JP6737565B2 - Separation membrane for blood treatment and blood treatment device incorporating the membrane - Google Patents
Separation membrane for blood treatment and blood treatment device incorporating the membrane Download PDFInfo
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Landscapes
- External Artificial Organs (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Description
本発明は、血液中の特定の物質を分離するために使用される血液処理用分離膜及びその膜を組み込んだ血液処理器に関する。 TECHNICAL FIELD The present invention relates to a separation membrane for blood treatment used for separating a specific substance in blood and a blood treatment device incorporating the membrane.
体外循環療法においては、選択的分離膜を用いた中空糸膜型血液処理器が広く使用されている。例えば慢性腎不全患者に対する維持療法としての血液透析において、急性腎不全や敗血症等の重篤な病態の患者に対する急性血液浄化療法としての持続血液ろ過、持続血液ろ過透析、持続血液透析等において、また開心手術中の血液への酸素付与又は血漿分離等において、中空糸膜型血液処理器が用いられている。
これらの用途においては、中空糸膜として、機械的強度や化学的安定性に優れ、また、透過性能の制御が容易なだけでなく、溶出物が少なく、生体成分との相互作用が少なく、生体に対して安全であることが求められている。
In the extracorporeal circulation therapy, a hollow fiber membrane blood treatment device using a selective separation membrane is widely used. For example, in hemodialysis as maintenance therapy for patients with chronic renal failure, in continuous hemofiltration, continuous hemofiltration dialysis, continuous hemodialysis, etc. as acute blood purification therapy for patients with serious disease states such as acute renal failure and sepsis, BACKGROUND ART A hollow fiber membrane-type blood processing device is used for oxygenation of blood or plasma separation during open heart surgery.
In these applications, as a hollow fiber membrane, it has excellent mechanical strength and chemical stability, and it is easy to control the permeation performance, and the amount of eluate is small and the interaction with biological components is small. To be safe against.
近年、機械的強度や化学的安定性、透過性性能の制御性の観点から、ポリスルホン系樹脂からなる選択的分離膜が急速に普及している。ポリスルホン系樹脂は疎水性高分子であるため、そのままでは膜表面の親水性が著しく不足し、血液適合性が悪く、血液成分との相互作用が引き起こされ、血液の凝固なども起こりやすくなり、さらには蛋白成分等の吸着により、透過性能が劣化しやすい。
そこでこの欠点を補うために、ポリスルホン系樹脂等の疎水性高分子に加え、ポリビニルピロリドン（ＰＶＰ）、ポリビニルアルコール、ポリエチレングリコール等の親水性高分子を含有させることで血液適合性を付与する検討がなされている。例えば、疎水性高分子と親水性高分子をブレンドした紡糸原液を用いて製膜し、乾燥させることや、製造された膜を親水性高分子を含む溶液と接触させた後、乾燥させることにより、親水性高分子を被覆させ、血液適合性を付与する方法などが知られている。
In recent years, from the viewpoint of mechanical strength, chemical stability, and controllability of permeation performance, selective separation membranes made of polysulfone-based resin have rapidly become popular. Since the polysulfone-based resin is a hydrophobic polymer, the hydrophilicity of the membrane surface is remarkably insufficient as it is, the blood compatibility is poor, the interaction with blood components is caused, and blood coagulation easily occurs. The permeation performance is likely to deteriorate due to adsorption of protein components and the like.
Therefore, in order to make up for this drawback, studies have been made to impart blood compatibility by incorporating hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyvinyl alcohol, and polyethylene glycol in addition to hydrophobic polymers such as polysulfone-based resins. Has been done. For example, a spinning stock solution prepared by blending a hydrophobic polymer and a hydrophilic polymer is used for film formation and drying, or the produced film is brought into contact with a solution containing a hydrophilic polymer and then dried. , A method of coating a hydrophilic polymer to impart blood compatibility is known.
