CN101161302A - Hollow fiber membrane type blood purifying device - Google Patents

Abstract

The present invention provides a hollow fiber film type blood purifying device, which is called dry or semi-dry hollow fiber film type blood purifying device filled with hollow fiber film formed with hydrophobic macromolecule and hydrophilic macromolecule, wherein, although it is sterilized with electron beam, the hydrophilic macromolecule dissolve out little, and the reduction of blood adaption can be restrained. By protecting hollow fiber film and controlling oxygen thickness around the film with special quality of moisture protection agent in the dry or semi-dry hollow fiber film type blood purifying device, the increase of dissolving out quality of the hydrophilic macromolecule from the hollow fiber film, and companied reduction of blood adaption can be greatly restrained.

Description

Doughnut membranous type apparatus for purifying blood

Technical field

The present invention relates to be used for the doughnut membranous type apparatus for purifying blood of the blood purification therapy of extracorporeal circulation formula.In more detail, relate to the apparatus for purifying blood that is called dry type or half dry type (Semi-dry) by electron beam irradiation disinfection, this doughnut membranous type apparatus for purifying blood light weight and operability excellence, and the stripping of hydrophilic macromolecule is few, and blood adaptability excellence.

Background technology

All the time, for doughnut membranous type apparatus for purifying blood, corresponding to the blood purification therapy of extracorporeal circulation formulas such as hemodialysis, blood filtration, separating plasma, plasma fraction fractional distillation and developed various devices, the device that safety, performance also improve is practical gradually.

As employed hollow-fibre membrane, mainly roughly be divided into the hollow-fibre membrane of cellulose-based high molecular hollow-fibre membrane and synthetic high polymer, but in recent years, polysulfones is that macromolecule is widely used as the pleurodiaphragmatic in terspace material in the middle of the latter.Polysulfones is high molecular being characterised in that, organism adaptability excellence has excellent patience to chemical reagent such as lonizing radiation, heating and acid, alkali.But because it is a hydrophobic polymer, thereby former state is used the affinity that then lacks with blood.Therefore, add to blood stimulate few polymer for example hydrophilic macromolecule such as polyvinylpyrrolidone, Polyethylene Glycol use as hydrophilic agent.

Doughnut membranous type apparatus for purifying blood roughly be divided into hollow-fibre membrane hollow inside and and the slit of container between the wet type of being filled up by aqueous medium and the non-wet type of not filled up by aqueous medium.The moisture content that the latter further divides into film is low to moderate the dry type of several percentage ratio degree and film by the half dry type (being also referred to as half wet type) of appropriate humidifications such as moisture, moistening protective agent.Dry type and half dry type are compared with wet type to have and also are difficult to the feature freezed under the light and low temperature of product weight, we can say to be excellent especially product form aspect the such circulation of carrying, keeping.

These doughnut membranous type apparatus for purifying blood before use must be to pack state by complete sterilization treatment.

The main stream approach of the sterilizing methods of the doughnut membranous type apparatus for purifying blood that is practical is following these three kinds of methods, promptly utilize gas sterilization, the autoclaving of utilizing high steam and the radiation gamma method of ethylene oxide gas etc., in recent years, electron beam irradiation method also is practical gradually.Wherein, there is the residual problem of ethylene oxide gas in the ethylene oxide gas method,, need outgases fully in order not to be subjected to toxic effect.In addition, owing to pressurize repeatedly and reduce pressure, thereby the processing time is long, because of material causes performance variation.In addition, the problem that has the material properties influence be subjected to constituting doughnut membranous type apparatus for purifying blood in autoclaving and the radiation gamma method.That is, need the thermostability of hollow-fibre membrane under moisture state in the former autoclaving, and have the situation that its performance can't be used according to remarkable reduction of material when sterilizing.There are not residual gas, stable on heating problem in the latter's the radiation gamma method, and the penetration power height of illuminated line, therefore, its sterilization as apparatus for purifying blood is excellent.But well-known is that the part of material because of irradiation energy chemical change takes place.For example, for the hollow-fibre membrane that forms by hydrophobic polymer and hydrophilic macromolecule, mainly be hydrophilic macromolecule modification and deterioration and from the hollow-fibre membrane stripping, perhaps because the crosslinked structure that causes changes, its result causes that through performance, intensity rerum natura or the blood adaptability of film reduce.

On the other hand, there is not the such worry to residual toxicity of ethylene oxide gas method in electron beam irradiation method, and the sterilization treatment time is long unlike autoclaving, ethylene oxide gas method, radiation gamma method, can the short time sterilization treatment.In addition, irradiation moment stops when using outage, energy is during than the low accelerator of 6MeV, does not need to worry the keeping to the radioactive substance as gamma-ray irradiation apparatus, and safe on the environment, and the cost aspect is cheapness also.In addition, with maximum different being of radiation gamma: the temperature of shone thing rises during sterilization, material degradation is little.Therefore, there is the wide advantage of the range of choice of material, the further from now on practicability of expectation.

But electron beam is compared with gamma-rays, and is little to the penetration power of object, thinks that its penetration range depends on the density of irradiated material.Therefore, at present practical only be to make operation with shapes such as glove, operation dress article relatively more even and that constitute by single material.For example, to there being the insufficient part of penetration power as wall thickness and when comprising the doughnut membranous type apparatus for purifying blood irradiating electron beam of shone thing of high density part, the quantity of X-rays X between each position in product distribute (ratio of maximum amount of radiation and minimum quantity of X-rays X) become big.Its result, problems such as material degradation, leachable are remarkable.Specifically, when the irradiation benchmark met maximum amount of radiation, the sterilization in minimum quantity of X-rays X position just became insufficient, on the contrary, the irradiation benchmark meets minimum quantity of X-rays X position and when sterilizing, at maximum amount of radiation position excessive exposure, produces material degradation, painted solidly.When material degradation was caused by hydrophilic macromolecule, the hydrophilic of film was impaired, and the result causes the blood adaptability to reduce.Like this, according to shone thing, the uniform irradiation electron beam also is not easy, and is attended by the uneven problem that causes of irradiation.

So,,, study from two kinds of main points of view of the approach of the approach of sterilization process and materials chemistry for object uniform irradiation electron beam to the shape of complexity.

As the approach of sterilization process, for example disclose in the patent documentation 1 to the dialysis apparatus of doughnut membranous type, when artificial lung carries out electron beam sterilization, with high accelerating potential irradiation and use masking material so that the technology that quantity of X-rays X distributes and diminishes; Disclose in the patent documentation 2 by full illumination operation and part and covered the illuminating method that operation is formed.But, among the former, need attach masking material at excessive illuminated portion to each different product, therefore, exist to form to have the veil of specific absorption quantity of X-rays X and be installed to trouble on the product, operating efficiency is low.The latter has attempted improving this problem, but operating efficiency is still low.In addition, when disclosing the assembly irradiating electron beam to the doughnut membranous type in the patent documentation 3, when having the product of specific density and thickness, technology from the irradiation of the direction more than 3 directions, must make shone thing rotation limit divide irradiating electron beam several times in the limit this moment, is difficult to the sterilizing methods as large-tonnage product.

On the other hand, approach as materials chemistry, known multiple additive that radical scavenger, antioxidant is such is mixing in resin material or make it coexist as near the resin technology, the method for deterioration during as the radiation exposure that suppresses to comprise electron beam and being widely studied.According to these methods, need not significantly to revise pitch time (tact time) that irradiation apparatus do not prolong irradiation and advantage such as also can effectively produce even if exist.But, in the additive, have is to be used for the apparatus for purifying blood of extracorporeal circulation formula from the consideration of safety aspect much, when being limited to doughnut membranous type apparatus for purifying blood, major part is as special the improving countermeasure of material degradation during to γShe Xianmiejun and by the material of specializing (for example, patent documentation 4,5 etc.).

In addition, the applicant finds: even if with the hollow-fibre membrane of the adhesive rate of specific free radical capture material and moisture content protection by radiation sterilization, also effective to reducing leachable and keeping the blood adaptability, and the rate first to file patent (patent documentation 8).But the detailed opinion when specifically being defined to radiation gamma for irradiation takes into account the minimizing leachable similarly and keeps the blood adaptability to electron beam, has the leeway that further studies in great detail.

