JP2008272352A - Hollow fiber membrane type blood purifier - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hollow fiber membrane type blood purifier quickly decolored even if a resin container of the hollow fiber membrane type blood purifier is discolored, preventing the deterioration of the hollow fiber membranes and suppressing eluate from the hollow fiber membranes when radiation-sterilizing the hollow fiber membrane type blood purifier filled with hollow fiber membrane bundles having a liquid deposit ratio of less than a saturation deposit ratio, and a radiation sterilization method. <P>SOLUTION: This hollow fiber membrane type blood purifier packed in a sterile bag and radiation-sterilized has the container filled with the hollow fiber membrane bundles having the liquid deposit ratio of less than the saturation deposit ratio; is formed with a hollow fiber membrane inside chamber and a hollow fiber membrane outside chamber by a potting part for fixing the both ends of the bundles to the both ends of the container; and has a fluid entrance connected to the hollow fiber membrane inside chamber, and a fluid entrance connected to the hollow fiber membrane outside chamber; and is characterized in that all of the fluid entrances are closed by airtight plug bodies and one or more of the airtight plug bodies airtightly closing the fluid entrances have oxygen absorption property. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a hollow fiber membrane blood purifier used particularly for medical applications. More specifically, the present invention relates to a hollow fiber membrane blood purifier using an airtight plug having an oxygen absorption capability in order to prevent discoloration of components and accelerate fading while suppressing membrane deterioration due to radiation sterilization.

  Hollow fiber membrane type modules using hollow fiber membranes are used for various types of industrial applications such as water treatment filtration modules and reverse osmosis modules, as well as hollow fiber membrane blood purification such as hemodialysis, blood filtration, plasma separation, and plasma component separation. Various types of medical devices have been developed for medical use, and those with improved safety and performance have been put into practical use. Above all, in medical applications, these hollow fiber membrane blood purifiers must be completely sterilized before use. As this sterilization method, since an object to be sterilized can be processed in a packaged state and the sterilization effect is excellent, irradiation sterilization by radiation irradiation is widely adopted as a preferable sterilization method. However, it has been known that the components used in the blood purifier deteriorate due to the irradiation energy of radiation, causing an increase in the amount of eluate to hot water or the like and an odor.

  As a method of irradiating radiation while preventing this damage, for example, as described in Patent Document 1, when gamma ray sterilization is performed, the hollow fiber membrane is brought into a wet state with a saturated moisture content or higher to obtain a hollow fiber membrane. Methods for preventing deterioration are known. However, in the above method, which is also referred to as a wet type, since the blood purifier is filled with sterilized water when the hollow fiber membrane is in a wet state with a saturated water content or higher, the weight of the hollow fiber membrane blood purifier is naturally the weight. It is large and inconvenient to transport and handle. In addition, there is a fear of freezing in the winter due to the wet state. In addition, it is necessary to pay special attention to prevent the growth of bacteria and the like, and in addition, in order to obtain a complete sterilization state in the wet type hollow fiber membrane blood purifier, it is necessary to increase the radiation dose. It was not always satisfactory.

  Therefore, in order to improve the defects of the wet type, a hollow fiber membrane type blood purifier called dry or semi-dry type in which the inside of the blood purifier is not filled with sterilized water has been studied. In these hollow fiber membrane blood purifiers, the liquid adhesion rate of the hollow fiber membrane remains at several percent to several hundred percent (less than the saturated liquid adhesion rate), and the internal space of the blood purifier is filled with a sterilized water or other filling liquid. Since it is not satisfied, the weight is significantly reduced. However, if there is no filling liquid, the surface of the material is easily exposed to high-concentration oxygen compared to dissolved oxygen in water, and decomposition and modification of the material due to oxidative degradation during irradiation sterilization still remains a problem, thus suppressing oxidative degradation. Various ideas have been made.

  For example, in Patent Document 2, in a dry type blood purifier incorporating a hollow fiber membrane having a water content of 30% or less, a coating was formed by incorporating a sterilizing protective agent such as glycerin or polyethylene glycol into the hollow fiber membrane. It is described that it is sterilized by irradiation in a state. However, since the above method focuses only on reducing the oxidative deterioration of the film material, members other than the film are not protected at all, and the deterioration cannot be avoided.

  On the other hand, a method for sterilizing the whole hollow fiber membrane blood purifier by blocking it from oxygen has been studied. For example, Patent Document 3 discloses a sterilization method in which a hollow fiber membrane type blood purifier is gamma sterilized by putting it in a sterilization bag made of a gas-impermeable material together with an oxygen scavenger, and Patent Document 4 uses a semipermeable membrane. A method is described in which the inside of the permeation apparatus is filled with an inert gas (for example, carbon dioxide gas or nitrogen gas) and then sterilized with gamma rays. In these methods, it can be said that it is a more preferable irradiation sterilization method in that deterioration of each component member such as a container and a potting material as well as a membrane material can be prevented over a long period of time. However, in the former case, when the blood purifier is enclosed in a sterilization bag together with the oxygen scavenger, the oxygen scavenger pack may come into contact with the uneven portions of the blood purifier and break. Therefore, if you try to fix the pack in the sterilization bag in advance, there is a risk that the pack will be pinched when sealing the bag, so take care of positioning for fixation and take a large margin for the sterilization bag. There was a waste of etc. On the other hand, in the latter case, not only equipment and processes for gas replacement are required, but in a porous material having a large surface area such as a hollow fiber membrane, adsorbed oxygen on the membrane surface is not excluded as much as possible. However, there was a problem that the deoxygenation state did not last and the desired effect could not be obtained.

  Even if an attempt is made to sterilize by irradiation after forming a deoxygenated state as described above, the oxygen contained in the blood purifier is actually gradually released and collected in an oxygen-impermeable sterilization bag, resulting in oxidation. It is also known that degradation occurs. For example, in Patent Document 5, it is considered that the gamma odor and strength reduction generated during irradiation sterilization and during storage are due to the action of the above-mentioned endogenous oxygen. Then, a method for improving the storage state by sealing in an oxygen-impermeable packaging material together with an oxygen scavenger is described. However, encapsulating an oxygen scavenger after sterilization is very complicated in operation, and the hollow fiber membrane blood purifier obtained by this method is subjected to irradiation sterilization even in a short time in the atmosphere. Therefore, the problem that eluate increases due to deterioration of the hollow fiber membrane material could not be avoided.

