JPH0318492B2 - - Google Patents

Description

[Detailed description of the invention]

<Technical Field> The present invention relates to a method for producing cellulose ester hollow fiber membranes. More specifically, the present invention relates to a method for producing a so-called plasma albumin-permeable hollow fiber membrane, which is a hollow fiber membrane whose main component is cellulose acetate, and which can recover albumin from plasma. <Prior Art> In recent years, therapeutic methods using hollow fiber membranes for the purpose of blood purification have been progressing, and plasma exchange therapy is one of them. Plasma exchange therapy is a therapy in which plasma is separated and fresh healthy plasma is injected to remove harmful high-molecular proteins from the patient's blood. It is attracting attention as a treatment method. Although this treatment method has shown excellent effects, there remain problems such as increased costs due to the use of large amounts of fresh plasma and hepatitis infection. For this reason,
If immune complexes and large molecular weight proteins can be removed from the patient's isolated plasma and albumin can be recovered, the above problems will be solved.
It is currently being intensively researched. Attempts have been made to use porous membranes to recover such albumin, and the pore diameter of the porous membrane for this purpose is approximately 0.1 μ at the most, and approximately 0.02 μ at the minimum. Several patent applications have already been filed for plasma separation membranes. In other words, for products made from cellulose acetate, for example, Japanese Patent Publication No. 31901/1983 discloses a method of obtaining a porous film by adding various alcohols, esters, ethers, and cyclic hydrocarbons to a solvent along with metal salts. It is proposed that the film be formed by However, as clearly shown in the examples, these methods have relatively large pore diameters,
Most of the membranes have a diameter of 0.1μ or more, and this method is not necessarily suitable for producing membranes for collecting albumin. <Object of the Invention> The present invention aims to obtain a hollow fiber membrane for recovering albumin from the plasma of such patients. That is, the purpose of the present invention is to efficiently recover albumin from plasma by adjusting the average pore diameter to approximately 0.01μ.
It is an object of the present invention to provide a method for advantageously producing cellulose ester hollow fiber membranes having a diameter of ~0.1μ, more preferably approximately 0.02μ to approximately 0.07μ. <Structure of the Invention> As a result of intensive research to achieve the above object, the present inventors found that a specific organic compound added to the spinning stock solution together with a solvent and the pores of the cellulose ester hollow fiber membrane obtained are unique. It was found that there is a relationship between
It was discovered that a hollow fiber membrane with excellent albumin permeability of about 0.1μ can be obtained very advantageously, and the present invention was achieved. That is, the present invention is based on the following general formula () [However, in formula (), R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ³ is a hydrogen atom,