Like this, by the approach of materials chemistry the peculiar problem when the apparatus for purifying blood to the doughnut membranous type carries out electron beam sterilization is done further improvement, such trial is almost unknown.

Except above-mentioned approach, also known several correlation techniques.For example, the blood adaptability excellence that the polysulfones that is shone by electron beam is a hollow-fibre membrane is disclosed in the patent documentation 6; Disclose in the patent documentation 7 when being assembled with the assembly irradiating electron beam of hollow-fibre membrane, the organic solvent that residues in the film is decomposed.But the former technology only is conceived to the concaveconvex structure and the adaptive cause effect relation of blood of film inner surface, lacks the concern of the membrane material deterioration that irradiation causes to electron beam.In addition, although the latter's technology has been caught this side of leachable, this technology only is conceived to reduce low-molecular-weight residual solvent, does not relate to the deterioration as the membrane material of resin material fully.

As described above, at present, be based on additive etc. materials chemistry method and improve this two aspect of the distinctive irradiation inhomogeneities of electron beam, carried out preventing the research of material degradation.But, for the approach of easier materials chemistry,, need further to improve suppressing deterioration and also satisfying on the such viewpoint of blood adaptability technical still insufficiently.

Patent documentation 1: Japanese kokai publication hei 8-275991 communique

Patent documentation 2: TOHKEMY 2000-334028 communique

Patent documentation 3: TOHKEMY 2000-135274 number

Patent documentation 4: No. 3076080 communique of Japan's special permission

Patent documentation 5: No. 3432240 communique of Japan's special permission

Patent documentation 6: TOHKEMY 2005-224604 communique

Patent documentation 7: TOHKEMY 2000-218140 communique

Patent documentation 8: Japanese Patent Application 2005-232154 number

Summary of the invention

The problem that invention will solve

In view of the above-mentioned problems, the object of the present invention is to provide and be filled with light weight hollow-fibre membrane, that be called half dry type that forms by hydrophobic polymer and hydrophilic macromolecule and the doughnut membranous type apparatus for purifying blood of operability excellence, wherein, although this device is by electron beam sterilization, the stripping of hydrophilic macromolecule is few, also can suppress the adaptive reduction of blood.

The method of dealing with problems

The inventor furthers investigate repeatedly in order to address the above problem, and the result thinks that the protection hollow-fibre membrane is extremely important in the middle of the attack of the free radical that produces because of electron beam sterilization.Therefore, found with the moistening protective agent protection hollow-fibre membrane of specified quantitative and the necessity of the oxygen concentration around the controlling diaphragm.Thus, in the doughnut membranous type apparatus for purifying blood of dry type or half dry type, successfully significantly suppressed this hydrophilic macromolecule from the increase of the stripping quantity of hollow-fibre membrane, follow in the adaptive reduction of this blood, finished the present invention thus.

That is, the invention provides following invention.

(1) a kind of doughnut membranous type apparatus for purifying blood, it is a device as described below; The hollow fiber membrane bundle that is formed by hydrophobic polymer and hydrophilic macromolecule is filled in the container; the end of this bundle is maintained at by the embedding layer and forms hollow-fibre membrane medial chamber and hollow-fibre membrane outer side chamber in the container; and possess the stream socket that leads to the hollow-fibre membrane medial chamber and lead to the stream socket of hollow-fibre membrane outer side chamber; wherein; this hollow-fibre membrane is that the moistening protective agent below 400% covers more than 60% with respect to its dry weight; and; the described hollow fiber membrane bundle of described apparatus for purifying blood inside and the described moistening protective agent space segment beyond taking up space is that gas more than 0.01% occupies by oxygen concentration, and described device is through electron beam sterilization.

(2) according to above-mentioned (1) described doughnut membranous type apparatus for purifying blood, wherein, the moistening protective agent is the mixture of water and polyhydric alcohol.

(3) according to above-mentioned (2) described doughnut membranous type apparatus for purifying blood, wherein, polyhydric alcohol is more than 0.2 times below 7.5 times with respect to the weight ratio of water.

(4) according to above-mentioned (2) or (3) described doughnut membranous type apparatus for purifying blood; wherein; constituting the protectant moisture of moistening is more than 40% and less than 100% to the adhesive rate of hollow-fibre membrane with respect to the dry weight of hollow-fibre membrane, and polyhydric alcohol is more than 20% below 300% to the adhesive rate of hollow-fibre membrane.

(5) according to each described doughnut membranous type apparatus for purifying blood of above-mentioned (1)～(4); wherein, the gas of described hollow fiber membrane bundle that occupies apparatus for purifying blood inside and space segment beyond described moistening protective agent takes up space is identical with aerial oxygen concentration basically.

(6) according to each described doughnut membranous type apparatus for purifying blood of above-mentioned (1)～(5), wherein, the thickness of embedding layer is below the above 12.5mm of 7.0mm, and the density of doughnut membranous part is 0.05g/cm ³Above 0.45g/cm ³Below.

(7) according to above-mentioned (1)～(6) described doughnut membranous type apparatus for purifying blood; wherein; when according to the drug release test method of hollow fiber type artificial kidney accrediting criterion the embedding layer being tested, product that can't see moistening protective agent and embedding agent substantially is as leachable.

(8) according to above-mentioned (7) described doughnut membranous type apparatus for purifying blood, wherein, the moistening protective agent carried out to the inner moistening protective agent solution that feeds of doughnut adhering to by solidify the back at the embedding layer of hollow-fibre membrane.

The invention effect

Doughnut membranous type apparatus for purifying blood of the present invention is the doughnut membranous type apparatus for purifying blood that is called as the light weight and the operability excellence of half dry type, although by electron beam sterilization, the stripping of the hydrophilic macromolecule that causes of sterilization but seldom, and blood adaptability excellence.Owing to need when electron beam sterilization, not use masking material, do not need to shine several times in addition, therefore exist by fairly simple operation with regard to producible advantage from all directions.

The specific embodiment

Below, the present invention is described in more detail.

Doughnut membranous type apparatus for purifying blood of the present invention, hollow fiber membrane bundle is filled in the container, be held by embedding agent between the Shu Duanyu container and form hollow-fibre membrane medial chamber and hollow-fibre membrane outer side chamber, have the stream socket that leads to the hollow-fibre membrane medial chamber and lead to the stream socket of hollow-fibre membrane outer side chamber.Illustrative words, the hemodialyzer of commercially available doughnut membranous type, blood filter, blood filtration dialyser, plasma separator, plasma fraction dephlegmator etc. are suitable therewith.By such structure, be suitable for the blood purification therapy of extracorporeal circulation formula.

Here the shape of said hollow-fibre membrane, size, Distillation properties are not particularly limited, and select suitable material to get final product according to the purpose of hemodialysis, blood filtration, separating plasma, albumen fractional distillation etc.Wherein, for material, control the reason of aperture and blood adaptability, chemical stability excellence during from the system film easily, the polymer mixed film that is formed by hydrophobic polymer and hydrophilic macromolecule is best suited for.

As hydrophobic polymer, can enumerate polysulfones system, polyacrylonitrile based, polymethyl methacrylate system, comprise polyethylene-based, polyamide-based, the polyester system, polyolefin of ethylene-vinyl alcohol copolymer etc.Among above-mentioned, polysulfones is a macromolecule owing to be aromatic compound, thereby the lonizing radiation toleration is excellent especially, and in addition, to heat, chemical treatment also very tolerance, safety is also excellent.Therefore, can select various film forming conditions and can carry out radiation sterilization, preferred especially as the employed membrane material of apparatus for purifying blood.In addition, the meaning of "～be " is not only to comprise homopolymer, also comprises with other monomeric copolymer, by the analog of chemical modification.

Here said polysulfones is that macromolecule (hereinafter referred to as PSf) is the general name with macromolecular compound of sulfone key, be not the material of special provision, for example can enumerating, repetitive is the polysulfones based polymer shown in following formula (1), formula (2), formula (3), formula (4) and the formula (5).Can also be to import in the part of these aromatic rings substituent modified polymer is arranged.From the viewpoint of industrial easy acquisition, preferred repeat units is the aromatic series polysulfones based polymer shown in formula (1), formula (2) and the formula (3), wherein, especially preferably has the polysulfones of the chemical constitution shown in (1) formula.This bisphenol type polysulfone resin is for example commercially available with the trade name of " Udel (registered trade mark) " by Solvay Advanced Polymers K.K., has several kinds according to degree of polymerization etc., is not subjected to special qualification.

