JP3651121B2 - Permselective separation membrane - Google Patents

Description

の繰り返し単位を有するものであるが、官能基を含んでいたり、アルキル系のものであってもよく、特に限定するものではない。
【００１２】
疎水性高分子の濃度としては、製膜可能でかつ膜としての特性を有する濃度範囲であれば良く、13〜20重量％が好ましい。高い透水性、大きな分画分子量を得るためにはポリマー濃度は下げるべきで、特に好ましくは13〜18重量％である。13重量％未満では、製膜原液の十分な粘度を得られにくくなる傾向があり、また、２０重量％を越えると貫通孔を形成しにくくなる場合がある。
【００１３】
親水性高分子とは、疎水性高分子と相溶性があり、かつ親水性を持つ高分子である。ポリビニルピロリドンが最も望ましいが、他に変性ポリビニルピロリドン、共重合ポリビニルピロリドン、ポリエチレングリコール、ポリ酢酸ビニル等が挙げられるが、これらに限定されるものではない。
【００１４】
親水性高分子は、特にポリビニルピロリドンの場合、分子量36万、16万、4 万、1 万のものが市販されており、これらが好適に用いられるが、もちろんそれ以外の分子量のものを使用してもかまわない。親水性高分子の添加の理由の１つとして増粘効果もあるため、添加量は高分子量のものを用いるほど少量で良く、また、孔径の大きい膜を得たい場合にも、高分子量のものを用いることが好ましい。
【００１５】
親水性高分子の添加量は、原液中１〜３０重量であることが好ましく、中でも、ポリビニルピロリドンの場合は、原液中、1 〜20重量％、特に3 〜10重量％が望ましい。また、分子量の異なるものを混合して用いることも好ましい。
【００１６】
溶媒とは、疎水性高分子及び親水性高分子を共に溶解する溶媒である。具体的には、ジメチルスルホキシド、ジメチルアセトアミド、ジメチルホルムアミド、Ｎ―メチル―２―ピロリドン、ジオキサン等、多種の溶媒が用いられるが、特にジメチルアセトアミド、ジメチルスルホキシド、ジメチルホルムアミド、Ｎ―メチル―２―ピロリドンが望ましい。
【００１７】
添加剤とは、上記溶媒と相溶性を持ち、親水性高分子の良溶媒となり、かつ、疎水性高分子の非溶媒又は膨潤剤となるものであれば何でも良く、例えば、水、メタノール、エタノール、イソプロパノール、ヘキサノール、１，４―ブタンジオール等がある。生産コストを考えると水が最も望ましい。添加剤は、疎水性高分子の凝固性を考え合わせた上で選択することが好ましい。
【００１８】
上記溶媒、添加剤は、２種類以上の化合物の混合系でも良い。
【００１９】
製造方法としては、まず疎水性高分子、親水性高分子を溶媒に混合溶解する。そこへ、添加剤を添加するが、特に水を用い、疎水性高分子がポリスルホン系樹脂の場合、水はポリスルホン系樹脂にとって凝固性が高いため、水の添加量は1.8 重量％以下、特に1.05〜1.70重量％が望ましい。また、ポリアクリロニトリルを用いた場合は、水の添加量は２〜６重量％、さらに２〜４重量％であることが好ましい。又、ポリアミドを用いた場合、水の添加量は、８重量以下、さらには２．５〜５重量％であることが好ましい。ポリスルホン系樹脂に対するこれら添加剤の凝固性は、水を１とした場合、メタノール約４．３倍、イソプロパノール約６．８倍、グリセリン約３．０倍、１，４−ブタンジオール約１．５倍であり、これを目安にそれぞれ添加量を決めることが好ましい。
【００２０】
本発明の選択透過性分離膜の形態としては、限定されるものではなく、平膜、中空糸膜などの形態で用いられる。
【００２１】
中空糸膜の形態とする場合、その中空糸膜の製造方法としては、従来知られている方法などが用いられるが、一方法として、次のように方法がある。即ち、上記原液を二重環状口金から吐出する際に内側に注入液を流し、乾式部を走行させた後に凝固浴へ導く。この際、乾式部の湿度に影響を与えるために、乾式部走行中に膜外表面からの水分の補給によって、外表面近傍での相分離挙動を速め、孔径拡大し、結果として透析の際の透過・拡散抵抗を減らすことも可能である。但し、相対湿度が高すぎると外表面での原液の凝固が支配的になり、かえって孔径が小さくなり、結果として透析の際の透過・拡散抵抗を増大する傾向がある。そのため、相対湿度としては60〜90％程度が好適である。また注入液組成としては、プロセス適性から、原液に用いた溶媒を基本とする組成からなるものを用いることが好ましい。注入液の濃度としては、例えばジメチルアセトアミドを用いたときは、45〜80重量％、さらには60〜75重量％の水溶液が好適に用いられる。
【００２２】
