JP2013009761A - Hollow fiber membrane type blood purification device and method for manufacturing hollow fiber membrane type blood purification device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a dry and polysulfone-based hollow fiber membrane type blood purification device having superior antioxidant performance and hemocompability, facilitating priming, and having high stability in antioxidation under a severe environment.SOLUTION: This hollow fiber membrane type blood purification device includes hollow fiber membranes containing a polysulfone resin 1, a hydrophilic polymer 2, and a fat-soluble vitamin 5. The abundance of the fat-soluble vitamin 5 in the hollow fiber membrane surface is not less than 0.5 mg and not more than 25 mg per gram of the hollow fiber membrane. A hydrophilic compound 3, including a water content, of not less than 5 mass% and not more than 50 mass% with respect to the dry-type weight of the hollow fiber membrane is attached to the hollow fiber membrane. The dry, hollow fiber membrane type blood purification device has been sterilized with radiation.

Description

  The present invention relates to a hollow fiber membrane blood purification device and a method for producing a hollow fiber membrane blood purification device.

Conventionally, hollow fiber membrane blood processing apparatuses using a selective permeable membrane have been widely used in the field of extracorporeal blood circulation, such as hemodialysis, oxygenation to blood during open-heart surgery, or plasma separation.
In recent years, particularly in the field of blood treatment membranes such as dialysis membranes, gas exchange membranes, and blood component separation membranes, blood treatment membranes comprising polysulfone resins (hereinafter sometimes referred to as polysulfone) are widely used. Has been.
If only a highly hydrophobic polysulfone is used as a constituent material of the blood treatment membrane, sufficient blood compatibility cannot be obtained, and therefore a complex with a hydrophilic polymer such as polyvinylpyrrolidone is generally used. .
Attempts have also been made to make blood treatment membranes not only play a role as separation membranes but also play a role in relieving oxidative stress that manifests in long-term dialysis patients.
For example, it is conceivable to use a separation membrane to eliminate peroxide that is a causative substance of oxidative stress, or to recover the antioxidant effect of a living body. Specifically, a hollow-fiber membrane blood purification device has been proposed in which vitamin E having various physiological functions such as in vivo antioxidant action, biological membrane stabilization action, and platelet aggregation inhibition action is coated on the surface of the dialysis membrane. (For example, refer to Patent Document 1).

The hollow fiber membrane blood purification device as described above, of course, needs to be completely sterilized in a hermetically sealed state before use, considering its application.
Known sterilization methods for hollow fiber membrane blood purification devices include gas sterilization methods using ethylene oxide gas, autoclave methods using high-pressure steam, and radiation sterilization methods such as γ rays and electron beams.
Among these, the gas sterilization method using ethylene oxide gas is concerned about the harmfulness to the human body due to residual ethylene oxide gas.
In addition, the autoclave method using high-pressure steam may significantly reduce the performance during sterilization depending on the material constituting the hollow fiber membrane blood purification apparatus.

Also, when the vitamin E-immobilized polysulfone membrane is sterilized using the autoclave method using the high-pressure steam, the fat-soluble vitamin causes local aggregation and cracks in the hollow fiber membrane, resulting in blood leakage. It has been pointed out that the possibility of occurrence increases (for example, see Patent Document 2).
On the other hand, radiation sterilization is a preferred sterilization method without causing problems of residual ethylene oxide gas and leakage of hollow fiber membranes.

By the way, the hollow fiber membrane-type blood purification apparatus as described above is roughly classified into a wet type in which the hollow interior of the hollow fiber membrane and the gap with the container are filled with an aqueous medium, and a dry type that is not filled with the aqueous medium. .
The dry type can be further classified into a type in which the moisture content of the membrane is as low as several percent or less (a dry type in a narrow sense) and a type in which the membrane is appropriately moistened with moisture, a humectant, or the like.
The latter is sometimes referred to as a semi-dry type as distinguished from a dry type in a narrow sense, but since the characteristics are almost the same, in the present specification, both are collectively referred to as a dry type.

The dry type described above has a feature that the product weight is lighter than that of the wet type, and it is difficult to freeze at a low temperature, and can be said to be a particularly excellent product form in terms of distribution such as transportation and storage.
However, it is known that when a dry type polysulfone-based blood treatment membrane is subjected to radiation sterilization treatment, the hydrophilic polymer constituting the hollow fiber membrane deteriorates and elutes, resulting in a decrease in blood compatibility.
In view of such a problem, radiation sterilization is performed while protecting the hollow fiber membrane with a specific amount of wet protective agent (see, for example, Patent Document 2), or oxygen in the vicinity of the membrane is protected with a specific amount of wet protective agent. There has been proposed a method for suppressing a decrease in blood compatibility by performing electron beam sterilization after controlling the concentration (see, for example, Patent Document 3).

JP 7-178166 A JP 2006-296931 A JP 2008-93228 A

By the way, in recent years, blood purification therapy is spreading all over the world, not only in Japan and Western countries, which are the current main use sites, but also in various regions such as China, India, Russia, Middle East countries, Latin America countries, Southeast Asia, etc. It is becoming used. Modules used in such a wide variety of countries have various management conditions as medical devices, and have a storage stability of 3 years in a normal temperature and humidity environment that is currently recognized as a general storage form. It is not enough to be guaranteed. For example, it is fully conceivable that the internal temperature rises to 60 ° C. or higher when a cargo container containing a blood purification device is exposed to direct sunlight in a container yard. Alternatively, it may be placed for a long time in an unexpected high temperature environment by long-term truck transportation in a large country such as the United States or ship transportation navigating the tropics (equator).
When the blood purification membrane according to the prior art as described above is exposed to such a harsh environment, there is a possibility that various characteristics are deteriorated, particularly, the antioxidant performance is deteriorated.

  Further, in the future, a medical device including a blood treatment membrane having a higher level of blood compatibility is being demanded.

However, according to the results of the present inventors conducting a blood compatibility model test aiming at a high level of blood compatibility, even a membrane obtained by the method disclosed in Patent Document 3 has sufficient blood for practical use. There is no compatibility and there is room for further improvement.
In addition, the blood purification membrane disclosed in Patent Document 3 needs to wash away the wet protective agent by priming before use, but it requires a large amount of physiological saline, which can be reduced. Is desired in the medical economy.
Furthermore, in Patent Document 3, vitamin E is exemplified as a wetting protective agent for protecting the hollow fiber membrane, but within the range disclosed in Patent Document 3, vitamin E is wetted in the hollow fiber membrane. As a result, the hydrophobic effect of vitamin E is too strong, and oily vitamin E that cannot be removed by priming clogs the micropores on the surface of the hollow fiber membrane. However, the hollow fiber membrane has a problem that it cannot play a role as a blood treatment membrane.
Furthermore, when a vitamin E-immobilized polysulfone membrane having a practical vitamin E (wetting protection agent) impregnation rate as a blood treatment membrane is dried and subjected to radiation sterilization treatment, practically sufficient blood compatibility is obtained. I know it ’s not.
Furthermore, conventional blood purification devices have low antioxidant stability in harsh environments, and there is a great risk in spreading the benefits of blood purification therapy using blood purification devices with excellent antioxidant properties to the whole world. It has become.

As described above, conventionally, a dry type polysulfone-based hollow fiber membrane blood purification device having practically good blood compatibility has not been obtained.
Furthermore, it is very difficult to obtain a dry type polysulfone-based hollow fiber blood purification device that has excellent antioxidant performance and blood compatibility, is easy to prime, and has high antioxidant stability under harsh environments. It is difficult to.

  Therefore, in the present invention, a dry type polysulfone-based hollow fiber membrane blood purification device having excellent antioxidant performance and blood compatibility, easy priming, and high anti-oxidation stability in harsh environments. It is an issue to provide.

As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention are excellent by protecting a hollow fiber membrane having a specific amount of a fat-soluble vitamin immobilized on the surface thereof with a specific amount of a hydrophilic compound. Found that it is possible to obtain a dry type polysulfone-based hollow fiber membrane blood purification device having anti-oxidation performance and blood compatibility, easy priming, and high anti-oxidation stability in harsh environments, The present invention has been completed.
That is, the present invention is as follows.

[1]
A hollow fiber membrane blood purification device comprising a hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer and a fat-soluble vitamin,
The abundance of the fat-soluble vitamin on the surface of the hollow fiber membrane is 0.5 mg to 25 mg per 1 g of the hollow fiber membrane,
The hollow fiber membrane has a hydrophilic compound of 5% by mass or more and 50% by mass or less including moisture attached to the dry weight of the hollow fiber membrane,
A dry-type hollow fiber membrane blood purification device that has been subjected to radiation sterilization.
[2]
The hollow fiber membrane blood purification apparatus according to [1], wherein the water content of the hydrophilic compound is 50% by mass or less.
[3]
The hollow fiber membrane blood purification apparatus according to [1] or [2], wherein the hydrophilic compound is a polyhydric alcohol.
[4]
The hollow fiber membrane blood purification apparatus according to [3], wherein the polyhydric alcohol is at least one selected from the group consisting of glycerin, mannitol, glycols, and polyethylene glycol.
[5]
For a hollow fiber membrane blood purification device comprising a hollow fiber membrane containing a polysulfone resin and a hydrophilic polymer,
Pass a mixed solution of a fat-soluble vitamin and a hydrophilic compound through at least the blood flow surface of the hollow fiber membrane, and then remove the solvent by drying.
Next, radiation sterilization is performed.
A method for producing a hollow fiber membrane blood purification device.
[6]
A method for producing the hollow fiber membrane blood purification device according to any one of [1] to [4],
For a hollow fiber membrane blood purification device comprising a hollow fiber membrane containing a polysulfone resin and a hydrophilic polymer,
Pass a mixed solution of a fat-soluble vitamin and a hydrophilic compound through at least the blood flow surface of the hollow fiber membrane, and then remove the solvent by drying.
Next, radiation sterilization is performed.
A production method for obtaining a hollow fiber membrane blood purification apparatus.
[7]
For a hollow fiber membrane blood purification apparatus comprising a hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin,
Pass a solution of the hydrophilic compound through at least the blood flow surface of the hollow fiber membrane, and then remove the solvent by drying,
Next, radiation sterilization is performed.
A method for producing a hollow fiber membrane blood purification device.
[8]
A method for producing the hollow fiber membrane blood purification device according to any one of [1] to [4],
For a hollow fiber membrane blood purification apparatus comprising a hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin,
Pass a solution of the hydrophilic compound through at least the blood flow surface of the hollow fiber membrane, and then remove the solvent by drying,
Next, radiation sterilization is performed.
A production method for obtaining a hollow fiber membrane blood purification apparatus.

