg. void volume at the time of wetting and a specified coefft. of sieving of albumin at the time of filtering blood. CONSTITUTION:A cuprammonium rayon spinning soln. having 4-12% concn. of cellulose and a hollow part forming agent which solidifies the spinning soln. slightly are ejected from a double spinneret, passed through a nonsolidifying atmosphere, introduced into a solidifying liq. and solidified to obtain a hollow fiber membrane made of regenerated cellulose. This membrane has a hollow part piercing through the membrane in the axial direction of the fiber and also has such characteristic values as 76-95% water-contg. void volume at the time of wetting and <=0.15 coefft. of sieving of albumin at the time of filtering blood.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a membrane that suppresses the loss of useful proteins in the blood such as albumin and efficiently removes toxic substances in the blood having a molecular weight of 10,000 or more. Specifically, the present invention relates to a membrane that selectively removes high molecular weight substances such as β2-microglobulin relative to albumin in blood purification therapy.

[Prior art] Complications such as anemia, hypertension, pigmentation, and bone and joint disorders are frequently observed in patients who are continuously receiving blood purification therapy due to chronic renal failure, etc., and it is important to investigate the causes of these complications. Research into countermeasures is underway. In general, the ability of blood purification membranes to remove substances has been taken up as a factor in the development of complications other than on the living side. That is, it is thought that various complications are caused as a result of accumulation of substances in the body that cannot be removed by blood purification membranes or substances that can be removed in an extremely small amount compared to the amount produced by the living body. However, there have been no cases where the mechanism of complication onset, including the identification of the etiological agent, has been clarified.
Conventionally, there has been a general demand for membranes that can efficiently remove urea with a molecular weight of 60 and poisonous substances with a molecular weight of about 5,000 at most. Blood purification therapy that mainly uses regenerated cellulose hollow fiber membranes (average pore radius of about 30 Å or less) has continued to be used as a blood purification membrane that satisfies this requirement.

In recent years, it has been revealed that the accumulation of β2-microglobulin in the body is greatly involved in the development of dialysis amyloidosis, including root canal syndrome among various complications, and β2-microglobulin can be efficiently removed. There is now a need for a blood purification membrane that can purify blood. Also, taking this opportunity,
The idea of removing substances with a molecular weight lower than albumin, which has a molecular weight of 166,000, and examining its therapeutic effects rapidly spread.

In response, large-pore hollow fiber membranes mainly made of synthetic polymer-based membrane materials, or adsorption removal hollow membranes focused on the removal of β2-microglobulin, have been developed (for example, 63-109871). However, since this method does not primarily rely on the diffusion permeation removal of substances, which is the basic concept of dialysis, but relies on adsorption phenomena, it is impossible to remove more than the saturated adsorption amount of the material, and it is not clinically sufficient. In order to obtain a sufficient amount of β2-microglobulin to be removed, a considerable amount of hollow fiber membrane is required. Further, in order to maintain the practical strength of the hollow fiber membrane, the total volume porosity (corresponding to the water-containing porosity in this specification) should be 75% or less. The higher the water-containing porosity of the membrane, the better the diffusion removal ability of a substance, so this value is not satisfactory for a diffusion-dependent hollow fiber membrane.

On the other hand, large-pore hollow fiber membranes using regenerated cellulose as a material are known to be used for virus separation, etc. (for example, JP-A-58-89626, JP-A-58-
89628, JP-A-59-204911, JP-A-612
54202), but since this is intended for the production of virus-free plasma, it has an extremely large pore size that actively allows substances such as albumin and globulin that should not pass through the blood purification membrane to pass through. That is, among regenerated cellulose membranes, there has been no known hollow fiber membrane having a pore size intermediate between such large-pore membranes and conventional blood purification membranes, which meets the purpose of the present invention.

[Problem to be solved by the invention]

Conventionally known hollow fiber membranes all remove substances through the mechanism of adsorption or filtration, and removal through the diffusion mechanism is expected in hemodialysis therapy, which is the most common blood purification method. was almost impossible.

Furthermore, synthetic polymer-based membranes may lose a considerable amount of useful proteins such as albumin, or because they focus on selective adsorption to β2-microglobulin, they are difficult to remove other high-molecular-weight wastes. There were problems such as it being unsuitable. Therefore, synthetic polymer membranes have been suitable for only extremely limited uses as blood purification membranes. In addition, these materials have relatively low material strength, and there are also problems in that the water-containing porosity of the hollow fiber membrane, which largely controls the diffusion removal ability of substances, cannot be increased too much, and the membrane thickness cannot be made very thin.

