JP2003260340A - Hydrophilic polysulfone membrane - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a polysulfone membrane with suppressed adsorption of proteins as a membrane for separation or concentration of antigens, enzymes or the like or for hemocatharsis by dialysis of blood or filtration of blood. <P>SOLUTION: The membrane comprises a polysulfone resin containing a hydrophilic polymer or a polymer having a hydrophilic segment. In the IR absorption spectra of the membrane measured at 100 points with a 20×20 μm angle of view, the number of measuring points satisfying an inequality of (Aco)/(Acc)≤0.15 is ≤5, wherein Aco is the intensity of the absorption peak indicating C=O near 1660 cm<SP>-1</SP>and Acc is the intensity of the absorption peak indicating the benzene ring C=C in the polysulfone near 1580 cm<SP>-1</SP>. The average μof the ratio (Aco)/(Acc) is ≥0.1 and <0.4. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a polysulfone-based membrane in which protein adsorption is suppressed, which comprises an antibody,
It is useful for separating and concentrating enzymes and blood purification such as hemodialysis and blood filters.

[0002]

2. Description of the Related Art Polysulfone polymers are excellent in radiation resistance and heat resistance, but polysulfone itself is hydrophobic and has a drawback that proteins such as platelets and blood cells in blood are easily adsorbed. Therefore, when used for blood purification such as separation and concentration of antibodies and enzymes, hemodialysis, blood filters, etc., it is used by blending hydrophilic polymers such as polyvinylpyrrolidone to impart blood compatibility. ing.

Various theories have been considered as to the reason why the blend of hydrophilic polymers is effective in suppressing the adsorption of proteins. For example, by improving the hydrophilicity of the contact surface with blood, Since the hydrophobic interaction is suppressed, the wiper effect of the hydrophilic polymer chain protruding from the contact surface is expressed, or the water layer structure which is considered to be formed on the hydrophilic polymer is It may interfere with the contact between antifreeze water and protein hydration water, which is a trigger for protein adsorption. However, if the content of such hydrophilic polymer is insufficient or if the blended hydrophilic polymer is unevenly dispersed in the polysulfone-based polymer, locally high hydrophobicity is obtained. It is considered that a part is generated, and that part easily causes protein adsorption.

The blended polyvinylpyrrolidone is crosslinked and insolubilized by irradiation with radiation. It is believed that the insolubilization can reduce the elution of polyvinylpyrrolidone into blood upon contact with blood, but if polyvinylpyrrolidone crosslinks too much, platelets will be activated when blood contacts the membrane surface. It is known (Japanese Patent Laid-Open No. 9-323031). The reason for this is not yet clear, but the degradation and cross-linking of the polyvinylpyrrolidone polymer chain by irradiation reduces the mobility of the molecular chain and reduces the wiper effect. It is conceivable that the surface of the polysulfone originally having a small amount of polysulfone is exposed, and platelets are adsorbed there.

As a polysulfone-based membrane in which protein adsorption is suppressed, attention is paid to the relationship between the sorbed water structure on the membrane surface and protein adsorption, and an infrared absorption spectrum measurement is performed to attempt to characterize the membrane in which protein adsorption is suppressed. Has been
Protein adsorption is a microscopic phenomenon, and even with the same hydrophilic surface, the dispersion state of hydrophilic parts may differ from a more microscopic viewpoint. Was not specified (JP-A-9-122462).

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a polysulfone-based membrane that overcomes the above-mentioned drawbacks and that suppresses protein adsorption.

[0007]

In order to solve the above problems, the present invention has the following constitution. That is, (1) a film made of a polysulfone resin containing a hydrophilic polymer or a polymer containing a hydrophilic segment, and having a viewing angle of 20 × 20 μm in an infrared absorption spectrum
When measured at 00 points, the intensity of the absorption peak derived from C = O near 1660 cm ^-1 (Aco) and the intensity of the absorption peak derived from benzene ring C = C of polysulfone near 1580 cm ^-1 (Ac
The ratio (Aco) / (Acc) of c) is 0.15 or less, the number of measurement points is 5 or less, and the average value μ of the ratio (Aco) / (Acc) is 0.1 or more and less than 0.4. A hydrophilic polysulfone-based membrane characterized by being present.