Among the present invention, hydrophilic macromolecule is present in the hollow-fibre membrane, and is used for film is implemented hydrophilic.As hydrophilic macromolecule, can enumerate polyvinylpyrrolidone (hereinafter referred to as PVP), Polyethylene Glycol, polyvinyl alcohol, polypropylene glycol etc., wherein, and from the effect of hydrophiling, the aspect of safety, preferred PVP.Also there are several kinds in PVP according to molecular weight etc., for example, can enumerate the K-15,30,90 (being ISP.Inc. makes) of PVP etc. as commercially available product.The molecular weight of the PVP that uses among the present invention (viscosity-average molecular weight) is 10,000～2,000,000, is preferably 50,000～1,500,000.Containing ratio in the film of hydrophilic macromolecule be the polymer total amount 3～20%, be preferably 3～10%.Containing ratio is 3% when following, and as the weak effect of hydrophilic agent, the hollow-fibre membrane of gained causes blood coagulation easily, and the blood adaptability reduces easily.In addition, containing ratio surpasses at 20% o'clock, and the viscosity of system pleurodiaphragmatic in terspace liquid is too high, and is therefore not preferred on producing.

The manufacture method of the hollow-fibre membrane of being made up of hydrophobic polymer and hydrophilic macromolecule can be used known dry-and wet-type masking technique.That is, at first, hydrophobic polymer and hydrophilic macromolecule are dissolved in the common solvent, modulate uniform spinning solution.As such cosolvent, at hydrophobic polymer is that polysulfones is that macromolecule, hydrophilic macromolecule are in the situation of polyvinylpyrrolidone, for example can enumerate dimethyl acetylamide (hereinafter referred to as DMAC), dimethyl sulfoxine, N-N-methyl-2-2-pyrrolidone N-, dimethyl formamide, sulfolane, diox equal solvent or by the above-mentioned solvent that the mixed liquor of solvent is formed more than 2 kinds.In addition, in order to control the aperture, can in spinning solution, add additives such as entry.

With hollow-fibre membrane system film the time, the spinning head of cast (tube-in-orificetype) is arranged in using mouthful, from the mouth of this spinning head spinning solution that spues in the air, be used to make liquid in the hollow that this spinning solution solidifies in the air to spuing from pipe simultaneously.Liquid can make water or based on the solidification liquid of water in the hollow, can decide it to form etc. according to the through performance as the hollow-fibre membrane of target, can not determine without exception, is fit to use the mixed solution of employed solvent of spinning solution and water usually.For example, use the DMAC aqueous solution etc. of 0～65 weight %.

From the spinning head spinning solution that liquid spues in hollow, its aloft running part divide a word with a hyphen at the end of a line, import in the coagulating bath that is arranged at the spinning head bottom, flood based on water, finish and solidify, process washing procedure etc., batch, obtain the bundle of hollow-fibre membrane with the hollow-fibre membrane coiling machine of moisture state, dry then.Perhaps can pass through washing procedure, then carry out drying in drying machine, obtain hollow fiber bundle, manufacture method is not particularly limited.

The shape of hollow-fibre membrane is used material cylindraceous usually, but can also use the material that has the shape of fin (fin) at the lateral surface of cylinder.Can use the hollow-fibre membrane of following size: thickness is 1～100 μ m, is preferably 5～50 μ m that internal diameter is 50～500 μ m, is preferably about 100～300 μ m.Distillation properties depends on its purposes, if be used for dialysis or filter the then suitable high hollow-fibre membrane of material permeance that uses from low molecular weight substance to the molecular weight littler than albumin; If be used for the albumen fractional distillation, then be fit to use low molecular protein to see through and hollow-fibre membrane that macromolecule protein, the such material of immune complex are difficult to see through; If be used for separating plasma, then be fit to use plasma fraction to see through but hollow-fibre membrane that the blood cell composition does not see through etc.

The manufacture method of doughnut membranous type apparatus for purifying blood uses known method to get final product.For example, hollow fiber membrane bundle can be inserted in the cylindrical container with fluidic gateway, and inject embedding agent such as polyurethane at two bundle ends to form the embedding layer, with this sealing both ends, then, cut-out is removed the embedding agent of the remainder after the curing and is made doughnut end face opening, and the head (header) with fluidic gateway is installed, thereby makes doughnut membranous type apparatus for purifying blood.By this method, can make doughnut membranous type apparatus for purifying blood as described below, promptly, hollow fiber membrane bundle is filled in the container, form hollow-fibre membrane medial chamber and hollow-fibre membrane outer side chamber, and possess stream socket that leads to the hollow-fibre membrane medial chamber and the stream socket that leads to the hollow-fibre membrane outer side chamber.

Among the present invention, the moistening protective agent be meant attached to hollow-fibre membrane whole on the whole to cover its surperficial liquid parts, have when electron beam sterilization protection and constitute the hydrophilic macromolecule of hollow-fibre membrane not by the function of deterioration.

The defencive function of the hydrophilic macromolecule deterioration that the moistening protective agent brings; be meant that specifically seizure because of the free radical that electron beam sterilization (also claiming the electron beam irradiation) produces, perhaps suppresses the reactivity of free radical with this radical reaction or makes free radical forfeiture reactivity in film.

As chemical compound with such function, what represent is the antioxidant of ascorbic acid, tocopherol and Polyphenols etc., more particularly, Vitamin A (its derivant and sodium ascorbate and ascorbyl palmitate), vitamin C and vitamin e vitamin classes such as (and salt of derivant and tocopheryl acetate and alpha-tocotrienol etc.) are used in expectation; Polyalcohols such as glycerol, mannitol, glycols; Saccharides such as glucose, mannose, xylose, ribose, fructose, trehalose; And comprise fatty acid of oleic acid, furan fatty acid, thioctic acid, linoleic acid, Palmic acid and these salt and derivant etc.

Moistening protective agent of the present invention makes when being Powdered it be dissolved or dispersed under the state in the solvent at above-claimed cpd and uses, and is oily or directly uses or make when liquid it to be dissolved or dispersed under the state in the solvent and use at above-claimed cpd.Among the present invention, comprise that dissolving or dispersive state are referred to as the moistening protective agent.As solvent, can use physiological solution such as normal saline solution, dialysis solution, transfusion and buffer or water, alcohol, alcohol-water solution.

The moistening protective agent adheres in the mode that covers the surface that has hydrophilic macromolecule fully in hollow-fibre membrane, specifically, covers the inner surface of hollow-fibre membrane and the pore surface of outer surface and thickness portion.The moistening protective agent can fill up the inside of the pore of hollow-fibre membrane, but owing to can cause weight increase, leakage, thereby preferably it is not filled up to hollow inside.

The moistening protective agent is not particularly limited to the attachment state of hollow-fibre membrane, for example thinks to the combination of film surface hydrophobicity during liposoluble substance, thinks during water-soluble substances only to keep on the film surface etc.But, do not needed the moistening protective agent when using in hospital, therefore preferably adhere to become before use to be washed, to be removed from hollow-fibre membrane easily.Therefore, the protectant major part of moistening be not by covalent bond, ionic bond etc. with the state of pleurodiaphragmatic in terspace material firm combining or at the surface-crosslinked and thawless state of film, and be preferably the state that only adheres to.

In addition; here said washing and remove and be meant the common pre-operation that carries out before use; for example; the washing operation of physiological aqueous solutions such as the normal saline solution by using hundreds of milliliter～several liters, dialysis solution; cover protectant at least 95% of hollow-fibre membrane and be washed, make the film surface-rendering that forms by hydrophobic polymer and hydrophilic macromolecule.

As known from the above; as the moistening protective agent; more preferably satisfy following key element simultaneously: the high molecular deterioration defencive function of possess hydrophilic property; and have the viscosity of appropriateness and be maintained at the film surface easily; do not form firm chemical bond with hydrophobic polymer, hydrophilic macromolecule, and easily by the physiological solution washing.Specifically, in the middle of the above-claimed cpd, glycerol, mannitol, glycols are (for example, ethylene glycol, diethylene glycol, propylene glycol, TEG), polyethylene glycols (for example, Polyethylene Glycol) etc. the polyalcohols radical-scavenging ability height of each molecule not only is also high to the dissolubility of water, physiological solution, therefore, as aqueous solution coverlay surface flecklessly easily, and washing easily.Therefore, preferred these aqueous solution, wherein, from as blood purification with the aperture retention agent of hollow-fibre membrane, the aspect that surface modifier has actual effect, the more preferably aqueous solution of glycerol or Polyethylene Glycol, most preferably glycerine water solution.