また、水可溶性親水性高分子を用いる場合、特にメディカル用途においては、該親水性高分子が溶出する可能性がある。このため、放射線および又は熱、化学処理などによって、親水性高分子を架橋不溶化処理することが好ましい。γ線・電子線を照射した場合は、高分子素材との共有結合も生じ該親水性高分子の溶出は抑えられる。熱処理の場合は、該親水性高分子自体がゲル化を起こし、高分子化・不溶化される。具体的には、熱処理温度としては、100 〜160 ℃が好ましく、さらには120 ℃〜150 ℃程度が好ましく、特に湿潤状態で行うことが好ましい。放射線処理としては、γ線・電子線などを照射すればよい。照射線量は、水浸漬状態で15〜35KGy 程度が好ましく、20KGy を越える線量を照射した場合は、滅菌処理を同時に行うことも可能である。
【００２３】
本発明においては、上記により、膜面積1.6m² において、in vitro での尿素のクリアランスが195ml/min 以上でかつリンのクリアランスが180ml/min 以上であり、アルブミンの透過率が0.5 ％以下であってβ2 -MG の1.8m² 換算クリアランスが44ml/min以上である選択透過性分離膜を得ることができる。
【００２４】
本発明により得られた選択透過性分離膜は、人工腎臓、人工肝臓、エンドトキシンフィルター、バイオリアクター等の医療用途等、各種用途に用いることができる。
【００２５】
以下、本発明の選択透過性分離膜の性能測定条件を記載する。
【００２６】
（１）透水性能の測定
端部を封止した１００００本からなるモジュールの中空糸内側に水圧100mmHg をかけ、外側へ流出してくる単位時間当たりの濾過量を測定する。透水性能は下記の式で算出する。
【００２７】
【数１】

ここでQWは濾過量(ml)、Hrは流出時間(hr)、P は圧力(mmHg)、A は膜面積(m² ) を示す。
【００２８】
（２）デキストランによる拡散性能測定
基本的には透析性能測定法と同様に行う。以下にその概要を示す。まずあらかじめ、選択透過性分離膜を37℃に保温した500ml の牛血清で血液側を200ml/min で50分灌流後、10分間20ml/minの速度で濾過をする（以上の工程を牛血清１時間灌流と定義する）。冷蔵庫で12時間保存後、2 リットルの生理食塩水でプライミング洗浄を行ってサンプルとする。分子量分布の異なるデキストラン（FULKA 社製 重量平均分子量 400,1000,2000,20000,50000,200000) を0.5mg/mlになるように限界濾過水に溶解する。この溶液を３７度に加熱、保温し、血液側（中空糸内側）に血液ポンプで流量200ml/min で送り、透析液側は限界濾過水を37℃に保ったものを500ml/min で送る。ここでは、濾過圧力がゼロになるように調整する。したがって、限外濾過が生じない条件で膜の拡散性能を測定する。平衡状態になるまで20分送り続け、その後、血液側入り口、出口、透析側をサンプリングする。サンプリングした溶液をＧＰＣカラム（東ソー GPXL3000）、カラム温度40℃、移動相を液クロ用純水1ml/min 、サンプル打ち込み量50μl で分析を行い、血液側の入り口、出口の濃度変化によってモジュールの総括物質移動係数を求める。この後デキストラン分子量が1 万の点のKo値を求める。
【００２９】
ここで、総括物質移動係数は以下の式を用いて算出する。
【００３０】
クリアランス
【数２】

ここでCBi はモジュール入口側濃度、 CBoはモジュール出口側濃度、QBはモジュール供給液量(ml/min)を示す。
【００３１】
【数３】

ここでA は面積(m² ) を示す。
【００３２】
（３）アルブミン透過率の測定
ヘマトクリット３０％、総蛋白量6.5g/dl の牛血（ヘパリン処理血）を用いて、中空糸内側に200ml/min で送る。その際、出口側の圧力を調整して、濾過量が10ml/minかかるようにし、濾液は血液槽に戻す。環流開始後1 時間後に中空糸側入り口、出口の血液、濾液をサンプリングする。血液側をBCG 法、濾液側をCBB 法キットによって分析し、その濃度からアルブミン透過率（％）を算出する。
【００３３】
【数４】

ここでCFは濾液中、CBi はモジュール入り口、 CBiはモジュール出口のアルブミン濃度を示す。
【００３４】
（４）in vitro β2 -MG 除去性能の測定
基本的には透析性能測定法と同様に行う。膜面積約25cm² のミニモジュール系で、フィルター処理を行った牛血清30mlに、ヒトβ2-MGを5mg/mlの濃度で溶解し中空糸内側に1ml/min で灌流し、中空糸外側には37℃に保ったPBS140mlを20ml/minの速度で密閉形で灌流した。4 時間灌流後中空糸内側・外側灌流液を採取し、クリアランスを算出し、膜面積1.8 ｍ² 換算値を求めた。
【００３５】
（５）尿素・リンのクリアランスの測定
血液側溶液として尿素1000ppm ・燐酸50ppm 含む生理食塩水50l 、透析液側溶液として生理食塩水100lを調製し、血液側流量200ml/min 、透析液側流量500ml/min として、透析器の血液側入口と出口の濃度を測定し、血液側基準と透析液側基準のクリアランスをそれぞれ算出しその平均値を用いた。
【００３６】
【実施例】
以下、実施例において、「部」は「重量部」を示す。
【００３７】
実施例１