(2) The hydrophilic polysulfone-based membrane as described in (1), wherein the hydrophilic polymer is polyvinylpyrrolidone.

(3) The hydrophilic polysulfone-based membrane according to (1), wherein the hydrophilic segment is polyvinylpyrrolidone.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The form of the separation membrane of the present invention is not particularly limited, and may be a flat membrane, a hollow fiber membrane or the like. However, the hollow fiber membrane type is preferable in view of the function of the artificial kidney and the treatment efficiency, that is, the securing of the surface area in contact with blood.

When the polymer solute is a protein and the polymer is highly hydrophobic, adsorption of a large amount of protein is observed. For this reason, it is possible to suppress adsorption to some extent by processing the polymer surface to be hydrophilic, but such hydrophilicization is not uniformly performed at a sufficient density on the polymer surface, and the hydrophobicity is strong. If a portion remains, it is considered that protein adsorption occurs in that portion.

Therefore, the content of the hydrophilic segment in the polysulfone resin containing the hydrophilic polymer, particularly the hydrophilic polymer having a C═O group or the polymer containing the hydrophilic segment having a C═O group and its planar As a result of investigating the correlation with protein adsorption using the infrared absorption spectrum in analyzing the dispersion state, it was found that the film was composed of a polysulfone resin containing a hydrophilic polymer or a polymer containing a hydrophilic segment. 1 when measured at 100 points with a 20 × 20 μm viewing angle in the spectrum
Intensity of absorption peak derived from C = O near 660 cm ^-1 (Aco)
And the benzene ring C = C of polysulfone near 1580 cm ^-1
Ratio (Aco) / (Ac of intensity (Acc) of absorption peak derived from
The number of measurement points where c) is 0.15 or less is 5 or less,
The hydrophilic polysulfone-based membrane having an average value μ of the ratio (Aco) / (Acc) of 0.1 or more and less than 0.4 has particularly low adsorption of proteins and the like, separation of antibodies and enzymes, concentration and hemodialysis, blood It was found to be useful for blood purification such as filters.

Examples of the polysulfone resin in the present invention include polysulfone and polyether sulfone.

The hydrophilic polymer in the present invention includes
Any water-soluble polymer containing a C = O group in the molecule may be used,
Examples thereof include polyvinylpyrrolidone, polyacrylic acid, polymethacrylic acid, and the like, with polyvinylpyrrolidone being preferred. Further, as the polymer containing a hydrophilic segment, the main chain is a block copolymer consisting of a hydrophilic segment containing a C = O group and a hydrophobic segment, the hydrophilic polymer containing a C = O group in the backbone of the polymer chain, such as polyvinyl. Pyrrolidone, a hydrophilic polymer having branches having hydrophobic segments, or conversely, having a hydrophobic trunk and having C═O groups, such as a graft copolymer made of polyvinylpyrrolidone can be mentioned. Examples of preferable hydrophobic segments include polystyrene segments and hydrophobic (meth) acrylate polymer segments such as polymethyl (meth) acrylate and polybutyl (meth) acrylate, and more preferably polystyrene segments.

The molecular weight of the hydrophilic polymer or the polymer containing a hydrophilic segment is preferably in the range of 30,000 daltons to 2 million daltons, more preferably 50,000 daltons to 1.5 million daltons.
If the molecular weight is too small, elution from the membrane increases, which is not preferable for use. If the molecular weight is too large, the miscibility with the polysulfone resin may deteriorate and the dispersibility may deteriorate.