Among the present invention, the hollow-fibre membrane in the doughnut membranous type apparatus for purifying blood is that moistening protective agent covering 60% or more, below 400% is necessary with respect to its dry weight.Adhesive rate was greater than 400% o'clock, and it is heavy that the weight of doughnut membranous type apparatus for purifying blood becomes, impaired as the advantage of half dry type, lacks operability.In addition, near usually by the room temperature of keeping, circulation (for example, about 20～40 ℃), drop adheres in container inner wall, sterilizing bag may become big, as the degraded appearance of product.

On the other hand, also has problem on the manufacture method.Greater than 400% o'clock, at the state modulated adhesive rate of bundle and when assembling, the outer surface of the hollow-fibre membrane that becomes was clamminess the moistening protective agent to the adhesive rate of hollow-fibre membrane, the easy set that becomes between the film, and therefore, the intrusion of embedding agent is obstructed, and becomes the reason of leakage.In addition, modulation during adhesive rate after assembling also may produce set and brings obstacle to dialytic efficiency.And then, the part densification of film and make the penetration power of electron beam weaken, therefore, when guaranteeing to sterilize necessary minimum quantity of X-rays X, the quantity of X-rays X in product distributes and becomes big, and material degradation increases the weight of, and leachable increases.

In addition, keeping, the conveyance of imagination under Product Status, during the following anti-drop impact of the state of considering doughnut membranous type apparatus for purifying blood traverse in carton, usually, dry type is because totally gently and the resistance to impact excellence.But, wet type because of drop impact make hollow-fibre membrane around water generates move, exist in that the film end produces stress concentration and danger that the film breakage takes place.On the other hand, when hollow-fibre membrane suitably had weight as half dry type, the stress concentration when level falls was than the easier generation of dry type.From this viewpoint, importantly the protectant adhesive rate of moistening on be limited to 400%.

Therefore, needing the protectant adhesive rate of moistening is below 400%, more preferably below 350%, be preferably below 300% especially.On the other hand, from protection effect aspect, needing lower limit is adhesive rate more than 60%.More preferably more than 80%, be preferably more than 100% especially.

Among the present invention, the protectant adhesive rate of aforementioned moistening is calculated with the protectant gross weight of moistening with respect to the dry weight of hollow-fibre membrane.Assay method is not particularly limited, and at the moistening protective agent when being fat-soluble, with this material of dissolving but do not dissolve the solvent extraction of pleurodiaphragmatic in terspace material, uses chromatograph of liquid, colour reagent to wait quantitatively.In addition, during water-soluble substances, by warm water, water hot extraction, and similarly quantitative.And then, when the moistening protective agent is aqueous solution, can also calculate moisture content in addition, and try to achieve with the adhesive rate and the moisture content sum of solute part by the mensuration program of moisture content described later.

Among the present invention, when the moistening protective agent is polyatomic alcohol water solution, polyhydric alcohol with respect to the ratio of water be preferably more than 0.2 times, below 7.5 times.During greater than 7.5 times, the local concentration that is attached to the polyhydric alcohol of film surface, film inside increases polyhydric alcohol with respect to the ratio of water, and attachment area becomes sticky thick, the result, and it is inhomogeneous that the lining state becomes easily, therefore insufficient on the contrary to the protection effect of electron beam irradiation.In addition, the freezing point of polyatomic alcohol water solution rises, and contained aqueous solution freezes easily in the pore of film, therefore, causes the damage of the structural change of following hollow-fibre membrane easily.

Therefore, polyhydric alcohol is preferably below 7.5 times with respect to the ratio of water.When particularly polyhydric alcohol is glycerol, more preferably the freezing point of glycerine water solution become below-10 ℃ below 5.7 times, the freezing point that is preferably glycerine water solution especially become below-30 ℃ below 3 times.

On the other hand, from protection effect aspect, lower limit is preferably 0.2 times.When particularly polyhydric alcohol is glycerol, more preferably the freezing point of glycerine water solution become below-10 ℃ more than 0.5 times, the freezing point that is preferably glycerine water solution especially become below-30 ℃ more than 1.2 times.Polyhydric alcohol is tried to achieve by following formula (1) with respect to the ratio of water.

[formula 1]

Polyhydric alcohol is with respect to ratio=glycerol weight (the g)/water weight (g) (1) of water

Among the present invention, when the moistening protective agent was polyatomic alcohol water solution, preferably adhering to respect to its dry weight in the hollow-fibre membrane in doughnut membranous type apparatus for purifying blood was polyhydric alcohol more than 20%, below 300%.When polyhydric alcohol adheres to aqueous solution, with the nt wt net weight of removing the polyhydric alcohol beyond this water constituent with respect to the ratio of the dry weight of hollow-fibre membrane adhesive rate as polyhydric alcohol.

Here, greater than 300% o'clock, it is heavy that the weight of doughnut membranous type apparatus for purifying blood becomes, impaired as the advantage of half dry type, lacks operability with respect to the adhesive rate of the dry weight of hollow-fibre membrane for polyhydric alcohol.Near usually by the room temperature of keeping, circulation (for example, about 20～40 ℃), it is big that tendency that drop adheres in container inner wall, sterilizing bag becomes, the degraded appearance of product.In addition, the local concentration that is attached to the polyhydric alcohol of film surface, film inside increases, and attachment area becomes sticky thick, the result, and it is inhomogeneous that the lining state becomes easily, therefore, insufficient on the contrary to the protection effect of electron beam irradiation.On the other hand, also has problem on the manufacture method.When assembling behind the state modulated adhesive rate of bundle, the cohesiveness of the outer surface of hollow-fibre membrane uprises, and film is set easily mutually, therefore the intrusion of embedding agent is obstructed, become the reason of leakage, when after assembling, modulating adhesive rate, also may bring obstacle when producing set to dialytic efficiency.Therefore, the adhesive rate of polyhydric alcohol is preferably below 300%, more preferably below 250%, be preferably below 200% especially.

On the other hand, from protection effect aspect, the preferred lower limit value is the adhesive rate more than 20%.According to the inventor's opinion, need the polyhydric alcohol adhesive rate more than 80% when following radiation gamma, but because the destruction that electron beam brings for the hydrophilic macromolecule of hollow-fibre membrane is little, thereby can be reduced to 20% among the present invention.The adhesive rate of polyhydric alcohol is become when so low, and the density of hollow fiber membrane bundle integral body reduces, and the quantity of X-rays X of electron beam is distributed become littler.In addition, in the pre-operation before using, can remove polyhydric alcohol reliably rapidlyer.Deterioration protection effect aspect from film more preferably more than 50%, is preferably more than 80% especially.

Among the present invention, polyhydric alcohol in the scope of aforementioned adhesive rate, water quantities with respect to the dry weight ratio of hollow-fibre membrane, be that moisture content is preferably more than 40%, less than 100%.If moisture content is more than 40%, then can suppress hematoblastic activation in the stage that contacts with the blood initial stage.Its concrete reason do not determine, is that hydrophilic macromolecule is water and state because the film surface is when becoming the moistening state of appropriateness but infer this, compares with exsiccant film extremely, uses the wettability at beginning initial stage to uprise, and the result improves to the affinity of blood.This is very important feature when using immediately behind the apparatus for purifying blood that needs the pre-operation half dry type.But moisture content is 100% when above, even if for there is not the state of moisture around film, because contained moisture freezes in the pore of film is followed the damage of the structural change of hollow-fibre membrane easily.In addition, when moisture content surpassed the equilibrium moisture content of film, superfluous moisture became water droplet, is attached in container inner wall, the sterilizing bag degraded appearance of product.