ポリスルホン（アモコ社 Udel-P3500）18部、ポリビニルピロリドン(BASF K30 ）9 部をジメチルアセトアミド71.95 部、水1.05部に加え、90℃12時間加熱溶解し、製膜原液とした。この原液を外径0.3mm 、内径0.2mm の２重環状口金から芯液としてジメチルアセトアミド65部、水35部からなる溶液を吐出させ、乾式長300mm 、相対湿度８８％中を通し、４０℃の２０％のジメチルアセトアミド水溶液中に導き、中空糸膜を製膜した。この中空糸膜を1.6m² になるように、ケースに充填し、ポッティングしてモジュールとした。湿潤状態でγ線照射後、尿素・リンのクリアランスの測定、アルブミン透過率を測定したところ、in vitro での尿素のクリアランスが196ml/min 、リンのクリアランスが181ml/min であり、アルブミンの透過率が0.12％であった。またβ2 -MG の1.8m² 換算クリアランスが44ml/minであった。
【００３８】
実施例２
ポリスルホン（アモコ社 Udel-P3500）18部、ポリビニルピロリドン（BASF K30 ）9 部をジメチルアセトアミド71.70 部、水1.30部に加え、90℃12時間加熱溶解し、製膜原液とした。この原液を外径0.3mm 、内径0.2mm の２重環状口金から芯液としてジメチルアセトアミド65部、水35部からなる溶液を吐出させ、乾式長350mm 、相対湿度７３％中を通し、４０℃の２０％のジメチルアセトアミド水溶液中に導き、中空糸膜を製膜した。この中空糸膜を1.6m² になるように、ケースに充填し、ポッティングしてモジュールとした。湿潤状態でγ線照射後、尿素・リンのクリアランスの測定、アルブミン透過率を測定したところ、in vitro での尿素のクリアランスが196ml/min 、リンのクリアランスが188ml/min であり、アルブミンの透過率が0.17％であった。またβ2 -MG の1.8m² 換算クリアランスが53ml/minであった。
【００３９】
実施例３
ポリスルホン（アモコ社 Udel-P3500）18部、ポリビニルピロリドン（BASF K30 ）12部をジメチルアセトアミド68.55 部、水1.45部に加え、90℃12時間加熱溶解し、製膜原液とした。この原液を外径0.3mm 、内径0.2mm の２重環状口金から芯液としてジメチルアセトアミド68部、水32部からなる溶液を吐出させ、乾式長350mm 、相対湿度８５％中を通し、４０℃の２０％のジメチルアセトアミド水溶液中に導き、中空糸膜を製膜した。この中空糸膜を1.6m² になるように、ケースに充填し、ポッティングしてモジュールとした。湿潤状態でγ線照射後、尿素・リンのクリアランスの測定、アルブミン透過率を測定したところ、in vitro での尿素のクリアランスが197ml/min 、リンのクリアランスが185ml/min であり、アルブミンの透過率が0.32％であった。またβ2 -MG の1.8m² 換算クリアランスが59ml/minであった。
【００４０】
比較例１
ポリスルホン( アモコ社 Udel-P3500）18部、ポリビニルピロリドン（BASF K30 ）9 部をジメチルアセトアミド72.00 部、水1.0 部に加え、90℃12時間加熱溶解し、製膜原液とした。この原液を外径0.3mm 、内径0.2mm の２重環状口金から芯液としてジメチルアセトアミド65部、水35部からなる溶液を吐出させ、乾式長300mm 、相対湿度８８％中を通し、４０℃の２０％のジメチルアセトアミド水溶液中に導き、中空糸膜を製膜した。この中空糸膜を1.6m² になるように、ケースに充填し、ポッティングしてモジュールとした。湿潤状態でγ線照射後、尿素・リンのクリアランスの測定、アルブミン透過率を測定したところ、in vitro での尿素のクリアランスが195ml/min 、リンのクリアランスが181ml/min であり、アルブミンの透過率が0.12％であった。またβ2 -MG の1.8m² 換算クリアランスが42ml/minであった。
【００４１】
【発明の効果】
本発明により、低アルブミン漏出性、高い低分子尿毒素選択透過性、高いβ₂ −ＭＧ除去性能を併せ持つ選択透過性分離膜が得られた。メディカル用途、例えば、血液透析、血液濾過、血液透析濾過等に利用した場合、腎不全患者の病体に良い治療成績が得られる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a selectively permeable separation membrane.
[0002]
[Prior art]