The most important points in the present invention are the hydrophilic polymer, the content of the polymer containing the hydrophilic segment in the polysulfone resin, and the dispersibility. First, in the infrared absorption spectrum, 1 at a viewing angle of 20 × 20 μm
When measured at 00 points, the intensity of the absorption peak derived from C = O near 1660 cm ^-1 (Aco) and the intensity of the absorption peak derived from benzene ring C = C of polysulfone near 1580 cm ^-1 (Ac
The ratio (Aco) / (Acc) of c) is 0.15 or less, and the number of measurement points must be 5 or less. When it exceeds 5, there are many weakly hydrophilic portions and Protein will be easily attached. The absorption peak intensity ratio (A
co) / (Acc) is an index showing the hydrophilicity of the membrane. Generally, the larger the value is, the higher the hydrophilicity is, and it is considered that protein adsorption is suppressed, but if it is too large, the elution from the membrane increases. There is a drawback that. Therefore, the ratio (Aco) /
It is necessary that the average value μ of (Acc) is 0.1 or more and less than 0.4. If it is less than 0.1, the hydrophilicity of the polysulfone resin is not sufficient, and if it exceeds 0.4, Elution of the hydrophilic polymer and the polymer containing the hydrophilic segment from the polysulfone resin increases, which is not preferable in practice.
Specifically, the measurement of the film of the present invention is performed by preparing 10 measurement samples from the same film, and performing 10 points from one sample, for a total of 100 points. Each measurement within one sample is
The 20 × 20 μm square has two viewing angles of 5 vertically.
Scanning is performed so that the viewing angles do not overlap with each other and the viewing angles are in contact with each other without a gap in a form in which the viewing angles do not overlap. The intensity of the absorption peak of the infrared absorption spectrum in the present invention is determined by the method described in the examples.

The membrane satisfying the above conditions can be obtained by spinning by a dry-wet method and irradiating with γ-ray in an aqueous solution containing glycerin. Furthermore, by adjusting the composition of the hydrophilic polymer and the polymer containing the hydrophilic segment, the film-forming conditions, and the post-treatment conditions, a film in which the hydrophilic polymer and the polymer containing the hydrophilic segment are properly blended with the polysulfone-based resin is obtained. be able to.

[0018]

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. First, the evaluation method used in this example will be described.

(1) Preparation of infrared absorption spectrum measurement sample It is necessary to immerse the measurement sample in water or the like for at least 1 hour in advance and thoroughly wash it. In the case of hollow fibers,
The membrane is cut in a plane passing through the tube axis and then washed. If the sample is a flat membrane, then 10 squares of about 5 mm square are sampled at locations as far apart from each other as possible, and if it is a hollow fiber, each of 10 threads is sampled as described above. Prepare the one cut along the plane passing through.

(2) Infrared absorption spectrum measurement A microscopic infrared absorption spectrum measurement device was used for measurement, and the viewing angle, which is the range of infrared light, was 20 μ × 2 in reflection mode.
Set to 0 μm. Since 10 points are measured for each sample, a total of 100 points will be measured. The measuring method in one sample is as follows. First, scan the viewing angles so that the respective measurement ranges do not overlap,
5 points vertically x 2 points horizontally, 2 points vertically x 5 points horizontally, or 10
Let us see the range of 0 μ × 40 μm. The measurement conditions are a resolution of 4 and an integration count of 64 times.

(3) Infrared absorption spectrum intensity Baseline correction of the obtained infrared absorption spectrum is performed. The correction is to make the absorption intensity 0 at the points of 1700 cm ^-1 and 1000 cm ^-1 . The intensity of the absorption peak derived from C = O near 1660 cm ^-1 (Aco) and the intensity of the absorption peak derived from the benzene ring C = C of polysulfone near 1580 cm ^-1 (Acc) were determined, and the ratio (Aco) / ( Acc),
The number of measurement points having a ratio of 0.15 or less and the average value (μ) of 100 measurement points are obtained.

(4) Evaluation of Platelet Adhesion Amount of platelet adhesion of each sample was evaluated when the sample was a hollow fiber. Cut the hollow fiber membrane to be measured to 12 cm in length, bundle 30 pieces into a small module, and perfuse fresh citric acid-added rabbit blood for 60 minutes at 0.59 ml / min, followed by 1 saline solution. Passed for a minute. Next, 100 cm of the hollow fiber was chopped and ultrasonically irradiated in physiological saline containing 0.5% Triton X-100 to quantify the lactate dehydrogenase released from the platelets adhered to the membrane surface. For the measurement of enzyme activity, Monotest LDH (Roche) was used. At this time, rabbit blood was used as perfusion blood.