On the other hand, moisture content is less than 40% o'clock, in the stage that contacts with the initial stage of blood, and platelet activation, and the tendency height that reduces of blood adaptability.Infer that its detailed reason is: as previously mentioned, be in film surface extremely during dry status, the transport properties of molecules of hydrophilic macromolecule reduces, and therefore, the hydrophilic high score is bedewed by water and is changed to water and state needs the time in use.When particularly moistening retention agent was polyhydric alcohol, viscosity uprised the adhesive rate deviation that causes to hollow-fibre membrane and becomes big, therefore occurs the extremely low hollow-fibre membrane of hydrophilic easily, and the possibility of result causes the adaptive reduction of blood.Powder, the concentrated solution of considering hydrophilic macromolecule can not be dissolved in water and dissolve when needing the time moment, thinks that this supposition is according to being appropriate.More preferably moisture content is more than 60%.

Among the present invention, the method that the adhesive rate and the moisture content of protectant adhesive rate of moistening or polyhydric alcohol is set in above-mentioned scope is not particularly limited.For example can enumerate, the protectant highly concentrated solution of hollow-fibre membrane and moistening is contacted after, feed the method for water with the succession of the scope that adhesive rate, moisture content is adjusted to regulation.Certainly, can be its opposite order.In addition; as other example, following method is arranged: the time of contact when optimizing moistening protective agent solution and contact, the concentration of this solution, the injection pressure in hollow-fibre membrane, be used to dispel the method for the lance ejection condition etc. of moistening protective agent solution with film stage.The loaded down with trivial details property of the latter's flow process is low, in addition, does not need to use the aqueous solution of high concentration, thereby the advantage that evenly is covered is easily arranged, so preferred.Particularly lance ejection also makes for example sticking moistening protective agent stretch at the film inner surface owing to not only effective to dispelling remaining moistening protective agent, thereby also has the effect of lining more equably.

These methods can also be brought the part of film making process into and each doughnut is carried out, and perhaps make behind the film under the state of the bundle of boundling and carry out.The former is provided with the protectant bath of moistening in the film production line and floods hollow-fibre membrane and get final product in system, among the latter bundle be impregnated in the protectant bath of moistening, perhaps applies the protectant spray of moistening (shower) and gets final product from restrainting the end.Perhaps, the semi-finished product of doughnut membranous type apparatus for purifying blood, promptly in the process of assembling, do not feed the method for free radical capture material solution under the state of securement head from the hollow-fibre membrane peristome of embedding portion; After installation has a head of the stream socket that leads to hollow-fibre membrane inside, stream socket from the head feeds the method for liquid; Feed the method for liquid from the stream socket (for example) of cylindrical container, can be these arbitrary methods if hemodialyzer then is the dialysis solution gateway.In the middle of these, even if owing to be that full-bodied liquid also can be the inner liquid that accurately feeds of hollow to the contact surface with blood, therefore, preferably from the method for the logical liquid of stream socket of the head of the hollow-fibre membrane peristome of the abortion product of apparatus for purifying blood or apparatus for purifying blood.

When operation is adhered to the moistening protective agent like this, for example, even if in that protectant glycerol, embedding agent with hydroxyl uses in the situation of aromatic compound as moistening, because embedding agent solidifies the in fact not stripping of product of glycerol and embedding agent.Therefore, do not generate such by-product, the probability step-down of stripping, the doughnut membranous type apparatus for purifying blood that can extremely be cleaned.

In addition; substantially can't see this product is meant as leachable: when testing with the embedding layer that does not give each part of the protectant doughnut membranous type of moistening apparatus for purifying blood giving the protectant doughnut membranous type of moistening apparatus for purifying blood according to the drug release test method of hollow fiber type artificial kidney accrediting criterion; absorbance when not giving the moistening protective agent in contrast; measure under wavelength 240～250nm give the moistening protective agent time absorbance the time, this value is below 0.005.

Among the present invention, the adhesive rate and the moisture content of polyhydric alcohol are measured by the following method.

Take out the hollow-fibre membrane of 5g part from doughnut membrane-type blood blood processor, the correct weight (A) of measuring the preceding hollow-fibre membrane of drying.Then, only remove with vacuum drier and to anhydrate, and measure the weight (B) of dried hollow-fibre membrane.

Then, use and only remove the above-mentioned dried hollow-fibre membrane sample that anhydrates, after this hollow-fibre membrane sample is all shredded, add the 300ml pure water, clog with stopper, with informed later washing 60 minutes, thus the polyhydric alcohol that extraction is adhered to.With this hollow-fibre membrane sample that informed later extraction is sheared, use the extract after the extraction, by liquid chromatograph standard measure polyhydric alcohol, the standard curve that uses the peak area by standard solution to obtain is tried to achieve the amount (C) of the polyhydric alcohol in this extract.And then, from this extract, only take out the hollow-fibre membrane sample be sheared, in vacuum drier, after the drying, measure the weight of exsiccant this hollow-fibre membrane sample that is sheared, with it as the hollow-fibre membrane weight (D) of not adhering to polyhydric alcohol and moisture.

Based on above measured value, the value of calculating from following formula (2) is a moisture content, and the value of calculating from formula (3) is the adhesive rate of polyhydric alcohol.

In addition, the polyhydric alcohol adhesive rate also can by (B-D)/try to achieve D} * 100.

And then the protectant adhesive rate of moistening also can be by being tried to achieve by the summation of following moisture content of trying to achieve and polyhydric alcohol adhesive rate, in addition, also can by (A-D)/try to achieve D} * 100.Among the embodiment described later, moisture content is tried to achieve by formula (2), and the polyhydric alcohol adhesive rate is tried to achieve by (3), and the protectant adhesive rate of moistening is tried to achieve by these summations.

[formula]

Moisture content (wt%)=(A-B)/D} * 100 (2)

Polyhydric alcohol adhesive rate (wt%)=(C/D) * 100 (3)

Among the present invention, obtaining from aspect hollow-fibre membrane generation leachable and the adaptive balance of blood, the oxygen concentration in the control doughnut membranous type apparatus for purifying blood is important.Oxygen concentration in the doughnut membranous type apparatus for purifying blood is low more, and the oxygen-derived free radicals that can suppress electron beam irradiation initiation more produces the high polymer main chain that causes and cuts off, is oxidation Decomposition that the result can suppress the stripping of hydrophilic macromolecule.Its on the other hand, hydrophilic macromolecule carries out crosslinked and membrane surface modification, the blood adaptability of film significantly reduces.In addition, not only there is the problem of hollow-fibre membrane modification, also has cylindrical container, the painted problem of head.

But, according to the inventor's opinion because the moistening protective agent that is prescribed of hollow-fibre membrane covers, even if thereby special deoxidation just by electron beam sterilization, also can improve the problem that above-mentioned oxygen causes.That is,, also can suppress the oxidation Decomposition of film, in addition, also can suppress the crosslinked of hydrophilic macromolecule, suppress the painted of cylindrical container, head even if under atmospheric condition.

And then, when deoxidation is carried out in apparatus for purifying blood inside, can further suppress the oxidation Decomposition of film.At this moment, needing the hollow fiber membrane bundle of apparatus for purifying blood inside and the moistening protective agent space segment beyond taking up space at least is that gas more than 0.01% occupies by oxygen concentration.Oxygen concentration in this gas is 0.01% when above, and the deterioration of hydrophilic macromolecule is suppressed, and leachable is suppressed to lower, and meanwhile, the crosslinked of the surplus of hydrophilic macromolecule is suppressed, and therefore can obtain excellent blood adaptability.And, for container, head, even if painted also only be temporary, the keeping in just fade soon.During opposite less than 0.01%, the painted of container, head fades hardly, and so the product appearance variation is not preferred.

More preferably the oxygen concentration in the gas is identical with atmospheric concentration basically.Here said identical with aerial oxygen concentration basically being meant: consider measurement deviation, oxygen concentration is 20.0～22.0%.Among the present invention, under the state that the wetted protective agent of hollow-fibre membrane covers, carry out electron beam sterilization, therefore, even if oxygen concentration than the concentration height that has the radiation sterilization operation under the common deoxidation state now, also can fully suppress the deterioration of pleurodiaphragmatic in terspace material.Therefore, do not need the existing deoxidizer that uses with radiation sterilization, special portion's material such as oxygen flow gas system packaging material not, in addition, do not need noble gas, nitrogen etc. are enclosed the operation of space segment, therefore very preferably yet.

