JP4889109B2 - Hollow fiber membrane blood purification device - Google Patents

Description

  The present invention relates to a hollow fiber membrane blood purification device used for extracorporeal circulation type blood purification therapy. More specifically, it is a blood purification device called dry or semi-dry sterilized by electron beam irradiation, and is a lightweight, excellent handleability, little hydrophilic polymer elution, and excellent blood compatibility. Type blood purification apparatus.

Conventionally, various hollow fiber membrane blood purification devices have been developed according to extracorporeal circulation type blood purification therapy such as hemodialysis, blood filtration, plasma separation, and plasma component fractionation, and safety and performance have also been improved. The product has been put into practical use.
The hollow fiber membranes used are roughly classified into cellulose polymers and synthetic polymers, but in recent years, polysulfone polymers are widely used as membrane materials among the latter. Polysulfone-based polymers are characterized by excellent biocompatibility and excellent resistance to radiation, heating, and chemicals such as acid and alkali, but because they are hydrophobic polymers, As it is, it lacks affinity with blood. Therefore, a hydrophilic polymer such as polyvinyl pyrrolidone or polyethylene glycol is added as a hydrophilizing agent, which is less irritating to blood.

Hollow fiber membrane blood purification devices are roughly classified into a wet type in which the gap inside the hollow fiber membrane and the container is filled with an aqueous medium, and a non-wet type that is not filled with an aqueous medium. The latter is further divided into a dry type with a low moisture content of several percent, and a semi-dry type (sometimes called a half-wet type) in which the membrane is moderately moistened with moisture or a humectant. May be. The dry type and semi-dry type have the characteristics that the product weight is lighter than the wet type and they are not easily frozen even at low temperatures, and can be said to be particularly excellent in terms of distribution in terms of transportation and storage.

These hollow fiber membrane blood purification devices need to be completely sterilized in a sealed package state before use.
The three mainstream sterilization methods for hollow fiber membrane blood purification devices that have been put to practical use are the gas sterilization method using ethylene oxide gas, the autoclave method using high-pressure steam, and the γ-ray irradiation method. Irradiation methods have come into practical use. Among these, in the ethylene oxide gas method, residual ethylene oxide gas becomes a problem, and it is necessary to perform sufficient degassing so as not to cause toxicity. Furthermore, since pressurization and depressurization are repeated, the processing time is long, and performance may change depending on the material. Further, the autoclave method and the γ-ray irradiation method have a problem that depends on the properties of the material constituting the hollow fiber membrane blood purification device. In other words, the former autoclave method requires heat resistance of the hollow fiber membrane in a wet state, and depending on the material, its performance may be significantly reduced during sterilization and may not be used. The latter γ-ray irradiation method is excellent as a sterilization method for a blood purification apparatus because it has no problem of residual gas and heat resistance and has a high permeability of the irradiation beam. However, it is well known that a part of the material undergoes a chemical change by irradiation energy. For example, in a hollow fiber membrane composed of a hydrophobic polymer and a hydrophilic polymer, the hydrophilic polymer is mainly denatured and deteriorated and eluted from the hollow fiber membrane. In some cases, permeation performance, strength properties, or blood compatibility deteriorated.

  On the other hand, the electron beam irradiation method does not worry about residual toxicity like the ethylene oxide gas method, and the sterilization time is not long, and the sterilization process is short, unlike the autoclave method, the ethylene oxide gas method, and the γ ray irradiation method. It is. In addition, irradiation is stopped instantly when the power is turned off, and when using an accelerator with energy lower than 6 MeV, consideration for storage of radioactive materials such as γ-ray irradiation facilities is unnecessary and environmental safety is high. It is inexpensive in terms of cost. Furthermore, a major difference from γ-ray irradiation is that the temperature rise and material deterioration of the irradiated object are small during sterilization. For this reason, there exists an advantage that the range of material selection is wide, and the further practical use is anticipated in the future.

  However, it is said that an electron beam has a small transmission power to an object as compared with a γ-ray, and its transmission distance depends on the density of the irradiated material. Therefore, hitherto, it has been put to practical use only for a surgical glove, a surgical gown or the like having a relatively uniform shape and comprising a single member. For example, when irradiated with an electron beam to a hollow fiber membrane blood purification device as an irradiated object containing a thick and high-density part, a part with insufficient permeability is generated, and the dose distribution between each part in one product (maximum The ratio of dose to minimum dose). As a result, problems such as material deterioration and elution are sometimes manifested. Specifically, if the irradiation standard is adjusted to the maximum dose, sterilization at the minimum dose position will be insufficient, and conversely, if the irradiation standard is adjusted to the minimum dose site to ensure sterilization, excessive irradiation will occur at the maximum dose position. Deterioration and coloring of the material will occur. When material degradation occurs in a hydrophilic polymer, the hydrophilicity of the membrane is impaired, leading to a decrease in blood compatibility. As described above, depending on the object to be irradiated, it is not easy to uniformly irradiate the electron beam, and there is a problem based on uneven irradiation.

Therefore, in order to uniformly irradiate an object having a complicated shape with an electron beam, studies have been made mainly from two viewpoints of an approach from a sterilization process and a material chemistry approach.
As an approach from the sterilization process, for example, in Patent Document 1, when sterilizing a hollow fiber membrane type dialysis device or an artificial lung with an electron beam, irradiation with a high acceleration voltage is performed and a dose distribution is reduced by using a shielding material. Japanese Patent Application Laid-Open No. 2004-260260 discloses an irradiation method including a whole irradiation step and a partial shielding step. However, in the former, since it is necessary to affix a shielding material to the over-irradiated part for each product, it is troublesome to form a shield having a specific absorbed dose and to be attached to the product, resulting in low work efficiency. It was. The latter attempted to improve the problem, but the work efficiency was still low. In addition, Patent Document 3 discloses a technique for irradiating a hollow fiber membrane type module from three or more directions when it has a product of a specific density and thickness when irradiating it with an electron beam. In this case as well, it was necessary to irradiate the electron beam several times while rotating the irradiated object, which was difficult to adopt as a sterilization method for mass-produced products.

  On the other hand, as a material chemistry approach, there are many known techniques for kneading additives such as radical trapping agents and antioxidants in resin materials, or coexisting them in the vicinity of the resin, including electron beams. It has been widely studied as a method for suppressing deterioration during irradiation. According to these methods, there is an advantage that it is not necessary to significantly modify the irradiation equipment, and the production can be efficiently performed without extending the irradiation tact time. However, many additives cannot be used in extracorporeal circulation type blood purification devices from the viewpoint of safety, and if limited to hollow fiber membrane blood purification devices, they are exclusively measures for improving material deterioration during γ-ray sterilization. Most of them were embodied (for example, Patent Documents 4 and 5).

In addition, the present applicant has found that the hollow fiber membrane protected with the adhesion rate and moisture content of a specific radical trap material is effective in reducing eluate and maintaining blood compatibility even when sterilized by radiation. A patent application was previously filed (Patent Document 8). However, it is specifically limited to detailed knowledge on γ-ray irradiation. Similarly, in the case of electron beam irradiation, there is room for further detailed examination in order to achieve both reduction of eluate and maintenance of blood compatibility. It remained.
Thus, few attempts have been made to improve the problems peculiar to electron beam sterilization of a hollow fiber membrane type blood purification apparatus by a material chemistry approach.