Example 1 Polysulfone (Tedel Amoco Udel P-350)
0) 18 parts, polyvinylpyrrolidone (K3 manufactured by BASF)
0) 9 parts of N, N-dimethylacetamide 72 parts, water 1
In addition to the parts, the mixture was heated and dissolved at 90 ° C. for 14 hours. This film-forming stock solution was discharged from an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm to discharge a solution consisting of 58 parts of dimethylacetamide and 42 parts of water as a core liquid, and a dry length of 35
After passing 0 mm, it was introduced into a coagulation bath of 100% water to obtain a hollow fiber. The obtained hollow fiber membrane was irradiated with γ-rays in an aqueous solution containing 0.5% of glycerin and 0.1% of polyvinylpyrrolidone (K90 manufactured by BASF). γ-ray irradiation dose is 25 kGy
Met. Ten hollow fibers were each cut along a plane passing through the tube axis and immersed in water for 1 hour or more, and then the infrared absorption spectrum was measured. The ratio (Aco) / (Acc) was 0.1.
The number of measurement points that are 5 or less is 0, and the ratio (Aco) / (Acc)
The average value μ of was 0.33. As a result of evaluating the amount of adhered platelets, it was 3.0 unit / cm.

Example 2 Polysulfone (Tedel Amoco Udel P-350)
0) 18 parts, polyvinylpyrrolidone (K3 manufactured by BASF)
0) 9 parts of N, N-dimethylacetamide 72 parts, water 1
In addition to the parts, the mixture was heated and dissolved at 90 ° C. for 14 hours. This film-forming stock solution was discharged from an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm to discharge a solution consisting of 58 parts of dimethylacetamide and 42 parts of water as a core liquid, and a dry length of 35
After passing 0 mm, it was introduced into a coagulation bath of 100% water to obtain a hollow fiber. The obtained hollow fiber membrane was irradiated with γ-ray in an aqueous solution containing 0.1% of glycerin. The absorbed dose of γ rays was 25 kGy. Ten hollow fibers were each cut along a plane passing through the tube axis and immersed in water for 1 hour or more, and then the infrared absorption spectrum was measured. The ratio (Aco) / (Acc) was 0.15.
The number of measurement points below was 0, and the average value μ of the ratio (Aco) / (Acc) was 0.32. As a result of evaluating the amount of adhered platelets, it was 7.2 unit / cm.

Comparative Example 1 The hollow fiber membrane obtained in the same manner as in Example 1 was irradiated with γ rays in pure water. The absorbed dose of γ rays was 25 kGy. 10 hollow fibers were cut along a plane passing through each tube axis and immersed in water for 1 hour or more, and then the infrared absorption spectrum was measured. The ratio (Aco) / (Acc) was 0.15 or less. The number of points is 7, and the average value μ of the ratio (Aco) / (Acc) is 0.
It was 29. As a result of evaluating the amount of adhered platelets, 53.5
It was unit / cm.

[0026]

According to the present invention, it is possible to provide a polysulfone-based membrane in which protein adsorption is suppressed as a membrane for blood purification such as separation and concentration of antibodies and enzymes, hemodialysis and blood filters.

Continued front page    F term (reference) 4C077 AA05 BB01 EE01 EE03 KK11                       LL02 LL05 NN04                 4D006 GA13 HA01 HA41 LA06 MA01                       MA03 MB09 MC36 MC40 MC62                       MC62X MC63 MC82 MC88                       NA05 NA10 NA13 NA16 NA42                       NA75 PA01 PB09 PB53 PC41                       PC47

Claims (3)

[Claims] 1. A film comprising a polysulfone-based resin containing a hydrophilic polymer or a polymer containing a hydrophilic segment, which has a C around 1660 cm ^-1 when measured at 100 points at a viewing angle of 20 × 20 μm in an infrared absorption spectrum. The ratio (Aco) / (Acc) of the intensity (Aco) of the absorption peak derived from ═O and the intensity (Acc) of the absorption peak derived from the benzene ring C = C of polysulfone near 1580 cm ⁻¹ is 0.15 or less. A hydrophilic polysulfone-based membrane, wherein the number of measurement points is 5 or less, and the average value μ of the ratio (Aco) / (Acc) is 0.1 or more and less than 0.4. 2. The hydrophilic polysulfone-based membrane according to claim 1, wherein the hydrophilic polymer is polyvinylpyrrolidone. 3. The hydrophilic polysulfone-based membrane according to claim 1, wherein the hydrophilic segment is polyvinylpyrrolidone.