  According to the present invention, a dry type polysulfone-based hollow fiber membrane blood purification device having excellent antioxidant performance and blood compatibility, easy priming, and high antioxidative stability in harsh environments Is obtained.

It is a model figure of the hollow fiber membrane before hydrophilic compound coating in a prior art. It is a model figure of the hollow fiber membrane after hydrophilic compound coating in a prior art. It is a model figure of the hollow fiber membrane after hydrophilic compound coating in the Example of this invention. It is a figure showing the influence which it has on the blood compatibility of the fat-soluble vitamin abundance in the hollow fiber membrane surface. It is a figure showing the influence which the hydrophilic compound adhesion amount has on blood compatibility and priming ease.

Hereinafter, a mode for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described with reference to the drawings.
The present invention is not limited to the following description, and various modifications can be made within the scope of the gist thereof.
In the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. Further, the positional relationship such as up, down, left, and right is based on the positional relationship shown in the drawings unless otherwise specified, and the dimensional ratio in the drawing is not limited to the illustrated ratio.

[Hollow fiber membrane blood purification device]
The hollow fiber membrane-type blood purification apparatus of the present embodiment includes a hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin, and the abundance of the fat-soluble vitamin on the surface of the hollow fiber membrane. The hydrophilic compound is 0.5 mg to 25 mg per 1 g of the hollow fiber membrane, and the hollow fiber membrane is 5% by mass to 50% by mass including moisture with respect to the dry weight of the hollow fiber membrane. Is a dry type hollow fiber membrane blood purification device that has been subjected to radiation sterilization treatment.

(Hollow fiber membrane)
The hollow fiber membrane constituting the hollow fiber membrane-type blood purification apparatus of this embodiment contains a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin.
<Polysulfone resin>
The polysulfone resin (hereinafter sometimes referred to as PSf) is a general term for polymer compounds having a sulfone bond, and is not particularly limited. For example, the polysulfone type | system | group polymer whose repeating unit is shown by following formula (1)-(5) is mentioned.
The bisphenol-type polysulfone polymer of the following formula (1) is commercially available from Solvay Advanced Polymers under the trade name “Udel” and from BASF Corporation under the trade name “Ultrazone”. There are several types depending on the degree of polymerization, but there is no particular limitation.

<Hydrophilic polymer>
Examples of the hydrophilic polymer include polyvinyl pyrrolidone (hereinafter sometimes referred to as PVP), polyethylene glycol, polyvinyl alcohol, polypropylene glycol, and the like. The stability of spinning and the above-described polysulfone resin (PSf) are exemplified. From the viewpoint of affinity with PVP, PVP is preferably used.
There are several types of PVP depending on the degree of polymerization. For example, from PSP, there are trade names of “Prasdon”, and there are those with different molecular weights such as K-15, 30, 90, etc. Can also be used.
In addition, the hollow fiber membrane according to the present embodiment has a hydrophilic polymer abundance ratio A (hereinafter referred to as “hollow fiber membrane of the hollow fiber membrane” depending on the total mass of the hydrophilic polymer and the polysulfone resin on the inner surface of the hollow fiber membrane). It is abbreviated as “the abundance ratio of the hydrophilic polymer on the inner surface”.) Is preferably 25% by mass or more and 100% by mass or less.
Here, “the abundance ratio of the hydrophilic polymer with respect to the total mass of the hydrophilic polymer and the polysulfone resin on the inner surface of the hollow fiber membrane” means the outermost layer portion inside the hollow fiber membrane (that is, blood is hollow fiber The ratio of the mass of the hydrophilic polymer to the total mass of the polysulfone resin and the hydrophilic polymer on the surface in contact with the membrane. Examples of the measurement method include a method using a measurement result by X-ray photoelectron spectroscopy (XPS). That is, the inner surface of the hollow fiber membrane is measured by XPS, and the ratio of the number of each atom on the surface is obtained from the peak intensity of atoms peculiar to the polysulfone resin and the hydrophilic polymer, respectively. The abundance A of the hydrophilic polymer can be calculated from the mass ratio of the compound.
Specifically, when polyvinyl pyrrolidone is used as the hydrophilic polymer, it is determined from the number of nitrogen atoms (derived from polyvinyl pyrrolidone) and the number of sulfur atoms (derived from polysulfone resin) at the inner surface of the hollow fiber membrane. It is done.
For example, when the polysulfone resin is composed of repeating units represented by the above formula (1), the abundance ratio A (polyvinyl pyrrolidone abundance ratio) of polyvinyl pyrrolidone on the inner surface of the hollow fiber membrane can be obtained by the following formula (6). it can.
Here, in the following formula (6), 111 is the formula weight of the repeating unit of polyvinylpyrrolidone, and 442 is the formula weight of the repeating unit of the polysulfone resin.

  The abundance A of the hydrophilic polymer is preferably 25% by mass or more and 100% by mass or less. When this abundance ratio is less than 25% by mass, blood compatibility tends to be lowered. On the other hand, when the abundance ratio A is too large, the amount of elution of hydrophilic polymer tends to increase. Therefore, 90 mass% or less is preferable, 80 mass% or less is more preferable, More preferably, it is 70 mass% or less.

<Fat-soluble vitamin>
The fat-soluble vitamin is generally a vitamin that is hardly soluble in water and soluble in alcohol and fats and oils.
For example, vitamin A, vitamin D, vitamin E, vitamin K, ubiquinone and the like can be mentioned, and vitamin E is particularly preferably used.
Examples of vitamin E include α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, β-tocopherol, γ-tocopherol, and δ-tocopherol.
In particular, α-tocopherol is particularly preferably used because it has various physiological functions such as in vivo antioxidant action, biological membrane stabilization action, and platelet aggregation inhibitory action.
Fat-soluble vitamins play a role in relieving oxidative stress that manifests in long-term dialysis patients. Specifically, they play a role in erasing peroxides that cause oxidative stress and restoring the antioxidant effect of living bodies.
In the hollow fiber membrane-type blood purification apparatus of this embodiment, it is considered that these effects are manifested by the presence of fat-soluble vitamins on the surface of the hollow fiber membrane in contact with blood.

(Fat-soluble vitamin on the surface of hollow fiber membrane)
In the hollow fiber membrane blood purification apparatus of the present embodiment, the amount of the fat-soluble vitamin on the surface of the hollow fiber membrane is 0.5 mg or more and 25 mg or less per 1 g of the hollow fiber membrane.
The method of adding fat-soluble vitamins to the hollow fiber membrane is the method of adding fat-soluble vitamins to the stock solution at the time of film formation to contain fat-soluble vitamins throughout the membrane, the fat-soluble vitamins and surfactants in the hollow inner solution To add a fat-soluble vitamin to the inner surface of the hollow fiber membrane (Patent No. 4038583), and after assembly, a fat-soluble vitamin solution comprising a fat-soluble vitamin and a solvent for the fat-soluble vitamin is added to the hollow fiber membrane. Various methods such as a method of attaching fat-soluble vitamins to the inner surface of the hollow fiber membrane by flowing into the part (for example, JP-A 2006-296931) are disclosed, but any method including other methods is disclosed. A method may be used.

If the abundance of fat-soluble vitamins on the hollow fiber membrane surface is less than 0.5 mg, it becomes difficult to control hydrophilic polymers during radiation sterilization and the cross-linking reaction, so that good blood compatibility cannot be obtained. .
Therefore, the amount of the fat-soluble vitamin on the hollow fiber membrane surface needs to be 0.5 mg or more, preferably 1.0 mg or more, more preferably 1.5 mg or more.
Also, if the abundance of fat-soluble vitamins on the hollow fiber membrane surface exceeds 25 mg, the hydrophobic effect of the fat-soluble vitamins themselves will increase, so that the antithrombogenicity will decrease, and when they are brought into contact with blood, There may be so-called residual blood that clots blood.
Therefore, the upper limit of the abundance of the fat-soluble vitamin on the hollow fiber membrane surface is 25 mg or less, preferably 18 mg or less, more preferably 15 mg or less.

The amount of fat-soluble vitamin present on the surface of the hollow fiber membrane constituting the hollow fiber membrane blood purification apparatus of the present embodiment was extracted from the surface of the hollow fiber membrane with an aqueous alcohol solution or an aqueous surfactant solution. Thereafter, it can be quantified by liquid chromatography.
In this specification, the hollow fiber membrane surface includes both the inner and outer surfaces of the hollow fiber membrane and the pore surface of the pore portion of the film thickness portion.

An example of a specific method for measuring the abundance of fat-soluble vitamins present on the surface of the hollow fiber membrane constituting the hollow fiber membrane blood purification apparatus is shown below. The method for measuring the abundance of fat-soluble vitamins is not limited to the following examples, and the sampling amount, concentration and amount of the extraction solution, temperature, time, flow rate, measuring device, etc. should be adjusted appropriately. Can do.
First, the hollow fiber membrane blood purification device is disassembled, the hollow fiber membrane is collected, washed with water, and then dried.
Subsequently, the dried hollow fiber membrane is weighed, for example, in a 4 g glass bottle, and for example, 80 mL of a 75 v / v% aqueous ethanol solution is added, and extraction of fat-soluble vitamins is performed while applying ultrasonic vibration for 60 minutes at room temperature. .
The quantitative operation is performed by liquid chromatography, and the amount of fat-soluble vitamin in the extract is obtained using a calibration curve obtained from the peak area of the fat-soluble vitamin standard solution.
Example of quantification method by liquid chromatographic method: High-performance liquid chromatograph apparatus (pump: JASCO PU-1580, detector: Shimadzu RID-6A, auto injector: Shimadzu SIL-6B, data processing: Tosoh GPC-8020, column oven : GL Sciences 556) is equipped with a column (ODP-506E packed column for PLC, manufactured by Shodex Asahipak), and methanol for high performance liquid chromatography, which is a mobile phase, at a column temperature of 40 ° C., for example, at a flow rate of 1 mL / min. Then, the fat-soluble vitamin concentration is determined from the area of the absorption peak in the ultraviolet region. From this concentration, the weight (mg / g) of the fat-soluble vitamin on the surface contained in the hollow fiber membrane is determined with an extraction efficiency of 100%.
In addition, a part of fat-soluble vitamin is inactivated by irradiation.
The amount of fat-soluble vitamin present on the surface of the hollow fiber membrane constituting the hollow fiber membrane-type blood purification apparatus of the present embodiment is the amount of fat-soluble vitamin present on the surface of the hollow fiber membrane including those deactivated by irradiation. is there.
On the other hand, the “antioxidation ability” described later is the amount of fat-soluble vitamin present on the surface of the hollow fiber membrane that has not been inactivated by irradiation.