For the method that oxygen concentration is modulated into below the atmospheric concentration, when doughnut membranous type apparatus for purifying blood is packaged in sterilizing bag, by using N ₂, He, CO ₂, inert gas replacement air such as Ar, He method so that use the method for oxygen absorbent to adjust in this sterilizing bag inboard and the oxygen concentration in the doughnut membranous type apparatus for purifying blood, but be not particularly limited in this.When using oxygen absorbent, do not produce other gas componant when preferably absorbing oxygen, perhaps do not lose activity because of radiation exposure makes oxygen absorbent.For example, preferably be main component and control the mode of its response speed,, can enumerate ferrum, zinc, copper, stannum etc. as reactive metal by catalyst with the reactive metal.Preferred especially is the material of main component with the activated ferric oxide.As such oxygen absorbent commercially available prod for example AGELESS (registered trade mark) of SANLING aerochemistry company manufacturing is arranged, but be not particularly limited in this.

According to the present invention, be controlled at particular range by protectant adhesive rate of the moistening that will illustrate before this and oxygen concentration and carry out electron beam sterilization, can obtain the doughnut membranous type apparatus for purifying blood of the few and blood adaptability excellence of the stripping of hydrophilic macromolecule.But, consider that the penetration power of electron beam is more weak, also be preferably as follows the density that limits the each several part in the apparatus for purifying blood.

The piece that density is the highest in the first apparatus for purifying blood partly is the thickness of embedding layer.When carrying out electron beam sterilization, the central shaft approximate horizontal of existence and apparatus for purifying blood ground shines, is the situation of traverse and the situation of shining, promptly placing vertically from central axis direction.When the apparatus for purifying blood of half dry type is carried out electron beam sterilization,, preferably place irradiation vertically, but embedding this moment layer has blocked penetrating of electron beam, is difficult to all uniform irradiations from improving the illumination efficiency of time per unit.

So the inventor studies, find that the thickness of embedding layer among the present invention is preferably more than the 7.0mm, below the 12.5mm.The thickness of embedding agent is during greater than 12.5mm, and a little less than the penetration power of electron beam, the quantity of X-rays X in product distributes and becomes big, thus material generation deterioration, and leachable increases.More preferably 12.3mm following, be preferably below the 12.0mm especially.On the contrary, the thickness of embedding layer is during less than 7.0mm, when having the irradiating electron beam abreast of relative blood trickling direction, the advantage that the penetration range of electron beam increases, but structurally, the embedding layer keeps the power of hollow fiber membrane bundle to die down, and perhaps the embedding layer of blood access one side caves in easily when the film contraction takes place, the trend that has the blood purification performance to reduce.Therefore, from the reason of intensity, lower limit be preferably 7.0mm above, more preferably 7.5mm above, be preferably more than the 9.0mm especially.

The material that forms the embedding agent of embedding layer is not particularly limited, and except widely used polyurethane resin in the hemodialyzer etc., also can enumerate epoxy resin, silicone resin etc.

Another is the density of the hollow-fibre membrane of most important performance in the decision apparatus for purifying blood.When carrying out electron beam sterilization, then block penetrating of electron beam, be difficult to all uniform irradiations if improve density.

So the inventor studies, find that the density of doughnut membranous part among the present invention is preferably 0.05g/cm ³More than, 0.45g/cm ³Below.The density of said here doughnut membranous part is meant: in the doughnut membranous type apparatus for purifying blood, comprise the hollow-fibre membrane weight in the unit volume of the part (length of this part is called the hollow-fibre membrane effective length) that only comprises hollow-fibre membrane in the middle of the part of hollow-fibre membrane and embedding agent.That is, can try to achieve by following formula (4).

[formula]

The density of doughnut membranous part=the comprise protectant hollow-fibre membrane weight of the moistening/sectional area * hollow-fibre membrane effective length of side (in the container Monday) (4)

The density of doughnut membranous part compares 0.45g/cm ³When big, the penetration power of electron beam weakens, and the quantity of X-rays X in product distributes and becomes big, thereby material carries out deterioration, and leachable increases.0.35g/cm more preferably ³Below, be preferably 0.31g/cm especially ³Below.On the contrary, the density of doughnut membranous part is less than 0.05g/cm ³The time, to compare with the volume of hollow-fibre membrane medial chamber, it is big that the ratio of the volume of hollow-fibre membrane outer side chamber becomes, thereby employed dialysis solution quantitative change is big, and the required dialysis solution expense of single treatment uprises.Therefore, from the reason of using, lower limit is preferably 0.05g/cm ³More than, 0.08g/cm more preferably ³More than, be preferably 0.12g/cm especially ³More than.

The said electron beam sterilization of the present invention is meant: carry out radiation sterilization after doughnut membranous type apparatus for purifying blood is packaged in sterilizing bag, its quantity of X-rays X preferably uses 5～50KGy.More preferably 15～30KGy, be preferably about 20KGy especially.

Embodiment

Below based on embodiment the present invention is carried out more specific description, but the present invention is not limited to following embodiment.At first, the employed various assay methods of embodiment are described.

The mensuration of oxygen concentration

For the oxygen concentration in the doughnut membranous type apparatus for purifying blood, before electron beam sterilization is handled, use trace oxygen analyzer (Iijima electronics industry (strain) is made, RO-102 type), under doughnut membranous type apparatus for purifying blood is enclosed state in the sterilizing bag, measure.

When measuring, in order to prevent that the outer air of sterilizing bag from flowing into, attach adhesion rubber (Iijima electronics industry (strain) manufacturing, adhesion rubber RG-1 type) in the sterilizing bag outside, the oxygen that adhesion rubber is penetrated determinator sucks probe, and measures the interior oxygen concentration of sterilizing bag.Hollow-fibre membrane is owing to have gas-premeable, thereby the inside and outside oxygen concentration of the hollow-fibre membrane in the sterilizing bag is considered as evenly.

The active mensuration of lactic acid dehydrogenase (LDH)

The blood adaptability of hollow-fibre membrane is estimated the tack on film surface with platelet, and the activity of the lactic acid dehydrogenase that the platelet that is attached to film is contained is come quantification as index.

Decompose apparatus for purifying blood, extract the blood purification hollow-fibre membrane, process this film two ends with silicone, the area that makes its effective length become 15cm, film inner surface becomes 50mm ², make micromodule.Make the 10ml normal saline solution (, Da of Otsuka Pharmaceutical Co., Ltd mound eat notes raw to this micromodule) flow into the doughnut inboard and wash (hereinafter referred to as " pre-operation ").Then, the human blood that 7ml is added heparin injects syringe pump, with the flow velocity of 1.44ml/min blood is fed in the micromodule, then respectively with the inboard of 10ml normal saline solution washing micromodule, with the 10ml normal saline solution washing outside.Take out hollow-fibre membrane from the micromodule of washing, then, it is shredded and puts into LDH mensuration with the SPITZ pipe, as the mensuration sample for the long 14cm of half amount of total radical.

Then, dissolving TritonX-100 (Nacalai Tesque in phosphate buffer solution (PBS) (making) with the pure pharmaceutical worker's industry of light (strain), Inc. make) and obtain the TritonX-100/PBS solution of 0.5 capacity %, this solution of 0.5ml is added in the SPITZ pipe of LDH mensuration usefulness, carry out 60 minutes ultrasonic Treatment then and be attached to the cell (mainly being platelet) of hollow-fibre membrane, the LDH in the extraction cell with destruction.This extract is got 0.05ml respectively, add again 2.7ml 0.6mM Sodium Pyruvate solution, 0.3ml1.277mg/ml nicotinamide adenine dinucleotide (NADH) solution and make its reaction, get its 0.5ml immediately respectively and measure the absorbance of 340nm.Residual solution further 37 ℃ of reactions 1 hour, is measured the absorbance of 340nm then, measure minimizing from firm reacted absorbance.Similarly, calculate the poor of absorbance by following formula (5) to not measuring absorbance with the film of reaction of blood.In this method, this minimizing amplitude is big more, and the LDH activity is high more, means that promptly platelet is many more to the adhesion amount on film surface.

Δ 340nm=(absorbances after 60 minutes of the reacted absorbance-sample just of sample)-(barren just reacted absorbance-after barren 60 minutes absorbance)

(5)

The mensuration of PVP stripping quantity

All use water for injection (Pharmacopeia of Japan) thorough washing doughnut membranous type apparatus for purifying blood more than the 1L in blood one side and dialysis solution one side, be blown into compressed air fully to remove liquid.Then, under state, with heating to 70 ℃ water for injection (Pharmacopeia of Japan) with 200ml/min to blood one side circulation 1 hour with dialysis solution one side seal of blood processor.Circulate after 1 hour, use the filter of hole dimension 0.45 μ m to filter the extract that reclaims, by HPLC (Shimadzu Seisakusho Ltd.'s system: LC-10AD/SPD-10AV) the PVP concentration in the mensuration filtrate.