Incidentally, in addition to the above approach, several related techniques are known. For example, Patent Document 6 discloses that a polysulfone-based hollow fiber membrane irradiated with an electron beam is excellent in blood compatibility. Patent Document 7 discloses that a module incorporating a hollow fiber membrane is irradiated with an electron beam. It is disclosed that the organic solvent remaining in the film is decomposed. However, the former technique focuses only on the causal relationship between the concavo-convex structure on the inner surface of the film and blood compatibility, and lacks the viewpoint of deterioration of the film material due to electron beam irradiation. In addition, although the latter technique captures the aspect of eluate, it is a technique that focuses only on the reduction of the low molecular weight residual solvent, and does not mention any deterioration of the film material that is a resin material.
As described above, conventionally, in addition to material chemical methods such as additives, studies have been made on prevention of material deterioration in two ways, that is, improvement of irradiation non-uniformity peculiar to electron beams. However, the relatively simple material chemistry approach is still technically insufficient from the viewpoint of satisfying blood compatibility while suppressing deterioration, and further improvement is necessary.
Japanese Patent Laid-Open No. 8-275991 JP 2000-334028 A JP 2000-135274 A Japanese Patent No. 3076080 Japanese Patent No. 3432240 JP 2005-224604 A JP 2000-218140 A Japanese Patent Application No. 2005-232154

  In view of the above problems, the object of the present invention is a hollow fiber blood purification device that is lightweight and has excellent handling properties, called a semi-dry type, filled with a hollow fiber membrane made of a hydrophobic polymer and a hydrophilic polymer. An object of the present invention is to provide a hollow fiber membrane-type blood purification apparatus in which elution of a hydrophilic polymer is small despite the electron beam sterilization, and a decrease in blood compatibility can be suppressed.

As a result of intensive studies to solve the above problems, the present inventors have thought that it is extremely important that the hollow fiber membrane is protected from radical attack generated by electron beam sterilization. For this purpose, the present inventors have found that it is necessary to control the oxygen concentration around the membrane while protecting the hollow fiber membrane with a specific amount of wet protective agent. As a result, in a dry or semi-dry type hollow fiber membrane blood purification apparatus, the increase in the amount of the hydrophilic polymer eluted from the hollow fiber membrane and the accompanying decrease in blood compatibility were successfully suppressed. The present invention has been completed.
That is, the present invention provides the following inventions.
(1) A hollow fiber membrane bundle composed of a hydrophobic polymer and a hydrophilic polymer is filled in a container, and an end portion of the bundle is held in the container by a potting layer so that a hollow fiber membrane inner chamber and a hollow fiber membrane outer chamber are formed. A hollow fiber membrane blood purification apparatus formed and having a fluid inlet / outlet leading to the hollow fiber membrane inner chamber and a fluid inlet / outlet leading to the hollow fiber membrane outer chamber, the hollow fiber membrane being 60% or more of its dry weight It is covered with a moisture protective agent of 400% or less, and the space other than the hollow fiber membrane bundle and the moisture protective agent occupied in the blood purification device is a gas having an oxygen concentration of 0.01% or more. A hollow fiber membrane blood purification device that is occupied and sterilized with an electron beam.
(2) The hollow fiber membrane blood purification apparatus according to the above (1), wherein the wet protective agent is a mixture of water and a polyhydric alcohol.
(3) The hollow fiber membrane-type blood purification apparatus according to (2), wherein the weight ratio of the polyhydric alcohol to water is 0.2 to 7.5 times.
(4) The adhesion rate of moisture constituting the wet protective agent to the hollow fiber membrane is 40% or more and less than 100% with respect to the dry weight of the hollow fiber membrane, and the adhesion rate of the polyhydric alcohol to the hollow fiber membrane is The hollow fiber membrane blood purification apparatus according to the above (2) or (3), which is 20% or more and 300% or less.
(5) Any of the above (1) to (4), wherein the gas occupying the space other than the hollow fiber membrane bundle and the wet protective agent inside the blood purification device has substantially the same oxygen concentration as the atmosphere 2. A hollow fiber membrane blood purification device according to 1.
(6) The above (1) to (5), wherein the thickness of the potting layer is 7.0 mm or more and 12.5 mm or less, and the density of the hollow fiber membrane part is 0.05 g / cm ³ or more and 0.45 g / cm ³ or less. The hollow fiber membrane-type blood purification apparatus according to any one of the above.
(7) When the potting layer is tested according to the eluate test method of the hollow fiber type artificial kidney approval standard, the reaction product of the wet protective agent and the potting agent is not substantially recognized as the eluate (1) to ( The hollow fiber membrane blood purification apparatus according to 6).
(8) The hollow fiber membrane blood purification according to (7), wherein the wet protective agent is adhered to the hollow fiber membrane by passing the wet protective agent solution through the hollow fiber after the potting layer is cured. apparatus.

  The hollow fiber membrane blood purification device of the present invention is a lightweight and excellent handleability hollow fiber membrane blood purification device called semi-dry, which is a hydrophilic polymer by sterilization despite electron beam sterilization. Elution is small and blood compatibility is excellent. In addition, since there is no need to use a shielding material during electron beam sterilization, and there is no need to irradiate it repeatedly from all directions, there is an advantage that it is produced by a relatively simple process.

Hereinafter, the present invention will be described in more detail.
In the hollow fiber membrane blood purification apparatus of the present invention, a hollow fiber membrane bundle is filled in a container, and a space between the bundle end and the container is held by a potting agent to form a hollow fiber membrane inner chamber and a hollow fiber membrane outer chamber. And a fluid inlet / outlet leading to the hollow fiber membrane inner chamber and a fluid inlet / outlet leading to the hollow fiber membrane outer chamber. For example, a commercially available hollow fiber membrane hemodialyzer, blood filter, hemofiltration dialyzer, plasma separator, plasma component fractionator and the like correspond to this. With such a structure, it is suitably used for extracorporeal circulation type blood purification therapy.

  The hollow fiber membrane referred to here is not particularly limited in its shape, dimensions, and fractionation characteristics, and may be selected appropriately according to its purpose, such as hemodialysis, hemofiltration, plasma separation, and protein fractionation. good. However, as a material, a polymer blend film composed of a hydrophobic polymer and a hydrophilic polymer is optimal because the pore diameter can be easily controlled during film formation and the blood compatibility and chemical stability are excellent.

  Examples of the hydrophobic polymer include polysulfone, polyacrylonitrile, polymethyl methacrylate, polyvinyls including ethylene vinyl alcohol copolymer, polyamides, polyesters, and polyolefins. Among the above, the polysulfone polymer is an aromatic compound, so that it is particularly excellent in radiation resistance, is very resistant to heat and chemical treatment, and is excellent in safety. Accordingly, various film forming conditions can be adopted and radiation sterilization can be performed, which is particularly preferable as a film material used in the blood purification apparatus. In addition, “to system” means not only a homopolymer but also a copolymer with another monomer and a chemically modified analog.

  The polysulfone-based polymer (hereinafter sometimes referred to as PSf) as used herein is a general term for polymer compounds having a sulfone bond, and is not particularly defined. For example, the repeating unit is represented by the following formula (1 ), Formula (2), formula (3), formula (4), and polysulfone-based polymer represented by formula (5). It may be a modified polymer in which a substituent is introduced into a part of these aromatic rings. Aromatic polysulfone-based polymers represented by the formula (1), formula (2) and formula (3) are preferred from the viewpoint of industrial availability, and among them, polysulfone having a chemical structure represented by formula (1) is preferred. Particularly preferred. This bisphenol-type polysulfone resin is commercially available, for example, from Solvay Advanced Polymers under the trade name “Udel (registered trademark)”, and there are several types depending on the degree of polymerization, but there is no particular limitation.