Furthermore, conventional membranes for removing high-molecular-weight substances generally have a problem in that they are somewhat inferior in their ability to remove low-molecular-weight substances such as raw wood and creatinine.

However, the present invention reduces the loss of albumin, which is a nutritional protein, to a level that does not pose a practical problem (100% per treatment).
g or less) and can widely remove high-molecular-weight waste products including β2-microglobulin with a molecular weight lower than that by a filtration and diffusion mechanism, and which is conventionally regenerated cellulose-based membrane. The purpose of the present invention is to provide a hollow fiber membrane that also maintains the ability to remove low molecular weight substances, which has been characterized by.

[Means to solve the problem]

The above object of the present invention is achieved by the following hollow fiber membrane.

That is, the water-containing porosity of the membrane when wet is 76 to 95%,
and the sieving coefficient of albumin in blood filtration is 0.1
This is a hollow membrane made of regenerated cellulose, characterized in that the particle diameter is 5 or less. Here, "wet J" means after the hollow fiber membrane has been immersed in pure water at 37°C for 1 hour or more.

There are various types of blood purification therapy, and even the same blood purification membrane exhibits different performance if used in different ways. In the most common hemodialysis therapy, if the sieving coefficient for albumin is 0.15 or less, loss of useful protein components does not pose a practical problem.

The main mechanisms for removing waste substances in blood purification therapy include ■filtration removal, ■diffusion removal, and ■adsorption removal, but because high molecular weight substances have a small diffusion coefficient,
In order to remove this, it has been believed that filtration or adsorption is the only mechanism of action. However, in normal hemodialysis therapy, which only removes about 2 to 31% of water per treatment, we cannot expect much from ``filtration removal'', and ``adsorption removal'' removes various substances and various substances through adsorption. As for the removal mechanism, the membrane performance deteriorates over time, so it is not preferred in blood purification therapy in which not only β2-microglobulin but also various body wastes are to be removed.

In other words, there is a need for a membrane that has less adsorption of substances and is also capable of effective "diffusion removal."

The hollow fiber membrane of the present invention is made of regenerated cellulose, which is known to have almost no adsorption of blood components including various proteins. The amount removed by diffusion is equivalent to or greater than the amount removed by this mechanism. In addition, since the membrane's essential waste removal mechanism is based on the diffusion principle, the apparent molecular weight fractionation property, that is, the selective removal property of not losing useful blood components with a molecular weight greater than albumin, is achieved through filtration. This has the advantage of being much better than the case alone.

The membrane pore radius, membrane thickness, membrane water-containing porosity, etc. are contributing factors to diffusion. The use of regenerated cellulose membranes has the advantage of superior mechanical strength, which allows the production of extremely thin membranes;
Moreover, it is suitable for the purpose of the present invention in that it can be formed into a membrane with excellent hydrophilicity and a large water-containing porosity. In addition, the large water-containing porosity guarantees a good ability to remove low-molecular-weight substances that cannot be found in other materials, making it more suitable for use as an artificial kidney.

The membrane porosity suitable for the purposes of the present invention is between 76 and 95%, more preferably between 80 and 95%. The "hydrous membrane porosity" referred to here refers to the apparent volume of the hollow fiber membrane when wet, the weight of the regenerated cellulose forming the hollow fiber membrane, and the volume of water in the wet hollow fiber membrane determined by density measurement. It is a fraction. That is, it is obtained by actually measuring or assuming each parameter included in the calculation formula below.

H(-): M water-containing porosity νs (c/rnin): spinning solution discharge amount ρs (g/rnin):
rnl): Spinning solution density C(-): Cellulose weight fraction in the spinning solution ω(c+n/m1n): Winding speed ρc(g/d): True density of cellulose (assumed to be 1.52) r, (cm): Outer radius ri when hollow fiber is wet (cm): Inner radius ri when hollow fiber is wet (-
): Elongation ratio in the fiber length direction when transitioning from dry state to wet state (actually measured at 37°C) Note: H + Vs + ρSr C and ω are actually measured at the time of hollow fiber creation ro and ri are actually measured using an X 200 microscope magnifier Regarding the removal of β2-microglobulin, a removal rate of 20% or more is desired in clinical use, but the sieving coefficient of β2-microglobulin is 0.3 or more, or the overall mass transfer coefficient is 2 × 10-'cm. This removal rate can be achieved by using a film that has a rate of at least 1.0 m/sec or a film that has both of these characteristics.