The condition of the HPLC of this moment is as follows.

Post: S houdex Asahipak GF-710HQ

Mobile phase: 50mM NaCl aqueous solution

Flow velocity: 1.0ml/min

Temperature: 30 ℃

Detect: 220nm

Sample size: 50 μ L

The mensuration of the leachable of embedding layer

The mensuration of the leachable of embedding layer is carried out as described below according to the drug release test method of hollow fiber type artificial kidney accrediting criterion.1 doughnut membranous type apparatus for purifying blood is decomposed, take out the embedding layer from both ends, then these are cut into the square size of about 1cm.To wherein adding 200ml water for injection (Pharmacopeia of Japan), slowly vibrate the limit on 40 ℃ of limits and heated 2 hours.After the cooling, get the 1.0ml upper clear liquid, add entry and accurately make 50ml.This experimental liquid as sample, with the experimental liquid that do not give the protectant doughnut membranous type of moistening apparatus for purifying blood in contrast, is measured the absorbance under the long 10mm of layer and the wavelength 240～250nm.

Embodiment 1

Make the uniform spinning solution of forming by 17 weight portion PSF (Solvay Advanced Polymers K.K. manufacturing, P-1700), 4 weight portion PVP (ISP.Inc. manufacturing, K-90), 79 weight portion dimethyl acetylamide (following, DMAC).Liquid uses 42% aqueous solution of DMAC in the hollow, spues from spinning head with spinning solution.At this moment, the discharge-amount of liquid makes that meeting dried thickness is that 45 μ m, internal diameter are 185 μ m in adjustment spinning solution and the hollow.The spinning solution that spues is impregnated in 60 ℃ the coagulating bath of being made up of water of being located at its 50cm below, through supersolidification operation, washing step, imports drying machine with 30m/ minute speed then, after 160 ℃ of dryings, batching and being with the polysulfones of Zhe is hollow-fibre membrane.

Then, will by 10000 hollow-fibre membranes that batch form to get one's things ready into the effective film area that is designed to hollow-fibre membrane be 1.5m ²Plastics system cylindrical container in, fix its both ends with the resin bonding of ammonia ester, cut off both ends of the surface, form the opening of hollow-fibre membrane.From opening in hollow-fibre membrane with 2.3 implantation concentration 28.2% glycerol in second (making superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), with the air of 0.3MPA it was sprayed for 10 seconds, then, at both ends securement head medicated cap (header cap).Clog blood flow discrepancy side nozzle, then, (the system AGELESS (registered trade mark) of SANLING aerochemistry society) puts into sterilizing bag with deoxidizer, and oxygen concentration is adjusted into 15.1%, uses the 20KGy irradiating electron beam then, and obtaining the effective film area is 1.5m ²Doughnut membranous type apparatus for purifying blood.

In this doughnut membranous type apparatus for purifying blood as the glycerol adhesive rate of the protectant polyhydric alcohol of moistening be 31.1%, moisture content is 79.0%.Measure the table 1 that the results are shown in of each performance.In addition, the effective film area of hollow-fibre membrane is meant: comprise in the doughnut membranous type apparatus for purifying blood in the middle of hollow-fibre membrane and the embedding agent part, include only the area of hollow fiber film of the part of hollow-fibre membrane.

Embodiment 2

In hollow-fibre membrane with 5.2 implantation concentration 60.5% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of the protectant polyhydric alcohol of moistening be 150.2%, moisture content is 98.0%.Measure the table 1 that the results are shown in of each performance.

Embodiment 3

In hollow-fibre membrane with 5 implantation concentration 63.0% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is adjusted into 10.2%, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of the protectant polyhydric alcohol of moistening be 151.8%, moisture content is 89.3%.Measure the table 1 that the results are shown in of each performance.

Embodiment 4

In hollow-fibre membrane with 5.1 implantation concentration 60.9% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is adjusted into 4.3%, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of the protectant polyhydric alcohol of moistening be 148.3%, moisture content is 95.2%.Measure the table 1 that the results are shown in of each performance.

Embodiment 5

In hollow-fibre membrane with 4.7 implantation concentration 65.3% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is adjusted into 0.98%, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of the protectant polyhydric alcohol of moistening be 146.2%, moisture content is 77.8%.Measure the table 1 that the results are shown in of each performance.

Embodiment 6

In hollow-fibre membrane with 4.2 implantation concentration 71.8% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is adjusted into 0.52%, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of the protectant polyhydric alcohol of moistening be 146.1%, moisture content is 57.3%.Measure the table 1 that the results are shown in of each performance.

Embodiment 7

In hollow-fibre membrane with 7.9 implantation concentration 74.0% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of the protectant polyhydric alcohol of moistening be 280.1%, moisture content is 98.2%.Measure the table 1 that the results are shown in of each performance.

Embodiment 8

In hollow-fibre membrane with 7.3 implantation concentration 83.5% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of the protectant polyhydric alcohol of moistening be 290.9%, moisture content is 57.3%.Measure the table 1 that the results are shown in of each performance.

Embodiment 9

In hollow-fibre membrane with 4.5 implantation concentration 36.8% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the adhesive rate of the glycerol of the protectant polyhydric alcohol of moistening be 26.9%, moisture content is 46.1%.Measure the table 1 that the results are shown in of each performance.

Embodiment 10

In hollow-fibre membrane with 7.4 second implantation concentration 69.9% Polyethylene Glycol (sheet mountain chemical industry (strain) manufacturing, one-level, PEG600) aqueous solution, and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the adhesive rate of the Polyethylene Glycol of the protectant polyhydric alcohol of moistening be 248.9%, moisture content is 97.0%.Measure the table 1 that the results are shown in of each performance.

Embodiment 11

In hollow-fibre membrane with 4.6 second implantation concentration 64.2% Polyethylene Glycol (sheet mountain chemical industry (strain) manufacturing, one-level, PEG600) aqueous solution, and oxygen concentration is adjusted into 0.45%, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the adhesive rate of the Polyethylene Glycol of the protectant polyhydric alcohol of moistening be 141.9%, moisture content is 79.2%.Measure the table 1 that the results are shown in of each performance.

Embodiment 12

In hollow-fibre membrane with 1.4 second implantation concentration 35.8% TEG (make with the pure pharmaceutical worker's industry of light (strain), TEG, 99%) aqueous solution, and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the adhesive rate of the TEG of the protectant polyhydric alcohol of moistening be 25.1%, moisture content is 45.0%.Measure the table 1 that the results are shown in of each performance.

Embodiment 13

In hollow-fibre membrane with 5.1 second implantation concentration 61.8% TEG (make with the pure pharmaceutical worker's industry of light (strain), TEG, 99%) aqueous solution, and oxygen concentration is adjusted into 1.03%, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the adhesive rate of the TEG of the protectant polyhydric alcohol of moistening be 152.2%, moisture content is 93.9%.Measure the table 1 that the results are shown in of each performance.