  In the present invention, the hydrophilic polymer is present in the hollow fiber membrane and is used to impart hydrophilicity to the membrane. Examples of the hydrophilic polymer include polyvinyl pyrrolidone (hereinafter sometimes referred to as PVP), polyethylene glycol, polyvinyl alcohol, polypropylene glycol, and the like. Among them, PVP is preferable from the viewpoint of hydrophilization effect and safety. There are several types of PVP depending on the molecular weight and the like. Examples of commercially available products include PVP K-15, 30, 90 (all manufactured by ISP Corporation). The molecular weight (viscosity average molecular weight) of PVP used in the present invention is 10,000 to 2,000,000, preferably 50,000 to 1,500,000. The content of the hydrophilic polymer in the film is 3 to 20%, preferably 3 to 10% of the total amount of the polymer. When the content is 3% or less, the effect as a hydrophilizing agent is diminished, and the resulting hollow fiber membrane is liable to cause blood coagulation and blood compatibility is liable to be lowered. On the other hand, when the content exceeds 20%, the viscosity of the film-forming stock solution is excessively increased, which is not preferable for production.

  As a method for producing a hollow fiber membrane comprising a hydrophobic polymer and a hydrophilic polymer, a known dry / wet film forming technique can be used. That is, first, the hydrophobic polymer and the hydrophilic polymer are dissolved in a common solvent to prepare a uniform spinning dope. As such a common solvent, when the hydrophobic polymer is a polysulfone-based polymer and the hydrophilic polymer is polyvinylpyrrolidone, for example, dimethylacetamide (hereinafter referred to as DMAC), dimethylsulfoxide, N-methyl-2 -Solvents such as pyrrolidone, dimethylformamide, sulfolane, dioxane, or a mixture of two or more of the above solvents. In order to control the pore size, additives such as water may be added to the spinning dope.

When forming a hollow fiber membrane, a tube-in-orifice type spinneret is used, and the spinning stock solution is simultaneously discharged from the orifice of the spinneret and the hollow inner solution for coagulating the spinning stock solution into the air from the tube. . As the hollow inner liquid, water or a coagulating liquid mainly composed of water can be used, and the composition and the like should be determined according to the permeation performance of the target hollow fiber membrane, but it is generally not determined. Is preferably a mixed solution of a solvent used in the spinning dope and water. For example, a 0 to 65% by weight DMAC aqueous solution is 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 dries. Alternatively, a hollow fiber bundle may be obtained through a washing process and then drying in a dryer, and the production method is not specified.

  A hollow fiber membrane is usually used in a cylindrical shape, but a hollow fiber membrane having a fin attached to the outer surface of the cylinder can also be used. As the dimensions, a hollow fiber membrane having a film thickness of 1 to 100 μm, preferably 5 to 50 μm, and an inner diameter of 50 to 500 μm, preferably about 100 to 300 μm can be used. Depending on the application, the fractionation characteristics depend on the application. For dialysis or filtration, hollow fiber membranes with high permeability from low molecular weight substances to substances with a molecular weight smaller than albumin, and for protein fractionation, low molecular weight proteins are permeated. A hollow fiber membrane that is difficult to permeate a substance such as a high molecular protein or an immune complex, or a hollow fiber membrane that permeates plasma components but does not permeate blood cell components is preferably used for plasma separation.

  A known method may be used for the method of manufacturing the hollow fiber membrane blood purification device. For example, a hollow fiber membrane bundle is inserted into a cylindrical container having a fluid inlet / outlet port, a potting agent such as polyurethane is injected into both ends of the bundle to form a potting layer, and both ends are sealed. It can be produced by cutting and removing the potting agent, opening the end face of the hollow fiber, and attaching a header having a fluid inlet / outlet. By this method, the hollow fiber membrane bundle is filled in the container, forming a hollow fiber membrane inner chamber and a hollow fiber membrane outer chamber, a hollow having a fluid inlet / outlet leading to the hollow fiber membrane inner chamber and a fluid inlet / outlet leading to the hollow fiber membrane outer chamber. A thread membrane blood purification device can be manufactured.

In the present invention, the wetting protection agent is a liquid component attached so as to cover the entire surface of the hollow fiber membrane, and has a function of protecting the hydrophilic polymer constituting the hollow fiber membrane from deterioration during electron beam sterilization. Say what you have.
Specifically, the function of protecting the deterioration of hydrophilic polymer by a wet protective agent is to capture radicals generated in the film by electron beam sterilization (also referred to as electron beam irradiation) or to react with the radicals to react with the radicals. It means to suppress or lose.

  Examples of compounds having such a function are typically antioxidants such as ascorbic acid, tocopherol and polyphenols, more specifically vitamin A (derivatives thereof and sodium ascorbate and palmitol ascorbic acid), vitamin C And vitamin E (and derivatives thereof and salts such as tocopherol acetate and α-tocotrienol), polyhydric alcohols such as glycerin, mannitol, glycols, and sugars such as glucose, mannose, xylose, ribose, fructose, trehalose , And fatty acids including oleic acid, furan fatty acid, thioctic acid, linoleic acid, palmitic acid and their salts and derivatives are desirable.

  The wet protective agent of the present invention is used in a state where it is dissolved or dispersed in a solvent when the above compound is in powder form, or as it is when it is oily or liquid, or in a state where it is dissolved or dispersed in a solvent. In the present invention, the wet protective agent is collectively referred to as a dissolved or dispersed state. As the solvent, physiological solutions such as physiological saline, dialysis solution, infusion solution and buffer solution, water, alcohol, and aqueous alcohol solution are used.

  The wet protective agent is attached so as to cover the entire surface where the hydrophilic polymer exists in the hollow fiber membrane, and specifically, the inner surface and the outer surface of the hollow fiber membrane and the pore surface of the film thickness portion. Covering. The wetting protective agent may fill the inside of the pores of the hollow fiber membrane, but the hollow inside causes an increase in weight and liquid leakage, so it is better not to fill this.

The state of adhesion of the wet protective agent to the hollow fiber membrane is not particularly limited. For example, in the case of a fat-soluble substance, hydrophobic binding to the membrane surface is considered, and in the case of a water-soluble substance, simple retention on the membrane surface is considered. . However, since the wet protection agent is no longer required for use in hospitals, it is preferable that the wet protection agent be easily cleaned and removed from the hollow fiber membrane before use. For this purpose, a state in which most of the wetting protective agent is firmly attached to the membrane material by a covalent bond, an ionic bond, or the like, or a state in which the wet protective agent is simply attached rather than a state of being crosslinked and insolubilized on the membrane surface is preferable.
The term “washing and removal” as used herein refers to a general priming operation performed before use, for example, a washing operation using a physiological aqueous solution such as several hundred milliliters to several liters of physiological saline or dialysate, and the hollow fiber. It means that at least 95% of the protective agent covering the membrane is washed to reproduce the membrane surface composed of a hydrophobic polymer and a hydrophilic polymer.

  Based on the above, wetting protection agents have a function of protecting the degradation of hydrophilic polymers and are easily retained on the membrane surface with an appropriate viscosity. It is more preferable to satisfy the requirement that it does not form a bond and is easily washed with a physiological aqueous solution. Specifically, among the above-mentioned compounds, polyhydric alcohols such as glycerin, mannitol, glycols (for example, ethylene glycol, diethylene glycol, propylene glycol, tetraethylene glycol) and polyglycols (for example, polyethylene glycol) are one. Not only has high radical scavenging ability per molecule, but also high solubility in water and physiological solutions, so that it is easy to cover the membrane surface as an aqueous solution without any spots and to be easily washed. Accordingly, these aqueous solutions are preferable, and among them, an aqueous solution of glycerin or polyethylene glycol is more preferable, and an aqueous glycerin solution is most preferable in that it has a proven track record as a pore diameter retaining agent or a surface modifier for blood purification hollow fiber membranes.

