CN104001427A

CN104001427A - Blood processing hollow fiber membrane, blood purifier and manufacturing method thereof

Info

Publication number: CN104001427A
Application number: CN201410058840.3A
Authority: CN
Inventors: 鸟田美和子; 川上淳也
Original assignee: Asahi Kasei Medical Co Ltd
Current assignee: Asahi Kasei Medical Co Ltd
Priority date: 2013-02-27
Filing date: 2014-02-20
Publication date: 2014-08-27
Anticipated expiration: 2034-02-20
Also published as: JP6059040B2; JP2014161631A; CN104001427B

Abstract

The invention refers to a blood processing hollow fiber membrane, a blood purifier and a manufacturing method thereof. The subject aims to obtain a blood processing hollow fiber membrane which maintain oxidation resistance under harsh environment such as high temperature preservation and change less due to lipid-soluble vitamin. The blood processing hollow fiber membrane comprises A-D; the surface of the blood processing hollow fiber membrane contains, calculating by membrane area, lipid-soluble vitamin in a scope above 10 mg/ m2 and below 300 mg/m2; the content of the lipid-soluble vitamin on the surface of the blood processing hollow fiber membrane is over 50 mass % of the whole content of the lipid-soluble vitamin of a blood processing hollow fiber membrane, wherein A is polyether sulfone resin, B is hydrophilic polymer, C is lipid-soluble vitamin and D is ketone and/ or alcohol with less than four carbons.

Description

Hollow-fibre membrane, blood purification and manufacture method thereof for blood treatment

Technical field

The present invention relates to blood treatment hollow-fibre membrane, especially to relate to polyether sulfone be hollow-fibre membrane for blood treatment, possess this blood treatment blood purification of hollow-fibre membrane and the manufacture method of this blood purification.

Background technology

All the time, in the blood purification therapy of kidney failure treatment etc., in order to remove urotoxin, the waste product in blood, be widely used the blood purification of the various hollow fiber membrane-types such as haemodialyser, blood filter or hemodiafiltration device, described blood purification possesses and has used the high molecular blood treatment such as cellulose, cellulose diacetate, primary cellulose acetate, polysulfones, polyether sulfone, polymethyl methacrylate, polyacrylonitrile hollow-fibre membrane as parting material.

The aspects such as the high production rate of the blood purification of these hollow fiber membrane-types when the height of the uremic material removal efficiency in reduction, the blood of circulating liquid measure and then assembly are produced are in vitro excellent.They are modified gradually, and the blood purification that especially possesses the hollow-fibre membrane that is fixed with liposoluble vitamin gets most of the attention, and described liposoluble vitamin alleviates the oxidative stress that long-term blood compatibility is impacted.

If describe as an example of haemodialysis example, for long-term dialysis patient, can be observed the symptoms such as dialysis amyloidosis (amyloidosis), arteriosclerotic disease, malignant tumour, anaemia, as one of its reason, can list the hyperfunction of oxidative stress.

Aforementioned oxidative stress refers to " oxidation reaction in organism is unbalance with anti-oxidant balance of reacting, the dominant state of oxidation reaction in organism ".

Known, for dialysis patient, by the Leukocytopoiesis free radical being activated with contacting of dialysis membrane by blood, by monocyte/macrophage induction inflammatory cytokine, the concentration of the vitamin E as one of antioxidants that still can cause in blood, exists in erythrocyte membrane reduces.That is, dialysis patient, in being subject to the state of strong oxidative stress, is pointed out: by suppressing this situation, improve patient's QOL(Quality of Life, quality of life), the possibility of prognosis is high.

About the method that alleviates the suffered oxidative stress of dialysis patient, various technology were proposed in the past.

As one of them, propose to use the dialyzing method of the hemodialysis membrane (haemodialyser) with oxidation resistance, report has multiple clinical examples.

As the main raw material(s) of aforementioned hemodialysis membrane, from reasons such as the versatility as resin, heat-resisting/radiation hardness characteristic, biocompatibles, polysulfones is that the synthetic macromolecule of the hydrophobicitys such as macromolecule becomes main flow in recent years.

On the other hand, because the hydrophobicity of the blood contacting surface of hemodialysis membrane is crossed when strong blood clotting can be occurred, conventionally use the hemodialysis membrane of having implemented surface modification by blend polymer, the hydrophilic macromolecule of itself and hydrophilic macromolecule (for example,, with reference to patent documentation 1 and 2.）。And then, propose to carry out by the inner surface to this hemodialysis membrane, film entirety the hydrophobic polymer film fixed lipid soluble vitamin that hydrophiling forms, thereby have the hollow-fibre membrane of high blood compatibility and non-oxidizability concurrently (for example,, with reference to patent documentation 3～5.）。

In recent years, blood purification therapy is promoted gradually in worldwide, not only use, and also bring into use gradually in various areas such as China, India, Russia, middle east, middle South American nations, Southeast Asia in the on-the-spot i.e. Japan of at present main use, American-European countries.This blood purification using in various countries is also varied as the controlled state of medicine equipment, only can ensure that be inadequate as common preservation form by the storage stability of 3 years under cognitive ambient temperature and moisture environment at present.For example there is following possibility: when the cargo container that accommodates blood purification bears direct sunlight in Container Yard, internal temperature rises to 60 DEG C and even higher, or, the Shipping navigating by water due to the long truck transport in the large area territories such as the U.S., in the torrid zone (equator) etc., thereby through being exposed to for a long time under hot environment more than normal temperature.

The hollow-fibre membrane that is fixed with liposoluble vitamin as described above is exposed to this harsh and unforgiving environments lower time, likely produce various characteristics deteriorated, especially antioxygenic property is deteriorated.

As the manufacture method of the hollow-fibre membrane that is fixed with liposoluble vitamin as described above, following the whole bag of tricks is proposed: in the time of the spinning of doughnut, in spinning solution, add liposoluble vitamin, the method that makes hollow-fibre membrane entirety contain liposoluble vitamin; In liquid in hollow, add liposoluble vitamin and surfactant, the method (for example,, with reference to patent documentation 2,6) that makes hollow-fibre membrane inner surface contain liposoluble vitamin; After assembling hollow fiber membrane-type blood purifier, the liposoluble vitamin solution of the solvent that comprises liposoluble vitamin and liposoluble vitamin is flow into the hollow bulb of hollow-fibre membrane, thereby make method (cladding process) that liposoluble vitamin is attached to the inner surface of hollow-fibre membrane (for example,, with reference to patent documentation 7.) etc.Wherein, aforementioned cladding process is excellent from the viewpoint of utilizing existing equipment, product line (product line-up) to realize to have various production diactinic, the hollow-fibre membrane that is fixed with liposoluble vitamin.

Prior art document

Patent documentation

Patent documentation 1: Japanese kokai publication hei 6-238139 communique

Patent documentation 2: No. 98/52683rd, International Publication

Patent documentation 3: Japanese kokai publication hei 9-66225 communique

Patent documentation 4: Japanese kokai publication hei 10-244000 communique

Patent documentation 5: Japanese kokai publication hei 11-347117 communique

Patent documentation 6: No. 4038583 description of Japanese Patent

Patent documentation 7: TOHKEMY 2006-296931 communique

Summary of the invention

the problem that invention will solve

But, in the manufacture method of the hollow-fibre membrane based on above-mentioned cladding process, there is following problem: reduce (for example diactinic reduction) and its performance to reduce the variation of ratio large to there is large performance in the process of matrix hollow-fibre membrane fixed lipid soluble vitamin.

Therefore, there are the following problems: to have uniform diactinic product in order obtaining, the multiple specifications in inspection operation need to be departed to product and get rid of yield (productivity ratio) step-down in industrial production as product loss.In order to suppress the aberrations in property of final products, it is effectively that the performance that suppresses to produce in the immobilization process of liposoluble vitamin reduces, but its means still belong to unknown.

Thereby, the present invention is in view of the problem points of above-mentioned prior art, its problem is, provides especially that the performance change that keeps oxidation resistance and caused by the immobilization of liposoluble vitamin under the harsh and unforgiving environments of High temperature storage etc. is few, the qualitative control of product when industrial production is easy to hollow-fibre membrane blood treatment for, possesses this blood treatment use blood purification of hollow-fibre membrane and manufacture method of this blood purification.

for the scheme of dealing with problems

The inventor etc. conduct in-depth research repeatedly in order to solve above-mentioned problem, found that: by the blood treatment that contains hydrophobic polymer, hydrophilic macromolecule and liposoluble vitamin hollow fiber type film, using polyether sulfone is that resin is as hydrophobic polymer, and further contain ketone and/or the alcohol of carbon number below 4, can solve above-mentioned problem, thereby complete the present invention.

, the present invention is as follows.

(1) a blood treatment hollow-fibre membrane, it comprises following A～D,

This blood treatment converts and contains 10mg/m with membrane area with the surface of hollow-fibre membrane ²above and 300mg/m ²the liposoluble vitamin of following scope,

Aforementioned blood treatment is more than the 50 quality % of liposoluble vitamin content of blood treatment hollow-fibre membrane entirety with the content of the liposoluble vitamin on hollow-fibre membrane surface,

A: polyether sulfone be resin,

B: hydrophilic macromolecule,

C: liposoluble vitamin,

D: ketone and/or the alcohol of carbon number below 4.