  On the other hand, if the hollow fiber membrane blood purifier module is sterilized by irradiation regardless of the wet type or dry type, in addition to the above-mentioned eluate and odor generation or strength reduction, the quality of the resin container may deteriorate. Are known. In order to prevent such coloring of the resin container, for example, Patent Documents 6 and 7 describe a resin composition containing a coloring inhibitor in order to prevent yellowing of the medical polycarbonate resin. However, in these methods using an additive called anti-coloring agent, the anti-coloring agent itself may be slightly colored even if the yellowing of the resin is suppressed, and the biological safety of the additive itself and prevention of elution There are problems such as requiring careful examination, and it has not always been a method that can be easily adopted.

  As described above, the coloring of the resin container has been studied from the viewpoint of not coloring the resin when irradiation sterilization is performed. However, as a result of more detailed examination by the applicant, the present inventors have found an example of fading in a relatively short period of time even when it is slightly colored by irradiation sterilization but cannot be ignored. Specifically, if the product is sterilized by irradiation in a deoxygenated state and stored as it is, the oxidative deterioration of the membrane material and the like is suppressed, but the colored resin container does not fade easily, and it is difficult to solve the defects of each member at the same time. However, an example of the fact that the release of the deoxygenated state in the middle suppresses the deterioration of the film material and at the same time promotes fading, has been filed in advance (Japanese Patent Application No. 2007-009181). As described above, regarding the resin container, it has been found that not only the prevention of coloration and the prevention of oxidative deterioration due to deoxygenation, but also the viewpoint of deliberately supplying oxygen after coloring to promote fading, is as described above. The examination example from a various viewpoint was not known conventionally.

As described above, irradiation sterilization of medical hollow fiber membrane blood purifiers has problems specific to each member such as coloring of resin containers of blood purifiers in addition to oxidative deterioration of membrane materials. Improvement measures were being considered. Among these, a great deal of attention was paid to the suppression of deterioration of the membrane material. The reason for this is that, in the hollow fiber membrane blood purifier, the region where the surface area in contact with the blood is an order of magnitude is a membrane material. This may be due to the fact that membrane breakage due to reduced strength and the elution of membrane components and denatured products are likely to cause serious problems. However, the hollow fiber membrane blood purifier is a solution that not only prevents the deterioration of the membrane material but also can easily solve the coloration of the resin container. It was not obtained.
JP-A-52-99697 JP-A-6-285162 JP-A-62-204754 JP 59-192373 A Japanese Patent Application Laid-Open No. 62-74364 JP 2001-72848 A JP 2006-249175 A

  In view of the above problems, the object of the present invention is to provide a hollow fiber membrane blood purifier when sterilizing a hollow fiber membrane blood purifier filled with a bundle of hollow fiber membranes whose liquid adhesion rate is less than the saturation adhesion rate. To provide a hollow fiber membrane blood purifier and a radiation sterilization method that quickly fades even if the resin container of the vessel is colored, and that the hollow fiber membrane does not deteriorate and that the leachate from the hollow fiber membrane is also suppressed. It is in.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have solved the above-described problems with a hollow fiber membrane blood purifier in which the inside is deoxygenated using an airtight plug having oxygen absorption capability. As a result, the present invention has been completed.

That is, this invention consists of the following embodiments.
(1) A hollow fiber membrane blood purifier packaged in a sterilization bag and sterilized by radiation, in which a hollow fiber membrane bundle having a liquid adhesion rate less than a saturation adhesion rate is filled in a container, and both ends of the bundle are Hollow fiber membrane inner chamber and hollow fiber membrane outer chamber are formed by potting parts fixed to both ends of the hollow fiber, and a hollow fiber provided with 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 In the membrane blood purifier, all of the fluid inlet / outlet are sealed with an airtight plug, and one or more of the airtight plugs sealed in the fluid inlet / outlet are disposed inside the hollow fiber membrane blood purifier. A hollow fiber membrane blood purifier characterized by having an oxygen absorption capacity.
(2) The hollow fiber membrane type blood according to (1), wherein the airtight plug body having oxygen absorption capacity has an oxygen absorbent housed in the internal space of the plug body communicating with the inside of the hollow fiber membrane blood purifier. Purifier.
(3) The airtight plug body having oxygen absorption capability has an oxygen absorption capability of 0.96 to 1.50 times the oxygen present in the hollow fiber membrane blood purifier (1) or (2) Hollow fiber membrane blood purifier.
(4) The hollow fiber membrane blood purifier according to any one of (1) to (3), wherein the liquid adhesion rate of the hollow fiber membrane is less than 400% by weight with respect to the dry weight of the membrane.
(5) The hollow fiber membrane blood purifier according to any one of (1) to (4), wherein the hollow fiber membrane is composed of a hydrophobic polymer and a hydrophilic polymer.
(6) The hollow fiber membrane blood purifier according to (5), wherein the hydrophobic polymer is a polysulfone polymer and the hydrophilic polymer is polyvinylpyrrolidone.
(7) The hollow fiber membrane blood purifier according to (6), wherein the amount of polyvinylpyrrolidone eluted from the hollow fiber membrane is 1 mg or less per 1.5 m ^{2 of the} surface area of the hollow fiber membrane.
(8) A hollow fiber membrane bundle having a liquid adhesion rate less than the saturation adhesion rate is filled in a container, and both ends of the bundle are fixed inside the both ends of the container by a potting material, whereby the hollow fiber membrane inner chamber and the hollow fiber membrane In the sterilization method in which an outer chamber is formed, a hollow fiber membrane blood purifier having a fluid inlet / outlet leading to the inner chamber of the hollow fiber membrane and a fluid inlet / outlet leading to the outer chamber of the hollow fiber membrane is packaged in a sterilization bag and irradiated with radiation. (1) to (8) by sealing all the fluid inlets and outlets with an airtight stopper and using a stopper having oxygen absorbing capacity as one or more of the airtight stoppers sealed at the fluid inlet and outlet. A radiation sterilization method for obtaining any one of the hollow fiber membrane blood purifiers.