Conventionally, many polymer compounds such as cellulose acetate, polyacrylonitrile, polymethyl methacrylate, and polyamide have been used as membrane materials for dialyzers. On the other hand, polysulfone-based resins have been used as engineering plastics originally, but because of their good heat stability, acid / alkali resistance, biocompatibility, and contamination resistance, they are attracting attention as semipermeable membrane materials. Has been. In general, membranes made of these many polymer materials have poor affinity with blood due to the hydrophobicity of the surface, and cannot be used for blood treatment as they are. Therefore, a method has been devised, in which a hydrophilic polymer, an inorganic salt or the like is mixed as a pore-forming material, and the pore is formed by leaching, and at the same time, the polymer surface is hydrophilized and used as a dialyzer.
[0003]
Among the dialyzers used for blood purification therapy such as hemodialysis, hemofiltration dialysis, and blood filtration, cellulose-based dialyzers represented by cellulose triacetate generally have high removal performance of low molecular weight uremic toxins. This membrane has an in vitro urea clearance of 195 ml / min or more and a phosphorus clearance of 180 ml / min or more and an albumin permeability of 0.5% or less in terms of a membrane area of 1.6 m 2. The clearance of MG was about 23 ml / min. In addition, in the conventional polysulfone-based dialyzer, the β2-MG removal performance is high, the in vitro 1.8 m ² conversion clearance is 44 ml / min or more, and the albumin permeability is 0.5% or less. In terms of an area of 1.6 m ² , the in vitro urea clearance was 192 ml / min or less and the phosphorus clearance was 177 ml / min or less, so that it did not have sufficient low molecule removal performance.
[0004]
[Problems to be solved by the invention]
In this way, it is very difficult to achieve both high-performance, low-molecular-weight uremic toxin removal performance and medium-molecular protein removal performance such as β2-MG. There was no selective separation membrane compatible with the above.
[0005]
As a result of intensive studies to overcome the above problems, the present inventors have achieved the present invention.
[0006]
[Means for Solving the Problems]
In order to achieve the above object, the present invention has the following configuration.