  In the present invention, the hollow fiber membrane in the hollow fiber membrane blood purification device needs to be covered with a wet protective agent of 60% or more and 400% or less with respect to its dry weight. When the adhesion rate is more than 400%, the weight of the hollow fiber membrane blood purification device becomes heavy, the advantages as a semi-dry type are impaired, and the handleability is lacking. Further, in the vicinity of room temperature (for example, about 20 to 40 ° C.) generally stored and distributed, the tendency of droplets to adhere to the inner wall of the container or the sterilization bag increases, and the appearance as a product is deteriorated.

  On the other hand, there is a problem in the manufacturing method. If the adhesion rate of the wet protective agent to the hollow fiber membrane is more than 400%, when the assembly rate is adjusted and assembled in a bundle state, the outer surface of the hollow fiber membrane becomes sticky and the membranes are easily fixed to each other. Intrusion of the agent is hindered, causing leakage. In addition, when the adhesion rate is adjusted after assembly, sticking may occur, which may hinder dialysis efficiency. Furthermore, since the membrane portion is densified and the transmission power of the electron beam is weakened, if the minimum dose required for sterilization is secured, the dose distribution in one product increases, the material deterioration progresses, and the amount of eluate increases.

  Also, considering the drop impact resistance when the hollow fiber membrane blood purification device is placed horizontally in a carton, assuming that the product is stored or transported, the dry type is generally lighter overall So it has excellent impact resistance. However, in the wet type, there is a risk that the water around the hollow fiber membrane moves due to a drop impact, stress concentration occurs at the end of the membrane, and the membrane breaks. On the other hand, when the hollow fiber membrane has a moderate weight as in the semi-dry type, stress concentration at the time of horizontal drop is more likely to occur than in the dry type. From this point of view, it is important to keep the upper limit of the adhesion rate of the wet protective agent to 400%.

  Therefore, the adhesion rate of the wet protective agent needs to be 400% or less, more preferably 350% or less, and particularly preferably 300% or less. On the other hand, from the viewpoint of the protective effect, an adhesion rate of 60% or more is necessary as the lower limit value. More preferably, it is 80% or more, and particularly preferably 100% or more.

  In the present invention, the adhesion rate of the wet protective agent is calculated as the total weight of the wet protective agent with respect to the dry weight of the hollow fiber membrane. The measurement method is not particularly limited, but when the wet protective agent is fat-soluble, extraction is performed with a solvent that dissolves the substance but does not dissolve the membrane material, and quantifies it using liquid chromatography, a coloring reagent, or the like. In the case of a water-soluble substance, it is extracted with warm water or hot water and quantified in the same manner. Further, when the wetting protectant is an aqueous solution, the moisture content can be calculated separately by the moisture content measurement procedure described later, and can be obtained as the sum of the adhesion rate of the solute portion and the moisture content.

In the present invention, when the wetting protectant is an aqueous polyhydric alcohol solution, the ratio of the polyhydric alcohol to water is preferably 0.2 to 7.5 times. When the ratio of polyhydric alcohol to water is more than 7.5 times, the local concentration of polyhydric alcohol adhering to the membrane surface or inside of the membrane increases, resulting in a sticky site. Since it tends to be uniform, the protection effect from electron beam irradiation is rather insufficient. Furthermore, since the freezing point of the aqueous polyhydric alcohol solution is increased and the aqueous solution contained in the pores of the membrane is likely to be frozen, damage associated with the structural change of the hollow fiber membrane is likely to occur.
Therefore, the ratio of polyhydric alcohol to water is preferably 7.5 times or less. In particular, when the polyhydric alcohol is glycerin, more preferably, the freezing point of the glycerin aqueous solution is 5.7 times or less at which the freezing point is −10 ° C. or less, and particularly preferably, the freezing point of the glycerin aqueous solution is at most 3 times or less. It is.

On the other hand, from the viewpoint of the protective effect, the lower limit is preferably 0.2 times. In particular, when the polyhydric alcohol is glycerin, it is more preferably 0.5 times or more that the freezing point of the glycerin aqueous solution is −10 ° C. or lower, and particularly preferably 1.2 It is more than double. The ratio of the polyhydric alcohol with respect to water is calculated | required by following formula (1).
[Formula 1]
Ratio of polyhydric alcohol to water = glycerin weight (g) / water weight (g) (1)

  In the present invention, when the wetting protectant is an aqueous polyhydric alcohol solution, 20% to 300% of the polyhydric alcohol is attached to the hollow fiber membrane in the hollow fiber membrane blood purification apparatus with respect to its dry weight. Preferably it is. When the polyhydric alcohol is adhered as an aqueous solution, the ratio of the net weight of the polyhydric alcohol excluding the water component to the dry weight of the hollow fiber membrane is defined as the polyhydric alcohol adhesion rate.

  Here, when the adhesion rate of the polyhydric alcohol with respect to the dry weight of the hollow fiber membrane is more than 300%, the weight of the hollow fiber membrane-type blood purification device becomes heavy, and the advantages as the semi-dry type are impaired and the handling property is lacking. In the vicinity of room temperature that is generally stored and distributed (for example, about 20 to 40 ° C.), the tendency of droplets to adhere to the inner wall of the container or the sterilization bag increases, and the appearance as a product deteriorates. In addition, the local concentration of polyhydric alcohol adhering to the film surface or inside of the film increases, and as a result of the adhering site becoming viscous, the covering state tends to be non-uniform, thus protecting from electron beam irradiation However, it becomes insufficient. On the other hand, there is a problem in the manufacturing method. When assembled after adjusting the adhesion rate in a bundle state, the adhesiveness of the outer surface of the hollow fiber membrane becomes higher and the membranes are more likely to stick to each other. If the adhesion rate is adjusted, the dialysis efficiency may be hindered when sticking occurs. Therefore, the adhesion rate of the polyhydric alcohol is preferably 300% or less, more preferably 250% or less, and particularly preferably 200% or less.

  On the other hand, from the viewpoint of the protective effect, the lower limit value is preferably an adhesion rate of 20% or more. According to the knowledge of the present inventors, when accompanied by γ-ray irradiation, a polyhydric alcohol adhesion rate of 80% or more was necessary, but the electron beam is small in damage to the hydrophilic polymer of the hollow fiber membrane. In the present invention, it could be reduced to 20%. When the adhesion rate of the polyhydric alcohol is lowered in this way, the density of the entire hollow fiber membrane bundle is lowered, so that the dose distribution of the electron beam can be made smaller. In addition, the polyhydric alcohol can be removed quickly and reliably in the priming operation before use. From the viewpoint of the effect of protecting the deterioration of the film, it is more preferably 50% or more, particularly preferably 80% or more.

  In the present invention, it is preferable that the polyhydric alcohol is in the above-mentioned adhesion rate range, and at the same time, the ratio of the moisture content to the dry weight of the hollow fiber membrane, that is, the moisture content is 40% or more and less than 100%. If the water content is 40% or more, platelet activation can be suppressed at the initial contact stage with blood. The detailed reason is not clear, but the hydrophilic polymer becomes hydrated when the membrane surface is in a moderately wet state, resulting in increased wettability at the beginning of use compared to an extremely dried membrane, It is presumed that the affinity for blood is improved. This is a very important feature when a semi-dry type blood purification device needs to be primed and used immediately. However, when the moisture content is 100% or more, even if there is no moisture around the membrane, the moisture contained in the pores of the membrane freezes, causing damage associated with the structural change of the hollow fiber membrane. It is easy to wake up. When the moisture content exceeds the equilibrium moisture content of the membrane, excessive moisture becomes water droplets and adheres to the inner wall of the container or the sterilization bag, and the appearance as a product is deteriorated.