ところで体外循環療法においては、血液処理器中の選択的分離膜に、血液を直接接触させて使用するため、使用前に選択的分離膜が滅菌処理されていることが必要である。
滅菌処理においては、エチレンオキサイドガス、高圧蒸気、放射線などが用いられていたが、エチレンオキサイドガス滅菌や高圧蒸気滅菌では残留ガスによるアレルギーや滅菌装置の処理能力、材料の熱変形等の問題があり、現在ではγ線や電子線などの放射線滅菌が主流となってきている。
一方で取扱い性、寒冷地保管時の凍結の問題などから、血液処理器としてドライ製品が主流となりつつある中、放射線滅菌による酸素存在下の滅菌工程では、発生ラジカルにより、親水性高分子の架橋反応や分解、ひいては酸化劣化等が生じ、それにより膜素材に変性が引き起こされ、血液適合性の低下原因となる。
By the way, in the extracorporeal circulation therapy, blood is used by bringing blood into direct contact with the selective separation membrane in the blood treatment device. Therefore, the selective separation membrane needs to be sterilized before use.
Ethylene oxide gas, high-pressure steam, radiation, etc. were used in the sterilization process, but there are problems with ethylene oxide gas sterilization and high-pressure steam sterilization such as allergies due to residual gas, the processing capacity of the sterilizer, and thermal deformation of materials. Currently, radiation sterilization using γ-rays and electron beams is becoming the mainstream.
On the other hand, dry products are becoming mainstream as blood processors due to handling and freezing problems in cold climates.In the sterilization process in the presence of oxygen by radiation sterilization, the generated radicals cause crosslinking of hydrophilic polymers. Reaction and decomposition, and eventually oxidative deterioration, etc. occur, which causes denaturation of the membrane material and causes deterioration of blood compatibility.
このような膜素材の劣化を防止する方法としては、ドライ製品でないものについては、膜モジュールに抗酸化剤溶液を充填してγ線滅菌することで膜の酸化劣化を防止する方法や、ＰＨ緩衝液やアルカリ水溶液を充填して滅菌することで充填液の酸化を抑制する方法が開示されている。 As a method for preventing such deterioration of the membrane material, for non-dry products, a method of preventing oxidative deterioration of the membrane by filling the membrane module with an antioxidant solution and performing γ-ray sterilization, or a PH buffer There is disclosed a method of suppressing the oxidation of the filling liquid by filling the liquid or an alkaline aqueous solution and sterilizing.
一方、ドライ製品に関しては、滅菌時の酸素濃度を０．００１％以上０．１％以下に抑制する方法が開示されている（特許文献１）。しかしながら特許文献１の技術においては、包装袋内を不活性ガスで置換して滅菌するか、包装袋内に脱酸素剤を封入し一定時間の経過後に滅菌するなどの必要があり、ドライ状態でかつ大気下の放射線滅菌で、十分な血液適合性を発現する技術は確立されていない。 On the other hand, regarding dry products, a method of suppressing the oxygen concentration during sterilization to 0.001% or more and 0.1% or less is disclosed (Patent Document 1). However, in the technique of Patent Document 1, it is necessary to replace the inside of the packaging bag with an inert gas for sterilization, or to seal the oxygen scavenger in the packaging bag and sterilize after a certain period of time. In addition, the technology to develop sufficient blood compatibility by radiation sterilization under air has not been established.
特許文献２には、ポリメトキシエチルアクリレート（ＰＭＥＡ）をガス交換用多孔質中空糸膜の外面に被覆することが開示されている。しかし、滅菌処理についての検討はない。 Patent Document 2 discloses coating the outer surface of a porous hollow fiber membrane for gas exchange with polymethoxyethyl acrylate (PMEA). However, there is no study on sterilization.
本発明は、血液適合性に優れ、大気下、ドライ状態で放射線滅菌しても血液適合性の低下の少ない血液処理用分離膜及びその膜を組み込んだ血液処理器を提供することを目的とする。 It is an object of the present invention to provide a separation membrane for blood treatment, which has excellent blood compatibility and has little deterioration in blood compatibility even when radiation sterilized in a dry state in the atmosphere, and a blood treatment device incorporating the membrane. ..
本発明者らが、上記課題を解決すべく鋭意検討した結果、少なくともポリスルホン系高分子とポリビニルピロリドンを含む分離膜に、ポリメトキシエチルアクリレート（ＰＭＥＡ）を含む被膜をコーティングした血液処理用分離膜は、非常に優れた血液適合性を有し、また、大気下で滅菌を行ってもその非常に優れた血液適合性が維持されることを見出し、本発明を完成した。 As a result of intensive studies conducted by the present inventors to solve the above problems, a separation membrane for blood treatment in which a separation membrane containing at least a polysulfone-based polymer and polyvinylpyrrolidone is coated with a film containing polymethoxyethyl acrylate (PMEA) is obtained. They have found that they have very good blood compatibility, and that even when they are sterilized in the atmosphere, their very good blood compatibility is maintained, and they completed the present invention.