[0007]
[Means for Solving the Problems]
That is, the amount of hydrophobic polymer in the film-forming stock solution containing four components consisting of a hydrophobic polymer, a hydrophilic polymer, a solvent and additives as essential components is 13 to 20% by weight, and the water concentration is 1.05 to 1.70% by weight. A permselective separation membrane having a membrane area of 1.6 m ² , an in vitro urea clearance at a blood flow rate of 200 ml / min and a phosphorus clearance of 180 ml / min or more, The permselective separation membrane has a permeability of 0.5% or less and a β2 -MG 1.8 m ² conversion clearance of 44 ml / min or more.
[0008]
BEST MODE FOR CARRYING OUT THE INVENTION
The method for producing the selectively permeable separation membrane of the present invention is shown below.
[0009]
First, a stock solution containing four components consisting of a hydrophobic polymer, a hydrophilic polymer, a solvent and additives as essential components is used.
[0010]
The hydrophobic polymer is not particularly limited, and examples thereof include polysulfone resin, polyamide, polyacrylonitrile, polymethyl methacrylate, etc. Among them, biocompatibility is excellent and strength is high. Polysulfone resin is preferably used.
[0011]
The polysulfone resin has the following formula:

However, it may be a functional group or an alkyl group, and is not particularly limited.
[0012]
The concentration of the hydrophobic polymer is not particularly limited as long as it is in a concentration range capable of forming a film and having characteristics as a membrane, and is preferably 13 to 20% by weight. In order to obtain high water permeability and a large molecular weight cut off, the polymer concentration should be lowered, particularly preferably 13 to 18% by weight. If it is less than 13% by weight, it tends to be difficult to obtain a sufficient viscosity of the film-forming stock solution, and if it exceeds 20% by weight, it may be difficult to form through holes.
[0013]
The hydrophilic polymer is a polymer that is compatible with the hydrophobic polymer and has hydrophilicity. Polyvinyl pyrrolidone is most desirable, but other examples include, but are not limited to, modified polyvinyl pyrrolidone, copolymerized polyvinyl pyrrolidone, polyethylene glycol, and polyvinyl acetate.
[0014]
In the case of polyvinyl pyrrolidone, hydrophilic polymers having molecular weights of 360,000, 160,000, 40,000 and 10,000 are commercially available, and these are preferably used. Of course, polymers having other molecular weights are used. It doesn't matter. One of the reasons for the addition of hydrophilic polymer is its thickening effect, so the amount added may be smaller as the higher molecular weight is used. Is preferably used.
[0015]
The addition amount of the hydrophilic polymer is preferably 1 to 30% by weight in the stock solution. In particular, in the case of polyvinylpyrrolidone, 1 to 20% by weight, particularly 3 to 10% by weight in the stock solution is desirable. It is also preferable to use a mixture of different molecular weights.
[0016]
The solvent is a solvent that dissolves both the hydrophobic polymer and the hydrophilic polymer. Specifically, various solvents such as dimethyl sulfoxide, dimethylacetamide, dimethylformamide, N-methyl-2-pyrrolidone, and dioxane are used. In particular, dimethylacetamide, dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone are used. Is desirable.
[0017]
The additive may be any additive as long as it is compatible with the above-described solvent, becomes a good solvent for the hydrophilic polymer, and becomes a non-solvent or swelling agent for the hydrophobic polymer. For example, water, methanol, ethanol , Isopropanol, hexanol, 1,4-butanediol and the like. In view of production costs, water is the most desirable. The additive is preferably selected in consideration of the coagulability of the hydrophobic polymer.
[0018]
The solvent and additive may be a mixed system of two or more kinds of compounds.
[0019]
As a production method, first, a hydrophobic polymer and a hydrophilic polymer are mixed and dissolved in a solvent. Additives are added there, especially when water is used and the hydrophobic polymer is a polysulfone resin, since water is highly coagulable for the polysulfone resin, the amount of water added is 1.8 wt% or less, especially 1.05. ~ 1.70% by weight is desirable. When polyacrylonitrile is used, the amount of water added is preferably 2 to 6% by weight, more preferably 2 to 4% by weight. When polyamide is used, the amount of water added is preferably 8 wt% or less, more preferably 2.5 to 5 wt%. The coagulability of these additives with respect to the polysulfone resin is about 4.3 times methanol, about 6.8 times isopropanol, about 3.0 times glycerin, about 1.5 times 1,4-butanediol when water is 1. It is preferable to determine the amount of addition based on this.