(2) according to the blood treatment hollow-fibre membrane aforementioned (1) Suo Shu, wherein, the aforementioned D comprising in hollow-fibre membrane for 1g blood treatment: the ketone of carbon number below 4 and/or the amount of alcohol are 2～3000 μ g.

(3) according to the blood treatment hollow-fibre membrane aforementioned (1) or (2) Suo Shu, wherein, being present in the gross mass that the quality of the hydrophilic macromolecule of the inner surface of aforementioned blood treatment hollow-fibre membrane is resin and aforementioned hydrophilic macromolecule with respect to aforementioned polyether sulfone is 25～34 quality %.

(4) according to the blood treatment hollow-fibre membrane described in any one in aforementioned (1)～(3), wherein, aforementioned liposoluble vitamin is vitamin E.

(5) blood purification, it possesses:

Blood treatment in aforementioned (1)～(4) described in any one with hollow-fibre membrane and

This blood treatment is contained in to inner cylindrical container with hollow-fibre membrane.

(6) manufacture method for blood purification, this blood purification comprises the blood treatment hollow-fibre membrane being made up of following A～D,

A: polyether sulfone be resin,

B: hydrophilic macromolecule,

C: liposoluble vitamin,

D: ketone and/or the alcohol of carbon number below 4,

The manufacture method of described blood purification possesses following operation:

The blood treatment that comprises aforementioned A, B is contained in to the operation of assembling blood purification in cylindrical container with hollow-fibre membrane;

Pass into and contain aforementioned C with the inner side of hollow-fibre membrane to aforementioned blood treatment: the organic solvent solution of liposoluble vitamin, thereafter, remove this organic solvent, by aforementioned C: the immobilized operation of liposoluble vitamin; And

Make aforementioned blood treatment hollow-fibre membrane contain aforementioned D: the ketone of carbon number below 4 and/or the operation of alcohol.

(7) blood purification, it is to manufacture by the manufacture method aforementioned (6) Suo Shu.

the effect of invention

According to the present invention, can obtain can keeping oxidation resistance and by the few blood treatment hollow-fibre membrane of the performance change that whether exists liposoluble vitamin to cause and possess the blood purification of this blood treatment hollow-fibre membrane under the harsh and unforgiving environments of High temperature storage etc.

Detailed description of the invention

Below, for being elaborated for implementing mode of the present invention (hereinafter referred to as " present embodiment ").The present invention is not limited to following record, can in the scope of its main idea, carry out various distortion and implement.

(blood treatment hollow-fibre membrane)

Hollow fiber type film for the blood treatment of present embodiment (following, sometimes referred to as hollow-fibre membrane.) comprise following A～D,

This blood treatment converts and contains 10mg/m with membrane area with the surface of hollow fiber type film ²above and 300mg/m ²the liposoluble vitamin of following scope,

Aforementioned blood treatment is more than the 50 quality % of liposoluble vitamin content of blood treatment hollow-fibre membrane entirety with the content of the liposoluble vitamin of doughnut plasma membrane surfaces,

A: polyether sulfone be resin,

B: hydrophilic macromolecule,

C: liposoluble vitamin,

D: ketone and/or the alcohol of carbon number below 4.

The blood treatment of present embodiment is the hollow-fibre membrane using in haemodialyser, blood filtration dialyzer, blood filter, continuous schedule blood filtration (dialysis) device, plasma separator, cascadeflow, ascites filter, ascites inspissator, artificial lung etc. with hollow-fibre membrane, has the aperture that is applicable to each purposes.

Consider oxidative stress that patient bears can because of external circulating therapy repeatedly, long-term accumulation, in high-frequency and the long-term haemodialysis of implementing or blood filtration dialysis, the blood purification that possesses the blood treatment hollow-fibre membrane of present embodiment is applicable to.

It should be noted that, the following description is all supposed as haemodialyser to record in the situation of the inner cavity circulation blood of hollow-fibre membrane, but present embodiment is not limited to following record, about the situation at the inner cavity circulation blood of hollow-fibre membrane not, in the situation of the outside of hollow-fibre membrane circulation blood, can backward read hollow-fibre membrane inside and outside.

(A: polyether sulfone is resin)

In the hollow-fibre membrane of present embodiment, as the hydrophobic polymer that is used to form this hollow-fibre membrane, using polyether sulfone is that resin (is designated as PES below, sometimes.）。

As PES, can list the polymer shown in following general formula (1).

As the PES shown in aforementioned formula (1), be not particularly limited, for example can list SUMIKA EXCEL PES (Sumitomo Chemical Co's system, ProductName), Ultrazone(BASF JAPAN LTD. system, ProductName) etc.These products are all extensively sold, and also easily obtain, therefore preferably.

In addition, about PES, from treatability, obtain and be easy to viewpoint, with 1(W/V) the DMF(dimethyl formamide of %) reduced viscosity that records of solution is preferably 0.30～0.60 scope, 0.36～0.50 scope more preferably.

It should be noted that, in above-mentioned formula (1), n is the degree of polymerization, can be for being worth arbitrarily.

In addition, A: polyether sulfone is that resin can also be that the polymer shown in mutual-through type (1) has been implemented the derivative of the chemical modifications such as substituting group and their mixture.

It should be noted that, all the time, as the hydrophobic polymer that is used to form hollow-fibre membrane, used the polysulfone resin shown in following general formula (2).

It should be noted that, in following formula (2), n is the degree of polymerization.

The inventor etc. surprisingly find: as the hydrophobic polymer that is used to form hollow-fibre membrane, polysulfone resin shown in the aforementioned formula (2) always using in the material that does not utilize vitamin E immobilization hollow-fibre membrane to use, and utilize the PES shown in aforementioned formula (1), thereby can improve the conservation rate of the oxidation resistance under harsh and unforgiving environments, and can suppress the performance in immobilized liposoluble vitamin operation to reduce.

About its technical reason, can infer: the high structure confining force that PES has is first cause.

In fact, the glass transition temperature of polyether sulfone (Tg) is 225 DEG C of left and right, for example, demonstrate than polysulfones (Tg; 190 DEG C) higher value, heat resistance is high.It can by pay close attention to high polymer main chain structure (conformation), have or not the alkyl that the free degree is high (polyether sulfone: without, polysulfones: have) to illustrate.That is, can think this be because, the filling of the macromolecular chain of polyether sulfone is tightr, interacts by force for resisting bonding between the strand of reduction of structure confining force, the reduction of described structure confining force is by causing from outside heat energy.

But, do not know all the time and suppress that the effect of the performance reduction in immobilized liposoluble vitamin operation is not only effective near Tg, also effective near room temperature, this is to find first in the present invention.

First, for suppressing, the effect of the performance change in immobilized liposoluble vitamin operation is carried out to following explanation near room temperature also effective the 1st reason.

Can think, the hollow-fibre membrane of present embodiment comprises PES and hydrophilic macromolecule described later and liposoluble vitamin described later, the liposoluble vitamin surface immobilized at hollow-fibre membrane not only rests on hollow-fibre membrane surface, its part also can enter in the base material of hollow-fibre membrane, plays a role as a kind of plasticizer.Its result, the structure confining force of hollow-fibre membrane reduces, and labile state is held in the surperficial hydrophilic macromolecule in hollow-fibre membrane, the distribution of liposoluble vitamin, likely affects through performance, antioxygenic property.Thereby, can infer: by the polyether sulfone high packed density of macromolecular chain is used as to base material, can suppress liposoluble vitamin and enter in hollow-fibre membrane.

Its result, can think: even the temperature province lower than Tg, in the time being exposed to extraneous factor, also can bring into play high structure confining force, can maintain controlling liposoluble vitamin distribution in pore morphology, the high molecular distribution of surface hydrophilicity and the hollow-fibre membrane that essence aperture exerts an influence of selecting permeability etc.Thus, can supposition can give play to the effect shown in above-mentioned.

Infer about the inventor etc., suppress the effect of the performance change in immobilized liposoluble vitamin operation near room temperature also effective the 2nd reason, can think by four-component described later to be the difference of the impact that is subject to of the ketone of carbon number below 4 and/or alcohol.Be described below in detail, can infer that this is because for PES, this four-component contributes to suppress the reduction of structure confining force, and for polysulfones is resin, cannot obtain this effect.

(B: hydrophilic macromolecule)

Hydrophilic macromolecule refers to water-soluble macromolecule, be not limited to below, for example, can list PVP (PVP), polyethylene glycol (PEG), polypropylene glycol (PPG), hydroxypropyl cellulose (HPC), starch, HES (HES), their copolymer, mixture etc.

Wherein, the hole shape of the hollow-fibre membrane of PVP and polyethylene glycol becomes second nature well, thereby preferably, from the stability of spinning, with aforementioned polyether sulfone be the viewpoint of the compatibility of resin, PVP is preferred.

There are multiple kinds according to the degree of polymerization in PVP.Be not limited to below, there is K-15,30, PVP that 90 equimolecular quantitys are different with the trade (brand) name of " Plasdone " in ISP company for example, all can use.

The hollow-fibre membrane of present embodiment comprises A: polyether sulfone is resin and B: hydrophilic macromolecule, but their form that exists is not particularly limited.For example, can be that the composition that compatibility is high carries out the form that polyblend forms each other; To comprising A: polyether sulfone is grafting B in the base material of hollow-fibre membrane of resin: the form that hydrophilic macromolecule forms.Or also can use polyether sulfone is the copolymerized macromolecule of resinous principle and hydrophilic macromolecule resinous principle.