  According to the present invention, since the blood purifier is sealed with an airtight plug having oxygen absorption capability, only the inside of the blood purifier can be deoxygenated. As a result, the hollow fiber membrane inside the container is suppressed from oxidative deterioration due to radiation sterilization, so that the effluent from the membrane is reduced. On the other hand, since the outside of the container can be exposed to oxygen while maintaining a sterilized state, even if the container is temporarily colored by radiation sterilization, it quickly fades from the outer surface side of the container due to the action of oxygen outside the container. As a result, it is possible to shorten the standing period which has conventionally been required for 1 to 2 months after sterilization for fading, which greatly contributes to shortening the inventory period of the hollow fiber membrane blood purifier.

  In addition, according to the present invention, since an airtight plug body to which oxygen absorption capability has been imparted in advance is used, it can be obtained with extremely simple equipment and procedures as compared with, for example, those manufactured in a deoxygenated state by a gas replacement method. be able to. In addition, as long as the plug is attached, there is also an effect that the internal deoxygenation state is excellent in sustainability.

Hereinafter, the present invention will be described in more detail.
In the hollow fiber membrane blood purifier of the present invention, a hollow fiber membrane inner chamber and a hollow fiber membrane outer chamber are formed by filling a bundle of hollow fiber membranes into a cylindrical resin container and potting both ends. It has been done. That is, a structure in which the inside of the hollow fiber membrane blood purifier is separated into the hollow fiber membrane inner chamber and the hollow fiber membrane outer chamber by providing potting portions that fix both ends of the bundle to both ends of the inner surface of the container. It is a structure represented by a known hollow fiber membrane type dialyzer.

  The hollow fiber membrane blood purifier is provided with 2 to 5 fluid inlets / outlets, for example, two fluid inlets / outlets (blood side inlets / outlets; hereinafter referred to as blood side ports) leading to the hollow fiber membrane inner chamber. ), And two fluid inlets / outlets (non-blood side inlet and outlet; hereinafter also referred to as non-blood side ports) leading to the hollow fiber membrane outer chamber are the most common. Other than this, only two blood-side ports, two blood-side ports and one non-blood-side port (a total of three), or the intermediate described in Japanese Patent Application Laid-Open No. 2004-524065 There may be two blood side ports, two non-blood side ports, and one replacement fluid port (a total of five) as in the dilution type, and there is no particular limitation. These fluid inlets and outlets are provided in the header caps that are crowned at both ends of the hollow fiber membrane inner chamber as the blood side port, and the shape provided in the vicinity of both ends of the cylindrical container is generally used as the non-blood side port. Is. Others include a header cap that also incorporates a non-blood side port. In the present invention, it is not necessary to limit to any.

  Specific examples of the hollow fiber membrane blood purifier referred to in the present invention include a hemodialyzer, a hemofilter, a hemodialyzer, a plasma separator, a plasma component fractionator, etc. This is called a hollow fiber membrane blood purifier.

  Such a hollow fiber membrane blood purifier can be produced by using a known method described in, for example, JP-A Nos. 2003-159325 and 2005-237755. That is, a bundle of hollow fiber membranes is inserted into a cylindrical resin container having a liquid inlet / outlet, and a potting agent such as polyurethane is injected into both ends of the bundle to seal both ends, and then the excess potting agent is cut off and hollowed out. What is necessary is just to attach the header cap which opened the thread | yarn end surface and provided the fluid inlet / outlet.

  The hollow fiber membrane referred to in the present invention is not particularly limited by its material, shape, dimensions, fractionation characteristics and the like. For example, a membrane used for blood purification such as hemodialysis, blood filtration, plasma separation, and plasma fractionation is preferable, and an appropriate one may be selected according to the purpose.

  Examples of hollow fiber membrane materials include polysulfone-based, regenerated cellulose-based, cellulose acetate-based, chemically modified cellulose-based cellulose-based, polyacrylonitrile-based, polymethylmethacrylate-based, polyvinyl-based, including ethylene vinyl alcohol copolymer, polyamide Polymer materials such as polyesters, polyesters, and polyolefins. Among these, for example, a hollow fiber membrane comprising a polysulfone-based polymer as described in JP-A-11-309353 and JP-A-2003-154240, and a hydrophilic polymer such as polyvinylpyrrolidone or polyethylene glycol. Is preferably used because it is easy to control the pore size, is excellent in biocompatibility, and has good chemical stability.

  In consideration of the mounting position of the airtight plug described later, it is preferable to use a hollow fiber membrane having high gas permeability. Although it is not necessary to specifically limit the gas permeability, for example, it is sufficient if it has a permeability that can be positioned as a high performance membrane in the field of hemodialysis membranes.

  In the present invention, the hollow fiber membrane in the hollow fiber membrane blood purifier has a liquid adhesion rate lower than the saturation adhesion rate. This is a state in which the periphery of the membrane is not completely filled with a liquid such as a filling liquid. These may be collectively referred to as dry or semi-dry types. The boundary line between dry and semi-dry is not strict, but in general, the liquid adhesion rate is about 2% to 50%, and the dry type is the dry type, the liquid adhesion rate is more than that, and the liquid Those having an adhesion rate less than the saturation adhesion rate are understood as semi-dry types. A hollow fiber membrane blood purifier incorporating such a hollow fiber membrane is also referred to as a dry or semi-dry type, and is lighter because the inside is not filled with a filling liquid.

  The hollow fiber membrane of the present invention needs to have a liquid adhesion rate lower than a saturation adhesion rate. By doing so, liquid that cannot be held by the hollow fiber membrane adheres as droplets to the inner wall of the container, or dissipates from the fluid inlet / outlet of the hollow fiber membrane blood purifier and adheres to the inner surface of the sterilization bag. Since it can suppress, the external appearance quality as a dry product or a semi-dry product is not impaired.

