JPH06104753B2 - Non-adsorbing hydrophilic hollow fiber porous membrane - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention provides a hydrophilic hollow suitable for sterilization of injectables, infusions, bulk stock solutions, water for use, etc., of various drugs in the pharmaceutical industry and purification of fine particles. A filamentous porous membrane and a method for producing the same.

[Conventional technology]

Conventionally, in the pharmaceutical industry, many microfilters have been used to remove bacteria or fine particles from the produced various chemical solutions.

Hydrophilic membranes consisting of many types of flat membranes (disks) or pleated cartridges have been used in these microfilters. The reason for this is that their use is mostly a one-time use and most are discarded.
It was applicable only to so-called disposable type applications, and could not be applied to applications where it is used repeatedly or is used continuously or intermittently for a long period of time. Due to this repeated use or long-term use, hollow fiber microfilters have recently been put into practical use. Due to the advantages of the membrane shape, this hollow fiber microfilter is capable of a so-called cross-flow parallel flow method, can prevent the attachment of suspensions (bacteria or fine particles) to the membrane surface, and Excessive performance can be recovered by washing and washing.

With the advent of this hollow fiber microfilter, the field of membrane purification expanded dramatically, such as application to so-called bioreactors and application to sterilizing enzymes. However, most of the hollow fiber membranes are made of a polyolefin membrane and are inherently hydrophobic, so that the membrane must be temporarily wet with ethyl alcohol or the like before it can be used as an actual liquid. Further, it is not preferable because it is necessary to prevent the membrane from being dried during the process as much as possible, and there is a possibility that dissolved components may be adsorbed to the membrane during the period.

In fact, infusions and injectables are relatively expensive, but they need to have a minimum hold-up amount and be easy to handle. Therefore, it is essential that the membrane can be used immediately even when it is in a dry state. It is becoming a condition.

In addition to this hollow fiber membrane made of polyolefin, a polyvinyl alcohol-modified membrane is also on the market, but in addition to its inherent mechanical weakness, its mechanical strength becomes even weaker after it has been dried, and it stabilizes repeatedly. It is practically impossible to use it, and it is rarely used in final filters for infusion products.

On the other hand, many methods have been proposed for making hydrophilic by chemically modifying a polyolefin hollow fiber membrane. A specific example thereof is a method of introducing a sulfone group or a carboxyl group by smoking smoke, sulfonation with sulfuric anhydride, chlorosulfonic acid or the like, or grafting acrylic acid or the like to polyolefin. According to this method, one purpose of hydrophilization is reached, and it is suitable for the purpose of producing a part of pure water and giving an additional function such as ion adsorption.

However, for example, when purifying a drug solution containing proteins, amino acids, salts, etc. with these membranes,
It was often the case that the liquid deteriorated due to adsorption to the membrane, reaction, etc. For this reason, despite its excellent mechanical performance, it cannot be used for the purification of infusions, injections and the like.

[Problems to be solved by the invention]

INDUSTRIAL APPLICABILITY The present invention can be used repeatedly for a long time when purifying bacteria or fine particles from a medical fluid such as an infusion solution or an injectable solution in the pharmaceutical industry, and can be immediately used in a dry state of the membrane. An object of the present invention is to provide a very useful microfilter membrane that does not deteriorate.

[Means for solving problems]

As a result of earnest research on a microfilter film that solves the above-mentioned problems, the present inventor has found that it can be achieved by the following means.

That is, a polyolefin or a copolymer of an olefin and a halogenated olefin, or a hollow fiber-like porous membrane made of polyvinylidene fluoride, a side chain containing a neutral hydroxyl group is grafted to the surface of the pores, and the content of the neutral hydroxyl group is high. However, the problem can be solved very effectively by the non-adsorptive hydrophilic hollow fiber porous membrane having an average pore diameter of 0.01 μm to 5 μm and a porosity of 20 to 80%, which is 0.1 to 5 meq / g of the membrane. understood.

The present invention will be described in more detail below.

The membrane to be graft-treated in the present invention is required to be a hydrophobic porous membrane such as polyolefin, copolymer of olefin and halogenated olefin, polyvinylidene fluoride, etc. Useful for maintaining properties.

Here, as the specific example of the above-mentioned polyolefin, a copolymer of an olefin and a halogenated olefin, a polyolefin resin, for example, polyethylene, polypropylene, polybutylene or a mixture of two or more of the above, or ethylene,
A copolymer of propylene, butene, hexene, tetrafluoroethylene, a mixture of two or more kinds of chlorotrifluoroethylene, or the like, or polyvinylidene fluoride resin is adopted.

