JPH07121345B2 - Non-adsorbing hydrophilic semipermeable membrane and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention provides a hydrophilic semi-preservative suitable for sterilization of injectables, infusions, bulk stock solutions, water for use, etc., consisting of various chemicals in the pharmaceutical industry, etc. The present invention relates to a conductive film and a manufacturing method thereof.

[Conventional technology]

Conventionally, in the pharmaceutical industry, in order to remove bacteria or pyrodiene from the produced various chemical solutions, many ultrapermeable membranes have been used.

Polysulfone (including polyether sulfone and the like) is generally used as a material for these ultrafiltration membranes, because polysulfone has relatively excellent heat resistance and is easily formed into a membrane.

On the other hand, polysulfone is relatively hydrophobic unlike, for example, polyacrylonitrile, polyamide, etc., so that if the membrane is dried as it is, it will not easily recover its original overperformance even if it is immersed in water again.

Furthermore, it was difficult to lower the molecular weight cut-off of polysulfone only by the film-forming technique, and thus treatments such as sulfonation and carboxylation were required.

Further, sulfonation or carboxylation is effective for excess of water (desalting function), but when a protein preparation liquid is purified with this membrane, adsorption or deterioration of the protein is often observed.

[Problems to be solved by the invention]

INDUSTRIAL APPLICABILITY The present invention is a useful semipermeable membrane for removing bacteria and pyrodiene-like substances from infusion solutions, injection solutions or process water of the pharmaceutical industry, etc., even when the membrane is dried, the overperformance can be easily recovered and the solution does not deteriorate. A membrane is provided.

Further, the present invention provides a polysulfone-based semipermeable membrane capable of cutting a protein having an extremely small molecular weight.

[Means for solving problems]

Here, as a result of earnest research on a semipermeable membrane which solves the above-mentioned problems, the present inventor has found that it can be achieved by the following means.

That is, a spherical protein in which a side chain containing a neutral hydroxyl group is grafted to a semipermeable membrane whose base material is polysulfone and the content of the neutral hydroxyl group is 0.1 to 8 meq / g of the membrane. Molecular weight cut off by 100
It has been found that the problem can be solved very effectively by using less than 10,000 non-adsorbing hydrophilic films.

The present invention will be described in more detail below.

The base material membrane to be graft-treated in the present invention is required to be a polysulfone membrane, because it has sufficient mechanical properties as a semipermeable membrane material.

Next, the monomer to be grafted to the hydrophobic polysulfone membrane must have at least one neutral hydroxyl group (alcoholic hydroxyl group) or a functional group as a precursor thereof, and must be graftable. . Specifically, esters of acrylic acid or methacrylic acid such as 2-hydroxyethyl-acrylate and 2-hydroxyethyl-methacrylate with polyhydric alcohols, alcohols having unsaturated bonds 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 it, a non-adsorptive aqueous membrane having a desired side chain containing a neutral hydroxyl group is obtained. be able to. Moreover, in the case of the product thus obtained, unlike the case where 2-hydroxyethyl-acrylate or the like is used, since the compound does not have an ester bond, the side chain is chemically extremely stable,
It does not easily undergo scientific 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 8 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 carry out the hydrophilic treatment while maintaining the excellent mechanical properties of the base material 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 grafted polysulfone membrane obtained according to the present invention is
It has a molecular weight cut-off of about 1 million or less in the globular protein.

Here, the globular protein refers to a globular protein that has a substantially spherical shape in water or blood, and examples thereof include insulin (molecular weight 6,000),
Cytochrome C (13,000 same), gamma globulin (5 same)
10,000), hemoglobin (60,000), apoferritin (48, same)
10,000) and liquid-free globulin (precipitation constant 19s, molecular weight 900,000).

The measurement of molecular weight cut-off is not standardized, but here the minimum molecular weight of a protein with a cut rate of 95% or more is obtained by passing a stock solution with a protein concentration of 0.025% through a semipermeable membrane at a pressure of 1 Kg / cm ^2. Refers to.

The polysulfone base material membrane may be in the form of a flat membrane, a tube, or a hollow fiber membrane, but for the purpose of the present invention, a hollow fiber having an inner diameter of 0.1 to 10 mm and a thickness of 0.05 to 5 mm. The type is preferable.

The method of grafting the functional group of the hydrophilic film of the present invention onto the substrate film may be a method such as a chemical treatment method, but the method of irradiating the substrate film with ionizing radiation is the best. In this method, the base material film is less likely to be chemically deteriorated, a free polymer is hard to be formed, and the semipermeable membrane produced in this way is mechanically and chemically excellent, and the overperformance is It has the advantage of being good.