  In the present invention, as will be described later, the deterioration of the hollow fiber membrane material is suppressed to some extent because it is in a deoxygenated state during irradiation sterilization. However, in order to further suppress oxidative degradation, it is more preferable that a liquid in which a radical trapping agent or an antioxidant is dissolved or dispersed is attached to the hollow fiber membrane.

  Specifically, the adhesion rate of the liquid is preferably less than 400%. When the liquid adhesion rate is 400% or more, as described above, the liquid droplets tend to adhere to the resin container or the sterilization bag, and the appearance quality as a dry product or a semi-dry product is impaired. Further, in the unlikely event that a liquid other than that impregnated in the hollow fiber membrane freezes, there is a possibility that the hollow fiber membrane may be seriously damaged. More preferably, it is 350% or less, More preferably, it is 300% or less. On the other hand, from the viewpoint of the effect of protecting the hollow fiber membrane against radiation, the liquid adhesion rate is preferably 120% or more. More preferably, it is 170% or more, More preferably, it is 220% or more.

  The radical trap material referred to in the present invention is not particularly limited as long as it is a compound that captures or reacts with the radical generated in the hollow fiber membrane during irradiation sterilization to suppress or lose the reaction activity of the radical. One example is an antioxidant, but polyhydric alcohols such as glycerin and glycols (for example, polyethylene glycol) are preferable because they can be used at low cost and are effective. If the concentration of the radical trapping material to be attached to the hollow fiber membrane is too low, the viscosity will be low, and it may ooze out from the hollow fiber and adhere to the inside of the container or sterilization bag. There is a tendency to disappear. On the other hand, when the concentration is too high, the viscosity increases, and the coating on the inner surface of the hollow fiber tends to be non-uniform. Therefore, for example, when the radical trap material is glycerin, the content is preferably 30 to 90 wt%, more preferably 45 to 80 wt%, and most preferably 50 to 75 wt%.

  Antioxidant is a general term for components that suppress the oxidation reaction widely, and is not limited as long as it can be used for medical purposes. For example, organic compounds include water-soluble and fat-soluble vitamins, and inorganic compounds include sulfites.

The liquid adhesion rate is measured by the following method. A hollow fiber membrane of about 5 g is taken out from the hollow fiber membrane blood purifier, and the weight (A) of the hollow fiber membrane before drying is accurately measured. Thereafter, the entire amount of the hollow fiber membrane sample is finely cut, and then 300 ml of pure water is added, and extraction cleaning with an ultrasonic cleaning device is repeated 5 times for 60 minutes to extract and wash the attached radical trap material, for example, glycerin. Further, only the 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 sample is measured, and this is hollow with no radical trap material and moisture attached thereto. The weight of the thread membrane (B). Based on the above measured values, the value calculated from the following equation (1) is the liquid adhesion rate.
Liquid adhesion rate (wt%) = 100 × (A−B) / B (1)

  In the present invention, by absorbing oxygen inside the hollow fiber membrane blood purifier, the volume of the internal air is reduced by about 21% at maximum, so that the inside of the hollow fiber membrane blood purifier has a negative pressure. Therefore, as described in the material of the plug body, a rigid material that can suppress deformation of the container is also suitable for the resin container, and generally used polypropylene resin, polystyrene resin, styrene-butadiene copolymer resin. It is sufficient if there is strength such as polycarbonate resin.

  Among these, those that are relatively markedly colored by irradiation sterilization are polystyrene resin, styrene-butadiene copolymer resin, and polycarbonate resin. However, polypropylene resin is low in resin cost, but heat shrinkage tends to occur during container molding, its deformation resistance is inferior, and the adhesive strength with polyurethane is weak. It is hard to say that it is generally superior. Also, polycarbonate resin has a higher resin cost than polypropylene and styrene-butadiene copolymer resin, and polystyrene resin has lower impact resistance than styrene-butadiene copolymer resin. There was a problem that it was necessary to do. On the other hand, a container made of a styrene-butadiene copolymer resin has the advantages of excellent impact resistance, low resin cost and container molding cost, and excellent deformation resistance due to heat. Therefore, even if there is some coloring, the merit of selecting this resin is great.

  As described in the background art, the present inventors have found an example in which even a resin that has been colored to a slight extent that cannot be ignored by irradiation sterilization is faded in a relatively short period of time. Specifically, if the resin container is sterilized by irradiation in the deoxygenated state and stored as it is, the colored resin container will not readily fade, but if it is released from the deoxygenated state and exposed to oxygen in the atmosphere, fading is promoted. It is a phenomenon. Among the above-mentioned general-purpose resins, the tendency is particularly strong in the styrene-butadiene copolymer resin, and therefore the present invention is particularly useful for this resin.

  In the present invention, it is necessary that all portions of the fluid inlet / outlet provided in the hollow fiber membrane blood purifier are sealed with an airtight plug. The airtight plug body referred to in the present invention has a close contact portion that is in close contact with the entire circumference of the outer peripheral portion or inner peripheral portion of the nozzle-like fluid inlet / outlet and that maintains the close contact state during handling or transportation. In addition, the flow of gas to the fluid inlet / outlet is blocked. In addition to the close contact portion, a pressure buffering portion, a gripping portion, or the like may be attached. Specifically, the balloon type shown in FIG. 1, the wrapping type shown in FIG. 2, the push-in type shown in FIG. 3 and the like can be exemplified. In the present invention, since it is necessary to make the inside of the hollow fiber membrane blood purifier be in a deoxygenated state, it is necessary to seal all the fluid inlets and outlets using such an airtight plug.

  The material of the airtight plug is not particularly limited, and it should be widely used from relatively hard resins such as polyethylene, polypropylene, polycarbonate, polystyrene, polyamide, polyacetal and soft materials such as butyl rubber, isoprene rubber, butadiene rubber and silicon rubber. Can do. Among them, resin materials such as polyethylene and polypropylene are particularly preferable materials because they have adhesiveness and plugging properties based on appropriate hardness and are already widely used as wrapping and push-in plugs. Also, in the present invention, when oxygen inside the hollow fiber membrane blood purifier is absorbed, the volume of air inside the container is reduced by about 21% at the maximum. The above-described polyethylene and polypropylene are preferable from this point of view. On the other hand, soft materials such as butyl rubber, isoprene rubber, butadiene rubber, and silicon rubber are excellent in adhesion, and are easy to buffer negative pressure due to oxygen absorption inside the container. Therefore, any of the balloon type, the wrapping type, and the pushing type is preferable. It is a material.