(C: liposoluble vitamin)

Liposoluble vitamin refers to the vitamin that is conventionally insoluble in water and dissolve in alcohol, grease.As liposoluble vitamin, be not limited to below, for example can list vitamin A, vitamin D, vitamin E, vitamin K and ubiquinone etc.Among these, even the viewpoint of also not bringing out infringement from excess ingestion, vitamin E is applicable to.

As vitamin E, be not limited to below, for example can list alpha-tocopherol, alpha-tocopherol acetate, Tocopheryl Nicotinate, betatocopherol, Gamma-Tocopherol, Delta-Tocopherol etc.Wherein, alpha-tocopherol has the various physiological actions such as biological interior antioxidation action, organism film static stabilization, platelet aggregation inhibitory action, thereby preferably.

< is present in the liposoluble vitamin amount > on hollow-fibre membrane surface

Be present in the aforementioned C on the hollow-fibre membrane surface of present embodiment: the amount of liposoluble vitamin is scaled 10mg/m with the membrane area of hollow-fibre membrane ²above and 300mg/m ²following scope.

The membrane area of the mentioned hollow-fibre membrane of the present invention refers to the effective total surface area of reality with the relevant hollow-fibre membrane that filters, dialyses, and represents with the product of mean inside diameter, pi, radical and the effective length of hollow-fibre membrane.

The amount of the surperficial liposoluble vitamin of hollow-fibre membrane can utilize following methods to measure.

First, dismounting hollow fiber membrane-type blood purifier, takes hollow-fibre membrane, implements dry processing after washing.

Then, take such as 0.2m of dried hollow-fibre membrane ²and be placed in vial, and add the tertiary octyl phenyl ether aqueous solution of the 1 quality % polyethylene glycol 80mL as the aqueous solution of surfactant, at room temperature apply ultrasonic vibration with 60 minutes while carry out the extraction of liposoluble vitamin.

Quantitative work utilizes liquid chromatography to carry out, and uses the calibration curve being obtained by the peak area of liposoluble vitamin standard liquid, obtains the liposoluble vitamin concentration of extract.

[utilizing an example of the quantitative approach of liquid chromatography]:

In the upper chromatographic column (the HPLC ODP-506E packed column that Shodex Asahipak company manufactures) of installing of highly effective liquid phase chromatographic device (pump: Japanese light splitting PU-1580, detector: Shimadzu RID-6A, automatic sampler: Shimadzu SIL-6B, data processing: eastern Cao GPC-8020, column oven: GL Sciences556), at 40 DEG C of column temperature, the high performance liquid chromatography as mobile phase is led to liquid with methyl alcohol with for example flow of 1mL/ minute, obtain liposoluble vitamin concentration by the area of the absworption peak of ultraviolet portion.Extraction efficiency is made as to 100%, is obtained the weight (mg/m of the contained surperficial liposoluble vitamin of hollow-fibre membrane by this concentration ²).

Convert and contain 10mg/m with the membrane area of hollow-fibre membrane in the surface of the hollow-fibre membrane of present embodiment ²above and 300mg/m ²the liposoluble vitamin of following scope.Be preferably 50～250mg/m ², 100～200mg/m more preferably ².

The content of liposoluble vitamin is scaled 10mg/m with the area of hollow-fibre membrane ²when above, the covering inequality of liposoluble vitamin can be prevented, excellent oxidation resistance can be brought into play.In addition, be 300mg/m ²when following, the hole that can suppress in hollow-fibre membrane is stopped up by liposoluble vitamin, can guarantee practical good liquid permeability.

It should be noted that, due to hollow-fibre membrane is preserved for a long time under the harsh and unforgiving environments of high temperature etc., liposoluble vitamin can part inactivation.

Be present in the surperficial liposoluble vitamin amount of the hollow-fibre membrane of present embodiment, the amount of the liposoluble vitamin on hollow-fibre membrane surface refer to comprise because of under harsh and unforgiving environments, preserve inactivation the liposoluble vitamin amount on hollow-fibre membrane surface of part.

On the other hand, " oxidation resistance " described later is equivalent among the surperficial liposoluble vitamin amount of hollow-fibre membrane not because preserve the liposoluble vitamin amount of inactivation under harsh and unforgiving environments.

As the method for adding liposoluble vitamin to hollow-fibre membrane, can list: after the assembling of blood purification of having carried out the hollow-fibre membrane of film forming, hollow fiber membrane-type, the liposoluble vitamin solution of the solvent that comprises liposoluble vitamin and liposoluble vitamin is flow into the hollow bulb of hollow-fibre membrane, thereby make liposoluble vitamin be attached to the method for hollow-fibre membrane inner surface.

(D: ketone and/or the alcohol of carbon number below 4)

The hollow-fibre membrane of present embodiment comprises aforementioned A: polyether sulfone is resin, B: hydrophilic macromolecule, C: liposoluble vitamin, also contains D: ketone and/or the alcohol of carbon number below 4.

By containing D: ketone and/or the alcohol of carbon number below 4, the maintenance of the oxidation resistance under the harsh and unforgiving environments of High temperature storage etc. of the hollow-fibre membrane of present embodiment and by the few characteristic aspect of performance change that whether has liposoluble vitamin and cause, can obtain more practical effect.

As aforementioned D: ketone, the alcohol of carbon number below 4, be not limited to below, for example can list acetone, MEK, methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol, ethylene glycol, glycerine, butanols, preferably use acetone, ethanol, isopropyl alcohol.While using such as ether system, the oxolane etc. beyond above-mentioned, because polyether sulfone can be swelling or dissolving and structure changes, therefore likely significantly reduction of performance.

All the time, in the operation of interpolation liposoluble vitamin, the performance that likely produces hollow-fibre membrane reduces, and is because the substrate resin compatibility of liposoluble vitamin and hollow-fibre membrane is low but still have a compatibility, the structure confining force reduction of substrate resin although this performance reduces.

Substrate resin and the liposoluble vitamin of supposing hollow-fibre membrane do not have compatibility completely, and liposoluble vitamin only adheres to the form of oil reservoir on the surface of film base material, is in resin and can not enter film base material polyether sulfone.

The inventor etc. by adding ketone and/or the alcohol of carbon number below 4 in liposoluble vitamin, successfully reduce the compatibility that liposoluble vitamin and polyether sulfone are resin, thereby having suppressed the base material that liposoluble vitamin enters hollow-fibre membrane is polyether sulfone is resin, its result, has suppressed the reduction of structure confining force.

On the other hand, the similar polysulfones of structure is owing to having alkyl at main chain, and therefore the compatibility of the ketone below 4 and/or alcohol is resin higher than polyether sulfone with carbon number, and its result cannot obtain the effect that compatibility reduces.

About making hollow-fibre membrane contain the ketone of carbon number below 4 and/or the method for alcohol, refer to aftermentioned.

The ketone of the contained carbon number of hollow-fibre membrane below 4 and/or the amount of alcohol are not particularly limited, and with respect to every 1g hollow-fibre membrane, are preferably 2～3000 μ g, more preferably 10～2000 μ g, 25～1500 μ g more preferably.

More than being made as 2 μ g, can reduce fully compatibility that liposoluble vitamin and polyether sulfone are resin, can guarantee hollow-fibre membrane structure confining force, can prevent the reduction of antioxygenic property.In addition, by being made as below 3000 μ g, peeling off of liposoluble vitamin can be prevented in the time of clinical use etc., reduction, the performance change of antioxygenic property can be prevented.

The ketone of the contained carbon number of hollow-fibre membrane below 4 and/or alcohol (D composition), can measure by the following method with respect to the content of every 1g hollow-fibre membrane.

[situation of the water blood purification of having filled]

Retrieve to reclaim by air blowing after the filling liquid in the blood purification of hollow fiber membrane-type, gained filling liquid is mixed, utilize gas-chromatography (GC) to calculate the ketone of carbon number below 4 and/or the concentration x(% of alcohol).

Thereafter, dismounting blood purification, takes out for example bundle of 2 hollow-fibre membranes, first measures the quality of the bundle of a hollow-fibre membrane.This quality is denoted as to (W ₁g)., add METHYLPYRROLIDONE, after stirring and dissolving, utilize gas-chromatography (GC) to calculate the ketone of carbon number below 4 and/or the concentration y(% of alcohol) thereafter.

In addition, measure the quality of the bundle of another hollow-fibre membrane taking out.This quality is denoted as to (W ₂g).Make it in vacuum drier, be dried to constant weight, measure dried quality.This quality is denoted as to (W ₃g).

Calculate and remove the contained ketone of carbon number below 4 and/or the quality D of alcohol in moisture hollow-fibre membrane afterwards _hg.

Calculate ketone and/or the alcohol amount (D of the carbon number in the hollow-fibre membrane that contains below 4 in the moisture after filling liquid reclaims by following formula (3)～(5) _tg) ketone and/or the alcohol amount (D of the carbon number, containing in the contained moisture of hollow-fibre membrane below 4 _wg) ketone and/or the alcohol amount (D of the carbon number that, the hollow-fibre membrane after removal moisture contains below 4 _hg).