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 the method of graft polymerization, irradiation is performed in the coexistence of a polysulfone base film and a monomer, and the simultaneous irradiation method of graft polymerization is used. There is a pre-irradiation method of contact-reacting and graft polymerizing. In the simultaneous irradiation method, since the graft polymerization of the monomer onto the polysulfone base material film proceeds, at the same time, only the monomer not involved in the graft polymerization is homopolymerized, which causes a problem that the pores of the polysulfone base material film are blocked. preferable. In the pre-irradiation method, before the monomer is brought into contact with the polysulfone substrate film, the substrate film is pre-irradiated with radiation, and the period of time before contacting with the monomer is minus 10
Graft polymerization is carried out by keeping the temperature below 50 ° C and contacting with the monomer at a low temperature below 50 ° C, preferably 15 ° C to 50 ° C. If the polysulfone base material film is not stored at low temperature after irradiation with radiation, the generated radicals are rapidly attenuated and the temperature is kept at room temperature (25 ° C).
The number halves after 30 minutes. 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, which is not involved in the graft polymerization, is generated, which may block the micropores of the polysulfone membrane, or a homopolymer which is not extracted in the post-treatment step after the reaction. A problem arises that things flow out after being made hydrophilic and cause secondary pollution. Further, if necessary, after the grafting, electron beam or γ-ray irradiation can be performed in the presence or absence of the crosslinking agent.

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 Example 1 DMAC was spun using the main solvent as the main solvent and coagulated in water to give an outer diameter of 1.3 m.
m, inner diameter 0.6mm polysulfone (brand P-3500. US UCC
Freeze-dry the semipermeable hollow fiber membrane, and use an electron accelerator (pressurization voltage 1.5MoV, electron beam current 1mA) in a nitrogen atmosphere 1
After irradiating an electron beam with 00KGY, dissolved oxygen was previously added to 5 pp
Grafting was applied to a vinyl acetate vapor having a size of m or less.

The graft membrane was further reacted with a 30% aqueous solution of caustic soda at 80 ° C for a total of 24 hours, and the molecular weight cutoff was 6,000 and the graft ratio was 3
An ultrahypermembrane (Example membrane-1) having a milliequivalent / gram membrane was obtained.

On the other hand, the same polysulfone base material film was similarly irradiated with an electron beam, and then acrylic acid was grafted to obtain an ultrapermeation film (molecular weight cutoff of 6,000, graft ratio of 2.5 meq / g film) (comparative example film- 1).

In addition, the above ultrapermeability film was further irradiated with an electron beam of 20 Mγ before drying.
Irradiation followed by crosslinking.

Further, for comparison, an untreated polysulfone membrane (molecular weight cutoff of 13,000) was used as Comparative Example membrane-2.

The overspeeds of these membranes and the water permeability retention rate when they are immersed in water, immediately dried and then immersed again in water are shown below.

Further, when the adsorbability of 0.1% vitamin B-12 solution of the above three kinds of membranes was measured, the adsorbability of the membranes to proteins was as follows.

The pH of the immersion liquid in the Comparative Example membrane-2 changed to 0.1 after the immersion.

Example 2 and Comparative Example 2 Allyl alcohol was added to a hollow fiber semipermeable membrane of polysulfone (outer diameter 1.0 mm, inner diameter 0.5 mm) obtained by substantially the same method as in Example 1 in the same manner as in Example 1. After electron beam irradiation, grafting was carried out to obtain Example membrane-2.

Further, by adjusting the solvent and the additive in the method of Example 1, a comparative example membrane having various molecular weight cutoffs was prepared.
3 and 4 were obtained. Permeability of these membranes and vitamin B
The rejection rate of -12 (molecular weight 1,000) is shown below.

The above results indicate that a semipermeable membrane having the ability to block a protein having a low molecular weight to a high degree even if the water permeability of the membrane is extremely reduced is difficult to achieve by polysulfone alone, and is realized by the present invention. It shows a thing.

The graft ratios in Examples 1 and 2 and Comparative Example 1 were all determined by the gravimetric method.

〔The invention's effect〕

The membrane of the present invention can be used as it is in a dry state, and is excellent in sanitary properties and many other points as a conventional ultrafiltration membrane for liquid purification including water for pharmaceutical industry.

Furthermore, according to the present invention, a polysulfone membrane having a low molecular weight cut-off can be produced without significantly reducing the water permeation rate, which is useful for improving the quality and improving the yield in the industry.

Claims (6)

[Claims] 1. A semipermeable membrane whose base material is polysulfone is grafted with side chains containing neutral hydroxyl groups, and the content of neutral hydroxyl groups is 0.1 to 8 milliequivalents per gram of membrane. , Molecular weight cut-off by globular protein is 100
10,000 or less non-adsorbing hydrophilic semi-permeable membrane. 2. The non-adsorbable hydrophilic semipermeable membrane according to claim 1, wherein the side chain is a vinyl alcohol monomer or polymer, or an allyl alcohol monomer or polymer. 3. A non-adsorptive hydrophilic film, wherein a grafting monomer having a neutral hydroxyl group is grafted by irradiating a semipermeable membrane whose base material is polysulfone with ionizing radiation. Manufacturing method. 4. The method for producing a non-adsorptive hydrophilic film according to claim 3, wherein the grafting monomer having a neutral hydroxyl group is allyl alcohol. 5. A grafting monomer having a neutral hydroxyl group precursor is grafted by irradiating a semipermeable membrane whose base material is polysulfone with ionizing radiation, and then the precursor is neutral hydroxyl group. A method for producing a non-adsorptive hydrophilic membrane, characterized by inducing 6. The non-claim according to claim 5, 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 membrane.