  On the other hand, if the water content is less than 40%, platelets are activated at the initial contact stage with blood, and the blood compatibility tends to decrease. The detailed reason for this is that, as described above, when the membrane surface is in an extremely dry state, the molecular mobility of the hydrophilic polymer is lowered. It is estimated that it takes time to change. In particular, when the wet retention agent is a polyhydric alcohol, the dispersion of the adhesion rate to the hollow fiber membrane is increased due to the increase in viscosity, so that a hollow fiber membrane with extremely low hydrophilicity is likely to appear, and as a result As a tendency to cause a decrease in blood compatibility. Considering that hydrophilic polymer powders and concentrates do not instantly dissolve in water, and that it takes time to dissolve, this presumed basis seems to be highly relevant. The moisture content is more preferably 60% or more.

  In the present invention, the method for setting the adhesion rate of the wet protective agent or the adhesion rate and moisture content of the polyhydric alcohol to the above ranges is not particularly limited. For example, a sequential method may be mentioned in which a high-concentration solution of a wet protective agent is brought into contact with the hollow fiber membrane, and then water is passed through to adjust the adhesion rate and moisture content to a predetermined range. Of course, the reverse order may be used. As another example, the contact time when the wet protective agent solution is brought into contact with the membrane, the concentration of the solution, the injection pressure into the hollow fiber membrane, the air flush conditions for blowing the wet protective agent solution, etc. There is a method to optimize and perform in one step. The latter is preferable because it has low process complexity and does not require the use of a high-concentration aqueous solution. In particular, the air flush is effective not only for blowing away the remainder of the wet protective agent, but also has an effect of coating more uniformly because, for example, a viscous wet protective agent is spread on the inner surface of the film.

  These methods can be carried out for each hollow fiber by being incorporated in a part of the film forming process, or can be performed in a bundled state after film formation. In the former case, a wet protection agent bath may be provided in the membrane production line and the hollow fiber membrane may be immersed, and in the latter case, the bundle may be immersed in a wet protection agent bath or a wet protection agent shower may be applied from the end of the bundle. Good. Alternatively, a semi-finished product of a hollow fiber membrane blood purification device, that is, a method of passing a radical trap material solution from the opening of the hollow fiber membrane of the 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.

When the wet protective agent is attached in this way, for example, even when glycerin having a hydroxyl group is used as the wet protective agent and an aromatic compound is used as the potting agent, the potting agent is cured, so potting with glycerin is possible. The reaction product with the agent does not substantially elute. Therefore, the possibility of elution is reduced without the generation of such a by-product, and an extremely clean hollow fiber membrane blood purification device can be obtained.
It should be noted that the reaction product is not substantially recognized as an eluate that a hollow fiber membrane blood purification device to which a wet protection agent is applied and a hollow fiber membrane blood purification device to which no wet protection agent is applied. When each potting layer was tested according to the eluate test method of the hollow fiber type artificial kidney approval standard, the wet protective agent at a wavelength of 240 to 250 nm was compared with the absorbance of the non-wet protective agent added. When the absorbance of the applied product is measured, the value is 0.005 or less.

In the present invention, the adhesion rate and moisture content of the polyhydric alcohol are measured by the following methods.
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.
Then, after using the dried hollow fiber membrane sample from which only water has been removed, the entire amount of the hollow fiber membrane sample is cut into pieces, then 300 ml of pure water is added, the stopper is plugged, and washing is performed with an ultrasonic cleaning device for 60 minutes. Thus, the adhering polyhydric alcohol is extracted. Polyhydric alcohol is quantified by liquid chromatographic method using the extracted solution after extracting the cut hollow fiber membrane sample with an ultrasonic cleaning device, and using a calibration curve obtained from the peak area of the standard solution Then, the amount (C) of the polyhydric alcohol in the extract is obtained. 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. The hollow fiber membrane weight (D) that is not used.
Based on the above measured values, the value calculated from the following equation (2) is the moisture content, and the value calculated from the equation (3) is the adhesion rate of the polyhydric alcohol.
In addition, a polyhydric alcohol adhesion rate can be calculated | required also by {(BD) / D} * 100.
Furthermore, the adhesion rate of the wet protective agent can be obtained by the sum of the moisture content and the polyhydric alcohol adhesion rate obtained below, or by {(AD) / D} × 100. In the examples described later, the moisture content was obtained from the formula (2), the polyhydric alcohol adhesion rate was obtained from (3), and the wet protection agent adhesion rate was obtained by summing them.
〔formula〕
Moisture content (wt%) = {(A−B) / D} × 100 (2)
Polyhydric alcohol adhesion rate (wt%) = (C / D) × 100 (3)

  In the present invention, it is important to control the oxygen concentration in the hollow fiber membrane blood purification device in order to balance the eluate production from the hollow fiber membrane and the blood compatibility. The lower the oxygen concentration in the hollow fiber membrane blood purification device, the more the polymer main chain breakage caused by the generation of oxygen radicals due to electron beam irradiation, that is, the oxidative degradation can be suppressed. Elution can be suppressed. On the other hand, the hydrophilic polymer may be cross-linked and the membrane surface may be denatured, which may greatly reduce the blood compatibility of the membrane. In addition to the modification of the hollow fiber membrane, there is a problem that the cylindrical container and the header are colored.

However, according to the knowledge of the present inventors, since the hollow fiber membrane is covered with a predetermined wetting protective agent, even if it is sterilized with an electron beam without deoxygenation in particular, the problem due to the above oxygen Can be improved. That is, oxidative decomposition of the film can be suppressed even under atmospheric conditions, and hydrophilic polymer crosslinking and coloration of the cylindrical container and header can be suppressed.
Furthermore, when deoxidizing the inside of the blood purification apparatus, oxidative decomposition of the membrane can be further suppressed. In this case, it is necessary that at least the space other than the hollow fiber membrane bundle and the wet protective agent in the blood purification apparatus is occupied by a gas having an oxygen concentration of 0.01% or more. If the oxygen concentration in the gas is 0.01% or more, the degradation of the hydrophilic polymer is suppressed and the eluate is kept low, and at the same time, excessive crosslinking of the hydrophilic polymer is suppressed, so that excellent blood Compatibility is obtained. Moreover, the containers and headers remain transient even if they are colored, and soon fade during storage. On the other hand, if it is less than 0.01%, the coloration of the container and the header hardly fades and the product appearance deteriorates, which is not preferable.

  More preferably, the oxygen concentration in the gas is substantially the same as that in the atmosphere. The oxygen concentration substantially the same as the atmosphere here means 20.0 to 22.0% in consideration of measurement variation. In the present invention, since the hollow fiber membrane is sterilized by electron beam in a state of being covered with a wet protective agent, even if the oxygen concentration is higher than the conventional radiation sterilization step in a general deoxygenated state, the membrane material is not deteriorated. Sufficiently suppressed. Therefore, special members such as oxygen scavengers and oxygen-impermeable packaging materials that have been used in the past for radiation sterilization are not required, and a process of sealing inert gas, nitrogen gas, or the like in the space is also unnecessary. It is very preferable.