D _T=W ₁×y/100···(3)

D _W＝x×W ₁×（W ₂-W ₃）/W ₃···（4）

D _H=D _T-D _W···(5)

By by aforementioned such D calculating that operates _hdivided by W ₂, calculate the ketone of carbon number below 4 and/or the amount of alcohol with respect to every 1g hollow-fibre membrane.

[situation of dry type blood purification]

Carry out the dismounting of hollow fiber membrane-type blood purifier, being dried in the drier of drier using calcium chloride etc., until reach constant weight.,, hollow fiber membrane bundle is taken out thereafter.Its quality of precision weighing (W ₄g) after, add METHYLPYRROLIDONE, after stirring and dissolving, utilize said method to calculate the ketone of carbon number below 4 and/or the concentration z(% of alcohol (D composition)).

Then, by W ₄calculate the quality with respect to the D composition of every 1g hollow-fibre membrane with z.

(being present in the ratio of the hydrophilic macromolecule of the inner surface of hollow-fibre membrane)

In the hollow-fibre membrane of present embodiment, the ratio that the hydrophilic macromolecule that is present in the inner surface of this hollow-fibre membrane is the gross mass of resin (PES) with respect to hydrophilic macromolecule and polyether sulfone (is abbreviated as " hydrophilic macromolecule exist rate " below sometimes.) be preferably that 25 quality % are above and 34 quality % following, more preferably 25～32 quality %, 25～30 quality % more preferably.

Herein, " hydrophilic macromolecule that is present in the inner surface of hollow-fibre membrane is the ratio of the gross mass of resin (PES) with respect to hydrophilic macromolecule and polyether sulfone " refers to, the outermost layer portion quality (surface that, hollow-fibre membrane contacts with blood), hydrophilic macromolecule of the inner side of hollow-fibre membrane is with respect to the ratio of the gross mass of PES and hydrophilic macromolecule.

The hydrophilic macromolecule that is present in the inner surface of aforementioned hollow-fibre membrane for example can utilize x-ray photoelectron spectroscopy (X-ray photoelectron spectrosopy:XPS) to measure with respect to the ratio of the gross mass of hydrophilic macromolecule and PES.; can measure with XPS the inner surface of hollow-fibre membrane; by PES and hydrophilic macromolecule separately the peak intensity of peculiar atom obtain the ratio of the quantity of each atom on this surface, calculated the rate that exists of above-mentioned hydrophilic macromolecule by the quality ratio of two compounds that obtain accordingly.

Particularly, while using PVP as hydrophilic macromolecule, can be obtained by the nitrogen-atoms number (being derived from PVP) of the inner surface of hollow-fibre membrane and number of sulfur atoms (being derived from PES).

For example, in the time that PES is made up of repetitive shown in above-mentioned general formula (1), there is rate in the rate A(PVP that exists that can obtain the PVP of the inner surface of hollow-fibre membrane by following formula (6)).

Herein, in following formula (6), the formula weight of 111 repetitives that are PVP, the formula weight of 232 repetitives that are PES.

As mentioned above, hydrophilic macromolecule to exist rate to be preferably 25 quality % above and below 34 quality %.

The rate that exists of hydrophilic macromolecule is that 25 quality % are when above, can guarantee sufficient blood compatibility, having rate is that 34 quality % are when following, can prevent from the time of High temperature storage etc., with respect to the reduction of the structure confining force of the hollow-fibre membrane of external factor, can keeping practical sufficient oxidation resistance, suppressing active reduction.

(being present in the ratio of the surperficial liposoluble vitamin of hollow-fibre membrane)

In the hollow-fibre membrane of present embodiment, the content that is present in the surperficial liposoluble vitamin of hollow-fibre membrane be the liposoluble vitamin of hollow-fibre membrane entirety the more than 50% of content, be preferably more than 55%, more preferably more than 70%.

As the assay method of the liposoluble vitamin content of hollow-fibre membrane entirety, first dismantle hollow fiber membrane-type blood purifier, take hollow-fibre membrane, after washing, implement dry processing.Then, in dried hollow-fibre membrane, add METHYLPYRROLIDONE, stir and dissolve.Quantitative work utilizes liquid chromatography to carry out, and uses the calibration curve being obtained by the peak area of liposoluble vitamin standard liquid, calculates the liposoluble vitamin amount in lysate.

As the assay method of liposoluble vitamin content that is present in hollow-fibre membrane surface, first, the blood purification of dismounting hollow fiber membrane-type, takes hollow-fibre membrane, implements dry processing after washing.Then, take such as 0.2m of dried hollow-fibre membrane ²and be placed in vial, and add the tertiary octyl phenyl ether aqueous solution of the 1 quality % polyethylene glycol 80mL as the aqueous solution of surfactant, at room temperature apply ultrasonic vibration with 60 minutes while carry out the extraction of liposoluble vitamin.Quantitative work for example utilizes following liquid chromatography to carry out, and uses the calibration curve being obtained by the peak area of liposoluble vitamin standard liquid, thereby can obtain concentration and the content of the liposoluble vitamin in extract.

[utilizing an example of the quantitative approach of liquid chromatography]:

In the upper chromatographic column (the HPLC ODP-506E packed column that Shodex Asahipak company manufactures) of installing of highly effective liquid phase chromatographic device (pump: Japanese light splitting PU-1580, detector: Shimadzu RID-6A, automatic sampler: Shimadzu SIL-6B, data processing: eastern Cao GPC-8020, column oven: GL Sciences556), at 40 DEG C of column temperature, the high performance liquid chromatography as mobile phase is led to liquid with methyl alcohol with for example flow of 1mL/ minute, obtain liposoluble vitamin concentration by the area of the absworption peak of ultraviolet portion.Extraction efficiency is made as to 100%, can be obtained the quality (mg/m of the contained liposoluble vitamin in the surface of hollow-fibre membrane by this concentration ²).

The ratio that is present in the liposoluble vitamin on hollow-fibre membrane surface can utilize following formula (7) to calculate.

Be the more than 50% of liposoluble vitamin that is present in hollow-fibre membrane entirety by making the ratio of the surperficial liposoluble vitamin that is present in hollow-fibre membrane, the oxidation resistance especially can keep High temperature storage time.

In the time of High temperature storage etc. under harsh and unforgiving environments, hydrophilic macromolecule is oxidized and easy free radical.Occurred free radical at the contained a large amount of hydrophilic macromolecules of doughnut film base material, in order to eliminate free radical, liposoluble vitamin has been given play to oxidation resistance, its result, and liposoluble vitamin is oxidized in a large number.Thereby, can infer: intensively there is liposoluble vitamin by the inner surface that makes hollow-fibre membrane, can guarantee a large amount of liposoluble vitamins not reacting with oxidized hydrophilic macromolecule, its result, oxidation resistance is kept.

(manufacture method of hollow-fibre membrane)

The hollow-fibre membrane of present embodiment can utilize known dry-and wet-type film technique to manufacture.

First, PES and hydrophilic macromolecule are dissolved in common solvent, prepare spinning solution.

As common solvent, be not limited to below, for example can list dimethylacetylamide (hereinafter referred to as DMAC.), dimethyl sulfoxide (DMSO), METHYLPYRROLIDONE, dimethyl formamide, sulfolane, diox equal solvent; Or by two or more solvent forming of above-mentioned solvent etc.

It should be noted that, in order to control the aperture of target hollow-fibre membrane, can in spinning solution, add the additives such as water.

PES concentration in spinning solution if can film forming and gained film have as seeing through in the concentration range of performance of film and be just not particularly limited, be preferably 5～35 quality %, 10～30 quality % more preferably.In order to reach high water permeability, PES concentration is preferably low, more preferably 10～25 quality %.

Concentration about the hydrophilic macromolecule in spinning solution with respect to PES, according to hydrophilic macromolecule with respect to the blending ratio of PES100 quality % be preferably 27 quality % following, more preferably 18～27 quality %, more preferably the mode of 20～27 quality % is adjusted.

When hydrophilic macromolecule exceedes 27 quality % with respect to the blending ratio of PES, the tendency that exists the stripping quantity of hydrophilic macromolecule to increase, in addition when less than 18 quality %, the reason of the leukopenia shape that likely can become that the hydrophilic macromolecule concentration that causes hollow-fibre membrane surface reduces, leucocyte concentration in patient's blood sharply reduces, therefore not preferred.

In the mill in the operation of hollow fiber film, in using mouthful, have the spinning head of pipe (tube-in-orifice) type, from the aperture of spinning head by spinning solution with for liquid in hollow that this spinning solution solidifies is ejected into from pipe simultaneously in the air.

As liquid in hollow, can make water or the solidification liquid taking water as main body, determine that according to the through performance of target hollow-fibre membrane its composition waits.Conventionally the solvent, using in suitable use spinning solution and the mixed solution of water.For example, can use the DMAC aqueous solution etc. of 0～65 quality %.And then, in hollow, in liquid, add the hydrophilic macromolecule of 0～2 quality %, also can adjust the amount of the hydrophilic macromolecule of hollow-fibre membrane inner surface.

Make the spinning solution spraying together with liquid in hollow from spinning head through free travel section, import to being arranged in the coagulating bath taking water as main body of spinning head bottom, flood and complete and solidify, process matting etc., the hollow-fibre membrane of moisture state is batched with coiling machine, obtain hollow fiber membrane bundle, be then dried processing.Or, after above-mentioned matting, in drying machine, be dried, also can obtain hollow fiber bundle.