The "removal rate" referred to here is calculated by correcting the change in blood concentration of β2 microglobulin in the blood of a dialysis patient before and after dialysis using the hematocrit value for hemoconcentration.

In addition, the average pore radius of the hollow fiber membrane of the present invention when wet is 40
-200 people are preferable, and 40-150 people are more preferable. This average pore radius can be calculated based on pore theory (for example, Artificial Organs Vol.
Page 1541-1544, 1986), it can be approximated by the following formula.

Here, f (q) = (1-2,105q+2.08
65q'-1,7068q'+0.72603q"
)/(1-0,75857q')Sn=(1q,)"q=rs/rPτ=10 formula, ■From formula, rp (cm): Average pore radius of the membrane r, (cm): Water Molecular diameter (1,07X 10
-8) D (cJ / 5ec): Diffusion coefficient of water (set to 2,97X10-S) Ak (-): In-plane bid opening rate τ (-): Oil according to pore theory (oil channel model) Road ratio g (
Pa-sec): Viscosity of water (0,691x 10-
) L p (c+ft / CTA/ se
c/Pa): Membrane water filtration coefficient (37”C, 200
Shell 1 (actually measured using a hollow fiber membrane module with a membrane area of approximately 100c+fl under g) P m (cm/5ec): Water diffusion transfer coefficient of the membrane (actually measured at 37°C) H (-): Water-containing void of the membrane Porosity (definition below) ΔX (CTI
): Thickness of hollow fiber membrane when wet, i.e. PIII, Lp
By actually measuring , r can be found using Equation 0.

Furthermore, other membrane structural parameters such as Akτ can also be determined by determining H based on the calculation formula for determining the membrane water-containing porosity (■1) described above.

The hollow fiber membrane according to the present invention having the above characteristics can be produced, for example, by the following method.

Cellulose concentration 4-12%, prepared by a known method
, preferably 4 to 8% cuproammonium rayon spinning solution, and a gas or liquid known non-coagulable hollow-forming agent (e.g. liquid halogenated carbon such as percrene, trichrene, trichlorotrifluoroethane; isopropyl millicarbon). Various esters such as state; air, nitrogen; so-called freon gas such as tetrafluoromethane, hexafluoroethane, various chlorofluorocarbon gases) or methanol, ethanol, propatool, acetone, methyl ethyl ketone;
Discharged from a double spinneret together with a hollow part forming agent that exhibits microcoagulability in the spinning solution, such as a liquid containing at least one selected from formic acid, acetic acid, propionic acid, and polyols such as glycerin, or an aqueous solution thereof. , and then introduced into a coagulation bath after passing through a non-coagulating atmosphere. As the coagulant, aqueous solutions such as caustic soda, sulfuric acid, hydrochloric acid, acetic acid, ammonium sulfate, acetone, and lower alcohols can be used, and sulfuric acid or ammonium sulfate aqueous solutions are preferred. By using sulfuric acid or ammonium sulfate aqueous solution, the hollow fiber membrane of the present invention having a larger pore diameter than conventional membranes can be easily obtained. After the coagulated filaments are refined with water and an inorganic acid, a membrane pore size retaining agent is applied thereto, followed by a drying process to obtain the desired hollow fiber membrane. As the membrane pore size maintaining agent, for example, glycerin, polyglycerin, liquid polyethylene oxide, sorbitol, etc. are used.

The membrane pore size can be designed depending on which waste products with a molecular weight of β2-microglobulin or higher are targeted for removal, but in order to obtain a hollow fiber membrane with an average pore radius of 40 to 200, ammonium sulfate is used as a coagulant. It is preferable to use an aqueous solution or sulfuric acid (aqueous solution) in combination with glycerin or liquid polyethylene oxide as a membrane pore size retaining agent.