  In the present invention, it is necessary that at least one of the airtight plugs sealed at the fluid inlet / outlet has an oxygen absorbing ability. The reason for this is that the inside of the hollow fiber membrane type blood purifier is separated by the hollow fiber membrane into the hollow fiber membrane inner chamber side and the outer chamber side. This is because if an airtight stopper having oxygen absorption ability is attached to the side communicating with the chamber and all others are sealed, the inside can be uniformly deoxygenated. Of course, if the oxygen-absorbing capacity of the airtight plug is the same, the oxygen-absorbing capacity is proportional to the number of plugs, so that the oxygen-absorbing capacity is proportional to the number of plugs. it can. When the gas permeability of the hollow fiber membrane is low, it may be attached to both the hollow fiber membrane inner chamber and the hollow fiber membrane outer chamber, and these may be appropriately adjusted according to the purpose.

  The oxygen-absorbing capacity of the hermetic plug is preferably such that it can absorb 0.96 times the oxygen present in the hollow fiber membrane blood purifier, more preferably 1.20 times, and even more preferably 1. 40 times. In the present invention, it is preferable that the oxygen concentration inside the hollow fiber membrane blood purifier is less than 4% during radiation sterilization due to the combination of the oxygen-absorbing ability and air tightness of such a plug, thereby reducing the amount of eluate. It can be significantly reduced. In the present invention, a state below this oxygen concentration is particularly referred to as a deoxygenated state. More preferably, it is less than 0.5%, More preferably, it is less than 0.1%. However, when a plug body having an oxygen absorption capacity of 1.50 times or more of oxygen present inside the hollow fiber membrane blood purifier is attached, the oxygen absorber storage portion of the plug body becomes large and the plug body is easily detached. Since problems such as an increase in the cost of the plug also occur, it is not necessary to have a higher oxygen absorption capacity than necessary. It is more preferable from the viewpoint of storage stability that the deoxygenated state is maintained not only before radiation sterilization but also after sterilization.

  Examples of plugs having oxygen absorption ability include plugs molded from organic or inorganic materials that absorb oxygen or absorb oxygen (easily oxidizable), plugs molded by kneading these materials into general-purpose polymers, Examples thereof include a plug whose surface is covered with these materials, or a plug whose materials are stored in an internal space. Among these, in consideration of the fact that the stopper is a member attached to the blood purifier and high safety is required, a stopper that is a known airtight stopper and communicates with the inside of the hollow fiber membrane blood purifier. Most preferably, these materials are housed in the body space in isolation. When the plug itself is formed of an oxygen-absorbing material, oxygen in the sterilization bag is also absorbed, so that the sterilization bag needs to be breathable.

  The oxygen-adsorbing or oxygen-absorbing organic or inorganic material is not particularly limited, but is preferably a material that does not generate other gas components during absorption of oxygen or loses oxygen-absorbing activity due to radiation irradiation. For example, an active metal as a main component and a reaction rate controlled by a catalyst is preferable. Examples of the active metal include iron, zinc, copper, tin and the like, and those having active iron oxide as a main component are particularly preferable. It is most convenient and effective to use a known oxygen absorbent as such a material. Oxygen absorbers have names such as AGELESS (registered trademark) (Mitsubishi Gas Chemical Co., Ltd.), Secur (registered trademark) (manufactured by Oe Chemical Industry Co., Ltd.), Sansokat (registered trademark) (Nittetsu Fine Products Co., Ltd.), etc. Products of various abilities are sold and can be easily obtained. Commercially available products can be used as they are because the oxygen absorbent fine powder is packed with a breathable protective material, but a certain amount of fine powder can be taken out from the oxygen absorption capacity and used or repackaged. You may use it.

  In order to prevent oxygen absorber powder from being scattered or mixed into the inside of the hollow fiber membrane blood purifier when the oxygen absorber is stored in the internal space of the airtight stopper. It is preferable to isolate the oxygen absorbent with a breathable partition material. That is, it is preferable to provide a gas-permeable partition member between the internal space of the plug body in which the oxygen absorbent is accommodated and the close contact portion to be crowned or pushed into the fluid inlet / outlet. Examples of the air-permeable partition material include a laminated material of perforated film and paper such as polyethylene, ethylene copolymer, and polypropylene, a material obtained by laminating a polyethylene terephthalate / polyethylene perforated film on the paper side of this laminated material, polyethylene, and the like. Examples thereof include, but are not limited to, microporous membranes made of polypropylene, nonwoven fabrics, and the like.

  Here, the shape and structure of the airtight plug body having the oxygen absorbing ability will be described with reference to the drawings. FIG. 1 is a schematic view showing a balloon-type silicon stopper 2 containing an oxygen absorbent, and is also referred to as a balloon stopper because of its external shape. This plug is made of soft silicon, and has a close contact portion 7 and a pressure buffer portion (balloon) 8 that wraps around the outer peripheral portion of the non-blood side port 6 (fluid inlet / outlet on the hollow fiber membrane outer chamber side). And the negative pressure generated as a result of oxygen absorption can be buffered by deflating the balloon. In this plug body 2, the internal space of the balloon 8 communicates with the inside of the blood purifier through the fluid inlet / outlet, so that the oxygen absorbent 1 is accommodated therein. In addition, since the air-permeable partition material 5 is provided at the boundary surface between the contact portion 7 and the balloon 8, the oxygen absorbent 1 does not enter the non-blood side port 6.