[0020]
The form of the selectively permeable separation membrane of the present invention is not limited, and it is used in the form of a flat membrane, a hollow fiber membrane or the like.
[0021]
When the hollow fiber membrane is used, a conventionally known method or the like is used as a method for producing the hollow fiber membrane, and one method is as follows. That is, when the stock solution is discharged from the double annular die, the injection solution is flowed inside, and after running the dry part, it is guided to the coagulation bath. At this time, in order to affect the humidity of the dry part, by replenishing moisture from the outer surface of the membrane during running of the dry part, the phase separation behavior near the outer surface is accelerated, the pore size is enlarged, and as a result, the dialysis is performed. It is also possible to reduce transmission / diffusion resistance. However, if the relative humidity is too high, the solidification of the stock solution on the outer surface becomes dominant, and the pore diameter becomes rather small, and as a result, the permeation / diffusion resistance during dialysis tends to increase. Therefore, the relative humidity is preferably about 60 to 90%. Moreover, it is preferable to use what consists of a composition based on the solvent used for undiluted | stock solution as an injection | pouring liquid composition from process suitability. As the concentration of the injection solution, for example, when dimethylacetamide is used, an aqueous solution of 45 to 80% by weight, further 60 to 75% by weight is preferably used.
[0022]
Moreover, when using a water-soluble hydrophilic polymer, especially in a medical use, this hydrophilic polymer may elute. For this reason, it is preferable to crosslink and insolubilize the hydrophilic polymer by radiation and / or heat, chemical treatment or the like. When γ-rays / electron beams are irradiated, covalent bonds with the polymer material also occur, and the elution of the hydrophilic polymer can be suppressed. In the case of heat treatment, the hydrophilic polymer itself gels and becomes polymerized / insoluble. Specifically, the heat treatment temperature is preferably 100 to 160 ° C, more preferably about 120 ° C to 150 ° C, particularly preferably in a wet state. As the radiation treatment, γ rays, electron beams, etc. may be irradiated. The irradiation dose is preferably about 15 to 35 KGy when immersed in water, and sterilization can be performed simultaneously when a dose exceeding 20 KGy is irradiated.
[0023]
In the present invention, as described above, in a membrane area of 1.6 m ² , in vitro urea clearance was 195 ml / min or more, phosphorus clearance was 180 ml / min or more, and albumin permeability was 0.5% or less. Thus, a selectively permeable separation membrane having a β2 -MG 1.8 m ² equivalent clearance of 44 ml / min or more can be obtained.
[0024]
The selectively permeable separation membrane obtained by this invention can be used for various uses, such as medical uses, such as an artificial kidney, an artificial liver, an endotoxin filter, and a bioreactor.
[0025]
Hereinafter, the performance measurement conditions of the selectively permeable separation membrane of the present invention will be described.
[0026]
(1) Measurement of water permeability The water pressure of 100 mmHg is applied to the inner side of the hollow fiber of the 10,000 modules with sealed end portions, and the amount of filtration per unit time flowing out to the outside is measured. The water permeability is calculated by the following formula.
[0027]
[Expression 1]

Here, QW is the amount of filtration (ml), Hr is the outflow time (hr), P is the pressure (mmHg), and A is the membrane area (m ² ).
[0028]
(2) Diffusion performance measurement with dextran Basically, it is performed in the same manner as the dialysis performance measurement method. The outline is shown below. First, perfuse the selective permeable separation membrane with 500 ml of bovine serum kept at 37 ° C for 50 minutes at 200 ml / min on the blood side, followed by filtration at a rate of 20 ml / min for 10 minutes (the above steps are the same for bovine serum 1). Defined as time perfusion). After 12 hours storage in the refrigerator, perform priming with 2 liters of physiological saline to prepare a sample. Dissolve dextran (weight average molecular weight 400, 1000, 2000, 20000, 50000, 50000, 200000) with different molecular weight distribution in ultrafiltration water to 0.5mg / ml. This solution is heated and kept at 37 ° C., and sent to the blood side (inside the hollow fiber) with a blood pump at a flow rate of 200 ml / min, and the dialysate side is sent with 500 ml / min of ultrafiltration water maintained at 37 ° C. Here, the filtration pressure is adjusted to zero. Therefore, the diffusion performance of the membrane is measured under conditions that do not cause ultrafiltration. Continue feeding for 20 minutes until equilibrium is reached, then sample blood inlet / outlet and dialysis side. The sampled solution is analyzed with a GPC column (Tosoh GPXL3000), the column temperature is 40 ° C, the mobile phase is 1 ml / min of pure water for liquid chromatography, and the sample injection volume is 50 μl. Determine the mass transfer coefficient. After this, the Ko value at the point where the dextran molecular weight is 10,000 is obtained.