(Hydrophilic compound on the surface of the hollow fiber membrane)
The hollow fiber membrane constituting the hollow fiber membrane-type blood purification apparatus of this embodiment has a hydrophilic compound of 5 mass% or more and 50 mass% or less including moisture attached to the dry weight of the hollow fiber membrane. Yes. That is, the hollow fiber membrane is covered with 5% by mass or more and 50% by mass or less of a hydrophilic compound including moisture with respect to the dry weight of the hollow fiber membrane.
The hydrophilic compound is not limited to a single hydrophilic substance, and the hydrophilic compound may contain moisture due to moisture absorption.
The hydrophilic compound adheres so as to cover the surface on which the above-described hydrophilic polymer exists in the hollow fiber membrane constituting the hollow fiber membrane blood purification apparatus of the present embodiment.
From the viewpoint of improving blood compatibility in the hollow fiber membrane type purification apparatus of the present embodiment, it is sufficient to coat only the inner surface of the hollow fiber membrane, but the outer surface of other hollow fiber membranes and the thickness of the film thickness portion are fine. The pore surface of the pores may also be covered.
The hydrophilic compound may fill the inside of the pores of the hollow fiber membrane, but the hollow inside (hollow part of the hollow fiber) causes an increase in weight and liquid leakage, so it is better not to fill this.

The hydrophilic compound is preferably attached so that it can be easily washed and removed when the hollow fiber membrane blood purification apparatus is actually used in a hospital.
In addition, washing | cleaning and removal here mean that the hydrophilic compound aqueous solution which covers the hollow fiber membrane is wash | cleaned by general priming operation performed before use, and the hollow fiber membrane surface is reproduced. Specific evaluation methods will be described in detail in Examples.

Examples of the hydrophilic compound that covers the hollow fiber membrane include polyhydric alcohols such as glycerin, mannitol, and glycols.
These hydrophilic compounds are easy to cover the surface of the hollow fiber membrane without any spots and are easily removed by washing.
Furthermore, from the viewpoint of protecting the hydrophilic polymer from radical species, polyhydric alcohols are preferred, and in particular, glycerin or polyethylene glycol is more preferred in that it has a track record as a pore diameter retainer or surface modifier for hollow fiber membranes, More preferred is glycerin.
Moreover, these hydrophilic compounds may be used alone or in a combination of two or more.

A predetermined additive may be mixed in the hydrophilic compound.
Examples of the additive include water-soluble vitamins such as vitamin C (and its derivatives and salts such as tocopherol acetate and α-tocotrienol), and sugars such as glucose, mannose, xylose, ribose, fructose, and trehalose.

The moisture content of the hydrophilic compound adhering to the hollow fiber membrane may be 0% by mass, that is, it may be in a completely dry state, but it is normal to absorb some moisture in the air and have a certain amount of moisture. Does not hinder the achievement of the object of the present invention.
In the present specification, the adhesion rate of a hydrophilic compound (for example, a polyhydric alcohol) refers to the adhesion rate of a hydrophilic compound containing moisture except in special cases. For example, glycerin, ethylene glycol, etc., which are examples of hydrophilic compounds, can absorb about 50% by mass of water in an environment of room temperature of 20 ° C. and relative humidity of 80%. To 50% by mass or less.

As described above, the hollow fiber membrane of the hollow fiber membrane-type blood purification apparatus according to the present embodiment contains 5% by mass or more and 50% by mass or less of a hydrophilic compound including moisture with respect to the dry weight of the hollow fiber membrane. It is attached.
When the adhesion rate of the hydrophilic compound (including moisture) to the hollow fiber membrane is more than 50% by mass with respect to the dry weight of the hollow fiber membrane, the priming ease before use is lost, and the advantages of the dry type are impaired.
There are various definitions of priming ease, but as an example, it can be judged by achieving the purpose with a smaller amount of use when the blood purification apparatus is washed with physiological saline to wash away water-soluble components.
For example, when the hollow fiber membrane blood purification device is a hemodialyzer, the evaluation can be performed by the following method using a standard dialyzer priming method as a model.
First, in order to wash the dialysate side, distilled water is passed through the dialysate side at 500 mL / min for 2 minutes. The flow path on the dialysate side is shut off, then distilled water is passed through the blood at 100 mL / min, and the effluent is sampled 50 mL each. The osmotic pressure is measured for each sampled fraction, and the amount of discharged liquid showing the same value as the osmotic pressure of distilled water is defined as the amount of washing liquid necessary for priming. This value can be adopted as one standard for the end of priming, and it can be determined that the smaller the value, the higher the priming ease. From the viewpoint of medical economy, this value is desired to be less than 300 mL.
From the viewpoint of ease of priming according to the example described above, the adhesion rate of the hydrophilic compound needs to be 50% by mass or less, preferably 40% by mass or less, more preferably 30% by mass or less.
On the other hand, from the viewpoint of protecting the above-described hydrophilic polymer constituting the hollow fiber membrane, the lower limit value requires an adhesion rate of 5% by mass or more, preferably 10% by mass or more, more preferably 15% by mass or more. It is.

The adhesion rate of the hydrophilic compound to the hollow fiber membrane is calculated as the ratio of the total weight of the hydrophilic compound to the dry weight of the hollow fiber membrane × 100 (mass%).
The method for measuring the adhesion rate of the hydrophilic compound is not particularly limited, and can be quantified by, for example, a liquid chromatography method.
As another method, it can be measured by the following method.

A hollow fiber membrane for 5 g is taken out from the hollow fiber membrane blood processing apparatus, and the weight (A) of the hollow fiber membrane before drying is accurately measured.
Thereafter, only water is removed with a vacuum dryer, and the weight (B) of the dried hollow fiber membrane is measured.
Thereafter, using the hollow fiber membrane sample after drying from which only water has been removed, the entire amount of the hollow fiber membrane sample is cut into pieces, and then 300 mL of pure water is added, stoppered, and washed with an ultrasonic cleaning device for 60 minutes. Thus, the adhering hydrophilic compound, for example, polyhydric alcohol is extracted.
A hydrophilic compound, such as a polyhydric alcohol, was obtained from the peak area of a standard solution by quantifying the extracted hollow fiber membrane sample using a liquid chromatograph method after extraction with an ultrasonic cleaning device. A calibration curve is used to determine the amount (C) of a hydrophilic compound, for example, a polyhydric alcohol, in the extract.
Further, only the cut hollow fiber membrane sample is taken out from the extract, dried with a vacuum dryer, and then the weight of the dried cut hollow fiber membrane sample is measured. The hollow fiber membrane weight (D) to which alcohol and moisture are not attached is used.

Based on the above measured values, the value calculated from the following formula (I) is the moisture content, and the value calculated from the following formula (II) is the adhesion rate of the pure polyhydric alcohol.
In the present specification, the term “polyhydric alcohol adhesion rate” refers to the adhesion rate of water-containing polyhydric alcohols, that is, the values obtained from the following formula (I) and the following formula (II), except in special cases. Is required.
Moisture content (mass%) = [(A−B) / D] × 100 (I)
Adhesion rate (mass%) of pure polyhydric alcohol = (C / D) × 100 (II)

In the hollow fiber membrane-type blood purification apparatus of the present embodiment, the adhesion rate of the hydrophilic compound to the hollow fiber membrane is set in the range of 5% by mass or more and 50% by mass or less including moisture with respect to the dry weight of the hollow fiber membrane. The method is not particularly limited.
For example, there is a sequential method in which a hydrophilic compound solution with a high concentration is brought into contact with the hollow fiber membrane, then water is passed through to adjust the adhesion rate to a predetermined range, and then the solvent is removed by drying.
As another example, a hydrophilic compound solution is prepared, and the contact time when contacting the hollow fiber membrane, the concentration of the solution, the injection pressure into the hollow fiber membrane, for blowing off the hydrophilic compound solution There is a method in which air blow (or air flash) conditions are optimized and performed in one step, and then the solvent is dried and removed.
The latter is preferable because it has low process complexity and does not require the use of a high-concentration solution.
In particular, the air flush is effective not only for blowing off the remainder of the hydrophilic compound solution, but also has an effect of more uniformly coating because, for example, the viscous hydrophilic compound solution is extended to the inner surface of the hollow fiber membrane. .

A method of setting the adhesion rate of the hydrophilic compound to the hollow fiber membrane within the range of 5% by mass or more and 50% by mass or less including moisture with respect to the dry weight of the hollow fiber membrane is incorporated into a part of the membrane production process and is hollow. It may be performed for each yarn film, or may be performed in a bundled state after film formation.
When carrying out every hollow fiber membrane, it is only necessary to immerse the hollow fiber membrane by providing a hydrophilic compound aqueous solution bath in the membrane production line. What is necessary is just to immerse in the bath of compound aqueous solution, or to shower the hydrophilic compound aqueous solution from the edge part of a bundle.
Alternatively, a semi-finished product of a hollow fiber membrane blood purification device, that is, a method of passing a hydrophilic compound aqueous solution from a hollow fiber membrane opening of a potting part without attaching a header in the middle of assembly, leading to the inside of the hollow fiber membrane After attaching the header having the fluid inlet / outlet, either a method of passing through the fluid inlet / outlet of the header or a method of passing through the fluid inlet / outlet of the cylindrical container (for example, dialysate inlet / outlet in the case of a hemodialyzer) may be used.
Among these, even a high-viscosity liquid can be surely passed through the hollow interior, which is the contact surface with blood, so the hollow fiber membrane opening of the semi-finished blood purification device or the header of the blood purification device A method of passing liquid from the fluid inlet / outlet is preferable.
Further, when fat-soluble vitamins are immobilized in the semi-finished product through a fat-soluble vitamin solution, it is more preferable that a certain amount of a hydrophilic compound is mixed in the solution because the fat-soluble vitamin and the hydrophilic compound can be immobilized at a time.
Although any method is accompanied by drying and removal of the solvent, especially when an aqueous solvent is used, the allowable amount of residual moisture is equivalent to the above allowable amount for moisture absorption, and is not particularly limited. Although not, the hydrophilic compound may have a moisture content of up to 50% by weight.