When sulfuric acid or ammonium sulfate aqueous solution is used as a coagulant, the structure of the inner surface of the hollow fiber membrane increases as the membrane thickness increases, in order to provide an anisotropic membrane in which the pore size increases from outside to inside in the direction of membrane thickness. The membrane becomes sparse and coagulates when it comes into contact with blood, making it unsuitable as a blood purification membrane. To avoid this, it is effective to smooth the inner surface of the hollow fiber membrane by reducing the thickness of the membrane or by using a microcoagulable hollow part forming agent to coagulate the hollow spinning liquid from the inner surface. It is. In addition, while the membrane pore diameter retaining agent adhesion rate of conventional regenerated cellulose hollow fiber membranes was at most 10% or less based on the weight of cellulose, in the hollow fiber membrane according to the present invention, it is preferably 10 to 200%. is 20-1
It is 60%.

〔Example〕

The hollow fiber membrane of the present invention will be specifically described in detail with reference to Examples below.

Example 1 A cuproammonium rayon solution with a cellulose concentration of 8% prepared by a known method as a spinning solution, and trichlorotrifluoroethane (liquid at normal temperature and normal pressure) as a hollow part forming agent were added at 5 and 8%, respectively, from a double spinneret. ml/min
After discharging at a rate of 3.0 ml/win and allowing it to fall about 25 cm in the air under its own weight, it was coagulated with a 25° Cl2O% ammonium sulfate aqueous solution and led onto a conveyor for the scouring process. 50°C warm water; 50″C12% on a conveyor where no forced mechanical tension is applied to this filament.
Sulfuric acid water: After scouring with 50°C hot water using a shower, unwrap it, apply glycerin using a membrane pore retaining agent applying device, run a tunnel type drying oven at 155°C, and then 80m/+ll1n of water. Winded at speed.

The amount of glycerin adhered to the hollow fiber membrane thus obtained was 130% based on cellulose.

The mass transfer coefficient for water was newly measured for this hollow fiber membrane, and the average pore radius of the membrane was calculated based on the above formula, which was 110 people. In addition, the in of this hollow fiber membrane
The viLro membrane permeation performance and the results when used clinically as a blood purifier with an effective membrane area of 1.0 mm were as shown in Tables 1 and 2.

In the in vitro test results shown in Table 1, β2-
Not only microglobulin but also β-lactoglobulin (-β-LG, molecular weight 35,000
), while the permeation of albumin is extremely low (it is a membrane that blocks the permeation of substances with a molecular size larger than albumin, and can remove substances with a molecular size smaller than that over a wide range of substance groups). It showed that there is.

In addition, the clinical data shown in Table 2 includes individual differences among patients and differences in dialysis conditions (amount of water removed, etc.) for each patient, and does not necessarily directly reflect the characteristics of the hollow fiber membrane itself. Both were shown to be extremely useful in practice.

Example 2 Spinning solution discharge i10.3d/n+in, using tetrafluoromethane (gas at normal temperature and pressure) as a hollow part forming agent, discharging amount 3.3 m/min, drying temperature 150°C
The winding speed was 90 m/min, and the other conditions were as per Example 1, with the amount of glycerin attached to cellulose being 5
A 0% hollow fiber membrane was obtained.

Further, as shown in Table 1, the characteristics of this hollow fiber membrane were effective in removing substances with a molecular size smaller than albumin.

Example 3 A cuproammonium rayon solution with a cellulose concentration of 8% prepared by a known method as a spinning solution and trichlorotrifluoroethane as a hollow part forming agent were each used at a rate of 4.55 threads/min and 2.18 m1 from a double spinneret. /min into the air and let it fall about 15cm under its own weight, then 2
It was coagulated with a 5°C12O% ammonium sulfate aqueous solution and introduced onto a conveyor for the scouring process.

On a conveyor where no forced mechanical tension is applied to this filament, 50°C warm water; 50°C, 2% sulfuric acid water;
After scouring with a shower in warm water at °C, unwrap the membrane, apply an 85% glycerin aqueous solution at 1.3 ml/min/2 filaments using a pore retaining agent applying device, and dry in a tunnel at 155 °C. 90 after running the furnace
It was wound up at a speed of m/min.

The amount of glycerin adhered to the hollow membrane thus obtained was 120% based on cellulose.

The structural specifications and in vitro J permeation performance of this hollow membrane were as shown in Table 1.