[0029]
Here, the overall mass transfer coefficient is calculated using the following equation.
[0030]
Clearance [2]

Where CBi is the module inlet side concentration, CBo is the module outlet side concentration, and QB is the module supply liquid volume (ml / min).
[0031]
[Equation 3]

Here, A represents the area (m ² ).
[0032]
(3) Measurement of albumin permeability Using bovine blood (heparin-treated blood) with a hematocrit of 30% and a total protein content of 6.5 g / dl, it is sent to the inside of the hollow fiber at 200 ml / min. At that time, the pressure on the outlet side is adjusted so that the filtration amount is 10 ml / min, and the filtrate is returned to the blood tank. One hour after the start of recirculation, the blood and filtrate at the inlet and outlet of the hollow fiber are sampled. Analyze the blood side with the BCG method and the filtrate side with the CBB method kit, and calculate albumin permeability (%) from the concentration.
[0033]
[Expression 4]

Here, CF is the filtrate, CBi is the module inlet, and CBi is the module outlet albumin concentration.
[0034]
(4) Measurement of in vitro β2 -MG removal performance Basically, it is performed in the same manner as the dialysis performance measurement method. In a mini-module system with a membrane area of approximately 25 cm ² , human β2-MG is dissolved at a concentration of 5 mg / ml in 30 ml of filtered bovine serum and perfused at 1 ml / min inside the hollow fiber. 140 ml of PBS maintained at 37 ° C. was perfused in a sealed manner at a rate of 20 ml / min. After perfusion for 4 hours, hollow fiber inner and outer perfusates were collected, clearance was calculated, and a membrane area equivalent to 1.8 m ² was obtained.
[0035]
(5) Measurement of urea / phosphorus clearance Prepare 50 l of physiological saline containing 1000 ppm urea and 50 ppm phosphoric acid as blood side solution and 100 l physiological saline as dialysate side solution, blood side flow rate 200 ml / min, dialysate side flow rate 500 ml The concentration at the blood inlet and outlet of the dialyzer was measured as / min, and the blood side reference and dialysate side reference clearances were calculated and the average values were used.
[0036]
【Example】
Hereinafter, in the examples, “part” means “part by weight”.
[0037]
Example 1
18 parts of polysulfone (Amoco Udel-P3500) and 9 parts of polyvinylpyrrolidone (BASF K30) were added to 71.95 parts of dimethylacetamide and 1.05 parts of water, and dissolved by heating at 90 ° C. for 12 hours to obtain a film forming stock solution. This undiluted solution was discharged from a double annular die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm as a core liquid, and a solution consisting of 65 parts of dimethylacetamide and 35 parts of water was passed through a dry length of 300 mm and a relative humidity of 88%. Guided into a 20% aqueous dimethylacetamide solution, a hollow fiber membrane was formed. The hollow fiber membrane was filled into a case so as to have a thickness of 1.6 m ² and potted to obtain a module. Measurement of urea / phosphorus clearance and albumin permeability after gamma irradiation in a wet state revealed that in vitro urea clearance was 196 ml / min, phosphorus clearance was 181 ml / min, and albumin permeability Was 0.12%. In addition, the clearance of β2 -MG converted to 1.8 m ² was 44 ml / min.