[Characteristics of hollow fiber membrane blood purification device]
(Blood compatibility by combining fat-soluble vitamins and hydrophilic compounds)
Conventionally, the blood compatibility of hollow fiber membrane blood purification devices has been progressively improved, and at present it seems to have reached a sufficiently practical level. It cannot be denied that there is still room for improvement, such as being indispensable and causing various complications due to repeated use over a long period of time.
The present inventors have developed a test method that imposes a stricter long-time incubation as compared with the conventional blood compatibility test as an indicator of further improvement in blood compatibility. As a conventional technique, a polysulfone hollow fiber membrane containing a hydrophilic polymer not containing a fat-soluble vitamin is covered with a glycerin aqueous solution exemplified as a “wetting protective agent”, and blood compatibility of the membrane obtained by performing electron beam sterilization As a result, the blood compatibility was evaluated by a more severe blood compatibility test that was newly developed, and it was found that there is still room for improvement in blood compatibility (see Patent Document 3 described above, which will be described in detail in Comparative Example 5 described later). ).
In the following, regarding blood compatibility, a level that “can be improved” that can be identified by a more severe test method developed by the present inventors is expressed as “insufficient”, but this is because a higher level was aimed at .
In Patent Document 3, the aqueous polyhydric alcohol solution has the ability to capture radical species generated during radiation sterilization. For this reason, the surface of the membrane responsible for blood compatibility deteriorates due to radical species (depolymerization or excessive polymerization). (Crosslinking) is described as being suppressed.
However, insufficient blood compatibility means that an aqueous glycerin solution may lack the ability to capture a large amount of radical species generated during radiation sterilization.
For this reason, in order to obtain higher radical species scavenging ability, vitamin E, which is also exemplified in Patent Document 3, is applied to the hollow fiber membrane to such an extent that the micropores on the surface of the hollow fiber membrane are not blocked. After sterilization, sufficient blood compatibility was not obtained.
Although the adhesion amount of vitamin E was a numerical value lower than 60 to 400% required as a “wetting protective agent” in Patent Document 3, even after sterilization by a ferric chloride aqueous solution reaction described later, The amount of vitamin E remaining in the hollow fiber membrane is sufficiently secured, and therefore has sufficient radical species scavenging ability, and it is thought that the lack of blood compatibility was due to lack of radical species scavenging ability. Absent.

As a result of further research, the present inventors surprisingly sterilized a hollow fiber membrane containing a fat-soluble vitamin with a much smaller amount of a hydrophilic compound than that required by the above-mentioned Patent Document 3. It has been found that the hollow fiber membranes subjected to have good blood compatibility.
The effect obtained by the present invention cannot be imagined from the knowledge so far. That is, Patent Document 3 exemplifies glycerin aqueous solution and vitamin E alone as “wetting protective agent”, but does not exemplify or suggest a combination thereof. Further, in Patent Document 3, it is described that what is necessary for blood compatibility is the ability of scavenging radical species of “wet protection agent”. However, hollow fiber already containing vitamin E having sufficient scavenging ability of radical species. It would be unexpected for a person skilled in the art to add glycerin, which has rather poor capturing ability, to the membrane, and in a much smaller amount than required by the above-mentioned Patent Document 3.

High blood compatibility is achieved by a technique in which a hollow fiber membrane containing a specific amount of a fat-soluble vitamin constituting the hollow fiber membrane-type blood purification apparatus of this embodiment is covered with a specific amount of a hydrophilic compound and further subjected to radiation sterilization. As described above, it is almost obvious that the mechanism for expressing the phenotype is not only due to the ability of the fat-soluble vitamin or hydrophilic compound to capture radical species.
The reason for improving blood compatibility is considered as follows.
As shown in FIG. 1, the surface of the blend film of the polysulfone resin and the hydrophilic polymer is present so that the hydrophilic polymer 2 protrudes from the base material 1 of the hydrophobic polysulfone resin.
Next, a model diagram when the fat-soluble vitamin is not contained in the hollow fiber membrane is shown in FIG. 2, and a model diagram when the fat-soluble vitamin is contained in the hollow fiber membrane is shown in FIG.
The fat-soluble vitamin is hydrophobic, and is present on the surface of the base material 1 of the polysulfone resin as shown in FIG.
When the oil film 5 is formed on the surface of the base material 1 of the polysulfone resin when the hydrophobic fat-soluble vitamin is applied when the hydrophilic compound is applied, the hydrophilic compound is also formed in the vicinity of the surface of the base material 1 of the polysulfone resin. As shown in FIG. 3, a hydrophilic polymer 6 carrying a large amount of the hydrophilic compound 3 is formed by selectively adhering to the existing hydrophilic polymer 2.
On the other hand, when the fat-soluble vitamin is not contained, as shown in FIG. 2, the hydrophilic compound 3 is also retained on the polysulfone membrane substrate 1, and the hydrophilic polymer carrying the hydrophilic compound aqueous solution 3 is retained. 4 is less than that of the hydrophilic polymer 6 in FIG.
That is, when the hydrophilic compound and the fat-soluble vitamin are present at the same time, the solution retention amount of the hydrophilic polymer 2 can be further increased as compared with the case where the hydrophilic compound is used alone.
Therefore, this state is effective for suppressing deterioration of the hydrophilic polymer 2.
In addition, as a result of increasing wettability at the beginning of use, affinity for blood is improved.
In view of this, when a hollow fiber membrane that does not contain a fat-soluble vitamin is covered with a hydrophilic compound, the hydrophilic polymer 2 is not sufficiently retained in solution, so that the protective effect from radical species is sufficiently exerted. It is thought that it was not done, and can be explained without contradiction.

(Stability over time of antioxidant capacity depending on the adhesion amount of hydrophilic compound)
Conventionally, evaluation of the temporal stability of the antioxidant capacity of the hollow fiber membrane blood purification device in storage in a harsh environment such as a high temperature that is not assumed as the storage environment of the hollow fiber membrane blood purification device is, for example, Evaluation can be made by measuring the antioxidant capacity after heat treatment in an environment of 60 ° C. for 3 weeks.
The fat-soluble vitamin responsible for the antioxidant ability of the hollow fiber membrane blood purification device is present on the surface of the hollow fiber membrane, but when the hydrophilic compound solution covering the hollow fiber membrane is a polyhydric alcohol, it is highly soluble in water. It has been found that by setting the weight ratio of the monohydric alcohol to a certain ratio or more, the blood purification apparatus after the heat treatment can retain effective antioxidant ability.
If common sense is considered, when fat-soluble vitamins and polyhydric alcohols coexist, fat-soluble vitamins with higher antioxidant capacity are first oxidized, which is expected to prevent oxidation of polyhydric alcohols. . This phenomenon contrary to common sense is considered to be due to the fact that the fat-soluble vitamin is adsorbed on the polysulfone membrane, which is a hydrophobic polymer, due to its hydrophobicity, and as a result, only the polyhydric alcohol aqueous solution comes into contact with the outside air. Therefore, it is considered that oxygen is consumed by oxidizing the polyhydric alcohol aqueous solution before oxygen (or active oxygen) reaches the fat-soluble antioxidant. Based on this principle, the weight ratio of the polyhydric alcohol to the water in the polyhydric alcohol aqueous solution is such that oxygen is consumed by the polyhydric alcohol aqueous solution and exhibits excellent antioxidant ability even under severe conditions. It is preferably 1 or more times (that is, a moisture content of 50% by mass or less), more preferably 2 or more times.

  On the other hand, the present inventors have found that the storage stability deteriorates even when the adhesion amount of the hydrophilic compound is too high. That is, when the hydrophilic compound acts as a radical scavenger, it itself is converted to a radical, but this radical is relatively stable (and hence useful as a radical scavenger) and, as a result, has a long life. In other words, the hydrophilic compound means that radicals generated during sterilization, or radicals generated by oxygen intrusion, heat, light, etc. accompanying storage in a harsh environment are easily pooled. From this viewpoint, the adhesion amount of the hydrophilic compound with respect to the dry weight of the hollow fiber membrane needs to be 50% by mass or less including moisture, preferably 40% by mass or less, and preferably 30% by mass or less. It is more preferable.

[Method for producing hollow fiber membrane blood purification device]
In the manufacturing method of the hollow fiber membrane blood purification device of the present embodiment, first, a hollow fiber membrane is prepared, followed by passing a predetermined mixed solution through the blood flow surface of the hollow fiber membrane, and drying and removing the solvent. In addition, radiation sterilization is performed.
The manufacturing method of the hollow fiber membrane blood purification apparatus of the present embodiment includes the following (first manufacturing method), (second manufacturing method), and (third manufacturing method).

(First manufacturing method)
A hollow fiber membrane containing a polysulfone resin and a hydrophilic polymer is prepared, and a hollow fiber membrane type blood purification device is manufactured using the hollow fiber membrane. A mixed solution of a soluble vitamin and a hydrophilic compound is passed through, the solvent is removed by drying, and then radiation sterilization is performed.