By above-mentioned method, making the quality of the hydrophilic macromolecule of the inner surface that is present in hollow-fibre membrane is more than 25 quality % and below 34 quality % with respect to the gross mass of aforementioned PES and hydrophilic macromolecule, can obtain the also slight hollow-fibre membrane that adheres to face such as antithrombotic, biocompatible excellence and albumen, blood platelet.

(manufacture method of the blood purification of hollow fiber membrane-type)

As the preferable production process of the blood purification of the hollow fiber membrane-type of present embodiment, for example, can list following methods: first, manufacture as described above hollow-fibre membrane, use this hollow-fibre membrane to manufacture assembly.

Particularly, above-mentioned hollow fiber membrane bundle is inserted into and is had in the cylindrical container of gateway that processed liquid is prescribed fluid, thereby inject the embedding agents such as polyurethane at fibre bundle two ends and form embedding layer by sealed at both ends, then, unnecessary embedding agent after solidifying is cut, make end face opening, the head of the gateway with fluid is installed.

Then, as described later by liposoluble vitamin immobilization, and then implement as described later sterilization treatment.The immobilization of liposoluble vitamin can independently be carried out as described later, also can carry out with the film forming of hollow-fibre membrane simultaneously.And then stage being fixed of hollow-fibre membrane that can also be before carrying out modularization.

< is to the immobilization operation > of hollow-fibre membrane fixed lipid soluble vitamin (C composition)

Operation to hollow-fibre membrane fixed lipid soluble vitamin can be used known method substantially.Wherein, cladding process from the viewpoint of can utilize existing equipment, product line to realize to have various diactinic liposoluble vitamin fixed films production be excellent.

As the process for fixation to hollow-fibre membrane fixed lipid soluble vitamin, particularly, can utilize following method to implement: when the film forming of hollow-fibre membrane, in film forming stoste, to add liposoluble vitamin, the method that makes hollow-fibre membrane entirety contain liposoluble vitamin; In hollow, in liquid, add liposoluble vitamin and surfactant, the method (for example, No. 4038583rd, Japanese Patent and patent documentation 2) that makes the inner surface of hollow-fibre membrane contain liposoluble vitamin; After the assembling of hollow fiber membrane-type blood purifier, the liposoluble vitamin solution of the solvent that comprises liposoluble vitamin, liposoluble vitamin is flow into the hollow bulb of hollow-fibre membrane, thereby make liposoluble vitamin be attached to the various methods such as the method (such as TOHKEMY 2006-296931 communique) of the inner surface of hollow-fibre membrane, also can use any means that comprises other method.

In the hollow-fibre membrane of present embodiment, the content of liposoluble vitamin is with respect to every 1m ²hollow-fibre membrane is 10mg～300mg, as the method for controlling as this scope, can list following methods.

Particularly, add liposoluble vitamin in the film forming stoste of hollow-fibre membrane time, can list as preferred method: be adjusted into 0.4 quality %～2 quality %, be preferably adjusted into the method for 0.8 quality %～1.5 quality % adding concentration.

Add concentration and be 0.4 quality % when above, can guarantee fully the surface amount of exposing of liposoluble vitamin, can obtain good oxidation resistance.On the other hand, by being below 2 quality %, doughnut film strength can be guaranteed fully in practical, the damaged risk of hollow-fibre membrane can be prevented.

And then by the hollow-fibre membrane of formation under drying regime with 100 DEG C～180 DEG C, preferably the scope of 110～180 DEG C applies heat treatment, thereby, even in the identical hollow-fibre membrane of the content of liposoluble vitamin, also can make more liposoluble vitamin intensively be distributed in surface.

Be more than 100 DEG C by making heating-up temperature, can bring into play the concentrated distribution effect of liposoluble vitamin, on the other hand, by being below 180 DEG C, can prevent softening, the diactinic variation of hollow-fibre membrane.

In addition, while interpolation in liquid, preferably, the concentration of liposoluble vitamin at 0.01～10 quality %, preferably adjust in the scope of 0.1～5 quality %, and is added to surfactant with the amount of 1/10～2 times of liposoluble vitamin in hollow.

Can list following method: while being coated with liposoluble vitamin solution to the blood purification of the hollow fiber membrane-type assembling, the coating fluid circulation stipulated time of 0.1～2.0 quality % liposoluble vitamin will be dissolved with in the alcohol solutions such as the propyl alcohol of 50～80 quality %, for example make liquid adapt to 30 seconds～60 minutes, preferably 1～10 minute, then utilize air purge that unnecessary coating fluid is blown away, then by the dry solvent of removing.

The immobilization operation > of the < ketone below 4 and/or alcohol (D composition) to hollow-fibre membrane fixed carbon atomicity

Can use following methods to make hollow-fibre membrane contain ketone and/or the alcohol of carbon number below 4.

For example can list following method: the blood purification of assembling hollow fiber membrane-type, make after the logical liquid of liposoluble vitamin solution, make under the steam atmosphere of its ketone below 4 and/or alcohol at carbon number dry.Particularly, by using carbon number the ketone below 4 and/or alcohol as apply solvent, consider drying condition, also can keep the ketone of carbon number below 4 and/or the steam atmosphere of alcohol.What make artificially to import is dry while containing the ketone of carbon number below 4 and/or alcohol with gas, can carry out to zero deflection the fixing of the ketone of carbon number below 4 and/or alcohol, thereby preferred.

The humidification operation > of < hollow-fibre membrane

Hollow fiber membrane-type blood purifier of the present invention can be with aqueous solution by hollow-fibre membrane humidification before sterilizing.By carrying out moistening hollow-fibre membrane with aqueous solution, it is stable that hollow-fibre membrane becomes, and causes that the situation of the performance change such as water permeability, dialysis performance, strainability tails off.Have by the method for water system solution wetted hollow-fibre membrane: to being filled with the method for filling aqueous solution in the container of hollow fiber membrane bundle; After filling aqueous solution in container, discharge method of liquid etc.

< sterilization treatment operation >

Preferably the blood purification of above-mentioned hollow fiber membrane-type is implemented to sterilization treatment.

Sterilizing methods can be any means such as radiation sterilization, steam sterilization.

The hollow-fibre membrane that comprises in a large number liposoluble vitamin can produce the risk that causes doughnut breakage because of heating extremely, therefore radiation sterilization more preferably.

In radiation sterilization, can use electron beam, gamma-rays, X ray etc., all can use.

The dose of radiation of radiation is generally 5～50kGy in the situation that of gamma-rays, electron beam, preferably in the dosage range of 20～40kGy, carries out radiation.

(stability of the antioxygenic property of the blood purification of hollow fiber membrane-type under harsh and unforgiving environments)

The oxidation resistance of the blood purification of the now commercially available hollow fiber membrane-type that is fixed with liposoluble vitamin is not observed variation (reduction) under 3 years preservation degree of ambient temperature and moisture.But, be that under harsh and unforgiving environments, oxidative deformation advances in problem of the present invention, its result, the oxidation resistance of the blood purification of hollow fiber membrane-type reduces.

About the evaluation of the ageing stability of the oxidation resistance of the preservation based under harsh and unforgiving environments, the oxidation resistance that for example can measure afterwards assembly for 6 days by heat treated under the environment at 60 DEG C is evaluated.While utilizing the method to evaluate, the oxidation resistance that known conduct is fixed with the preproduction of the blood purification of the existing type hollow fiber membrane-type of liposoluble vitamin reduces.If oxidation resistance significantly reduces, the clinical effectiveness of being brought into play by oxidation resistance also reduces, and it is important therefore suppressing oxidation resistance reduction.

The inventor etc. conduct in-depth research repeatedly, result is surprisingly found: make to the liposoluble vitamin of the fixing specified quantitative of the hollow-fibre membrane that comprises PES and hydrophilic macromolecule so that contain the ketone of carbon number below 4 and/or alcohol formation time, the stability of the oxidation resistance under harsh and unforgiving environments significantly improves.

As mentioned above, the amount of the ketone of the carbon number in the hollow-fibre membrane of present embodiment below 4 and/or alcohol is preferably 2～3000 μ g, 10～2000 μ g more preferably with respect to every 1g hollow-fibre membrane.Ketone and/or the alcohol of carbon number below 4 has protection liposoluble vitamin, makes its effect that maintains oxidation resistance is still to belong to unknown.In addition, as hollow-fibre membrane raw material, by using PES, can obtain above-mentioned effect, therefore can think that PES and carbon number ketone and/or the alcohol below 4 may have interaction, cooperative effect.In any case, in embodiment, illustrate like that as described later, its effect is obvious.

Embodiment

Below, further describe the present invention by embodiment, the present invention is not limited to following embodiment.

First, describe for the various assay methods that use in embodiment.

The content > of the liposoluble vitamin of < hollow-fibre membrane entirety

The blood purification of dismounting hollow fiber membrane-type, takes hollow-fibre membrane, implements dry processing after washing.

Then, in dried hollow-fibre membrane 0.5g, add METHYLPYRROLIDONE 50mL, stir and dissolve.

Quantitative work is undertaken by liquid chromatography, uses the calibration curve being obtained by the peak area of liposoluble vitamin standard liquid, obtains the liposoluble vitamin amount of extract.