The method for adjusting the oxygen concentration to the atmospheric concentration or less is that when the hollow fiber membrane blood purification device is packaged in a sterilization bag, the oxygen concentration inside the sterilization bag and the hollow fiber membrane blood purification device is set to N ₂ , He, CO 2, _Ar, how to replace the air in an inert gas such as He, but further adjusted by a method of using the oxygen absorbent is not particularly limited thereto. When an oxygen absorbent is used, it is preferable that other gas components are not generated when oxygen is absorbed, or the activity of the oxygen absorbent is not lost by radiation irradiation. For example, a type in which an active metal is the main component and the reaction rate is controlled by a catalyst is preferable, and examples of the active metal include iron, zinc, copper, and tin. In particular, those based on active iron oxide are preferred. As a product marketed as such an oxygen absorbent, for example, there is AGELESS (registered trademark) manufactured by Mitsubishi Gas Chemical Co., but is not particularly limited thereto.

  According to the present invention, a hollow fiber excellent in blood compatibility with less elution of hydrophilic polymer by sterilizing by electron beam sterilization by controlling the adhesion rate and oxygen concentration of the wet protective agent described so far to a specific range. A membrane blood purification apparatus is obtained. However, considering that the transmission power of electron beams is relatively weak, it is also preferable to specify the density of each part in the blood purification apparatus as follows.

  One of them is the thickness of the potting layer which is the most dense mass part in the blood purification apparatus. When performing electron beam sterilization, there are a case where the central axis of the blood purification apparatus is irradiated substantially horizontally, that is, a case of horizontal placement, and a case of irradiation from the central axis direction, that is, a case of vertical placement. When sterilizing a semi-dry type blood purification device with electron beam, vertical irradiation is preferable to increase the irradiation efficiency per unit time, but in that case, the potting layer blocks the transmission of the electron beam, and the whole is uniform. It becomes difficult to be irradiated.

In view of the above, the inventors have found that the thickness of the potting layer is preferably 7.0 mm or more and 12.5 mm or less in the present invention. If the thickness of the potting agent is greater than 12.5 mm, the electron beam transmission power is weakened, and the dose distribution in one product increases, resulting in material deterioration and increased elution. More preferably, it is 12.3 mm or less, and particularly preferably 12.0 mm or less. On the contrary, when the potting layer is thinner than 7.0 mm, there is an advantage that the transmission distance of the electron beam is increased when the electron beam is irradiated in parallel to the direction of blood flow. However, when the force for holding the hollow fiber membrane bundle is weakened or the membrane contracts, the potting layer on the blood inlet / outlet side tends to sink, and the blood purification performance tends to be lowered. Therefore, the lower limit value is preferably 7.0 mm or more, more preferably 7.5 mm or more, and particularly preferably 9.0 mm or more for reasons of strength.
The material of the potting agent that forms the potting layer is not particularly limited, and examples thereof include epoxy resins and silicone resins in addition to polyurethane resins generally used for hemodialyzers and the like.

The other is the density of the hollow fiber membrane that defines the most important performance in the blood purification apparatus. When performing electron beam sterilization, if the density increases, the transmission of the electron beam is blocked, and the whole is difficult to be irradiated uniformly.
Thus, as a result of investigations by the present inventors, in the present invention, it has been found that the density of the hollow fiber membrane part is preferably 0.05 g / cm ³ or more and 0.45 g / cm ³ or less. The density of the hollow fiber membrane part referred to here is the part of the hollow fiber membrane type blood purification device that contains only the hollow fiber membrane and the potting agent (the length of this part is the hollow fiber membrane). The hollow fiber membrane weight per unit volume (referred to as the effective membrane length). That is, it can be obtained by the following equation (4).
〔formula〕
Density of hollow fiber membrane portion = weight of hollow fiber membrane including wet protective agent / (cross-sectional area of container inner peripheral side × effective length of hollow fiber membrane) (4)

When the density of the hollow fiber membrane part is higher than 0.45 g / cm ³ , the transmission power of the electron beam is weakened, and the dose distribution in one product is increased, so that the deterioration of the material advances and the eluate increases. More preferably, it is 0.35 g / cm ³ or less, and particularly preferably 0.31 g / cm ³ or less. On the other hand, when the density of the hollow fiber membrane part is lower than 0.05 g / cm ³ , the volume ratio of the hollow fiber membrane outer chamber is larger than the volume of the hollow fiber membrane inner chamber, so that the dialysate to be used The volume becomes enormous and the dialysis solution cost for one treatment becomes expensive. Thus, using the lower limit reasons is preferably at 0.05 g / cm ³ or more, more preferably 0.08 g / cm ³ or more, and particularly preferably 0.12 g / cm ³ or more.

Electron beam sterilization as used in the present invention refers to sterilization by irradiation after packaging a hollow fiber membrane blood purification apparatus in a sterilization bag, and the dose is preferably 5 to 50 kGy. More preferably, it is 15-30 kGy, Especially preferably, it is 20 kGy vicinity.
[Example]

  EXAMPLES Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to the following examples. First, various measurement methods used in Examples will be described.

[Measurement of oxygen concentration]
Regarding the oxygen concentration in the hollow fiber membrane blood purification device, the hollow fiber membrane blood purification device is sterilized using a trace oxygen analyzer (RO-102 type, manufactured by Iijima Electronics Co., Ltd.) before the electron beam sterilization treatment. It measured in the state enclosed with the bag.
At the time of measurement, in order to prevent the inflow of air outside the sterilization bag, an adhesive rubber (made by Iijima Electronics Co., Ltd., adhesive rubber RG-1 type) is attached to the outside of the sterilization bag, and the oxygen suction of the measuring device is applied to the adhesive rubber. A probe was inserted and the oxygen concentration in the sterile bag was measured. Since the hollow fiber membrane has gas permeability, it was considered that the oxygen concentration inside and outside the hollow fiber membrane in the sterilization bag was uniform.

[Measurement of Lactate Dehydrogenase (LDH) Activity]
The blood compatibility of the hollow fiber membrane was evaluated by the adhesion of platelets to the membrane surface, and quantified using the activity of lactate dehydrogenase contained in the platelets attached to the membrane as an index.
A blood purification hollow fiber membrane collected by disassembling the blood purification apparatus was processed with silicon so that the effective length was 15 cm and the area of the inner surface of the membrane was 50 mm ² to prepare a mini module. To this mini module, 10 ml of physiological saline (Otsuka Pharmaceutical Co., Ltd., Otsuka raw food injection) was poured inside the hollow fiber and washed (hereinafter referred to as “priming”). Thereafter, heparinized human blood was set in a 7 ml syringe pump and passed through the minimodule at a flow rate of 1.44 ml / min, and then the inside of the minimodule was washed with 10 ml and the outside with 10 ml with physiological saline. . 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, ultrasonic treatment was performed for 60 minutes to destroy cells (mainly platelets) adhering to the hollow fiber membrane, and LDH in the cells was extracted. 0.05 ml of this extract was taken, and further reacted with 2.7 ml of 0.6 mM sodium pyruvate solution and 0.3 ml of 1.277 mg / ml nicotinamide adenine dinucleotide (NADH) solution. 0.5 ml was sampled and the absorbance at 340 nm was measured. The remaining solution was further reacted at 37 ° C. for 1 hour, and then the absorbance at 340 nm was measured, and the decrease in absorbance immediately after the reaction was measured. Similarly, the absorbance of the membrane not reacted with blood was also measured, and the difference in absorbance was calculated by the following formula (5). In this method, the larger the decrease, the higher the LDH activity, that is, the greater the amount of platelets attached to the membrane surface.