Next, as a monomer to be grafted on these hydrophobic membranes, one or more neutral hydroxyl groups (alcoholic hydroxyl groups) or a functional group which is a precursor thereof, and
It must be graftable. Specifically, 2-hydroxyethyl-acrylate, esters of polyhydric alcohol with acrylic acid or methacrylic acid such as 2-hydroxyethyl-methacrylate, and alcohols having an unsaturated bond such as allyl alcohol, and vinyl acetate, Enol esters such as vinyl propionate may be mentioned. Particularly preferred are alcohols and enol esters having unsaturated bonds. For example, by grafting allyl alcohol or the like onto the hydrophobic membrane, or by grafting vinyl acetate or the like and then hydrolyzing the same,
A non-adsorptive hydrophilic membrane having a desired side chain containing a neutral hydroxyl group can be obtained. Moreover, since the product thus obtained does not have an ester bond, unlike the case where 2-hydroxyethyl-acrylate or the like is used,
The side chains are chemically extremely stable and do not easily undergo chemical changes even under conditions such as acid and alkali.

The concentration of the hydroxyl group in the side chain thus obtained can be arbitrarily adjusted, but the effect of the present invention is that 0.1 to 5 meq, preferably 1 to 3 meq is required per gram of the membrane.

Here, 1 gram of the film is a value based on a considerably macroscopic weight of the film, and does not mean, for example, a weight obtained by taking out only a part of the film surface or a part of the inside. In order to perform hydrophilic treatment while maintaining the excellent mechanical properties of the base film, it is easier to achieve the purpose by preferentially grafting the surface of the pores as much as possible. Therefore, the term "1 gram of the base film" as used herein means a value measured evenly over the entire surface of the film, and does not mean the weight from a microscopic viewpoint.

The porous membrane grafted according to the present invention has an average pore size of
It is in the range of 0.01μ to 5μ. Here, the average pore size is
It refers to the value obtained by the method described in ASTM F316-70, which is usually called the air flow method, and it is determined from the ratio by measuring the air permeation flux of dry and wet membranes by changing the air pressure. Is.

The range of the average pore diameter in the present invention is set from the viewpoint of practical performance, and in the range other than this range, it is unsuitable from the viewpoint of the permeation rate or the effect of removing fine particles.

Secondly, the porosity of the porous membrane obtained according to the present invention is in the range of 20 to 80%. Here, the porosity refers to the porosity measured by the weight change before and after immersing the membrane in a liquid such as water in advance and then drying. When the porosity is outside the range of the present invention, it is not preferable in terms of permeation rate, mechanical properties and the like.

The pore structure of the porous base material film obtained in the present invention can be obtained by various molding processes.
Specifically, a so-called stretching method or an etching method produced by chemical treatment after electron beam irradiation can also be applied, but as the pore structure, a direct hole through type void obtained by a stretching method or an etching method is used. Rather than the pore structure, a three-dimensional network structure formed by, for example, the micro phase separation method or the mixed extraction method disclosed in JP-B-59-37292, JP-B-40-957 and JP-B-47-17460 is used. Those having are preferred. In particular, JP-A-55-
The significance of the present invention has been clarified by the establishment of the technology for manufacturing the structure shown in Japanese Patent No. 131028, and a method for manufacturing a material having excellent performance that cannot be obtained by the conventional technology can be achieved.

The hollow fiber membrane of the substrate used in the present invention has an inner diameter of 0.1 to 1
A hollow fiber porous membrane having a thickness of 0 mm and a thickness of 0.05 to 5 mm is preferable.

The method of grafting the functional group of the hydrophilic film of the present invention onto the base material film includes methods such as a chemical treatment method, but the most effective method is to irradiate the base material film with ionizing radiation.
In this method, the base film is less likely to be chemically deteriorated, it is difficult to form a free polymer, and the porous film thus produced is mechanically and chemically excellent,
Good overperformance.