Example 4 A cuproammonium rayon solution with a cellulose concentration of 6% prepared by a known method as a spinning solution, and tetrafluoromethane as a hollow part forming agent were added to each K from a double spinneret.
After discharging into the air at a rate of 6.17m/min and 2.45m/min and dropping it by its own weight, 25
Coagulate with a 111% caustic soda aqueous solution at 111°C, and process the filamentous body in 45°C warm water according to the known tension scouring method;
C12% sulfuric acid water; 90m of 45°C warm water
/min. The wound yarn was immersed in a 30% glycerin aqueous solution for 30 minutes, and then unwound and passed through a 145"c tunnel dryer at both entrance and exit speeds of 60 m/min. A dry hollow fiber membrane was obtained.

The amount of glycerin adhered to the hollow fiber membrane thus obtained was 160% based on cellulose.

The structural specifications and inv1tro membrane permeation performance of this hollow fiber membrane were as shown in Table 1.

Example 5 A cuproammonium rayon solution with a cellulose concentration of 8% prepared by a known method as a spinning solution and trichlorotrifluoroethane as a hollow part forming agent were each used for 12. oml/min, 2.40 m/min into the air, and after dropping about 30 cm under its own weight, 2.
It was coagulated with a 5°C12O% ammonium sulfate aqueous solution and introduced onto a conveyor for the scouring process. At 50°C on a conveyor where no forced mechanical tension is applied to this filament.
Warm water; 5o"C 12% sulfuric acid water; 50°C hot water. After performing one-step scouring with warm water, unwrap, apply 85% glycerin aqueous solution using a pore-retaining agent applying device, and dry in a tunnel type drying oven at 145°C. After running at a speed of 90 m/min, the glycerin adhesion amount per cellulose was 140%.
A hollow fiber membrane was obtained.

The structural specifications and in vitro membrane permeation performance of this hollow fiber membrane were as shown in Table 1.

Reference example Spinning liquid discharge! A hollow fiber membrane was obtained under the same conditions as Example 1 except that the speed was 21.7 d/min.

When heparinized whole cow blood was poured through this hollow fiber membrane, blood clots occurred, making the membrane unsuitable for use as a blood purification membrane. The cause of this blood clot is that the dried membrane containing glycerin has a thickness of 32 μm.
This is thought to be because it is as thick as Ill and its inner surface has extremely rough undulations under a scanning electron microscope.

Comparative Example 1 A cuproammonium rayon hollow membrane, which has been conventionally used for artificial kidneys, was obtained according to a known method. As shown in Table 1, this method has an excellent ability to remove low molecular weight substances such as urea, but has a low ability to remove substances in the high molecular weight range such as β2 microglobulin, and is not suitable for the purpose of the present invention.

Comparative Example 2 A cuproammonium rayon hollow fiber membrane having an inner diameter of 250 mm, a membrane thickness of 25 mm, and an average pore radius of 250 mm was obtained according to the method for manufacturing a large-pore cellulose membrane disclosed in JP-A-59-204912. As shown in Table 1, this product showed an extremely high removal ability for β2-microglobulin with a sieving coefficient of 1.0, but on the other hand, the sieving coefficient for albumin, which is a useful blood protein, was also high at 0.982. Therefore, when used as a blood purification membrane, excessive loss of useful proteins is expected, making it unsuitable for the purpose of the present invention.

[Operation and Effects of the Invention] The hollow fiber membrane of the present invention has a water-containing porosity of 76 to 95% when wet and an albumin sieving coefficient of 0.15 or less in blood filtration. Sieving coefficient is 0.3 or more or its overall mass transfer coefficient is 2X
It is suitable for filtration and diffusion removal of β2-microglobulin and β2-microglobulin, and has excellent ability to remove high molecular weight substances other than β2-microglobulin. Moreover, loss of useful proteins such as albumin during blood purification therapy, particularly hemodialysis therapy, can be suppressed to a level that does not pose a practical problem.

In other words, the hollow fiber membrane according to the present invention removes waste products with a lower molecular weight than albumin and substances in the high molecular weight range such as β2 microglobulin without substantially losing useful blood components with a higher molecular weight than albumin. It is a blood purification membrane that can remove a wide range of substances, including substances.

Claims (1)

[Claims] 1. Regeneration characterized by having a hollow part continuously extending in the axial direction of the fibers, having a water-containing porosity of 76 to 95% when wet, and having an albumin sieving coefficient of 0.15 or less in blood filtration. Cellulose hollow fiber membrane.