Δ340 nm = (absorbance immediately after sample reaction−absorbance after 60 minutes of sample) − (absorbance immediately after reaction of blank−absorbance after 60 minutes of blank) (5)

[Measurement of PVP elution amount]
The hollow fiber membrane blood purification device is thoroughly washed with 1 L or more of water for injection (JP) on both the blood side and the dialysate side, and compressed air is blown out to sufficiently drain the liquid. Then, in a state where the dialysate side of the blood processing apparatus is sealed, the blood is circulated for 1 hour at 200 ml / min to the blood side with water for injection (JP) heated to 70 ° C. After circulating for 1 hour, the recovered extract is filtered through a filter having a pore size of 0.45 μm, and the PVP concentration in the filtrate is measured by HPLC (manufactured by Shimadzu Corporation: LC-10AD / SPD-10AV).
The HPLC conditions at this time are as follows.
Column: Shodex Asahipak GF-710HQ
Mobile phase: 50 mM NaCl aqueous solution Flow rate: 1.0 ml / min
Temperature: 30 ° C
Detection: 220nm
Injection: 50microliter

[Measurement of eluate from potting layer]
The eluate from the potting layer was measured according to the eluate test method of the hollow fiber type artificial kidney approval standard as follows. One hollow fiber membrane blood purification device is disassembled and a potting layer is collected from both ends, and then cut into a size of about 1 cm square. To this was added 200 ml of water for injection (Japanese Pharmacopoeia), and the mixture was heated while gently shaking at 40 ° C. for 2 hours. After cooling, take 1.0 ml of the supernatant and add water to make exactly 50 ml. Using this test solution as a sample, the absorbance at a wavelength of 240 to 250 nm is measured at a layer length of 10 mm, using as a control the test solution of a hollow fiber membrane blood purification apparatus to which no wetting protective agent is applied.

Uniform comprising 17 parts by weight of PSf (manufactured by Solvay Advanced Polymers, P-1700), 4 parts by weight of PVP (manufactured by ISP, K-90), 79 parts by weight of dimethylacetamide (hereinafter referred to as DMAC) A spinning dope was prepared. A 42% aqueous solution of DMAC was used as the hollow inner solution, and was 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 stock solution for spinning is immersed in a 60 ° C. coagulation bath made of water provided below 50 cm, passed through the coagulation step and the water washing step at a speed of 30 m / min, introduced into a dryer, and dried at 160 ° C. The crimped polysulfone-based hollow fiber membrane 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. An aqueous solution of glycerin (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) having a concentration of 28.2% is injected into the hollow fiber membrane for 2.3 seconds from the open end and flushed with 0.3 MPa air for 10 seconds, and then both ends. A header cap was attached. After plugging the blood inflow / outflow nozzle, put it in a sterilization bag with oxygen scavenger (AGELESS (registered trademark) manufactured by Mitsubishi Gas Chemical Company), adjust the oxygen concentration to 15.1%, and then irradiate with 20 kGy electron beam. Thus, a hollow fiber membrane blood purification device having an effective membrane area of 1.5 m ² was obtained.
In this hollow fiber membrane blood purification apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol as a wet protective agent, was 31.1%, and the moisture content was 79.0%. The results of measuring various performances are shown in Table 1. The effective membrane area of the hollow fiber membrane refers to the area of the hollow fiber membrane that includes only the hollow fiber membrane among the portions including the hollow fiber membrane and the potting agent in the hollow fiber membrane blood purification apparatus.

Except that an aqueous solution of 60.5% glycerin (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was poured into the hollow fiber membrane for 5.2 seconds, and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
In this hollow fiber membrane-type blood treatment apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol as a wet protective agent, was 150.2%, and the moisture content was 98.0%. The results of measuring various performances are shown in Table 1.

Example 1 except that an aqueous solution of 63.0% glycerin (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was poured into the hollow fiber membrane for 5 seconds and the oxygen concentration was adjusted to 10.2%. A hollow fiber membrane blood purification device was obtained under the same conditions.
In this hollow fiber membrane-type blood treatment apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol as a wet protective agent, was 151.8%, and the moisture content was 89.3%. The results of measuring various performances are shown in Table 1.

Example 1 except that an aqueous solution of 60.9% glycerin (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was poured into the hollow fiber membrane for 5.1 seconds and the oxygen concentration was adjusted to 4.3%. A hollow fiber membrane blood purification device was obtained under the same conditions as in Example 1.
In this hollow fiber membrane-type blood treatment apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol as a wet protective agent, was 148.3%, and the moisture content was 95.2%. The results of measuring various performances are shown in Table 1.

Example 1 except that a 65.3% aqueous glycerin solution (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) was injected into the hollow fiber membrane for 4.7 seconds, and the oxygen concentration was adjusted to 0.98%. A hollow fiber membrane blood purification device was obtained under the same conditions as in Example 1.
In this hollow fiber membrane-type blood treatment apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol as a wet protective agent, was 146.2%, and the moisture content was 77.8%. The results of measuring various performances are shown in Table 1.

Example 1 except that an aqueous glycerin solution (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) having a concentration of 71.8% was injected into the hollow fiber membrane for 4.2 seconds and the oxygen concentration was adjusted to 0.52%. A hollow fiber membrane blood purification device was obtained under the same conditions as in Example 1.
In this hollow fiber type blood treatment apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol as a wet protective agent, was 146.1%, and the moisture content was 57.3%. The results of measuring various performances are shown in Table 1.

Example 1 except that a 74.0% aqueous glycerin solution (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) was injected into the hollow fiber membrane for 7.9 seconds, and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification device was obtained under the same conditions as in Example 1.
In this hollow fiber membrane type blood treatment apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol as a wet protective agent, was 280.1%, and the moisture content was 98.2%. The results of measuring various performances are shown in Table 1.

Example 1 except that an aqueous solution of glycerin having a concentration of 83.5% (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was injected into the hollow fiber membrane for 7.3 seconds and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification device was obtained under the same conditions as in Example 1.
In this hollow fiber membrane type blood treatment apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol as a wet protective agent, was 290.9%, and the moisture content was 57.3%. The results of measuring various performances are shown in Table 1.

Except that an aqueous solution of 36.8% glycerin (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was injected into the hollow fiber membrane for 4.5 seconds, and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
In this hollow fiber membrane type blood treatment apparatus, the adhesion rate of glycerin, which is a polyhydric alcohol serving as a wetting protective agent, was 26.9%, and the moisture content was 46.1%. The results of measuring various performances are shown in Table 1.

Except that an aqueous solution of polyethylene glycol having a concentration of 69.9% (manufactured by Katayama Chemical Co., Ltd., first grade, PEG600) was injected into the hollow fiber membrane for 7.4 seconds, and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification apparatus was obtained under the same conditions as in Example 1.
In this hollow fiber membrane blood processing apparatus, the adhesion rate of polyethylene glycol, which is a polyhydric alcohol serving as a wet protective agent, was 248.9%, and the moisture content was 97.0%. The results of measuring various performances are shown in Table 1.

Except that an aqueous solution of polyethylene glycol having a concentration of 64.2% (manufactured by Katayama Chemical Co., Ltd., first grade, PEG600) was injected into the hollow fiber membrane for 4.6 seconds, and the oxygen concentration was adjusted to 0.45%. A hollow fiber membrane blood purification apparatus was obtained under the same conditions as in Example 1.
In this hollow fiber membrane-type blood treatment apparatus, the adhesion rate of polyethylene glycol, which is a polyhydric alcohol serving as a wet protection agent, was 141.9%, and the moisture content was 79.2%. The results of measuring various performances are shown in Table 1.