<Manufacturing process of hollow fiber membrane>
The hollow fiber membrane can be produced by utilizing a known dry / wet film forming technique.
First, a polysulfone resin and a hydrophilic polymer are dissolved in a common solvent to prepare a spinning dope.
As such a common solvent, when the hydrophilic polymer is PVP, for example, a solvent such as dimethylacetamide (hereinafter referred to as DMAC), dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, dioxane and the like. Or the solvent etc. which mixed 2 or more types of the said solvent are mentioned.
In addition, an additive such as water may be added to the spinning dope for controlling the pore diameter of the target hollow fiber membrane.
In the step of forming the hollow fiber membrane, a tube-in-orifice type spinneret is used, and the spinning stock solution is discharged from the spinneret orifice into the air simultaneously with the hollow inner solution for coagulating the spinning stock solution.
As the hollow inner liquid, water or a coagulating liquid mainly composed of water can be used, and its composition or the like may be determined according to the permeation performance of the target hollow fiber membrane. In general, a mixed solution of a solvent and water used for the spinning dope is preferably used. For example, a 0-65 mass% DMAC aqueous solution etc. are used.
The spinning dope discharged from the spinneret together with the hollow inner liquid travels through the idle running part and is introduced into the coagulation bath mainly composed of water installed at the bottom of the spinneret to complete the coagulation. Then, it winds up with a wet hollow fiber membrane winder to obtain a bundle of hollow fiber membranes, and then performs a drying treatment. Alternatively, after passing through the washing step, drying may be performed in a dryer to obtain a hollow fiber bundle.

<Manufacturing process of hollow fiber membrane blood purification device>
The hollow fiber membrane blood purification apparatus of the present embodiment inserts the above-described bundle of hollow fiber membranes into a cylindrical container having a predetermined fluid inlet / outlet as a liquid to be treated, and a potting agent such as polyurethane at both ends of the bundle. Can be manufactured by forming a potting layer and sealing both ends, and then cutting and removing excess potting agent after curing to open the end face and attaching a header having a fluid inlet / outlet.

<Liquid passing process>
A mixed solution of fat-soluble vitamin and hydrophilic compound is passed through the blood flow surface of the hollow fiber membrane to adhere the fat-soluble vitamin and hydrophilic compound mainly to the blood flow surface of the hollow fiber membrane, and then the solvent is removed. To fix both.
At this time, the adhesion rate of the hydrophilic compound to the hollow fiber membrane is 5% by mass or more and 50% by mass or less with respect to the dry weight of the hollow fiber membrane, including its moisture, and the fat-soluble vitamin hollow fiber The abundance on the membrane surface is controlled to be 0.5 mg or more and 25 mg or less per 1 g of the hollow fiber membrane.
The method of controlling the adhesion rate is a method of adjusting the concentration of the mixed solution, a method of adjusting the amount of permeation by changing the contact time, injection pressure or temperature when passing through and contacting the membrane, and adhering the mixed solution. Thereafter, a method for adjusting the liquid removal rate of the solution by air blow or the like may be appropriately selected or combined.
Further, the fat-soluble vitamin and the hydrophilic compound do not need to be attached at the same time. The fat-soluble vitamin solution may be fixed first, and then the hydrophilic compound solution may be fixed. In particular, in order to intentionally impart moisture to the hollow fiber membrane, it is preferable to fix them sequentially rather than simultaneously fixing them.

<Dry solvent removal step>
The solvent can be removed by drying with a gas such as air or nitrogen or by vacuum drying, and the method is not particularly limited. Also, the temperature at that time is not particularly limited.

<Radiation sterilization process>
The hollow fiber membrane blood purification device described above is irradiated with radiation and sterilized.
In the radiation sterilization method, an electron beam, a gamma ray, an X-ray or the like can be used, and any of them may be used.
The irradiation dose of radiation is usually 5 to 50 kGy in the case of γ rays and electron beams, but in the present embodiment, irradiation is preferably performed in a dose range of 20 to 40 kGy.
By radiation sterilization under such conditions, the hydrophilic polymer constituting the hollow fiber membrane is partially crosslinked, and elution of the hydrophilic polymer can be suppressed while maintaining good blood compatibility.

(Second manufacturing method)
A hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin is produced, and a hollow fiber membrane blood purification device is produced using the hollow fiber membrane. Subsequently, blood of the hollow fiber membrane is produced. A hydrophilic compound solution is passed through the distribution surface, the solvent is removed by drying, and then a radiation sterilization treatment is performed.

<Manufacturing process of hollow fiber membrane>
The hollow fiber membrane can be produced by utilizing a known dry / wet film forming technique.
First, a polysulfone polymer, a hydrophilic polymer, and a fat-soluble vitamin are dissolved in a common solvent to prepare a spinning dope.
As such a common solvent, when the hydrophilic polymer is PVP, for example, a solvent such as dimethylacetamide (hereinafter referred to as DMAC), dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, dioxane and the like. Or the solvent etc. which mixed 2 or more types of the said solvent are mentioned.
In addition, an additive such as water may be added to the spinning dope for controlling the pore diameter of the target hollow fiber membrane.
At this time, the amount of the fat-soluble vitamin is adjusted so that the amount of the fat-soluble vitamin on the hollow fiber membrane surface is 0.5 mg or more and 25 mg or less per 1 g of the hollow fiber membrane. Specifically, it can be adjusted by adjusting the concentration of the fat-soluble vitamin added to the spinning dope, or by applying a heat treatment at 110 ° C. or higher in the drying step described later.

In the step of forming the hollow fiber membrane, a tube-in-orifice type spinneret is used, and the spinning stock solution is discharged from the spinneret orifice into the air simultaneously with the hollow inner solution for coagulating the spinning stock solution.
As the hollow inner liquid, water or a coagulating liquid mainly composed of water can be used, and its composition or the like may be determined according to the permeation performance of the target hollow fiber membrane. In general, a mixed solution of a solvent and water used for the spinning dope is preferably used. For example, a 0-65 mass% DMAC aqueous solution etc. are used.
The spinning dope discharged from the spinneret together with the hollow inner liquid travels through the idle running part and is introduced into the coagulation bath mainly composed of water installed at the bottom of the spinneret to complete the coagulation. Then, it winds up with a wet hollow fiber membrane winder to obtain a bundle of hollow fiber membranes, and then performs a drying treatment. Alternatively, after passing through the washing step, drying may be performed in a dryer to obtain a hollow fiber bundle.

<Manufacturing process of hollow fiber membrane blood purification device>
The hollow fiber membrane blood purification apparatus of the present embodiment inserts the above-described bundle of hollow fiber membranes into a cylindrical container having a predetermined fluid inlet / outlet as a liquid to be treated, and a potting agent such as polyurethane at both ends of the bundle. Can be manufactured by forming a potting layer and sealing both ends, and then cutting and removing excess potting agent after curing to open the end face and attaching a header having a fluid inlet / outlet.

<Liquid passing process>
Immobilization is carried out by passing a solution of a hydrophilic compound through the blood flow surface of the hollow fiber membrane to adhere the hydrophilic compound mainly to the blood flow surface of the hollow fiber membrane, and then removing the solvent.
At this time, the adhesion rate of the hydrophilic compound to the hollow fiber membrane is controlled so as to be 5% by mass or more and 50% by mass or less with respect to the dry weight of the hollow fiber membrane including its moisture.
The method of controlling the adhesion rate is a method of adjusting the solution concentration of the hydrophilic compound, a method of adjusting the amount of permeation by changing the contact time, injection pressure or temperature when passing through and contacting the membrane, and the mixed solution A method of adjusting the drainage rate of the solution by air blow or the like after the attachment may be appropriately selected or combined.

<Dry solvent removal process, radiation sterilization process>
Solvent drying and radiation sterilization can be performed in the same manner as in the first method.

(Third production method)
A hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin is prepared, and a hollow fiber membrane blood purification device is manufactured using the hollow fiber membrane, followed by blood circulation of the hollow fiber membrane. A hydrophilic polymer solution is passed through the surface, and then the solvent is dried and removed, followed by radiation sterilization.
<Manufacturing process of hollow fiber membrane>
A spinning dope is prepared by the same method as the first production method except that the fat-soluble vitamin is dissolved in the hollow internal solution used in the membrane-forming step, and the hollow fiber is produced in the membrane-forming step.
A surfactant or the like may be added to the hollow internal solution in order to improve the solubility of the fat-soluble vitamin. By adjusting the concentration of the fat-soluble vitamin added to the hollow internal solution, the amount of the fat-soluble vitamin on the surface of the hollow fiber membrane is adjusted to 0.5 mg or more and 25 mg or less per 1 g of the hollow fiber membrane.

<Manufacturing process of hollow fiber membrane blood purification device, liquid passing process, solvent drying and removing process, radiation sterilization process>
It carries out similarly to the 2nd manufacturing method mentioned above.

Hereinafter, although a specific Example and a comparative example with this are given and demonstrated, this invention is not limited to a following example.
First, various measurement methods used in Examples will be described.

[Amount of fat-soluble vitamin present on the surface of the hollow fiber membrane]
A specific method for measuring the amount of fat-soluble vitamin present on the surface of the hollow fiber membrane will be described.
The hollow fiber membrane blood purification device was disassembled to collect the hollow fiber membrane, washed with water, and then vacuum dried at 40 ° C.
4 g of the dried hollow fiber membrane was weighed into a glass bottle, 80 mL of a 75 v / v% ethanol aqueous solution was added, and the fat-soluble vitamin was extracted while applying ultrasonic vibration for 60 minutes at room temperature.
The quantitative operation was performed by liquid chromatography, and the amount of fat-soluble vitamin in the extract was determined using a calibration curve obtained from the peak area of the fat-soluble vitamin standard solution.
That is, a high-performance liquid chromatograph (pump: JASCO PU-1580, detector: Shimadzu RID-6A, auto injector: Shimadzu SIL-6B, data processing: Tosoh GPC-8020, column oven: GL Sciences 556), column ( Attach Shodex Asahipak ODP-506E packed column for HPLC) at a column temperature of 40 ° C. and pass high-performance liquid chromatography methanol as the mobile phase at a flow rate of 1 mL / min. The soluble vitamin concentration was determined.
From this concentration, the extraction efficiency was set to 100%, and the weight (mg / g) of the fat-soluble vitamin present on the hollow fiber membrane surface was determined.
The partially oxidized fat-soluble vitamin was also included in the amount of fat-soluble vitamin present on the surface of the hollow fiber membrane.
For this reason, in order to determine the amount of the partially oxidized fat-soluble vitamin, the fat-soluble vitamin used for preparing the calibration curve was previously irradiated with 50 kGy radiation in the air, and a peak group used for area calculation was obtained in advance.