The ionizing radiation used is α-rays, β-rays, γ-rays, accelerated electron rays, X-rays, etc., but electron rays or γ-rays are preferable for practical use. As a method of graft polymerization, irradiation is performed in the coexistence of a porous substrate and a monomer, and a simultaneous irradiation method in which graft polymerization is performed, and irradiation is performed only on the porous substrate in advance, and then the monomer is added to the porous substrate. Although there is a pre-irradiation method of contact-reacting and graft-polymerizing, in the simultaneous irradiation method, at the same time as the graft polymerization of the monomer onto the porous substrate proceeds, only the monomer not involved in the graft polymerization is homopolymerized, and The pre-irradiation method is preferable because it causes a problem of blocking pores. In the pre-irradiation method, the substrate is pre-irradiated with radiation before the monomer is contacted with the porous substrate, and the
Graft polymerization is carried out by keeping the temperature below 10 ° C and contacting with the monomer at a low temperature of 50 ° C or lower, preferably 15 ° C to 50 ° C. If the porous substrate is not stored at a low temperature after irradiation with radiation, the generated radicals are rapidly attenuated, and the number thereof is halved after 30 minutes at room temperature (25 ° C). At the same time, the generated radicals react with a small amount of adsorbed oxygen, resulting in a defect that the heat resistance and chemical resistance of the target substance are impaired. Further, when the graft polymerization temperature is 60 ° C. or higher, a homopolymer of a monomer that is not involved in the graft polymerization is formed, and the pores of the porous substrate are blocked, or the homopolymer is not extracted in the post-treatment step after the reaction. The problem arises that the thermal polymer flows out after being hydrophilized and causes secondary pollution.

Hereinafter, the configuration and effects of the present invention will be specifically described by way of examples, but they do not limit the present invention.

〔Example〕

Example 1 and Comparative Examples 1 and 2 Compositions of 23.1 parts by weight of finely divided silicic acid (Nipsil VN3LP), 55.4 parts by weight of diptyl terephthalate (DBP), and 21.5 parts by weight of polypropylene resin powder [Asahi Kasei Polypropylene-M8231] were premixed. After that, it was extruded into a hollow fiber with an inner diameter of 0.7 mm and a thickness of 0.25 mm using a 30 mm twin-screw extruder, and then 1,1,1-
After dipping in trichlorethane [Fluorocene VG (trade name)] for 60 minutes to extract DBP, caustic soda 4 at a temperature of 60 ° C
After immersing in a 0% aqueous solution for about 20 minutes to extrude finely divided silicic acid, it was washed with water and dried.

The porous material thus obtained was then charged with an electron accelerator (pressurizing voltage 1.5M
After irradiation with 100 KGY in a nitrogen atmosphere using eV and an electron beam current of 1 mA), it was exposed to vinyl acetate vapor having dissolved oxygen of 0.1 ppm or less in advance for grafting.

This graft membrane is further treated with a 30% aqueous solution of caustic soda at 80 ° C for 24 hours.
After reacting for a time, an example membrane having an average pore diameter of 0.15μ, a porosity of 62%, and a hydroxyl group of 2.5 meq / g was obtained.

For comparison, an untreated polypropylene hollow fiber membrane extruded and extracted under the same conditions as in Example was subjected to sulfonation in the same manner as in JP-A-56-57836, Example 6). 0.5 meq / g membrane (average pore size 0.16
A film of Comparative Example 1 having a μ-porosity of 65% was obtained.

In addition, in the example membrane, the untreated membrane after extraction of DBP and silicic acid anhydride was used as the membrane of Comparative Example 2 in the following experiment.

In addition, here, the quantification of the hydroxyl group of the example film and the sulfone group of the comparative film was as follows.

[Quantification of hydroxyl group]

After the membrane after alkali treatment is thoroughly washed with water and dried, an appropriate amount of acetic anhydride-pyridine mixed solution (1: 3 volume ratio) is added, and the mixture is heated in a sealed container at 60 ° C for 2.5 hours. After cooling, water was added to change excess acetic anhydride to acetic acid, a mixed indicator of cresol red and thymol blue was added, and titration was performed using standard alkali hydroxide.

[Quantification of sulfone group]

The sulfonated porous membrane was dipped in 1N HCl aqueous solution to form H type, washed with water, and then dipped in 1N CaCl ₂ aqueous solution to release the released HCl.
Was titrated with 0.1N NaOH aqueous solution using phenolphthalein as an indicator.

Table 1 shows the over-characteristics of the films of the third type.

The data in Table 1 shows a part of the excellent chemical liquid purification effect of the examples of the present invention.

Examples 2 and 3 and Comparative Example 3 25.2 parts by weight of ethylene-tetrafluoroethylene copolymer (trade name: Aflon COP), 53.4 parts by weight of chlorotrifluoroethylene oligomer (trade name: Daifloyl # 20), silicone oil (trade name: KF- 96) 6.5 parts by weight and 14.9 parts by weight of finely divided silica were premixed, and then extruded in the same extruder as in Example 1, and then chlorotrifluoroethylene oligomer, silicone oil, and finely divided silica were extracted, and the same operation as in Example 1 was performed. An example membrane having an average pore diameter of 0.14μ, a porosity of 62%, and a hydroxyl group content of 4.0 meq / gram was obtained.