, at highly effective liquid phase chromatographic device (the UV-2075plus intelligent UV/VIS detector that JASCO company manufactures, PU-2080plus intelligent HPLC pump, CO-2065plus intelligent column oven, AS-2057plus intelligent injector) upper chromatographic column (Inertsil C8-3 μ m(4.6 φ × 250mm)+ODP-506E(4.6 φ × 250mm that installs)), at 40 DEG C of column temperature, the METHYLPYRROLIDONE as mobile phase is led to liquid with the flow of 0.5mL/ minute, utilize UV detector to obtain liposoluble vitamin concentration by the area of the absworption peak of wavelength 295nm.Obtain by this concentration and the quality of the hollow-fibre membrane dissolving the liposoluble vitamin concentration containing in hollow-fibre membrane entirety.

< is present in the content > of the surperficial liposoluble vitamin of hollow-fibre membrane

The amount of the surperficial liposoluble vitamin that is present in hollow-fibre membrane is measured in following operation.

The blood purification of dismounting hollow fiber membrane-type, takes hollow-fibre membrane, carries out vacuum drying after washing at 40 DEG C.

Take dried hollow-fibre membrane 0.2m ²and be placed in vial, add the TritonX-100(KISHIDA CHEMICAL Co. of 1 quality %, Ltd., chemistry with) aqueous solution 80mL, at room temperature applied ultrasonic vibration with 60 minutes while carry out the extraction of liposoluble vitamin.

; in the upper chromatographic column (the HPLC ODP-506E packed column that Shodex Asahipak company manufactures) of installing of highly effective liquid phase chromatographic device (pump: Japanese light splitting PU-1580, detector: Shimadzu RID-6A, automatic sampler: Shimadzu SIL-6B, data processing: eastern Cao GPC-8020, column oven: GL Sciences556); at 40 DEG C of column temperature, the high performance liquid chromatography as mobile phase is circulated with the flow of 1mL/ minute with methyl alcohol, obtain liposoluble vitamin concentration by the area of the absworption peak of ultraviolet portion.

Extraction efficiency is made as to 100%, is obtained the weight (mg/m of the surperficial liposoluble vitamin that is present in hollow-fibre membrane by this concentration ²).

The quality that is present in the surperficial liposoluble vitamin of hollow-fibre membrane refers to the quality of the liposoluble vitamin going out from the surface extraction of hollow-fibre membrane.

It should be noted that, due to sterilization treatment partial oxidation liposoluble vitamin be also contained in the surperficial liposoluble vitamin amount that is present in hollow-fibre membrane within.Therefore, for the oxidized liposoluble vitamin amount of determining section, in advance the liposoluble vitamin for production standard curve is applied the radiation of 50kGy at air, pre-determine partial oxidation the absworption peak of liposoluble vitamin, be included in the peak group for reference area, carried out accumulation calculating.

By the quality (mg/m of liposoluble vitamin contained in the surface of hollow-fibre membrane ²) be shown in following table 1.

It should be noted that, in table 1, by the quality status stamp of the liposoluble vitamin contained surface of hollow-fibre membrane be " VE content ".

The content of the surperficial liposoluble vitamin of < hollow-fibre membrane is with respect to the ratio > of the content of the liposoluble vitamin of hollow-fibre membrane entirety

According to as above operating the content of liposoluble vitamin that record, hollow-fibre membrane entirety and being present in the content of the liposoluble vitamin on hollow-fibre membrane surface, obtain the content of surperficial liposoluble vitamin of hollow-fibre membrane with respect to the ratio of the content of the liposoluble vitamin of hollow-fibre membrane entirety.

It should be noted that, in table 1, be labeled as " inner surface VE measures (%) ".

< is present in the ratio > of the hydrophilic macromolecule of the inner surface of hollow-fibre membrane

The ratio that is present in the hydrophilic macromolecule of the inner surface of hollow-fibre membrane refers to that the hydrophilic macromolecule (quality) of the inner surface that is present in hollow-fibre membrane is the ratio of resin and hydrophilic macromolecule sum (quality) with respect to polyether sulfone.

In following table 1, be labeled as " inner surface PVP measures (%) ".

First, dismounting hollow fiber type blood processor, takes out hollow-fibre membrane.

The bundle that hollow-fibre membrane is bundled into 50 × 20cm left and right with line floods an evening in the bucket of filling distilled water.

It should be noted that, the distilled water in bucket will supplement fresh distilled water often, makes its spill-over.

Take out hollow fiber membrane bundle, cut into 5cm, the refrigerator of putting into-40 DEG C freezes it.Now, in 0.3～0.4torr(holder) carry out night freeze drying under the vacuum of left and right.

Dried hollow-fibre membrane is cut along its length, expose inner surface, on two-sided tape, arrange several, as sample.

The following operation of ratio that is present in the hydrophilic macromolecule of the inner surface of hollow-fibre membrane is obtained.

The mensuration of hydrophilic macromolecule is used the sub-light-dividing device of X-ray photoelectric (Thermo Fisher Scientific K.K. manufactures, ESCALAB250) to carry out under following condition.

Condition determination

Excitaton source: mono.AlK α 15kV × 10mA

Analyzed area

Full spectrum scanning (Survey scan): 0～1,100eV

Narrow domain scanning (Narrow scan): C1s, O1s, N1s, S2p

Logical energy (Pass Energy): 100eV

Obtain concentration of element by the areal intensity of the Narrow Scan spectrum obtaining, database (library) relative sensitivity coefficient of operative installations, quantitatively calculate.Use relative sensitivity coefficient be, C1s:0.296, O1s:0.711, S2p:0.666, N1s:0.477.

For being that resin has used the polyether sulfone shown in above-mentioned formula (1), used the computational methods of the ratio of the PVP of the inner surface that is present in hollow-fibre membrane of the hollow-fibre membrane of PVP as hydrophilic macromolecule as polyether sulfone, carry out following explanation.

The S2p being obtained by mensuration is derived from polyether sulfone, and N1s is derived from PVP.

The formula weight of the repetitive of polyether sulfone is 232, and the formula weight of the repetitive of PVP is 111.

The concentration of element of S2p is designated as to S, when the concentration of element of N1s is designated as to N, obtains the ratio of the PVP of the inner surface that is present in hollow-fibre membrane by following formula (8).

Iron reducing activity conservation rate > under 60 DEG C of heating of <

The effect of reduction when preventing from preserving under harsh and unforgiving environments, oxidation resistance, evaluates with following methods.

The blood purification of the hollow fiber membrane-type after completing for firm manufacture and the oxidation resistance separately of blood purification of having preserved the hollow fiber membrane-type of 6 days in the thermostat of 60 DEG C, measure by following method.

In addition, use the value of the oxidation resistance of measuring, utilize following formula (9), calculate 60 DEG C of iron reducing activity conservation rates under heating.

First, ferric chloride hexahydrate is dissolved in to pure water, preparation 0.3w/v% (amount (g) of the solute in the solution 100mL) aqueous solution.

The blood purification of dismounting hollow fiber membrane-type, takes hollow-fibre membrane, after washing, and vacuum drying at 40 DEG C.

Take the dried hollow-fibre membrane of 1g and 20mL ferric chloride aqueous solutions and be placed in vial, under 60mmHg, deaeration is after 10 minutes, under vibration, hatched and (be present in the liposoluble vitamin on hollow-fibre membrane surface by the reduction of iron (III) ion, generate iron (II) with 30 DEG C × 4 hours.）。

2 of the 0.5w/v% of the aqueous solution after 2.6mL is hatched, 0.7mL ethanol, preparation in addition, 2 '-bipyridyl ethanol water 0.7mL mixes, under vibration within 30 DEG C × 30 minutes, to hatch (iron (II) forms complex compound with bipyridyl, colour developing).

Use spectrometer to measure the absorbance of the liquid having developed the color under the 520nm.

The liposoluble vitamin ethanolic solution that working concentration is known replaces hollow-fibre membrane, carry out same hatching, the mensuration of chromogenic reaction, absorbance, production standard curve, with the form of the quality equivalence value of liposoluble vitamin obtain the oxidation resistance that 1g hollow-fibre membrane shown (by after decimal point first round up).

< is at the water permeability reduced rate > that contains liposoluble vitamin front and back

Measure liposoluble vitamin is fixed on to hollow-fibre membrane before and water permeability afterwards, blood purification, evaluate the reduced rate of the water permeability before and after fixing.

Measure the permeable amount of the blood purification of hollow fiber membrane-type by following method.

Under certain pressure (200mmHg), temperature (37 DEG C) condition, will in blood purification, all filter with pure water, measure and filter the required time.

According to the above results, calculate water permeability (UFR(mL/mmHg/hr/m ²)).

Utilize said method to measure respectively the water permeability of the blood purification of the hollow fiber membrane-type of liposoluble vitamin immobilization front and back, utilize following formula (10) to calculate performance reduced rate.

Whether < there is the comparison > of the aberrations in property that liposoluble vitamin brings

The deviation of the water permeability of measuring in the project of comparison of aforementioned < performance measurement > before and after the immobilization of liposoluble vitamin.

Particularly, calculate standard deviation by measured value, calculate σ (after liposoluble vitamin immobilization)/σ (before liposoluble vitamin immobilization) based on this.

It should be noted that, in table 1, be labeled as " σ (having VE)/σ (without VE) ".