Table 1

	Embodiment 1	Embodiment 2	Embodiment 3	Embodiment 4	Embodiment 5	Embodiment 6	Embodiment 7	Embodiment 8	Embodiment 9	Embodiment 10	Embodiment 11	Embodiment 12	Embodiment 13
														Moistening protective agent	Glycerol	Glycerol	Glycerol	Glycerol	Glycerol	Glycerol	Glycerol	Glycerol	Glycerol	PEG	PEG	TEG	TEG
Moistening protective agent adhesive rate (wt%)	110.1	248.2	241.1	243.5	224.0	203.4	378.3	348.2	73.0	355.9	221.1	70.1	246.1
														Polyhydric alcohol adhesive rate (wt%)	31.1	150.2	151.8	148.3	146.2	146.1	280.1	290.9	26.9	248.9	141.9	25.1	152.2
Moisture content (wt%)	79.0	98.0	89.3	95.2	77.8	57.3	98.2	57.3	46.1	97.0	79.2	45.0	93.9
														Embedding layer thickness (mm)	12.3	10.8	10.4	9.9	10.2	11.8	8.9	9.1	12.0	9.5	11.9	8.7	8.0
Density (the g/cm of doughnut portion 3)	0.17	0.28	0.28	0.28	0.26	0.25	0.39	0.37	0.14	0.37	0.26	0.14	0.28
														Oxygen concentration (%)	15.1	21.7	10.2	4.3	0.98	0.52	21.9	21.8	21.9	21.9	0.45	21.9	1.03
LDH activity (Δ abs/hr/m 2)	17.8	13.8	13.5	16.0	15.0	17.1	13.8	17.8	16.4	15.2	16.6	15.7	17.3
														PVP stripping quantity (mg)	0.25	0.19	0.18	0.10	0.05	0.03	0.13	0.04	0.21	0.15	0.07	0.22	0.04
Product appearance	Well	Well	Well	Well	Well	Well	Well	Well	Well	Well	Well	Well	Well
														The leachable of embedding layer (absorbance maximum abs)	-	0.002	0.001	-	-	-	-	-	-	-	-	-	-

PEG: Polyethylene Glycol

TEG: TEG

Comparative example 1

In hollow-fibre membrane with 2.5 implantation concentration 13.3% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of free radical capture material be 16.1%, moisture content is 104.9%.Measure the table 2 that the results are shown in of each performance.At this moment, the LDH activity uprises, and as this reason, the glycerol that is estimated as the free radical capture material evenly is not covered to hollow-fibre membrane.

Comparative example 2

In hollow-fibre membrane with 8.9 implantation concentration 72.7% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of free radical capture material be 309.2%, moisture content is 116.3%.Measure the table 2 that the results are shown in of each performance.At this moment, glycerine water solution is attached to several places that doughnut membranous type blood processor is inner and bag is inboard.

Comparative example 3

In hollow-fibre membrane with 1.1 implantation concentration 27.6% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of free radical capture material be 15.3%, moisture content is 40.1%.Measure the table 2 that the results are shown in of each performance.At this moment, the LDH activity uprises, and as this reason, the glycerol that is estimated as the free radical capture material evenly is not covered to hollow-fibre membrane.

Comparative example 4

In hollow-fibre membrane with 1.7 implantation concentration 80.3% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of free radical capture material be 9.9%, moisture content is 70.4%.Measure the table 2 that the results are shown in of each performance.At this moment, the LDH activity uprises, and as this reason, the glycerol that is estimated as the free radical capture material evenly is not covered to hollow-fibre membrane.

Comparative example 5

In hollow-fibre membrane with 7.8 implantation concentration 82.9% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of free radical capture material be 310.3%, moisture content is 63.8%.Measure the table 2 that the results are shown in of each performance.At this moment, glycerine water solution is attached to several places that doughnut membranous type blood processor is inner and bag is inboard.

Comparative example 6

In hollow-fibre membrane with 7.5 implantation concentration 90.3% glycerol in second (make, superfine) aqueous solutions with the pure pharmaceutical worker's industry of light (strain), and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of free radical capture material be 325.9%, moisture content is 35.2%.Measure the table 2 that the results are shown in of each performance.At this moment, glycerine water solution is attached to several places that doughnut membranous type blood processor is inner and bag is inboard.

Comparative example 7

Glycerol (with the pure pharmaceutical worker's industry of light (strain) manufacturing, superfine) aqueous solution with implantation concentration 85.1% in hollow-fibre membrane in 3.9 seconds, and oxygen concentration is a concentration under the atmosphere, in addition, obtain doughnut membranous type apparatus for purifying blood by the condition identical with embodiment 1.

In this doughnut membranous type blood processor as the glycerol adhesive rate of free radical capture material be 159.2%, moisture content is 27.8%.Measure the table 2 that the results are shown in of each performance.At this moment, the LDH activity uprises, and as this reason, the glycerol that is estimated as the free radical capture material evenly is not covered to hollow-fibre membrane.

Table 2

	Comparative example 1	Comparative example 2	Comparative example 3	Comparative example 4	Comparative example 5	Comparative example 6	Comparative example 7
								The moistening protective agent	Glycerol	Glycerol	Glycerol	Glycerol	Glycerol	Glycerol	Glycerol
Moistening protective agent adhesive rate (wt%)	121.0	425.5	55.4	80.3	374.1	361.1	187.0
								Polyhydric alcohol adhesive rate (wt%)	16.1	309.2	15.3	9.9	310.3	325.9	159.2
Moisture content (wt%)	104.9	116.3	40.1	70.4	63.8	35.2	27.8
								Embedding layer thickness (mm)	10.5	6.5	10.8	10.2	14.0	6.7	10.4
Density (the g/cm of doughnut portion 3)	0.18	0.43	0.13	0.15	0.39	0.38	0.23
								Oxygen concentration (%)	21.9	21.9	21.8	21.9	21.8	21.7	21.9
LDH activity (Δ abs/hr/m 2)	40.1	18.1	26.3	30.8	19.2	17.3	23.0
								PVP stripping quantity (mg)	1.3	0.17	1.4	1.7	0.3	0.15	1.0
Product appearance	In container and product bag, can confirm water droplet	Polyurethane is recessed in drop, the water droplet that can confirm glycerol in container and the product bag	Well	Well	Superfluous polyurethane stops up the dialysis solution nozzle can be confirmed glycerol in container and product bag drop	Polyurethane is recessed in the drop that can confirm glycerol in container and the product bag	Well

Industrial utilizability

Hollow fiber membrane type blood purifier of the present invention is the hollow fiber membrane type blood purifier that is called as light weight and the operability excellence of half dry type, wherein, although this device is by electron beam sterilization, the stripping of the hydrophilic macromolecule that sterilization causes is few, and blood adaptability is excellent. Therefore, in the blood purification therapy of the circulation-types such as haemodialysis, blood filtration, plasma separation, plasma fraction fractionation, not only in use, and also can effectively use when being included in when carrying and keeping.

Claims (8)

1. doughnut membranous type apparatus for purifying blood; it is a device as described below: the hollow fiber membrane bundle that is formed by hydrophobic polymer and hydrophilic macromolecule is filled in the container; the end of this bundle is maintained at by the embedding layer and forms hollow-fibre membrane medial chamber and hollow-fibre membrane outer side chamber in the container; and possess the stream socket that leads to the hollow-fibre membrane medial chamber and lead to the stream socket of hollow-fibre membrane outer side chamber; wherein; this hollow-fibre membrane is that the moistening protective agent below 400% covers more than 60% with respect to its dry weight; and; the described hollow fiber membrane bundle of described apparatus for purifying blood inside and the described moistening protective agent space segment beyond taking up space is that gas more than 0.01% occupies by oxygen concentration, and described device is through electron beam sterilization.

2. doughnut membranous type apparatus for purifying blood according to claim 1, wherein, described moistening protective agent is the mixture of water and polyhydric alcohol.

3. doughnut membranous type apparatus for purifying blood according to claim 2, wherein, polyhydric alcohol is more than 0.2 times below 7.5 times with respect to the weight ratio of water.

4. according to claim 2 or 3 described doughnut membranous type apparatus for purifying blood; wherein; constituting the protectant moisture of moistening is more than 40% and less than 100% to the adhesive rate of hollow-fibre membrane with respect to the dry weight of hollow-fibre membrane, and polyhydric alcohol is more than 20% below 300% to the adhesive rate of hollow-fibre membrane.

5. according to each described doughnut membranous type apparatus for purifying blood of claim 1～4; wherein, the gas of described hollow fiber membrane bundle that occupies apparatus for purifying blood inside and space segment beyond described moistening protective agent takes up space is identical with aerial oxygen concentration basically.

6. according to each described doughnut membranous type apparatus for purifying blood of claim 1～5, wherein, the thickness of embedding layer is below the above 12.5mm of 7.0mm, and the density of doughnut membranous part is 0.05g/cm ³Above 0.45g/cm ³Below.

7. according to each described doughnut membranous type apparatus for purifying blood of claim 1～6; wherein; when according to the drug release test method of hollow fiber type artificial kidney accrediting criterion the embedding layer being tested, product that can't see moistening protective agent and embedding agent substantially is as leachable.

8. doughnut membranous type apparatus for purifying blood according to claim 7, wherein, the moistening protective agent carried out to the inner moistening protective agent solution that feeds of doughnut adhering to by solidify the back at the embedding layer of hollow-fibre membrane.