すなわち、本発明は、以下のとおりである。
ポリスルホン系高分子とポリビニルピロリドンを含有する分離膜と、
該分離膜の表面に設けられ、ポリメトキシエチルアクリレート（ＰＭＥＡ）を含む被膜と、
を有する血液処理用分離膜。
また、本発明の別の態様は、以下のとおりである。
ポリスルホン系高分子とポリビニルピロリドンを含有する分離膜を製膜する工程と、
前記分離膜の表面に、ポリメトキシエチルアクリレート（ＰＭＥＡ）、水及び有機溶媒を含有するコート液をコーティングする工程と、
を有する血液処理用分離膜の製造方法。
That is, the present invention is as follows.
A separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone,
A coating provided on the surface of the separation membrane and containing polymethoxyethyl acrylate (PMEA);
A separation membrane for treating blood, which comprises:
Further, another aspect of the present invention is as follows.
A step of forming a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone,
Coating the surface of the separation membrane with a coating liquid containing polymethoxyethyl acrylate (PMEA), water and an organic solvent;
A method for producing a separation membrane for blood treatment, comprising:
本発明の血液処理用分離膜及び該膜を組み込んだ血液処理器は、大気下、ドライ状態で放射線滅菌された場合であっても、非常に優れた血液適合性を発現できる。 The separation membrane for blood treatment of the present invention and the blood treatment device incorporating the membrane can exhibit extremely excellent blood compatibility even when radiation-sterilized in a dry state under the atmosphere.
以下、本発明を実施するための形態（以下、「本実施形態」という。）について以下詳細に説明する。なお本発明は以下の実施形態に限定されるものでなく、その要旨の範囲内で種々変形して実施することができる。 Hereinafter, modes for carrying out the present invention (hereinafter, referred to as “the present embodiment”) will be described in detail. The present invention is not limited to the following embodiments, and various modifications can be carried out within the scope of the gist.
本実施形態の血液処理用分離膜は、ポリスルホン系高分子とポリビニルピロリドンとを含む分離膜を含み、その分離膜の表面に血液適合性を付与するためのポリメトキシエチルアクリレートを含む被膜を有する。 The separation membrane for blood treatment of the present embodiment includes a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone, and has a coating film containing polymethoxyethyl acrylate for imparting blood compatibility to the surface of the separation membrane.
まず、ポリスルホン系高分子とポリビニルピロリドンとを含む分離膜について説明する。
＜ポリスルホン系高分子＞
本実施形態において、ポリスルホン系高分子とは、スルホン（−ＳＯ2−）基をその構造内に含有する高分子である。ポリスルホン系樹脂の具体例としては、ポリフェニレンスルホン、ポリスルホン、ポリアリルエーテルスルホン、ポリエーテルスルホン及びこれらの共重合体等が挙げられる。
ポリスルホン系高分子としては、１種を単独で用いてもよく、また、２種以上の混合物を用いても良い。
First, a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone will be described.
<Polysulfone-based polymer>
In the present embodiment, the polysulfone-based polymer is a polymer containing a sulfone (—SO 2 —) group in its structure. Specific examples of the polysulfone-based resin include polyphenylene sulfone, polysulfone, polyallyl ether sulfone, polyether sulfone, and copolymers thereof.
As the polysulfone-based polymer, one kind may be used alone, or a mixture of two or more kinds may be used.
中でも分画性を制御する観点で、下記式（１）又は下記式（２）で示されるポリスルホン系高分子が好ましい。
（−Ａｒ−ＳＯ2−Ａｒ−Ｏ−Ａｒ−Ｃ（ＣＨ3）2−Ａｒ−Ｏ−）ｎ （１）
（−Ａｒ−ＳＯ2−Ａｒ−Ｏ−）ｎ （２）
式（１）及び式（２）中、Ａｒはベンゼン環を、ｎはポリマーの繰り返しを表し、１以上の整数である。
Among them, the polysulfone-based polymer represented by the following formula (1) or the following formula (2) is preferable from the viewpoint of controlling the fractionation property.