Separately, allyl alcohol was grafted instead of vinyl acetate in Example 1 to obtain an example membrane (average pore diameter 0.16μ, porosity 60%) having a membrane of 2.5 meq / g.

The overperformance of the two example membranes is shown in Table 2. For reference, a commercially available modified polyvinyl alcohol film (Kuraray SF-401) is shown as Comparative Example 3.

In addition, when 1% γ-amino acid acid model solution was passed through the membranes of Examples 2 and 3 to measure the overspeed and the retention rate,
After passing 4 m ³ / m ² , the retention rates were 70 and 65%, respectively. Then, after washing this with an aqueous solution of caustic soda and the above sterilization operation and measuring its overspeed, each was 100%.
%, 98%.

This fact shows that the membrane of the present invention can be repeatedly used in the case of actual chemical overshoot.

〔The invention's effect〕

Since the membrane of the present invention has a high water permeability retention rate after drying and little external contamination during use, it can be used repeatedly when used as a terminal final filter of an actual chemical solution, and in particular, since it can be incorporated into a plant and continuously used. In the chemical liquid purification, the effect is significant in that the handling of the refining device is extremely simple and labor saving is achieved.

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Claims (7)

[Claims] 1. A hollow fiber-like porous membrane made of polyolefin or a copolymer of olefin and halogenated olefin, or polyvinylidene fluoride, having side chains containing neutral hydroxyl groups grafted to the surface of pores, and neutral hydroxyl groups. A non-adsorptive hydrophilic hollow fiber porous membrane having a group content of 0.1 to 5 milliequivalents per gram of membrane, an average pore diameter of 0.01 to 5 µ, and a porosity of 20 to 80%. 2. The non-adsorbing hydrophilic hollow fiber porous membrane according to claim 1, wherein the side chain is a vinyl alcohol monomer or polymer, or an allyl alcohol monomer or polymer. 3. The non-adsorbing property according to claim 1, wherein the pore structure of the membrane has a substantially three-dimensional network structure, and the membrane shape is a hollow fiber shape having an inner diameter of 0.1 to 10 mm and a thickness of 0.05 to 5 mm. Hydrophilic hollow fiber porous membrane. 4. A hollow fiber-like porous membrane made of polyolefin or a copolymer of olefin and halogenated olefin or polyvinylidene fluoride, with side chains containing neutral hydroxyl groups grafted to the surface of pores, and neutral hydroxyl groups. In the method for producing a non-adsorptive hydrophilic hollow fiber porous membrane having an average pore diameter of 0.01 μ-5 μ and a porosity of 20-80%, the content of which is 0.1 to 5 milliequivalents per gram of membrane, a substantially three-dimensional network is obtained. A non-adsorbing hydrophilic hollow-fiber-like porous film characterized by grafting a grafting monomer having a neutral hydroxyl group to the surface of pores by irradiating the hollow-fiber-like porous film having the above structure with ionizing radiation. Membrane manufacturing method. 5. The method for producing a non-adsorptive hydrophilic hollow fiber porous membrane according to claim 4, wherein the grafting monomer having a neutral hydroxyl group is allyl alcohol. 6. A hollow fiber-like porous membrane made of polyolefin or a copolymer of olefin and halogenated olefin or polyvinylidene fluoride is grafted with a side chain containing a neutral hydroxyl group up to the surface of pores, and a neutral hydroxyl group. In the method for producing a non-adsorptive hydrophilic hollow fiber porous membrane having a content of 0.1 to 5 milliequivalent per gram of the membrane, an average pore diameter of 0.01 µ to 5 µ, and a porosity of 20 to 80%, a substantially three-dimensional network is obtained. By irradiating the hollow fiber-like porous membrane having the above structure with ionizing radiation, the grafting monomer having a neutral hydroxyl group precursor is grafted to the surface of the pores, and then the precursor is induced to a neutral hydroxyl group. A method for producing a non-adsorbing hydrophilic hollow fiber-like porous membrane, comprising: 7. The non-claim according to claim 6, wherein the grafting monomer having a neutral hydroxyl group precursor is vinyl acetate, and the induction of the precursor to a neutral hydroxyl group is hydrolysis of an ester bond. A method for producing an adsorptive hydrophilic hollow fiber porous membrane.