[0038]
Example 2
18 parts of polysulfone (Amoco Udel-P3500) and 9 parts of polyvinylpyrrolidone (BASF K30) were added to 71.70 parts of dimethylacetamide and 1.30 parts of water, and dissolved by heating at 90 ° C. for 12 hours to obtain a film forming stock solution. This undiluted solution is discharged from a double annular die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm as a core liquid, and a solution consisting of 65 parts of dimethylacetamide and 35 parts of water is passed through a dry length of 350 mm and a relative humidity of 73% at 40 ° C. Guided into a 20% aqueous dimethylacetamide solution, a hollow fiber membrane was formed. The hollow fiber membrane was filled into a case so as to have a thickness of 1.6 m ² and potted to obtain a module. Measurement of urea / phosphorus clearance and albumin permeability after gamma irradiation in a wet state revealed that in vitro urea clearance was 196 ml / min, phosphorus clearance was 188 ml / min, and albumin permeability Was 0.17%. Further, β2 -MG 1.8 m ² equivalent clearance was 53 ml / min.
[0039]
Example 3
18 parts of polysulfone (Amoco Udel-P3500) and 12 parts of polyvinylpyrrolidone (BASF K30) were added to 68.55 parts of dimethylacetamide and 1.45 parts of water, and dissolved by heating at 90 ° C. for 12 hours to obtain a film forming stock solution. This undiluted solution was discharged from a double annular die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm as a core liquid, and a solution consisting of 68 parts of dimethylacetamide and 32 parts of water was passed through a 350 mm dry length and 85% relative humidity at 40 ° C Guided into a 20% aqueous dimethylacetamide solution, a hollow fiber membrane was formed. The hollow fiber membrane was filled into a case so as to have a thickness of 1.6 m ² and potted to obtain a module. Measurement of urea / phosphorus clearance and albumin permeability after γ-irradiation in a wet state revealed an in vitro urea clearance of 197 ml / min and phosphorus clearance of 185 ml / min, and albumin permeability. Was 0.32%. Further, β2 -MG 1.8 m ² equivalent clearance was 59 ml / min.
[0040]
Comparative Example 1
18 parts of polysulfone (Amoco Udel-P3500) and 9 parts of polyvinylpyrrolidone (BASF K30) were added to 72.00 parts of dimethylacetamide and 1.0 part of water, and dissolved by heating at 90 ° C. for 12 hours to obtain a film forming stock solution. This undiluted solution is discharged from a double annular die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm as a core liquid, and a solution consisting of 65 parts of dimethylacetamide and 35 parts of water is passed through a dry length of 300 mm and a relative humidity of 88% at 40 ° C. Guided into a 20% aqueous dimethylacetamide solution, a hollow fiber membrane was formed. The hollow fiber membrane was filled into a case so as to be 1.6 m ² and potted to obtain a module. Measurement of urea / phosphorus clearance and albumin permeability after γ-irradiation in a wet state showed that in vitro urea clearance was 195 ml / min, phosphorus clearance was 181 ml / min, and albumin permeability Was 0.12%. Further, β2 -MG 1.8 m ² equivalent clearance was 42 ml / min.
[0041]
【The invention's effect】
According to the present invention, a selectively permeable separation membrane having both low albumin leakage, high low molecular weight uremic toxin selective permeability, and high β ₂ -MG removal performance was obtained. When used for medical applications such as hemodialysis, hemofiltration, hemodiafiltration, etc., good therapeutic results can be obtained for the pathology of patients with renal failure.

Claims (5)

Selection with a hydrophobic polymer amount of 13 to 20% by weight and a water concentration of 1.05 to 1.70% by weight in a film-forming stock solution comprising four components consisting of a hydrophobic polymer, a hydrophilic polymer, a solvent and additives as essential components Permeability of albumin, which is a permeable separation membrane with a membrane area of 1.6 m ² and an in vitro urea clearance of 195 ml / min and a phosphorus clearance of 180 ml / min at a blood flow rate of 200 ml / min. Is a permselective separation membrane characterized by having a β2 -MG 1.8 m ² conversion clearance of 44 ml / min or more. 2. The selectively permeable separation membrane according to claim 1, wherein the separation membrane comprises polysulfone as a main component. The selectively permeable separation membrane according to claim 1 or 2, wherein the separation membrane is made of a hydrophilic polymer. The selectively permeable separation membrane according to claim 3, wherein the hydrophilic polymer contains polyvinylpyrrolidone. The selectively permeable separation membrane according to claim 3 or 4, wherein the hydrophilic polymer has been subjected to crosslinking water insolubilization treatment.