[Adhesion rate of hydrophilic compound to hollow fiber membrane]
A hollow fiber membrane for 5 g was taken out from the hollow fiber membrane blood purification device, and the weight (A) of the hollow fiber membrane before drying was accurately measured.
Thereafter, only water was removed with a vacuum dryer, and the weight (B) of the dried hollow fiber membrane was measured.
Thereafter, using the hollow fiber membrane sample after drying from which only water has been removed, the entire amount of the hollow fiber membrane sample is cut into pieces, and then 300 mL of pure water is added, stoppered, and washed with an ultrasonic cleaning device for 60 minutes. As a result, the adhering hydrophilic compound was extracted.
Polyhydric alcohol is quantified by liquid chromatographic method (conditions are given in the description) using the extract after extracting the cut hollow fiber membrane sample with an ultrasonic cleaning device, and from the peak area of the standard solution Using the obtained calibration curve, the weight (C) of the hydrophilic compound in the extract was determined.
High-performance liquid chromatograph (pump: JASCO PU-1580, detector: Shimadzu RID-6A, autoinjector: Shimadzu SIL-6B, data processing: Tosoh GPC-8020, column oven: GL Sciences 556), column (Shodex) Manufactured by SUGAR SH1011 (H91186)), a 0.01N sulfuric acid aqueous solution as a mobile phase was passed at a flow rate of 1 mL / min at a column temperature of 40 ° C., and a refractometer was used as a detector.
Further, only the cut hollow fiber membrane sample was taken out from the extract, dried with a vacuum dryer, and then the weight of the dried cut hollow fiber membrane sample was measured. This was attached with a hydrophilic compound and moisture. No hollow fiber membrane weight (D).
Based on the above measured values, the value calculated from the following formula (I) is the moisture content of the hollow fiber membrane, and the value calculated from the following formula (III) is the adhesion rate of the hydrophilic compound.
Moisture content (% by mass) of hollow fiber membrane = [(A−B) / D] × 100 (I)
Adhesion rate of hydrophilic compound (% by mass) = [(AD) / D] × 100 (III)

[Antioxidant capacity]
The antioxidant ability of the hollow fiber membrane blood purification device was measured by the following method.
First, ferric chloride hexahydrate was dissolved in pure water to prepare a 0.3 w / v% (solute amount (g) in 100 mL of solution) aqueous solution.
The hollow fiber membrane blood purification device was disassembled to collect the hollow fiber membrane, washed with water, and then vacuum dried at 40 ° C.
1 g of the hollow fiber membrane after drying and 20 mL of ferric chloride aqueous solution were weighed in a glass bottle, degassed for 10 minutes at 60 mmHg, and then incubated at 30 ° C. for 4 hours under shaking (exists on the surface of the hollow fiber membrane). The fat-soluble vitamin reduced iron (III) ions to produce iron (II).
The incubated aqueous solution was mixed with 2.6 mL of ethanol, 0.7 mL of ethanol, and 0.7 mL of a separately prepared 0.5 w / v% 2,2′-bipyridylethanol aqueous solution, and incubated at 30 ° C. for 30 minutes under shaking ( Iron (II) and bipyridyl form a complex and color).
The absorbance at 520 nm of the colored liquid was measured using a spectrometer.
Using a fat-soluble vitamin ethanol solution with a known concentration instead of the hollow fiber membrane, the same incubation, color reaction, and absorbance measurement were performed to create a calibration curve, and the antioxidant ability expressed by 1 g of the hollow fiber membrane Was determined as the weight equivalent value of the fat-soluble vitamin.
When the weight equivalent value of the fat-soluble vitamin present on the hollow fiber membrane surface per 1 g of the hollow fiber membrane is 0.4 mg or more, the antioxidant ability is judged as good. It was judged that the oxidation ability was not good and was marked as x.

[Measurement of lactate dehydrogenase (LDH) activity]
The blood compatibility of the hollow fiber membrane was evaluated by the adhesion of platelets to the surface of the hollow fiber membrane, and quantified using the activity of lactate dehydrogenase (LDH) contained in the platelets attached to the hollow fiber membrane as an index.
The hollow fiber membrane for blood purification collected by disassembling the hollow fiber membrane-type blood purification device has an effective length of 15 cm and an inner surface area of 50 mm ² (56 filaments because a hollow fiber membrane having an inner diameter of 185 μm is used). A mini module was prepared by bonding both ends with an epoxy adhesive.
The mini-module was washed by flowing 3 mL of physiological saline (Otsuka Pharmaceutical Co., Ltd., Otsuka raw food injection) inside the hollow fiber membrane at a flow rate of 0.6 mL / min (hereinafter referred to as “priming”).
Thereafter, 15 mL of heparin-added blood was adjusted to 37 ° C. and circulated in the mini module at a flow rate of 1.2 mL / min for 4 hr. After circulation, the inside of the mini-module was washed with 10 mL and the outside with 10 mL with physiological saline.
A hollow fiber membrane having a length of 56 filaments and a length of 7 cm was collected from the washed mini-module, and then cut into a spitz tube for LDH measurement as a measurement sample.
Half of the entire 14 cm long hollow fiber membrane was collected from the washed mini-module, and then cut into a Spitz tube for LDH measurement as a measurement sample.

Next, LDH measurement was performed on 0.5 vol% Triton X-100 / PBS solution obtained by dissolving Triton X-100 (manufactured by Nacalai Tesque) in phosphate buffer solution (PBS) (manufactured by Wako Pure Chemical Industries, Ltd.). After adding 0.5 mL to the Spitz tube for use, centrifuge (2700 rpm x 5 min) to submerge the hollow fiber membrane in the solution, and perform shaking extraction for 60 minutes to destroy cells (mainly platelets) attached to the hollow fiber membrane Then, LDH in the cells was extracted. 0.05 mL of this extract was collected, and further reacted by adding 2.7 mL of a 0.6 mM sodium pyruvate solution and 0.3 mL of a 1.277 mg / mL nicotinamide adenine dinucleotide (NADH) solution. After reacting at 1 ° C. for 1 hour, absorbance at 340 nm was measured. Similarly, the absorbance of the membrane (blank) not reacted with blood was also measured, and the difference in absorbance was calculated by the following formula (IV).
Furthermore, LDH was evaluated by the value obtained by the following formula (V) obtained by dividing the value obtained by the following formula (IV) by the effective membrane area.
In this method, the larger the decrease, the higher the LDH activity, that is, the greater the amount of platelets attached to the surface of the hollow fiber membrane, and the lower the 50 the LDH activity, the better the blood compatibility. Judged that there was.
Δ340 nm = absorbance after 60 minutes of sample−absorbance after 60 minutes of blank (IV)
LDH = Δ340 nm / effective membrane area (V)
FIG. 4 shows the relationship between the amount of fat-soluble vitamins on the surface of the hollow fiber membrane and the LDH activity.
In FIG. 4, the unit (mg / g HF) on the horizontal axis means the amount of fat-soluble vitamin present on the surface of the hollow fiber membrane per 1 g of the hollow fiber membrane.
When the amount of fat-soluble vitamin is 0.5 mg or more and 25.0 mg or less per 1 g of the hollow fiber membrane, the LDH is good, whereas 0.4 mg or 25.0 mg which is less than 0.5 mg outside this range is added. In the case of exceeding 26.2 mg, it was found that LDH was not good.
FIG. 5 shows the relationship between the adhesion rate (mass%) of the hydrophilic compound including moisture and the relationship between LDH activity (left vertical axis) with respect to the dry weight of the hollow fiber membrane.
When the adhesion rate of the hydrophilic polymer including moisture was 5% by mass or more, the LDH activity was good.

[Evaluation of priming properties]
The nozzles (inlet and outlet) leading to the outside of the hollow fiber membrane of the hollow fiber membrane type blood purification apparatus were plugged, and the nozzle inlet leading to the hollow part was placed downward to stand upright.
A silicone tube inserted in a physiological saline (Otsuka Pharmaceutical, Otsuka raw food injection) bottle is connected to a nozzle at the entrance that leads to the hollow part of the blood purification device via a pump (Metech Line Flow LF-300 blood pump). did. Another silicon tube was inserted into the nozzle leading to the outlet from the hollow portion to obtain a sample liquid collection site.
Saline was passed through at a rate of 100 mL / min, and 10 fractions of the sample solution were collected from the collection site in 50 mL increments.
The osmotic pressure of the sample solution was ADVANCED INSTRUMENTS, INC. Measurements were made using a Model 3250 Osmometer.
Since the osmotic pressure of physiological saline measured with this measuring instrument was 286 to 287 mOsm, the fraction showing a value of 287 mOsm or less (that is, the total amount of physiological saline used) is defined as the amount of washing water required for priming. did.
FIG. 5 shows the relationship between the adhesion rate (mass%) of the hydrophilic compound including water and the amount of washing water necessary for priming (right vertical axis) with respect to the dry weight of the hollow fiber membrane.
It was found that the amount of washing water necessary for priming is also in a practically favorable range when the adhesion rate of the hydrophilic polymer including moisture is in the range of 5% by mass or more and 50% by mass or less.

[Model test for storage at high temperatures or for long periods (acceleration over time)]
The hollow fiber membrane blood purification devices of Examples and Comparative Examples described later were heat-treated (accelerated over time) for 3 weeks in a 60 ° C. constant temperature bath.
The antioxidant ability of the hollow fiber membrane blood purification apparatus after the heat treatment was evaluated by the measurement method of [Antioxidant ability] described above.
The antioxidant ability of the hollow fiber membrane blood purification device after the heat treatment was carried out for the hollow fiber membrane blood purification devices of Examples 12 and 13 and Comparative Examples 9 and 10, which will be described later. The measurement results are shown.

[Example 1]
17 parts by mass of PSf (manufactured by Solvay Advanced Polymers, Inc., P-1700) 4 parts by mass of PVP (manufactured by ISP, K-90) Uniform spinning dope comprising 79 parts by mass of dimethylacetamide (hereinafter referred to as DMAC) Was prepared.
Here, PSf represents a polysulfone resin, and PVP represents polyvinylpyrrolidone.