  FIG. 2 is a schematic view showing a wrapping type hard plug 3 containing an oxygen absorbent, and is also referred to as a wrapping type plug from the appearance. This plug is also made of soft silicon, and has a close contact portion 7 and a grip portion 9 that wraps around the outer peripheral portion of the non-blood side port 6 (fluid inlet / outlet on the hollow fiber membrane outer chamber side), and thus has excellent adhesiveness, and Because of its softness, there is no risk of the plug body cracking due to negative pressure. In this plug body 3, since the internal space of the grip portion 9 communicates with the inside of the blood purifier via the fluid inlet / outlet, the oxygen absorbent 1 is accommodated therein. In addition, since the air-permeable partition material 5 is provided at the boundary surface between the close contact portion 7 and the grip portion 9, the oxygen absorbent 1 is not mixed into the non-blood side port 6.

  FIG. 3 is a schematic view showing the push-in type silicon stopper 4 in which an oxygen absorbent is accommodated, and is also referred to as a push-in stopper from the appearance. This plug is made of soft silicon, and has a close contact portion 7 and a grip portion 9 that are pushed into the inner peripheral portion of the non-blood side port 6 (fluid inlet / outlet on the hollow fiber membrane outer chamber side), and thus has excellent adhesiveness. In this plug body 4, since the internal space of the grip portion 9 communicates with the inside of the blood purifier via the fluid inlet / outlet, the oxygen absorbent 1 is accommodated therein. In addition, since the air-permeable partition material 5 is provided at the boundary surface between the close contact portion 7 and the grip portion 9, the oxygen absorbent 1 is not mixed into the non-blood side port 6. Three specific examples of the airtight plug having oxygen absorbing ability are shown, but the present invention is not limited to this example.

  In the present invention, as described above, when all of the fluid inlet / outlet ports are sealed with an airtight plug, only one of the airtight plugs having an oxygen absorption capacity is used, and the hollow fiber membrane blood purification device is used. Only the inside of the vessel can be deoxygenated. In other words, the inside of the wet blood purifier called plugging can be deoxygenated by a process generally performed. As a result, even if radiation sterilization is performed, it is possible to suppress oxidative degradation that the hollow fiber membrane, the potting agent, and the inner surface side of the container and the header undergo. On the other hand, the outer surface of the container and header can be exposed to the air atmosphere while maintaining the sterilized state as long as they are packaged in a sterilization bag. If the resin container has a fading property, fading can be promoted. Therefore, it does not require a long storage period until the coloration of the container is faded, and the problem of deterioration of the appearance of the product due to the coloration is also solved.

  In the present invention, the hollow fiber membrane blood purifier tightly sealed as described above needs to be packaged in a sterilization bag so as to be shielded from the external environment by heat sealing or the like and sterilized by radiation. As long as the sterilization bag used in the present invention is resistant to radiation irradiation and can prevent permeation of microorganisms, any sterilization bag can be used, and a commercially available sterilization bag for gas sterilization or high-pressure steam sterilization, or a laminate for radiation sterilization You can use film. For example, a nylon / polyethylene laminate sheet is preferable from the viewpoint of bag-making property and cost, but is not limited thereto.

  However, it may be effective to supply oxygen to the surface of the container without destroying the sterilized state in order to quickly discolor the container coloring caused by radiation sterilization. Considering this point, the hollow fiber membrane blood purifier sealed as described above may be packaged in an oxygen-permeable sterilization bag or an oxygen-impermeable sterilization bag in the atmosphere. When it is used, oxygen necessary for fading the container color can be supplied without limitation, which is particularly preferable.

  The radiation sterilization may be performed in such a state that it is packaged in a sterilization bag. However, the radiation sterilization in the present invention means irradiation sterilization using an electron beam, gamma ray, etc., and sterilizes the hollow fiber membrane blood purifier. There is no particular limitation as long as the irradiation conditions can be processed. For example, the irradiation dose is 5 to 50 kGy, more preferably 15 to 30 kGy, and even more preferably around 15 to 25 kGy for both electron beams and γ rays.

  In the present invention, in order to suppress oxidative deterioration of the hollow fiber membrane, it is preferable that the inside of the hollow fiber membrane blood purifier is in a deoxygenated state when sterilizing with radiation. In the present invention, it is necessary to go through a series of steps of sealing all the fluid inlets and outlets, packaging them in a sterilization bag, and sterilizing with radiation, but the inside is in a deoxygenated state between the completion of the sealing and the start of sterilization. There is no particular limitation on the timing of packaging in a sterilized bag. Regarding the deoxygenated state, the oxygen concentration inside the hollow fiber membrane blood purifier can be arbitrarily controlled by controlling the time from the completion of sealing to the start of sterilization. Moreover, the time to reach the target oxygen concentration can also be controlled according to the oxygen absorption capacity (type and amount of oxygen absorbent).

[Example]
Hereinafter, the present invention will be described more specifically based on examples and comparative examples, but the present invention is not limited to the following examples. The sterilization conditions and results of Examples and Comparative Examples are summarized in Tables 1 and 2. A method for measuring the evaluation items used in the examples will be described.

[Measurement of oxygen concentration]
The oxygen concentration in the hollow fiber membrane blood purifier was measured using a trace oxygen analyzer (Iojima Electronics Co., Ltd., RO-102 type), with the hollow fiber membrane blood purifier removed from the sterile bag. It was measured.
At the time of measurement, in order to prevent the inflow of air outside the plug body, an adhesive rubber (made by Iijima Electronics Co., Ltd., adhesive rubber RG-1 type) is attached to the outside of the plug body, and the oxygen suction probe of the measuring device is attached to the adhesive rubber. The oxygen concentration in the plug was measured by piercing. Since the hollow fiber membrane used in the examples has high gas permeability, it was considered that the oxygen concentration was uniform on both the inner side and the outer side of the hollow fiber membrane.
Further, the oxygen concentration in the sterilization bag was measured in the same manner. That is, the adhesive rubber was affixed to the outside of the sterilization bag, and the oxygen concentration in the sterilization bag was measured by inserting an oxygen inhalation probe of a measuring device into the adhesive rubber.