The assay > of the ketone of < carbon number below 4 and/or alcohol, diethyl ether, oxolane

Utilize following method measure in the blood purification of hollow fiber membrane-type, the ketone of carbon number below 4 and/or alcohol (being designated as below D composition), diethyl ether, oxolane, with respect to the content of every 1g hollow-fibre membrane.

[situation of the water blood purification of having filled]

First, reclaim the recovery of the filling liquid in the blood purification that carries out hollow fiber membrane-type by air blowing.

Reclaim about blowing, use the pipe pump (pump line internal diameter 8mm) that speed setting is 20rpm, import the air of 5 minutes from artery side ports to quiet Veins side ports, filling liquid is reclaimed.

, from artery side ports to dislysate downside port import the air of 5 minute, filling liquid is reclaimed thereafter.

Gained filling liquid is mixed, by gas-chromatography (GC) carry out D composition, diethyl ether, oxolane quantitatively.

Use the calibration curve that obtained by the peak area of this D composition, diethyl ether, oxolane, obtain the concentration x(% of the D composition that reclaims in liquid, diethyl ether, oxolane).

Particularly, gas-chromatography (GC-2014/GC14B processed of Shimadzu Seisakusho Ltd.) is connected with automatic sampler (AOC-20i/AOC-17), is calculated by the absworption peak that utilizes fid detector (hydrogen flame ionization type detector) to obtain.

, carry out the dismounting of hollow fiber type blood purification, take out the bundle of the hollow-fibre membrane of 2 about 0.25g, first measure the quality of the bundle of a hollow-fibre membrane thereafter.This quality is denoted as to (W ₁g).

, add METHYLPYRROLIDONE, after stirring and dissolving, utilize gas-chromatography (GC) to calculate the concentration y(% of the ketone of carbon number below 4 and/or alcohol, diethyl ether, oxolane) thereafter.

Calculate ketone and/or the alcohol amount (D of the carbon number in the hollow-fibre membrane that contains below 4 in the moisture after filling liquid reclaims by following formula (11)～(13) _tg) ketone and/or the alcohol amount (D of the carbon number, containing in the contained moisture of hollow-fibre membrane below 4 _wg) ketone and/or the alcohol amount (D of the carbon number that, the hollow-fibre membrane after removal moisture contains below 4 _hg).

DT=W1×y/100··.(II)

D _W＝x×W ₁×（W ₂-W ₃）/W ₃···（12）

DH=D _T-D _w···(13)

Calculate D by aforementioned such operation _hdivided by W ₂, calculate the amount of ketone below 4 of carbon number with respect to every 1g hollow-fibre membrane and/or alcohol, diethyl ether, oxolane.

[situation of dry type blood purification]

Carry out the dismounting of hollow fiber membrane-type blood purifier, being dried in the drier of drier using calcium chloride etc., until reach constant weight, take out the hollow fiber membrane bundle of about 0.25g.Precision weighing quality (W ₄g) after, add METHYLPYRROLIDONE 50mL, after stirring and dissolving, utilize said method to calculate the concentration z(% of D composition, diethyl ether and oxolane).

By W ₄calculate the amount with respect to D composition, diethyl ether and the oxolane of every 1g hollow-fibre membrane with z.

(embodiment 1)

To comprise polyether sulfone (PES) (4800P processed of Sumitomo Chemical Co) 17.5 quality %, as PVP (PVP) (BASF JAPAN LTD. K90 processed) the 3.5 quality % of hydrophilizing agent, as the water 1.0 quality % of non-solvent, triethylene glycol (TEG) (Mitsubishi chemical Co., Ltd's system) 31.2 quality %, as the spinning solution of dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) the 46.8 quality % of solvent from remaining the outboard slot ejection of dual spinning head of 45 DEG C, water as internal liquid is sprayed from the inner side squit hole of double-deck spinning head, make it with air gap length 600mm, spin fast 60m/ minute by behind the air gap, be immersed in the coagulating bath (DMAc:TEG: water=6:4:90) of 70 DEG C.

Thereafter, in the pure water of 45 DEG C, clean 1 minute, in the pure water of 80 DEG C, clean 90 seconds, batch in reel, obtain the hollow-fibre membrane of internal diameter 199.0 μ m, thickness 29.5 μ m.

In the cylinder that approximately 10,000 insertions of gained hollow-fibre membrane are made up of polyethylene film, cut into after the length of regulation, the moisture content that is dried to hollow-fibre membrane in the hot-air drier of 40 DEG C reaches 1.5 quality %, obtains bundle (bandle).

The hollow-fibre membrane assembling blood purification that uses operation like this and obtain, by after ends with polyurethane resin bonding, cuts out resin, and making doughnut membrane area is 1.5m ²assembly.

Then, at the temperature of 24 DEG C, import inner cavity logical liquid 52 seconds from nozzle to hollow-fibre membrane from the blood of blood purification by dissolve covering solution that 0.03 quality % vitamin E forms in the aqueous solution of isopropyl alcohol (IPA) 57 quality %, make its contact vitamin E.

, carry out air flash distillation, remove the residual liquid of inner cavity, then ventilate 30 minutes with the dry air of 24 DEG C of IPA atmosphere, solvent seasoning is removed, thereby cover vitamin E thereafter.

As humidification operation; the blood effluent road and the filtrate effluent road that are filled to blood purification as the protectant sodium pyrosulfite 0.06 quality % of sterilizing and then the aqueous solution that comprises the sodium carbonate 0.03 quality % for adjusting pH will be comprised; under the state of each sealed nozzle; carry out 25kGy radiation sterilization with gamma-rays, thereby obtain blood purification of the present invention.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 10.0mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 70 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 34 quality %, 1g hollow-fibre membrane is 2000 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 2)

In spinning solution, PVP(BASF JAPAN LTD. K90 processed) be that 3.0 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) they are that 47.3 quality %, the vitamin E concentration that covers solution are 0.45 quality %, in addition, use the same method and obtain blood purification with embodiment 1.

The content of the surperficial vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 70 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 25 quality %, 1g hollow-fibre membrane is 950 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 3)

In spinning solution, PVP (PVP) (BASF JAPAN LTD. K90 processed) is that 3.3 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) are 47.0 quality %.

As covering solution, use the isopropyl alcohol 57 quality % aqueous solution that are dissolved with 0.45 quality % vitamin E.This covering solution inner cavity to hollow-fibre membrane at the temperature of 20 DEG C is led to after liquid, carry out immediately air flash distillation, remove after the residual liquid of inner cavity, ventilate 45 minutes with the dry air of 24 DEG C of isopropyl alcohol atmosphere, solvent seasoning is removed.Other condition is used method similarly to Example 1 and is obtained blood purification.

The content of the surperficial vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 30 quality %, 1g hollow-fibre membrane is 200 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 4)

As covering solution, use the isopropyl alcohol 57 quality % aqueous solution that are dissolved with 0.90 quality % vitamin E.By this covering solution at the temperature of 40 DEG C after 120 seconds of the logical liquid of the inner cavity of hollow-fibre membrane, carry out immediately air flash distillation, remove after the residual liquid of inner cavity, with the dry air ventilation of 40 DEG C of isopropyl alcohol atmosphere 80 minutes, solvent seasoning is removed.Other condition is used method similarly to Example 1 and is obtained blood purification.

The content of the surperficial vitamin E of the hollow-fibre membrane in gained blood purification is 300mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 55 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 34 quality %, 1g hollow-fibre membrane is 10 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 5)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is 3.0 quality %.Covering in solution, use ethanol and do not use isopropyl alcohol, be dissolved with the vitamin E of 0.45 quality %.In addition, the dry gas that the alcohol atmosphere of alcohol vapour is sneaked in dry utilization carries out.Other condition is used method similarly to Example 1 and is obtained blood purification.

The content of the surperficial vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 70 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the amount of alcohol containing in 25 quality %, 1g hollow-fibre membrane is 2000 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 6)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is 3.0 quality %.Covering in solution, use acetone and do not use isopropyl alcohol, be dissolved with the vitamin E of 0.45 quality %.In addition, the dry gas that the acetone of acetone steam is sneaked in dry utilization carries out.Other condition is used method similarly to Example 1 and is obtained blood purification.

The content of the surperficial vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 70 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the amounts of acetone containing in 25 quality %, 1g hollow-fibre membrane is 2000 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 7)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is that the content of 3.7 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) is 46.6 quality %.Cover the vitamin E that is dissolved with 0.45 quality % in solution.

In 52 seconds of the logical liquid of inner cavity by from covering solution to hollow-fibre membrane, make its contact vitamin E.

, carry out air flash distillation, remove after the residual liquid of inner cavity, ventilate 45 minutes with the dry air of 24 DEG C of isopropyl alcohol atmosphere, solvent seasoning is removed thereafter.Other condition is used method similarly to Example 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 38 quality %, 1g hollow-fibre membrane is 200 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 8)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is that the content of 3.3 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) is 47.0 quality %.Cover the vitamin E that is dissolved with 0.45 quality % in solution.In 52 seconds of the logical liquid of inner cavity by from covering solution to hollow-fibre membrane, make its contact vitamin E.

, carry out air flash distillation, remove after the residual liquid of inner cavity, ventilate 90 minutes with the dry air of 60 DEG C of isopropyl alcohol atmosphere, solvent seasoning is removed thereafter.Other condition is used method similarly to Example 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 30 quality %, 1g hollow-fibre membrane is 1 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 9)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is that the content of 3.3 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) is 47.0 quality %.Cover the vitamin E that is dissolved with 0.45 quality % in solution.