As the hollow inner liquid, a 42% by weight aqueous solution of DMAC was used and discharged from the spinneret together with the spinning stock solution.
At that time, the discharge amounts of the spinning solution and the hollow inner solution were adjusted so that the film thickness after drying was 45 μm and the inner diameter was 185 μm.
The discharged spinning stock solution is immersed in a 60 ° C. coagulation bath made of water provided 50 cm below, passed through a coagulation step and a water washing step (water washing treatment) at a speed of 30 m / min, and then introduced into a dryer. After drying for 2 minutes and further heat treatment at 160 ° C. for 0.5 minutes, the polysulfone-based hollow fiber membrane provided with crimps was wound up.
Next, a bundle of 10,000 wound hollow fiber membranes is loaded into a plastic cylindrical container designed so that the effective membrane area of the hollow fiber membrane is 1.5 m ^2, and both ends thereof are urethane resin Then, both ends were cut to form an open end of the hollow fiber membrane.
Glycerin (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) and α-tocopherol were added to an aqueous solution consisting of 57 parts by mass of 2-propanol (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) and 43 parts by mass of distilled water (Otsuka Pharmaceutical). 100 mL of a solution prepared by dissolving (special grades manufactured by Wako Pure Chemical Industries, Ltd.) to a concentration of 5 mass% and 0.5 mass%, respectively, is blown into the hollow fiber membrane for 10 seconds with 0.3 MPa air. (Hereinafter, it may be simply referred to as air blow) and the excess solution was discharged. Next, it was dried with dry air at 40 ° C. for 1 hour. After drying, header caps were attached to both ends.
After plugging the blood inflow / outflow nozzle, 20 kGy of electron beam was irradiated to obtain a hollow fiber membrane blood purification apparatus having an effective membrane area of 1.5 m ² .
The amount of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane blood purification apparatus is 7 mg per 1 g of membrane, and the adhesion rate of glycerin, which is a polyhydric alcohol as a hydrophilic compound, is hollow. The dry weight of the yarn membrane was 14% by mass (including moisture), and the moisture content of glycerin was 5% by mass.
The results of measuring various performances are shown in Table 1 below.

[Example 2]
PSf (manufactured by Solvay Advanced Polymers, P-1700) 17 parts by mass PVP (manufactured by ISP, K-90) 4 parts by mass α-tocopherol (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) 0. A uniform spinning stock solution consisting of 78.5 parts by mass of DMAC 78.5 parts by mass was prepared.
A polysulfone-based hollow fiber membrane is wound up in the same manner as in Example 1, and a bundle of 10,000 hollow fiber membranes wound up is made of plastic designed so that the effective membrane area of the hollow fiber membrane is 1.5 m ² . It loaded in the cylindrical container, the both ends were adhere | attached and fixed with the urethane resin, and both ends were cut | disconnected, and the open end of the hollow fiber membrane was formed.
100 mL of an aqueous solution consisting of 95 parts by weight of distilled water (Otsuka Pharmaceutical) and 5 parts by weight of glycerin (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) was passed through the hollow fiber membrane and blown for 10 seconds with 0.3 MPa air. Next, it was dried with dry air at 40 ° C. for 1 hour. After drying, header caps were attached to both ends.
After plugging the blood inflow / outflow nozzle, 20 kGy of electron beam was irradiated to obtain a hollow fiber membrane blood purification apparatus having an effective membrane area of 1.5 m ² .
The amount of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane blood purification apparatus is 7 mg per 1 g of the membrane, and the glycerin adhesion rate as a polyhydric alcohol is the dry weight of the hollow fiber membrane. The water content of glycerin was 12% by mass (including water) and 5% by mass.
The results of measuring various performances are shown in Table 1 below.

Example 3
The amount of α-tocopherol was 0.3 parts by mass, drying after washing with water in the spinning process was performed at 120 ° C. for 2 minutes, and further, heat treatment was performed at 120 ° C. for 0.5 minutes.
Other conditions were the same as in Example 2, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane is 0.5 mg per 1 g of membrane, and the glycerin adhesion rate, which is a polyhydric alcohol, is that of the hollow fiber membrane. The moisture content of glycerin was 13% by mass (including moisture) and 6% by mass based on the dry weight.
The results of measuring various performances are shown in Table 1 below.

Example 4
The amount of α-tocopherol was changed to 0.5 parts by mass, drying after the water washing treatment in the spinning step was performed at 120 ° C. for 2 minutes, and further, heat treatment was performed at 130 ° C. for 0.5 minutes.
Other conditions were the same as in Example 2, and a hollow fiber membrane blood purification device was obtained.
The amount of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane-type blood purification apparatus is 1.5 mg per 1 g of membrane, and the adhesion rate of glycerol, which is a polyhydric alcohol, is that of the hollow fiber membrane. The moisture content of glycerin was 13% by mass (including moisture) and 6% by mass based on the dry weight.
The results of measuring various performances are shown in Table 1 below.

Example 5
The amount of α-tocopherol was changed to 1.0 part by mass, drying after washing with water in the spinning process was performed at 120 ° C. for 2 minutes, and further, heat treatment was performed at 170 ° C. for 0.5 minutes.
Other conditions were the same as in Example 2, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane is 18 mg per gram of the membrane, and the glycerin adhesion rate as a polyhydric alcohol is the dry weight of the hollow fiber membrane. 14% by mass (including water), and the moisture content of glycerin was 7% by mass.
The results of measuring various performances are shown in Table 1 below.

Example 6
The α-tocopherol was adjusted to 2.5 parts by mass, drying after the water washing treatment in the spinning step was performed at 120 ° C. for 2 minutes, and further heat treatment was performed at 180 ° C. for 0.5 minutes.
Other conditions were the same as in Example 2, and a hollow fiber membrane blood purification device was obtained.
The amount of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane blood purification apparatus is 25 mg per 1 g of membrane, and the glycerin adhesion rate as a polyhydric alcohol is the dry weight of the hollow fiber membrane. 14% by mass (including water), and the moisture content of glycerin was 9% by mass.
The results of measuring various performances are shown in Table 1 below.

Example 7
The glycerin concentration of the solution passed through the hollow fiber membrane opening end was set to 2% by mass. Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane is 6 mg per gram of the membrane, and the glycerin adhesion rate as a polyhydric alcohol is the dry weight of the hollow fiber membrane. 5% by mass (including water), and the moisture content of glycerin was 7% by mass.
The results of measuring various performances are shown in Table 1 below.

Example 8
The glycerin concentration of the solution passed through the hollow fiber membrane opening end was 10% by mass. Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane is 6 mg per gram of the membrane, and the glycerin adhesion rate as a polyhydric alcohol is the dry weight of the hollow fiber membrane. 30% by mass (including water), and the moisture content of glycerin was 6% by mass.
The results of measuring various performances are shown in Table 1 below.

Example 9
The glycerin concentration of the solution passed through the hollow fiber membrane opening end was 18% by mass. Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane is 6 mg per gram of the membrane, and the glycerin adhesion rate as a polyhydric alcohol is the dry weight of the hollow fiber membrane. The moisture content of glycerin was 50% by mass (including water) and 6% by mass.
The results of measuring various performances are shown in Table 1 below.

Example 10
The glycerin concentration of the solution passing through the hollow fiber membrane opening end was 3% by mass. Other conditions were the same as in Example 1, and a fat-soluble vitamin (α-tocopherol) and glycerin were applied and dried to obtain a hollow fiber membrane blood purification apparatus with a header attached. The obtained hollow fiber membrane blood purification apparatus was allowed to stand for 30 days in a room temperature of 20 ° C. and a relative humidity of 90% for sufficient moisture absorption, and then header caps were attached to both ends.
After plugging the blood inflow / outflow nozzle, 20 kGy of electron beam was irradiated to obtain a hollow fiber membrane blood purification apparatus having an effective membrane area of 1.5 m ² .
The amount of fat-soluble vitamin (α-tocopherol) present on the membrane surface of the hollow fiber membrane in this hollow fiber membrane blood purification apparatus is 6 mg per gram of membrane, and the glycerin adhesion rate, which is a polyhydric alcohol, is determined by the dry weight of the hollow fiber membrane. The moisture content of glycerin was 11% by mass (including moisture) and 50% by mass.
The results of measuring various performances are shown in Table 1 below.

Example 11
Tetraethylene glycol (manufactured by Wako Pure Chemical Industries, Ltd., trial special grade) was used instead of glycerin. Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
The abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane blood purification apparatus is 7 mg per 1 g of membrane, and the adhesion rate of tetraethylene glycol, which is a polyhydric alcohol, is that of the hollow fiber membrane. The moisture content of tetraethylene glycol was 14% by mass (including moisture) and 5% by mass based on the dry weight.
The results of measuring various performances are shown in Table 1 below.

[Comparative Example 1]
The amount of α-tocopherol was changed to 0.2 parts by mass, and the water-washed drying was performed at 120 ° C. for 2 minutes, followed by further heat treatment at 120 ° C. for 0.5 minutes.
Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
The abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane-type blood purification apparatus is 0.4 mg per 1 g of membrane, and the adhesion rate of glycerol, which is a polyhydric alcohol, is that of the hollow fiber membrane. The dry weight was 14% by mass (including moisture), and the moisture content of glycerin was 6% by mass.
The results of measuring various performances are shown in Table 2 below.
The LDH activity value was high, and good blood compatibility could not be obtained.

[Comparative Example 2]
The amount of α-tocopherol was changed to 3.0 parts by mass, and the water washing treatment was dried at 120 ° C. for 2 minutes, followed by further heat treatment at 180 ° C. for 0.5 minutes.
Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
The amount of fat-soluble vitamin (α-tocopherol) present on the membrane surface of the hollow fiber membrane in this hollow fiber membrane blood purification apparatus is 26 mg per gram of membrane, and the glycerin adhesion rate, which is a polyhydric alcohol, is the dry weight of the hollow fiber membrane. The moisture content of glycerin was 13% by mass (including water) and 6% by mass.
The results of measuring various performances are shown in Table 2 below.
The LDH activity value was high, and good blood compatibility could not be obtained.