(-Ar-SO 2 -Ar-O -Ar-C (CH 3) 2 -Ar-O-) n (1)
(-Ar-SO 2 -Ar-O- ) n (2)
In the formulas (1) and (2), Ar represents a benzene ring and n represents a repeating polymer, and is an integer of 1 or more.
式（１）で示されるポリスルホン系高分子としては、例えば、ソルベイ社から「ユーデル（商標）」の名称で、ビーエーエスエフ社から「ウルトラゾーン（商標）」の名称で市販されているものが挙げられる。また、式（２）で示されるポリエーテルスルホンとしては、例えば、住友化学株式会社から「スミカエクセル（商標）」の名称で市販されているものが挙げられ、重合度等によっていくつかの種類が存在するので、これらを適宜利用することができる。 Examples of the polysulfone-based polymer represented by the formula (1) include those commercially available under the name "Udel (trademark)" from Solvay and under the name "Ultrazone (trademark)" from BSF. To be Examples of the polyether sulfone represented by the formula (2) include those commercially available from Sumitomo Chemical Co., Ltd. under the name of "Sumika Excel (trademark)", and there are several kinds depending on the degree of polymerization and the like. Since they exist, these can be used appropriately.
＜ポリビニルピロリドン＞
ポリビニルピロリドンとは、Ｎ−ビニルピロリドンをビニル重合させた水溶性の親水性高分子であり、親水化剤や孔形成剤として中空糸膜の素材として広く用いられている。
ポリビニルピロリドンとしては、例えば、ビーエーエスエフ社から「ルビテック（商標）」の名称でそれぞれいくつかの分子量のものが市販されているので、これらを適宜利用することができる。
ポリビニルピロリドンとしては、１種類を単独で用いてもよく、また、２種類以上の混合物を用いてもよい。
<Polyvinylpyrrolidone>
Polyvinylpyrrolidone is a water-soluble hydrophilic polymer obtained by vinyl polymerization of N-vinylpyrrolidone, and is widely used as a material for hollow fiber membranes as a hydrophilizing agent and a pore forming agent.
As polyvinylpyrrolidone, for example, several commercially available polyvinylpyrrolidones having a molecular weight of "Lubitec (trademark)" are commercially available from BSF Corporation, and these can be appropriately used.
As the polyvinylpyrrolidone, one kind may be used alone, or a mixture of two or more kinds may be used.
分離膜は、その構成成分として、ポリスルホン系高分子とポリビニルピロリドン以外の構成成分が含まれていてもよい。その他の構成成分としては、例えば、ポリヒドロキシエチルメタクリレート、ポリヒドロキシプロピルメタクリレート、ポリヒドロキシブチルメタクリレート等のポリヒドロキシアルキルメタクリレート、ポリエチレングリコールが挙げられる。その他の構成成分の含有量に限定はなく、２０質量％以下としてよいし、１０質量％以下としてもよいし、５質量％以下としてもよい。また、その他の構成成分を全く含まなくてもよい。
また、本実施形態の分離膜においては、ポリスルホン系高分子に対するポリビニルピロリドンの比率を２７質量％以下とすると、ポリビニルピロリドンの溶出量を抑制することができるので好ましい。より好適には、１８質量％以上とすることにより、分離膜表面のポリビニルピロリドン濃度を好適な範囲に制御でき、タンパク質吸着を抑制する効果を高められ、血液適合性に優れた血液処理用分離膜とすることができる。
The separation membrane may include a constituent component other than the polysulfone-based polymer and polyvinylpyrrolidone as the constituent component. Examples of other components include polyhydroxyethyl methacrylate, polyhydroxypropyl methacrylate, polyhydroxyalkyl methacrylate such as polyhydroxybutyl methacrylate, and polyethylene glycol. The content of the other constituent components is not limited, and may be 20% by mass or less, 10% by mass or less, or 5% by mass or less. Further, the other constituent components may not be contained at all.