[Formula] (where R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) or an alkyl group having 1 to 3 carbon atoms. When R ¹ and R ³ are both alkyl groups, they may cooperate with each other to form a ring. ] At least one nitrogen-containing compound represented by 10 to
A spinning stock solution containing 40% by weight, 15 to 25% by weight of cellulose ester mainly composed of cellulose acetate, 0.1 to 5% by weight of divalent metal salt, and 30 to 74.9% by weight of a mixed solvent of ketone and lower alcohol. The present invention provides a method for producing a hollow fiber membrane selectively permeable to plasma albumin, which is characterized by performing wet spinning using a plasma albumin permselective membrane. The present invention will be explained in more detail below. The cellulose ester in the present invention refers to cellulose acetates such as cellulose diacetate and cellulose triacetate, nitrocellulose, etc., and preferably cellulose acetate is used as the main component. In the present invention, as a component other than cellulose acetate as the main component, a polymer compound soluble in the spinning dope of the present invention other than cellulose ester can also be used. Examples of the nitrogen-containing compound represented by the general formula () include linear amides such as formamide, dimethylformamide, N-dimethylacetamide, and propionamide, N-methylpyrrolidone, ε-caprolactam, γ-parerolactam,
Examples include cyclic amides such as α-piperidone, and ureas such as urea, dimethylurea, tetramethylurea, and diethylurea. Among the nitrogen-containing compounds represented by the formula (), formamide, dimethylformamide, N-methylpyrrolidone, ε-caprolactam and urea are preferred. In addition, the ketone in the present invention has 3 carbon atoms.
-5 ketones, and preferred ones include acetone, methyl ethyl ketone, and the like. Furthermore, the lower alcohol of the present invention has 2 to 2 carbon atoms.
5 monohydric alcohol, preferably methanol, ethanol, etc. As the divalent metal salt of the present invention, calcium chloride, magnesium chloride, etc. are preferred. Two or more types of each of these ketones, lower alcohols, and salts may be used, but usually one type of each is used. Preferably, in the production method of the present invention, for example, a polymer compound mainly composed of cellulose acetate and an acetone-methanol mixed solvent are added with nitrogen of the general formula () that is considered to have an affinity for the acetate group of the polymer. Using a spinning stock solution prepared by adding containing compounds and further adding calcium chloride,
It uses wet spinning. The spinning dope of the present invention preferably contains a polymer such as cellulose acetate in an amount of 15 to 25% by weight from the viewpoint of spinning stability such as spinning viscosity and hollow fiber membrane performance. The concentration of a divalent metal salt, such as calcium chloride, contained in the spinning stock solution is preferably in the range of 0.1 to 5.0% by weight, and more preferably in the range of 1.0 to 3.0% by weight, in order to control the pore diameter of the hollow fiber membrane obtained. Range is preferred. By reducing the calcium chloride concentration, hollow fiber membranes with small pore diameters can be easily obtained. Further, the concentration of the nitrogen-containing compound of formula () contained in the spinning dope is preferably in the range of 10 to 40% by weight, particularly preferably 20 to 30% by weight, in order to increase the pore diameter of the hollow fiber membrane. Furthermore, the mixing weight ratio of ketones and lower alcohols in the spinning dope is 2.5/1 in terms of polymer solubility, spinning stability, etc.
It is preferable that it is in the range of ~4/1. Note that the spinning dope may contain water and other components within a range that does not adversely affect the spinnability and hollow fiber membrane performance. The spinning stock solution may be prepared by any conventionally known method, but for example, a nitrogen-containing compound is added to a polymer compound, the mixture is well stirred, and then a methanol solution of calcium chloride dihydrate is added and mixed. Then, acetone is added and dissolved for 5 hours or more while stirring, and if necessary, post-treatment such as filtration is performed. In the present invention, wet spinning is carried out using a spinning dope obtained in this way using an annular nozzle. Any annular nozzle may be used as long as a predetermined hollow fiber membrane can be obtained.
The coagulating liquid outside the hollow fibers and the coagulating liquid inside the hollow fibers used in the wet spinning include water-lower alcohol, water-ketone, water-lower alcohol-
It is preferable to use a mixed liquid system of ketones, etc., and may contain a nitrogen-containing compound represented by the above formula (), salts such as calcium chloride, and other compounds. In the method for manufacturing a hollow fiber membrane of the present invention, it is also possible to control the average pores by adjusting the composition of the coagulating liquid outside the hollow fiber and the coagulating liquid inside the hollow fiber, and the manufacturing method Depending on the method, it is also possible to obtain a so-called anisotropic hollow fiber membrane in which the density differs between the inside and outside of the hollow fiber membrane. That is, by using a coagulating liquid with a higher solidifying rate, it is possible to form an anisotropic structure with a denser structure than that on the other side. The hollow fiber membrane obtained by the production method of the present invention has an average pore diameter in the range of about 0.01μ to about 0.1μ, more preferably in the range of about 0.02μ to about 0.07μ. It has a characteristic of high selective permeability of albumin therein. This will be explained in more detail by giving examples below.
The present invention is not limited in any way by these Examples. In the examples, "part" means "part by weight"