[Measurement of elution amount of polyvinylpyrrolidone (PVP)]
The inner chamber (blood side) and outer chamber (dialysate side) of the hollow fiber membrane blood purifier were thoroughly washed with 1 L or more of water for injection (JP), and the liquid was sufficiently discharged by blowing compressed air. Then, with the non-blood side port (dialysate side) sealed, water for injection (JP) heated to 70 ° C. was circulated in the inner chamber at 200 ml / min for 1 hour. 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 manufactured by Showa Denko, mobile phase: 50 mM NaCl aqueous solution, flow rate: 1.0 ml / min, temperature: 30 ° C., detection: 220 nm, injection: 50 μl.
In this example, PVP is used as a hydrophilizing agent for the hollow fiber membrane, and PVP oxidized and deteriorated by irradiation is eluted. Therefore, the amount of elution was used as an index of the degree of oxidation deterioration. It shows that the smaller the oxidative degradation, the smaller the amount of eluate.

According to a known spinning method (WO 2005/046763 pamphlet), a dry bundle comprising about 10,000 polysulfone-based hollow fiber membranes made of polysulfone and polyvinylpyrrolidone and positioned as a high performance membrane was prepared. This bundle is made of a styrene-butadiene copolymer designed so that the effective membrane area of the hollow fiber membrane is 1.5 m ² and ^two fluid inlets and outlets leading to the outer chamber of the hollow fiber membrane are provided near both ends. After filling the cylindrical container and potting both ends with urethane resin, both end surfaces were cut to form the open end of the hollow fiber membrane, and a product after cutting was obtained.
A glycerin (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) solution having a concentration of 61 wt% is injected into the hollow fiber membrane for 5 seconds from the open end of the product after cutting, and then flashed for 4.5 seconds under a pressure of 0.3 MPa to dry the hollow fiber membrane. The liquid adhesion rate with respect to was adjusted to 240 wt%. A header cap provided with a fluid inlet / outlet communicating with the hollow fiber membrane inner chamber was attached to both ends to obtain a semi-dry type hollow fiber membrane blood purifier.

Next, the two fluid inlets / outlets leading to the outer chamber of the hollow fiber membrane were sealed with an airtight balloon type silicon stopper containing an oxygen absorbent shown in FIG. The oxygen absorbent is obtained by weighing 2 g of oxygen absorbent powder taken from AGELESS (registered trademark) (SS-200, manufactured by Mitsubishi Gas Chemical Co., Ltd.) and repackaging it into a non-woven fabric. After the insertion, a breathable partition material was fixed to the boundary between the balloon portion and the crown portion with an adhesive to prevent inflow into the fluid inlet / outlet. On the other hand, the fluid inlet / outlet leading to the inner chamber of the hollow fiber membrane was sealed with an airtight push-in silicone stopper that did not contain an oxygen absorbent. The hollow fiber membrane blood purifier thus plugged was placed in an oxygen-impermeable sterilization bag of a nylon / polyethylene laminate sheet, and the open portion of the sterilization bag was heat sealed to shut off from the external atmosphere.
In this state, the hollow fiber membrane blood purifier was left in a deoxygenated state for 2 days, and then sterilized with gamma rays at an irradiation dose of 25 kGy. The oxygen concentration in the hollow fiber membrane blood purifier prepared by the same operation was 0.01% and was sufficiently deoxygenated. On the other hand, the oxygen concentration in the sterilization bag was 21%.
After sterilization, the discoloration of the container was observed over time. Immediately after the irradiation, the color was pale blue-green, but the color faded completely after 5 days. Moreover, it was 0.25 mg / 1.5m < ² > when the amount of eluate was measured.

The same treatment as in Example 1 was performed, except that the product after cutting was sterilized without being injected with an aqueous glycerin solution. After the hollow fiber membrane blood purifier produced by the same operation was left for 2 days, the oxygen concentration in the hollow fiber membrane blood purifier was measured and found to be 0.01%. The oxygen concentration in the sterile bag was 21%.
When the stored color after sterilization was observed over time for the discoloration of the container, it was colored pale blue-green immediately after irradiation, but completely discolored after 5 days. Moreover, it was 0.71 mg / 1.5m < ² > when the amount of eluate was measured.

The same treatment as in Example 1 was performed except that the liquid adhesion rate of the glycerin aqueous solution was changed to 390%. This adhesion rate is a state in which the appearance quality of the product is not impaired, such as water droplets adhering to the inner wall of the container, or dissipating from the fluid inlet / outlet of the container and adhering to the inner surface of the sterilization bag. After the hollow fiber membrane blood purifier produced by the same operation was left for 2 days, the oxygen concentration in the hollow fiber membrane blood purifier was measured and found to be 0.01%. The oxygen concentration in the sterile bag was 21%.
When the stored color after sterilization was observed over time for the discoloration of the container, it was colored pale blue-green immediately after irradiation, but completely discolored after 5 days. Moreover, it was 0.21 mg / 1.5m < ² > when the amount of eluate was measured.

The same treatment as in Example 1 was performed, except that the hard plug shown in FIG. 2 was used as an airtight plug having oxygen absorption capability. The hollow fiber membrane blood purifier prepared in the same manner was left for 2 days, and then the oxygen concentration in the hollow fiber membrane blood purifier was measured to be 0.01%. The oxygen concentration in the sterile bag Was 21%.
When the discoloration of the container was observed over time for storage after sterilization, it was colored pale blue-green immediately after irradiation, but completely discolored after 5 days. The eluate was measured and found to be 0.24 mg / 1.5 m ² .

[Comparative Example 1]
All the fluid inlets and outlets were treated in the same manner as in Example 1 except that they were sealed with an airtight push-in silicone stopper that did not contain an oxygen absorbent. After the hollow fiber membrane blood purifier produced by the same operation was left for 2 days, the oxygen concentration in the hollow fiber membrane blood purifier and in the sterile bag was measured and found to be 21%.
When the stored color after sterilization was observed over time for the discoloration of the container, it was colored pale blue-green immediately after irradiation, but completely discolored after 5 days. However, the amount of eluate was as large as 23.00 mg / 1.5 m ² .