[Comparative Example 3]
The glycerin concentration of the solution passed through the hollow fiber membrane opening end was 1% by mass.
Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane is 6 mg per gram of the membrane, and the glycerin adhesion rate as a polyhydric alcohol is the dry weight of the hollow fiber membrane. 2% by mass (including moisture), and the moisture content of glycerin was 5% by mass.
The results of measuring various performances are shown in Table 2 below.
The LDH activity value was high, and good blood compatibility could not be obtained.

[Comparative Example 4]
The glycerin concentration of the solution passed through the hollow fiber membrane opening end was 22% by mass.
Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the abundance of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane is 6 mg per gram of the membrane, and the glycerin adhesion rate as a polyhydric alcohol is the dry weight of the hollow fiber membrane. The moisture content of glycerin was 6% by mass with respect to 59% by mass (including moisture).
The results of measuring various performances are shown in Table 2 below.
In this comparative example, the amount of washing water required for priming was as large as 350 mL, and could not satisfy medical economic requirements.

[Comparative Example 5]
The solution passed through the open end of the hollow fiber membrane was glycerin (65 parts by mass) and distilled water (35 parts by mass), and drying after air blowing was not performed.
Other conditions were the same as in Example 2, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the amount of fat-soluble vitamins on the membrane surface of the hollow fiber membrane was 7 mg per gram of membrane, the adhesion rate of glycerol, which is a polyhydric alcohol, was 181%, and the moisture content of glycerol was 67%. It was.
The results of measuring various performances are shown in Table 2 below.
In this comparative example, the amount of washing water required for priming was as large as 350 mL, and could not satisfy medical economic requirements.
Although this comparative example corresponds to the hollow fiber membrane blood purification device disclosed in Patent Document 3, the LDH activity value was high and good blood compatibility could not be obtained.

[Comparative Example 6]
The solution passed through the open end of the hollow fiber membrane was glycerin (65 parts by mass) and distilled water (35 parts by mass), and drying after air blowing was not performed.
Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the amount of fat-soluble vitamin (α-tocopherol) present on the membrane surface of the hollow fiber membrane is 0 mg per 1 g of membrane, and the glycerin adhesion rate, which is a polyhydric alcohol, is the dry weight of the hollow fiber membrane. 181% by mass (with water), and the moisture content of glycerin was 67% by mass.
The results of measuring various performances are shown in Table 2 below.
In this comparative example, the LDH activity value was high, and good blood compatibility was not obtained.

[Comparative Example 7]
The solution passed through the open end of the hollow fiber membrane was glycerin (5 parts by mass) and distilled water (95 parts by mass), and drying after air blowing was not performed.
Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the amount of fat-soluble vitamin (α-tocopherol) present on the membrane surface of the hollow fiber membrane is 0 mg per 1 g of membrane, and the glycerin adhesion rate, which is a polyhydric alcohol, is the dry weight of the hollow fiber membrane. 14% by mass (including water), and the moisture content of glycerin was 5% by mass.
The results of measuring various performances are shown in Table 2 below.

[Comparative Example 8]
The solution passed through the open end of the hollow fiber membrane was a solution in which α-tocopherol was dissolved in an aqueous solution consisting of 57 parts by mass of 2-propanol and 43 parts by mass of distilled water to a concentration of 0.5% by mass.
Other conditions were the same as in Example 1, and a hollow fiber membrane blood purification device was obtained.
In this hollow fiber membrane blood purification apparatus, the amount of fat-soluble vitamin on the membrane surface of the hollow fiber membrane is 6 mg per 1 g of membrane, and the glycerin adhesion rate as a polyhydric alcohol is 0% by mass with respect to the dry weight of the hollow fiber membrane. (Including moisture).
The results of measuring various performances are shown in Table 2 below.
In this comparative example, the LDH activity value was high, and good blood compatibility was not obtained.

  In Tables 1 and 2, “mg / gHF”, which is a unit of the amount of surface fat-soluble vitamin, means the weight (mg) of surface fat-soluble vitamin per 1 g of the hollow fiber membrane to be measured.

  As shown in Table 1, the hollow fiber membrane blood purification devices of Examples 1 to 11 all have practically good antioxidant performance, blood compatibility, and washing water necessary for priming The amount of was also found to be in a practically good range.

Example 12
The α-tocopherol concentration of the solution passed through the open end of the hollow fiber membrane was 0.15% by mass, the glycerin concentration was 2%, and other conditions were the same as in Example 1 to obtain a hollow fiber membrane blood purification device. .
The amount of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane-type blood purification apparatus is 1.5 mg per 1 g of membrane, and the adhesion rate of glycerol, which is a polyhydric alcohol, is that of the hollow fiber membrane. The dry weight was 5% by mass (including moisture), and the moisture content of glycerin was 5% by mass.
The results of measuring various performances are shown in Table 3 below.

Example 13
The solution passed through the open end of the hollow fiber membrane had an α-tocopherol concentration of 0.15% by mass and a glycerin concentration of 19%, and the other conditions were the same as in Example 1 to obtain a hollow fiber membrane type blood purification device.
The amount of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane-type blood purification apparatus is 1.5 mg per 1 g of membrane, and the adhesion rate of glycerol, which is a polyhydric alcohol, is that of the hollow fiber membrane. 50% by mass (including moisture) relative to the dry weight, and the moisture content of glycerin was 5% by mass.
The results of measuring various performances are shown in Table 3 below.

[Comparative Example 9]
The solution passed through the open end of the hollow fiber membrane had an α-tocopherol concentration of 0.15 mass% and a glycerin concentration of 1%, and the other conditions were the same as in Example 1 to obtain a hollow fiber membrane blood purification apparatus.
The amount of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane-type blood purification apparatus is 1.5 mg per 1 g of membrane, and the adhesion rate of glycerol, which is a polyhydric alcohol, is that of the hollow fiber membrane. The dry weight was 2% by mass (including moisture), and the moisture content of glycerin was 5% by mass.
The results of measurement of various performances are shown in Table 4 below.

[Comparative Example 10]
The solution passed through the open end of the hollow fiber membrane had an α-tocopherol concentration of 0.15 mass% and a glycerin concentration of 22%, and the other conditions were the same as in Example 1 to obtain a hollow fiber membrane blood purification apparatus.
The amount of fat-soluble vitamin (α-tocopherol) on the membrane surface of the hollow fiber membrane in this hollow fiber membrane-type blood purification apparatus is 1.5 mg per 1 g of membrane, and the adhesion rate of glycerol, which is a polyhydric alcohol, is that of the hollow fiber membrane. The dry weight was 60% by mass (including moisture), and the moisture content of glycerin was 5% by mass.
The results of measurement of various performances are shown in Table 4 below.

As shown in Table 3, the hollow fiber membrane blood purification devices of Examples 12 and 13 are both practically good antioxidants before and after the time-lapse accelerated test which is a model test for storage at high temperature or for a long time. Had performance.
Although Comparative Example 9 and Comparative Example 10 were practically sufficient for normal antioxidant ability, the antioxidant ability after the time-lapse accelerated test was inferior enough for practical use.

  The hollow fiber membrane blood purification apparatus of the present invention has industrial applicability as a blood purification apparatus for performing extracorporeal blood circulation therapy.

DESCRIPTION OF SYMBOLS 1 PSf film | membrane 2 Hydrophilic polymer 3 Hydrophilic compound aqueous solution 4 Hydrophilic polymer carrying the hydrophilic compound aqueous solution 5 Fat-soluble vitamin oil film 6 Hydrophilic polymer carrying many hydrophilic compound aqueous solutions

Claims (8)

A hollow fiber membrane blood purification device comprising a hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer and a fat-soluble vitamin,
The abundance of the fat-soluble vitamin on the surface of the hollow fiber membrane is 0.5 mg to 25 mg per 1 g of the hollow fiber membrane,
The hollow fiber membrane has a hydrophilic compound of 5% by mass or more and 50% by mass or less including moisture attached to the dry weight of the hollow fiber membrane,
A dry-type hollow fiber membrane blood purification device that has been subjected to radiation sterilization.   The hollow fiber membrane blood purification apparatus according to claim 1, wherein the water content of the hydrophilic compound is 50 mass% or less.   The hollow fiber membrane blood purification apparatus according to claim 1 or 2, wherein the hydrophilic compound is a polyhydric alcohol.   The hollow fiber membrane blood purification apparatus according to claim 3, wherein the polyhydric alcohol is at least one selected from the group consisting of glycerin, mannitol, glycols, and polyethylene glycol. For a hollow fiber membrane blood purification device comprising a hollow fiber membrane containing a polysulfone resin and a hydrophilic polymer,
Pass a mixed solution of a fat-soluble vitamin and a hydrophilic compound through at least the blood flow surface of the hollow fiber membrane, and then remove the solvent by drying.
Next, radiation sterilization is performed.
A method for producing a hollow fiber membrane blood purification device. It is a manufacturing method of the hollow fiber membrane type blood purification device according to any one of claims 1 to 4,
For a hollow fiber membrane blood purification device comprising a hollow fiber membrane containing a polysulfone resin and a hydrophilic polymer,
Pass a mixed solution of a fat-soluble vitamin and a hydrophilic compound through at least the blood flow surface of the hollow fiber membrane, and then remove the solvent by drying.
Next, radiation sterilization is performed.
A production method for obtaining a hollow fiber membrane blood purification apparatus. For a hollow fiber membrane blood purification apparatus comprising a hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin,
Pass a solution of the hydrophilic compound through at least the blood flow surface of the hollow fiber membrane, and then remove the solvent by drying,
Next, radiation sterilization is performed.
A method for producing a hollow fiber membrane blood purification device. It is a manufacturing method of the hollow fiber membrane type blood purification device according to any one of claims 1 to 4,
For a hollow fiber membrane blood purification apparatus comprising a hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin,
Pass a solution of the hydrophilic compound through at least the blood flow surface of the hollow fiber membrane, and then remove the solvent by drying,
Next, radiation sterilization is performed.
A production method for obtaining a hollow fiber membrane blood purification apparatus.