Further, in the separation membrane of the present embodiment, it is preferable that the ratio of polyvinylpyrrolidone to the polysulfone-based polymer is 27% by mass or less because the elution amount of polyvinylpyrrolidone can be suppressed. More preferably, by setting the content to 18% by mass or more, the concentration of polyvinylpyrrolidone on the surface of the separation membrane can be controlled within a suitable range, the effect of suppressing protein adsorption can be enhanced, and the separation membrane for blood treatment is excellent in blood compatibility. Can be
分離膜の形状に限定はないが、分離膜は中空糸形状を有していることが好ましい。また、透過性能の観点からは、クリンプが付与されていることがさらに好ましい。 The shape of the separation membrane is not limited, but the separation membrane preferably has a hollow fiber shape. Further, from the viewpoint of the transmission performance, it is more preferable that crimp is provided.
次に、ポリメトキシエチルアクリレート（ＰＭＥＡ）を含む被膜について説明する。
ＰＭＥＡの血液適合性については、田中 賢，人工臓器の表面を生体適合化するマテリアル，ＢＩＯ ＩＮＤＵＳＴＲＹ，Ｖｏｌ２０，Ｎｏ．１２，５９−７０ ２００３ に詳細に述べられている。
その中で、ＰＭＥＡおよびその比較のために側鎖構造の異なる（メタ）アクリレート系ポリマーを作成し、血液を循環させたときの血小板，白血球，補体，凝固系の各種マーカーを評価したところ，「ＰＭＥＡ表面は他の高分子に比べて血液成分の活性化が軽微であった。また，ＰＭＥＡ表面はヒト血小板の粘着数が有意に少なく粘着血小板の形態変化が小さいことから血液適合性に優れる」と記載されている。
このように、ＰＭＥＡは、単に構造中にエステル基があるから血液適合性が良いというのではなく、その表面に吸着した水分子の状態が血液適合性に大きな影響を与えると考えられている。
Next, a coating containing polymethoxyethyl acrylate (PMEA) will be described.
Regarding blood compatibility of PMEA, Ken Tanaka, Material for biocompatible surface of artificial organ, BIO INDUSTRY, Vol 20, No. 12, 59-70 2003.
Among them, PMEA and (meth)acrylate polymers having different side chain structures were prepared for comparison, and various markers of platelets, leukocytes, complement and coagulation system when blood was circulated were evaluated. "The activation of blood components on PMEA surface was less than that of other macromolecules. In addition, PMEA surface has excellent blood compatibility because adhesion number of human platelets is significantly less and morphological change of adhesion platelets is small. It is described as ".
As described above, it is considered that PMEA is not simply good in blood compatibility because it has an ester group in its structure, but that the state of water molecules adsorbed on the surface of PMEA greatly affects blood compatibility.
このようにＰＭＥＡは生体適合性ポリマーとしては既知の物質であるが、これを表面に塗布した分離膜の血液適合性をより向上させるためには、表層におけるその存在量を多くすることが特に重要であることが分かった。 As described above, PMEA is a known substance as a biocompatible polymer, but in order to further improve the blood compatibility of the separation membrane applied to the surface thereof, it is particularly important to increase its abundance in the surface layer. It turned out that
ポリスルホン系高分子とポリビニルピロリドンを含有する分離膜はポーラス体であるため、その上にコート液を塗布すると、コート液が分離膜中へ孔を通じて浸透してしまう場合がある。特に、コート液の溶媒の種類によっては分離膜の孔径を大きくすることもあり、その場合には、浸透がより一層起こりやすくなる。
また、コート液の溶媒の種類によっては、コート液が分離膜上に塗布された際、その表面から流れ出てしまって、表面にとどまることができないこともある。
このように、分離膜上に塗布されたＰＭＥＡが、塗布後も分離膜の表層に存在する量には、コート時に用いられるＰＭＥＡを含むコート液の溶媒の種類と組成が影響すると考えられる。
すなわち、ＰＭＥＡを溶解したコート溶液は、ポーラスな分離膜の表面上に塗布された際に、そのまま表面にとどまってＰＭＥＡを表面にとどめるようなものであることが重要である。
Since the separation membrane containing the polysulfone-based polymer and polyvinylpyrrolidone is a porous body, when the coating solution is applied onto it, the coating solution may permeate into the separation membrane through the pores. In particular, the pore size of the separation membrane may be increased depending on the type of solvent of the coating liquid, and in that case, permeation is more likely to occur.
In addition, depending on the type of solvent of the coating liquid, when the coating liquid is applied onto the separation membrane, it may flow out from the surface and may not be able to stay on the surface.