, carry out air flash distillation, remove after the residual liquid of inner cavity, ventilate 15 minutes with the dry air of the isopropyl alcohol atmosphere of 24 DEG C, solvent seasoning is removed thereafter.Other condition is used method similarly to Example 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 30 quality %, 1g hollow-fibre membrane is 3500 μ g with respect to the ratio of PES and PVP (PVP) sum.

(embodiment 10)

Cover after vitamin E, do not implement humidification, carry out radiation sterilization, condition is in addition used method similarly to Example 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 100mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 70 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 34 quality %, 1g hollow-fibre membrane is 3000 μ g with respect to the ratio of PES and PVP (PVP) sum.

(comparative example 1)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is that the content of 3.3 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) is 47.0 quality %.Cover the vitamin E that is dissolved with 1.5 quality % in solution.

In 52 seconds of the logical liquid of inner cavity by from covering solution to hollow-fibre membrane, make its contact vitamin E., carry out air flash distillation, remove after the residual liquid of inner cavity, with the dry air ventilations of 24 DEG C 45 minutes, solvent seasoning is removed thereafter.Other condition is used the method identical with embodiment 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 350mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 30 quality %, 1g hollow-fibre membrane is 200 μ g with respect to the ratio of PES and PVP (PVP) sum.

(comparative example 2)

By cover solution at the temperature of 50 DEG C to 52 seconds of the logical liquid of the inner cavity of hollow-fibre membrane, make its contact vitamin E., carry out air flash distillation, remove after the residual liquid of inner cavity, with the dry air ventilations of 24 DEG C 45 minutes, solvent seasoning is removed thereafter.Other condition is used method similarly to Example 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 40 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 30 quality %, 1g hollow-fibre membrane is 200 μ g with respect to the ratio of PES and PVP (PVP) sum.

(comparative example 3)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is that the content of 3.3 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) is 47.0 quality %.Cover in solution, use diethyl ether and do not use isopropyl alcohol, be dissolved with the vitamin E of 0.45 quality %.

, carry out air flash distillation, remove after the residual liquid of inner cavity, ventilate 30 minutes with the dry air of the diethyl ether atmosphere of 24 DEG C, solvent seasoning is removed thereafter.Other condition is used method similarly to Example 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the diethyl ether amount containing in 30 quality %, 1g hollow-fibre membrane is 2000 μ g with respect to the ratio of PES and PVP (PVP) sum.

(comparative example 4)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is that the content of 3.3 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) is 47.0 quality %.Cover in solution, use oxolane and do not use isopropyl alcohol, be dissolved with the vitamin E of 0.45 quality.

, carry out air flash distillation, remove after the residual liquid of inner cavity, ventilate 30 minutes with the dry air of the oxolane atmosphere of 24 DEG C, solvent seasoning is removed thereafter.Other condition is used method similarly to Example 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the oxolane amount containing in 30 quality %, 1g hollow-fibre membrane is 2000 μ g with respect to the ratio of PES and PVP (PVP) sum.

(comparative example 5)

In spinning solution, the content of PVP (PVP) (BASF JAPAN LTD. K90 processed) is that the content of 3.3 quality %, solvent dimethylacetylamide (DMAc) (Mitsui Chemicals, Inc's system) is 47.0 quality %.Cover in solution, use isopropyl alcohol, be dissolved with the vitamin E of 0.45 quality.

In 10 seconds of the logical liquid of inner cavity by from covering solution to hollow-fibre membrane, make its contact vitamin E.

, carry out air flash distillation, remove after the residual liquid of inner cavity, with the dry air ventilations of 24 DEG C 480 minutes, solvent seasoning is removed thereafter.Other condition is used method similarly to Example 1 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90 quality %, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA containing in 30 quality %, 1g hollow-fibre membrane measures below detection limit with respect to the ratio of PES and PVP (PVP) sum.

(comparative example 6)

Do not use polyether sulfone (PES), used polysulfones (PS) (Solvay Advanced Polymers, L.L.C. system, P-1700).Other condition is used method similarly to Example 3 and is obtained blood purification.

The surperficial content of vitamin E of the hollow-fibre membrane in gained blood purification is 150mg/m ², be present in inner surface vitamin E with respect to the ratio of vitamin E that is present in hollow-fibre membrane entirety be 90%, the PVP (PVP) that is present in hollow-fibre membrane inner surface is that the IPA amount containing in 30 quality %, 1g hollow-fibre membrane is 200 μ g with respect to the ratio of PES and PVP (PVP) sum.

For the blood purification of above-described embodiment and comparative example, the iron reducing activity conservation rate by the reduced rate of the water permeability before and after the immobilization of vitamin E and deviation ratio (after immobilization/immobilization before) and after preserving under harsh environment is shown in table 1.

[table 1]

In aforementioned table 1, every purpose and meaning are as follows.

VE content: the content of the surperficial vitamin E of hollow-fibre membrane

IPA: isopropyl alcohol

EtOH: ethanol

Inner surface PVP amount: be present in hollow-fibre membrane inner surface, PVP is with respect to PES(or PS) with the quality ratio of PVP sum

Inner surface VE amount: the vitamin E that is present in hollow-fibre membrane inner surface is with respect to the quality ratio of vitamin E that is present in hollow-fibre membrane entirety

The water permeability reduced rate causing because containing VE: add after vitamin E with respect to water permeability reduced rate before adding, blood purification

Iron reducing activity conservation rate under 60 DEG C of heating: after preserving under the environment of 60 DEG C with respect to the ratio of oxidation resistance of the blood purification before preserving

σ (having VE)/σ (without VE): the ratio of the standard deviation of the measured value of water permeability before and after the immobilization of vitamin E, blood purification

Known with comparative example 1 by comparative example 3: the surperficial content of vitamin E of hollow-fibre membrane can affect reduction, the deviation of the water permeability of the blood purification after vitamin E immobilization.

In addition, known with comparative example 2 by comparative example 3: the vitamin E that is present in hollow-fibre membrane surface can affect iron reducing activity conservation rate with respect to the ratio of the vitamin E that is present in hollow-fibre membrane entirety.

In addition, by embodiment 1,5,6 and comparative example 3,4 are compared known: by selecting the alcohol of carbon number below 4, ketone as D composition, can bring into play above-mentioned effect.

Known with comparative example 5 by comparative example 3: in hollow-fibre membrane, to contain D composition the maintenance of iron reducing activity, performance reduction or deviation are suppressed to have effect.

In addition, known with comparative example 6 by comparative example 3: in the time that the material of hollow-fibre membrane is polysulfones, can not bring into play above-mentioned effect, to be therefore necessary for polyether sulfone be resin to material.

utilizability in industry

About blood treatment hollow-fibre membrane of the present invention, even if use the haemodialyser of preserving under the harsh environment such as High temperature storage, also can provide the applicable dialysis therapy that oxidative stress is low to patient, in addition, contain liposoluble vitamin in industrial production hollow-fibre membrane time, the product of producing homogeneous is a problem in the past, but by the present invention, can easily produce the product of homogeneous.Blood treatment of the present invention industrially has utilizability with hollow-fibre membrane as blood purifications such as haemodialyser, blood filter or hemodiafiltration devices.

Claims

1. a blood treatment hollow-fibre membrane, it comprises following A～D,

Described blood treatment is more than the 50 quality % of liposoluble vitamin content of blood treatment hollow-fibre membrane entirety with the content of the liposoluble vitamin on hollow-fibre membrane surface,

A: polyether sulfone be resin,

B: hydrophilic macromolecule,

C: liposoluble vitamin,

D: ketone and/or the alcohol of carbon number below 4.

2. blood treatment hollow-fibre membrane according to claim 1, wherein, the described D comprising in hollow-fibre membrane for 1g blood treatment: the ketone of carbon number below 4 and/or the amount of alcohol are 2～3000 μ g.

3. blood treatment hollow-fibre membrane according to claim 1 and 2, wherein, being present in the gross mass that the quality of the hydrophilic macromolecule of the inner surface of described blood treatment hollow-fibre membrane is resin and described hydrophilic macromolecule with respect to described polyether sulfone is 25～34 quality %.

4. according to the blood treatment hollow-fibre membrane described in any one in claim 1～3, wherein, described liposoluble vitamin is vitamin E.

5. a blood purification, it possesses:

Blood treatment in claim 1～4 described in any one with hollow-fibre membrane and

6. a manufacture method for blood purification, this blood purification comprises the blood treatment hollow-fibre membrane being made up of following A～D,

A: polyether sulfone be resin,

B: hydrophilic macromolecule,

C: liposoluble vitamin,

D: ketone and/or the alcohol of carbon number below 4,

The blood treatment that comprises described A, B is contained in to the operation of assembling blood purification in cylindrical container with hollow-fibre membrane;

Pass into and contain described C with the inner side of hollow-fibre membrane to described blood treatment: the organic solvent solution of liposoluble vitamin, thereafter, remove this organic solvent, by described C: the immobilized operation of liposoluble vitamin; And

Make described blood treatment hollow-fibre membrane contain described D: the ketone of carbon number below 4 and/or the operation of alcohol.

7. a blood purification, it is manufactured by manufacture method claimed in claim 6.