An aqueous solution of tetraethylene glycol (Tetraethylene glycol, 99%, manufactured by Wako Pure Chemical Industries, Ltd.) having a concentration of 35.8% was injected into the hollow fiber membrane for 1.4 seconds, and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification apparatus was obtained under the same conditions as in Example 1 except that.
In this hollow fiber membrane type blood treatment apparatus, the adhesion rate of tetraethylene glycol, which is a polyhydric alcohol serving as a wet protection agent, was 25.1%, and the moisture content was 45.0%. The results of measuring various performances are shown in Table 1.

An aqueous solution of tetraethylene glycol (Tetraethylene glycol, 99%, manufactured by Wako Pure Chemical Industries, Ltd.) having a concentration of 61.8% was injected into the hollow fiber membrane for 5.1 seconds, and the oxygen concentration was adjusted to 1.03%. A hollow fiber membrane blood purification apparatus was obtained under the same conditions as in Example 1 except that.
In this hollow fiber membrane blood processing apparatus, the adhesion rate of tetraethylene glycol, which is a polyhydric alcohol serving as a wet protection agent, was 152.2%, and the moisture content was 93.9%. The results of measuring various performances are shown in Table 1.

Comparative Example 1

Except that an aqueous solution of glycerin having a concentration of 13.3% (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was injected into the hollow fiber membrane for 2.5 seconds, and the oxygen concentration was kept at the atmospheric concentration. A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
The adhesion rate of glycerin, which is a radical trap material in this hollow fiber membrane blood processing apparatus, was 16.1%, and the water content was 104.9%. Table 2 shows the results of various performance measurements. At this time, although the LDH activity is high, it is presumed that this is because the hollow fiber membrane is not uniformly coated with glycerin, which is a radical trap material.

Comparative Example 2

Example: Except that an aqueous solution of 72.7% glycerin (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was injected into the hollow fiber membrane for 8.9 seconds and the oxygen concentration was kept at atmospheric concentration A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
The adhesion rate of glycerin, which is a radical trap material in this hollow fiber membrane blood processing apparatus, was 309.2%, and the moisture content was 116.3%. Table 2 shows the results of various performance measurements. At this time, the glycerin aqueous solution had adhered to several places inside the hollow fiber membrane type blood treatment apparatus and inside the bag.

Comparative Example 3

Except that an aqueous solution of glycerin having a concentration of 27.6% (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was poured into the hollow fiber membrane for 1.1 seconds, and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
In this hollow fiber membrane blood processing apparatus, the adhesion rate of glycerin, which is a radical trap material, was 15.3%, and the moisture content was 40.1%. Table 2 shows the results of various performance measurements. At this time, although the LDH activity is high, it is presumed that this is because the hollow fiber membrane is not uniformly coated with glycerin, which is a radical trap material.

Comparative Example 4

Example: Except that an aqueous solution of 80.3% glycerin (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was injected into the hollow fiber membrane for 1.7 seconds and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
The adhesion rate of glycerin, which is a radical trap material in this hollow fiber membrane blood processing apparatus, was 9.9%, and the moisture content was 70.4%. Table 2 shows the results of various performance measurements. At this time, although the LDH activity is high, it is presumed that this is because the hollow fiber membrane is not uniformly coated with glycerin, which is a radical trap material.

Comparative Example 5

Except that an aqueous solution of glycerin having a concentration of 82.9% (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was injected into the hollow fiber membrane for 7.8 seconds and the oxygen concentration was kept at atmospheric concentration. A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
The adhesion rate of glycerin, which is a radical trap material in this hollow fiber membrane blood processing apparatus, was 310.3%, and the water content was 63.8%. Table 2 shows the results of various performance measurements. At this time, the glycerin aqueous solution had adhered to several places inside the hollow fiber membrane type blood treatment apparatus and inside the bag.

Comparative Example 6

Example, except that an aqueous solution of 90.3% glycerin (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was injected into the hollow fiber membrane for 7.5 seconds and the oxygen concentration was kept at atmospheric concentration A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
The adhesion rate of glycerin, which is a radical trap material in this hollow fiber membrane blood processing apparatus, was 325.9%, and the moisture content was 35.2%. Table 2 shows the results of various performance measurements. At this time, the glycerin aqueous solution had adhered to several places inside the hollow fiber membrane type blood treatment apparatus and inside the bag.

Comparative Example 7

Example: Except that an aqueous solution of glycerin having a concentration of 85.1% (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was injected into the hollow fiber membrane for 3.9 seconds and the oxygen concentration was kept at atmospheric concentration A hollow fiber membrane blood purification device was obtained under the same conditions as in 1.
The adhesion rate of glycerin, which is a radical trap material in this hollow fiber membrane blood processing apparatus, was 159.2%, and the moisture content was 27.8%. Table 2 shows the results of various performance measurements. At this time, although the LDH activity is high, it is presumed that this is because the hollow fiber membrane is not uniformly coated with glycerin, which is a radical trap material.

Industrial applicability

  The hollow fiber membrane blood purification device of the present invention is a lightweight and excellent handleability hollow fiber membrane blood purification device called semi-dry, which is a hydrophilic polymer by sterilization despite electron beam sterilization. Elution is small and blood compatibility is excellent. Therefore, in extracorporeal circulation type blood purification therapy such as hemodialysis, blood filtration, plasma separation, and plasma component fractionation, it can be used not only during use but also during transportation and storage.

Claims (7)

A hollow fiber membrane bundle composed of a hydrophobic polymer and a hydrophilic polymer is filled in a container, and the end of the bundle is held in the container by a potting layer to form a hollow fiber membrane inner chamber and a hollow fiber membrane outer chamber, A hollow fiber membrane blood purification apparatus having a fluid inlet / outlet leading to a hollow fiber membrane inner chamber and a fluid inlet / outlet leading to a hollow fiber membrane outer chamber, wherein the hollow fiber membrane is 60% or more and 400% or less with respect to its dry weight. The wet protective agent is a mixture of water and a polyhydric alcohol, and the adhesion rate of water constituting the protective agent to the hollow fiber membrane is 40 with respect to the dry weight of the hollow fiber membrane. % And less than 100%, and the space other than the space occupied by the hollow fiber membrane bundle and the wet protective agent inside the blood purification apparatus is occupied by a gas having an oxygen concentration of 0.01% or more, Hollow fiber membrane blood purification sterilized by electron beam Location. The hollow fiber membrane blood purification apparatus according to claim 1 , wherein the weight ratio of the polyhydric alcohol to water is 0.2 to 7.5. The hollow fiber membrane type blood purification device according deposition rate of the hollow fiber membrane to claim 1 or 2 or less 300% 20% or more of a polyhydric alcohol. The hollow fiber membrane according to any one of claims 1 to 3 , wherein a gas occupying a space portion other than that occupied by the bundle of hollow fiber membranes and the wet protective agent in the blood purification apparatus has substantially the same oxygen concentration as the atmosphere. Type blood purification device. The thickness of the potting layer is less than 7.0 mm 12.5 mm, density of the hollow fiber membrane unit according to one of 0.05 g / cm ³ or more 0.45 g / cm ³ or less is claims 1-4 Hollow fiber membrane blood purification device. When tested potting layer according elution test method of the hollow fiber type artificial kidney approval standards, a reaction product of a wetting protective agents and potting agents to any one of claims 1 to 5 do not substantially observed as eluate The hollow fiber membrane-type blood purification apparatus as described. The hollow fiber membrane-type blood purification apparatus according to claim 6 , wherein the wet protective agent is attached to the hollow fiber membrane by passing the wet protective agent solution into the hollow fiber after the potting layer is cured.