Thus, it is considered that the amount and the composition of the solvent of the coating liquid containing PMEA used at the time of coating influences the amount of PMEA applied on the separation membrane that remains on the surface layer of the separation membrane after coating.
That is, it is important that the coating solution in which PMEA is dissolved is such that when it is applied on the surface of the porous separation membrane, it remains on the surface as it is and PMEA remains on the surface.
そして、本発明者らが鋭意研究したところ、コート液の溶媒が水と有機溶媒の混合物である場合、水と有機溶媒の混合比によって、ＰＭＥＡが表面にとどまる量が大きく変わることが分かった。
具体的には、有機溶媒の混合比率が小さいほど、ＰＭＥＡは分離膜表面にとどまりやすい傾向にある。その理由は明らかではないが、コート液の溶媒中の有機溶媒の混合比率が大きいと、ＰＭＥＡはコート液に良く溶解しているため、コート液を分離膜上にコートした時にＰＥＭＡも膜内に浸透し表面にとどまりにくいが、有機溶媒の混合比率が小さいと、ＰＭＥＡのコート液に対する溶解度が小さいため、コート液を分離膜上にコートした時に、有機溶媒が先に膜内に浸透するなどして溶媒中の有機溶媒／水のバランスが崩れると、ＰＭＥＡがコート液から析出し分離膜表面上に残るためではないかと推定される。
Then, as a result of intensive studies by the present inventors, it was found that when the solvent of the coating liquid is a mixture of water and an organic solvent, the amount of PMEA remaining on the surface largely changes depending on the mixing ratio of water and the organic solvent.
Specifically, the smaller the mixing ratio of the organic solvent, the easier the PMEA tends to stay on the surface of the separation membrane. Although the reason for this is not clear, when the mixing ratio of the organic solvent in the solvent of the coating liquid is large, PMEA is well dissolved in the coating liquid, so that when the coating liquid is coated on the separation membrane, PEMA also remains in the membrane. Although it does not easily permeate and stay on the surface, if the mixing ratio of the organic solvent is small, the solubility of PMEA in the coating solution is small, so when the coating solution is coated on the separation membrane, the organic solvent may first permeate into the membrane. If the balance of the organic solvent/water in the solvent is lost, PMEA is presumed to be deposited from the coating liquid and remain on the surface of the separation membrane.
また、ＡＴＲ−ＩＲ法においては、試料に入射した波は試料にわずかにもぐり込んで反射するため、このもぐり込み深さ領域の赤外吸収を測定できることが知られているところ、本発明者らは、このＡＴＲ−ＩＲ法の測定領域が、前述の「表層」の深さとほぼ等しいことも見出した。すなわち、ＡＴＲ−ＩＲ法の測定領域とほぼ等しい深さ領域における血液適合性が、その試料（血液処理用分離膜）の血液適合性を支配し、その領域にＰＭＥＡを特定量以上存在させることで（換言すると、ＡＴＲ−ＩＲによる赤外吸収曲線におけるＰＭＥＡ由来のピーク強度を用いてＰＭＥＡの量を規定することで）、一定の血液適合性を有する血液処理用分離膜を提供できることに想到し、本発明のより好ましい態様を完成させた。
なお、ＡＴＲ−ＩＲ法による測定領域は、空気中での赤外光の波長、入射角、プリズムの屈折率、試料の屈折率等に依存し，通常、膜表面から１μｍ以内の領域である。
In addition, in the ATR-IR method, since the wave incident on the sample slightly digs into the sample and is reflected, it is known that the infrared absorption in the digging depth region can be measured. It was also found that the measurement area of this ATR-IR method is almost equal to the depth of the above-mentioned "surface layer". That is, the blood compatibility in a depth region that is almost equal to the measurement region of the ATR-IR method controls the blood compatibility of the sample (separation membrane for blood treatment), and PMEA is present in that region in a specific amount or more. (In other words, by defining the amount of PMEA using the peak intensity derived from PMEA in the infrared absorption curve by ATR-IR), it is possible to provide a blood treatment separation membrane having a certain blood compatibility, A more preferred embodiment of the present invention has been completed.
The measurement region by the ATR-IR method depends on the wavelength of infrared light in the air, the incident angle, the refractive index of the prism, the refractive index of the sample, and the like, and is usually a region within 1 μm from the film surface.