means. Furthermore, the average pore diameter of the hollow fiber membranes in the Examples was measured by a simple method called the water permeation method described below. That is, it was calculated by the following formula by passing a certain amount of water and measuring the flow rate and pressure loss. D ² = 32y・d・j/Pr・△P where D: average pore diameter d: membrane thickness J: water permeation rate y: viscosity of water Pr: porosity of hollow fiber membrane △P: pressure loss, respectively means. Example 1 18.5% by weight of cellulose acetate with a degree of acetylation of 52%, 20% by weight of formamide, 10% by weight of urea, _CaCl2 .
2H ₂ O2 wt%, acetone/methanol (3/1)
A dope having a composition of 49.5% by weight was prepared, and after filtration, wet spinning was performed using an annular nozzle. The coagulation bath composition was water-methanol-acetone (50:
40:10), and the internal coagulating liquid of the hollow fiber is water-ethanol-formamide (50:40:10). A hollow fiber with an inner diameter of 200 μm and a membrane thickness of 70 μm was obtained, and the pore diameter was 400 μm. Using the obtained hollow fibers, both ends were fixed with polyurethane so that the outer surface area was 1 m ² to prepare a hollow fiber separator. An overexperiment was conducted at 37° C. for 1 hour so that bovine plasma containing 5,000 units of pepperin per separator permeated from the inside to the outside of the hollow fiber. In addition, the permeation amount at that time is 20ml/min, and 100
A partial circulation method of ml/min was used. Albumin and immunoglobulin M were analyzed in the plasma stock solution and the permeate during the first hour of operation. As a result, the permeability of albumin was 90% and that of immunoglobulin M was 41%. Example 2 250 parts of formamide was added to 185 parts of cellulose acetate with a degree of acetylation of 52%, and 150 parts of methanol in which 10 parts of CaCl _{2.2H 2} O was dissolved were added and mixed, followed by acetone.
When 405 parts were added and dissolved with stirring, cellulose acetate was 18.5 parts.
wt%, formamide 25 wt% _{, CaCl2.2H2O}
A spinning stock solution containing 1% by weight and 5.5% by weight of acetone-methanol can be prepared. After spinning, hollow fibers were spun using an annular nozzle. The coagulating liquid used had the same composition as in Example 1. A hollow fiber with an inner diameter of 300 μm and a wall thickness of 80 μm was obtained, and the pore diameter thereof was 350 Å. Example 3 Using cellulose acetate with a degree of acetylation of 52%, a spinning stock solution composition was prepared as follows. i.e. cellulose acetate
20% by weight, N-methylpyrrolidone 25% by weight,
After passing through a spinning stock solution with a composition of 3% by weight of CaCl ₂ 2H ₂ O and 52% by weight of acetone/methanol (3/1),
By wet spinning using an annular nozzle, hollow fibers with an inner diameter of 300 μm and a wall thickness of 50 μm were obtained, and the pore diameter was 450 μm.
It was Å. Example 4 Cellulose acetate 90% by weight with a degree of acetylation of 52%, degree of nitrification
12% cellulose nitrate, 10% by weight, mixed cellulose esters 18.5% by weight, formamide 25% by weight,
A dope with a composition of 3% by weight of CaCl ₂ 2H ₂ O and 55.5% by weight of acetone/methanol (3/1) was prepared.
Wet spinning was carried out using the same coagulating liquid as in Example 1 using a post-filtering annular nozzle. A hollow fiber with an inner diameter of 250 μm and a wall thickness of 60 μm was obtained, and the pore diameter was 300 Å. Comparative Example 1 Same as in Example 2, 18.5% by weight of cellulose acetate, 25% by weight of formamide, 56.5% by weight of acetone-methanol at a weight ratio of 3:1, and _CaCl2 .
A stock solution without 2H ₂ O was prepared and hollow fibers were spun to obtain hollow fibers with an inner diameter of 300μ and a wall thickness of 80μ.
The pore diameter was approximately 60 Å, and almost no albumin permeability was observed. Comparative Example 2 A stock solution was prepared in the same manner as in Example 2 except that formamide was not used to create a stock solution containing 18.5% by weight of cellulose acetate, 1% by weight of CaCl ₂ 2H ₂ O, and 80.5% by weight of acetone-methanol solution. Then, the hollow fibers were spun to obtain hollow fibers with an inner diameter of 300μ and a wall thickness of 80μ. The pore diameter was as large as about 1000 Å, and the permeability of albumin was 100% and the permeability of immunoglobulin M was also 80% or more, so that good permselectivity for albumin could not be obtained. <Effects of the Invention> According to the present invention, an albumin-permeable hollow fiber membrane for recovering albumin in plasma can be obtained very easily. That is, according to the present invention, a hollow fiber membrane having an average pore diameter suitable for selective permeation of aluminium can be obtained very stably and easily. In particular, the effect of the present invention is that the average pore diameter is approximately
The pore diameter can be easily controlled within the range of 0.01 to 0.1μ, particularly within the range of 0.02 to 0.07μ, by adjusting the hollow fiber manufacturing conditions.

Claims (1)

[Claims] 1 The following general formula (I) [However, in formula (), R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ³ is a hydrogen atom, [Formula] (where R ⁴ and R ⁵ are , which are the same or different and represent a hydrogen atom or an alkyl group having ¹ to ³ carbon atoms. In some cases, they may cooperate with each other to form a ring. ] At least one nitrogen-containing compound represented by 10 to
A spinning stock solution containing 40% by weight, 15 to 25% by weight of cellulose ester mainly composed of cellulose acetate, 0.1 to 5% by weight of divalent metal salt, and 30 to 74.9% by weight of a mixed solvent of ketone and lower alcohol. A method for producing a hollow fiber membrane selectively permeable to plasma albumin, which comprises performing wet spinning using a plasma albumin selectively permeable hollow fiber membrane.