[Comparative Example 2]
The same treatment as in Example 1 was performed except that the liquid adhesion rate of the glycerin aqueous solution was changed to 500%. After the hollow fiber membrane blood purifier produced by the same operation was left for 2 days, the oxygen concentration in the hollow fiber membrane blood purifier was measured and found to be 0.01%. The oxygen concentration in the sterile bag was 21%.
When the stored color after sterilization was observed over time for the discoloration of the container, it was colored pale blue-green immediately after irradiation, but completely discolored after 5 days. Moreover, it was 0.19 mg / 1.5m < ² > when the amount of eluate was measured.
However, in this case, since the liquid adhesion rate of the glycerin aqueous solution was 500%, water droplets adhered to the inner wall of the container, and the appearance quality as a semi-dry product was impaired.

[Comparative Example 3]
The same treatment as in Example 1 was performed except that the two fluid inlets and outlets leading to the hollow fiber membrane inner chamber were opened. The hollow fiber membrane blood purifier prepared by the same operation was left for 2 days, and then the oxygen concentration in the hollow fiber membrane blood purifier was measured. As a result, it was 3.00%, and the oxygen concentration in the sterile bag was 21%.
When the stored color after sterilization was observed for the discoloration of the container over time, it was colored pale blue-green immediately after irradiation and completely discolored after 5 days. Moreover, it was 2.5 mg / 1.5m < ² > when the amount of eluate was measured.

[Comparative Example 4]
The same treatment as in Example 1 except that AGELESS (registered trademark) (AGELESS SS-200, manufactured by Mitsubishi Gas Chemical Co., Inc.) was put together in a sterilization bag and heat sealed with all the fluid inlets and outlets open. Was given. After the hollow fiber membrane blood purifier produced by the same operation was left for 2 days, the oxygen concentration in the hollow fiber membrane blood purifier and in the sterile bag was measured and found to be 0.01%.
Stored products after sterilization had a low eluate amount of 0.24 mg / 1.5 m ² , but the pale blue-green color of the colored container immediately after irradiation did not fade even after half a year, and the appearance quality of the product was impaired. It was in a state.

[Comparative Example 5]
The same treatment as in Example 1 was performed except that nitrogen gas was poured into the sterilization bag at 2 L / min with all the fluid inlets and outlets being opened, and the flow of nitrogen gas was replaced three times. did. After the hollow fiber membrane blood purifier produced by the same operation was left for 2 days, the oxygen concentration in the hollow fiber membrane blood purifier and in the sterile bag was measured and found to be 3.20%.
The stored product after sterilization had an eluate amount of 2.51 mg / 1.5 m ² . The pale blue-green color of the colored container immediately after irradiation faded after 30 days.

  The hollow fiber membrane blood purifier of the present invention is excellent in fading color of the container while suppressing deterioration of the hollow fiber membrane due to radiation sterilization because only the inside of the container is deoxygenated by the stopper having oxygen absorption ability. . As a result, the inventory period for fading can be shortened and shipped, and it can be suitably used for medical applications such as treatment of various diseases by blood purification. Moreover, since it is a dry or semi-dry type, it can be used particularly suitably in a cold region where there is a problem of freezing.

It is the schematic which shows the oxygen absorbent accommodation silicon stopper (balloon type) which concerns on the Example of this invention. It is the schematic which shows the oxygen absorber accommodation hard stopper (wrapping type) which concerns on the Example of this invention. It is the schematic which shows the oxygen absorbent accommodation silicon stopper (push-in type) which concerns on the Example of this invention.

Explanation of symbols

1 Oxygen absorber 2 Silicon stopper (balloon type)
3 Hard stopper (wrapping type)
4 Silicon stopper (push-in type)
5 Breathable partition material 6 Non-blood side port 7 Adhering part 8 Pressure buffer part 9 Gripping part

Claims (8)

  A hollow fiber membrane blood purifier packaged in a sterilization bag and sterilized by radiation, the container is filled with a bundle of hollow fiber membranes whose liquid adhesion rate is less than the saturation adhesion rate, and both ends of the bundle are connected to both ends of the container. A hollow fiber membrane blood having a hollow fiber membrane inner chamber and a hollow fiber membrane outer chamber formed by a potting portion fixed to the inner wall, 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 In the purifier, all portions of the fluid inlet / outlet are sealed with an airtight stopper, and at least one of the airtight stoppers sealed at the fluid inlet / outlet is an oxygen absorption capacity inside the hollow fiber membrane blood purifier. A hollow fiber membrane blood purifier characterized by comprising:   2. The hollow fiber membrane blood purification device according to claim 1, wherein the airtight plug body having oxygen absorption capacity is one in which an oxygen absorbent is housed in a plug body internal space communicating with the inside of the hollow fiber membrane blood purification device. vessel.   The hollow fiber membrane according to claim 1 or 2, wherein the airtight plug having oxygen absorption capability has an oxygen absorption capability 0.96 to 1.50 times that of oxygen present in the hollow fiber membrane blood purifier. Type blood purifier.   The hollow fiber membrane blood purifier according to any one of claims 1 to 3, wherein the liquid adhesion rate of the hollow fiber membrane is less than 400 wt% with respect to the dry weight of the membrane. The hollow fiber membrane blood purifier according to any one of claims 1 to 4, wherein the hollow fiber membrane comprises a hydrophobic polymer and a hydrophilic polymer.   The hollow fiber membrane blood purifier according to claim 5, wherein the hydrophobic polymer is a polysulfone polymer and the hydrophilic polymer is polyvinylpyrrolidone. The hollow fiber membrane blood purifier according to claim 6, wherein the amount of polyvinylpyrrolidone eluted from the hollow fiber membrane is 1 mg or less per 1.5 m ^{2 of the} inner surface area of the hollow fiber membrane. A hollow fiber membrane bundle having a liquid adhesion rate less than the saturation adhesion rate is filled in the container, and both ends of the bundle are fixed inside the both ends of the container by a potting material, so that the hollow fiber membrane inner chamber and the hollow fiber membrane outer chamber are In a sterilization method in which a hollow fiber membrane type blood purifier 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 is packaged in a sterilization bag and irradiated with radiation, The plug according to any one of claims 1 to 8, wherein all of the portions are sealed with an airtight plug, and a plug having an oxygen absorption capacity is used as one or more of the airtight plugs sealed with the fluid inlet / outlet. Radiation sterilization method for obtaining a hollow fiber membrane blood purifier.