ポリメトキシエチルメタクリレート（ＰＭＥＡ）が分離膜表面に存在することは、分離膜の熱分解ガスクロマトグラフ質量分析により確認できる。ＰＭＥＡの存在は分離膜の表面に対する全反射赤外吸収（ＡＴＲ−ＩＲ）測定で、赤外吸収曲線の１７３５ｃｍ-1付近にピークが見られれば推定されるが、この付近のピークは他の物質に由来する可能性もある。そこで、熱分解ガスクロマトグラフ質量分析を行い、ＰＭＥＡ由来の２−メトキシエタノールを確認することでＰＭＥＡと断定する。 The presence of polymethoxyethyl methacrylate (PMEA) on the surface of the separation membrane can be confirmed by thermal decomposition gas chromatography mass spectrometry of the separation membrane. The presence of PMEA is estimated by a total reflection infrared absorption (ATR-IR) measurement on the surface of the separation membrane, and a peak near 1735 cm -1 in the infrared absorption curve is estimated, but the peak near this peak is determined by other substances. May also be derived from. Therefore, pyrolysis gas chromatograph mass spectrometry is performed, and 2-methoxyethanol derived from PMEA is confirmed, so that it is determined to be PMEA.
本実施形態における血液処理用分離膜が実用上十分な血液適合性を示すには、ＡＴＲ−ＩＲで測定されるポリメトキシエチルメタクリレート（ＰＭＥＡ）由来のエステル基−Ｏ−Ｃ＝Ｏの赤外吸収ピーク（１７３５ｃｍ-1付近）のピーク強度Ｐ１のポリスルホン系高分子由来のＣ＝Ｃ（Ａｒ内のＣ＝Ｃ）の赤外吸収ピーク（１５９５ｃｍ-1付近）のピーク強度Ｐ２に対する比（Ｐ１／Ｐ２）が０．０５以上であることが好ましく、０．０７以上であることがより好ましく、さらに好ましくは、０．０９以上である。 In order for the separation membrane for blood treatment in the present embodiment to exhibit practically sufficient blood compatibility, infrared absorption of ester group —O—C═O derived from polymethoxyethyl methacrylate (PMEA) measured by ATR-IR. the ratio to the peak intensity P2 of the infrared absorption peak (1595Cm around -1) peak (C = C in Ar) C = C derived from a polysulfone-based polymer of the peak intensity P1 of (1735 cm around -1) (P1 / P2 ) Is preferably 0.05 or more, more preferably 0.07 or more, and further preferably 0.09 or more.
本実施形態の血液処理用分離膜の血液適合性が非常に優れている理由は明らかではないが、分離膜に含まれるポリビニルピロリドン（ＰＶＰ）とポリメトキシエチルメタクリレート（ＰＭＥＡ）との間に何等かの相互作用（例えば、ＰＶＰとＰＭＥＡの間の分子同士の絡み合い）によるアンカー効果が生じているためと推定される。 It is not clear why the separation membrane for blood treatment of the present embodiment is very excellent in blood compatibility, but there is something between the polyvinylpyrrolidone (PVP) and the polymethoxyethylmethacrylate (PMEA) contained in the separation membrane. It is presumed that the anchor effect is caused by the interaction (for example, the entanglement of molecules between PVP and PMEA).
前述のＰＭＥＡ由来のピーク（１７３５ｃｍ-1付近）とポリスルホン系高分子由来のピーク（１５９５ｃｍ-1付近）のピーク強度比（Ｐ１／Ｐ２）は、コーティング時に使用するコート液の溶媒の組成（具体的には有機溶媒と水の混合比）を変化させることにより調節することが出来る。具体的には、有機溶媒の量が多いほど、ＡＴＲ−ＩＲを実施したときのポリメトキシエチルメタクリレート（ＰＭＥＡ）由来のピーク（１７３５ｃｍ-1付近）のピーク強度Ｐ１は弱くなり、有機溶媒量が少ないほどＰＭＥＡ由来のピーク（１７３５ｃｍ-1付近）のピーク強度Ｐ２は強くなる。 The peak intensity ratio (P1/P2) between the peak derived from PMEA (around 1735 cm −1 ) and the peak derived from a polysulfone-based polymer (around 1595 cm −1 ) is the composition of the solvent of the coating solution used during coating (specifically Can be adjusted by changing the mixing ratio of the organic solvent and water). Specifically, the larger the amount of organic solvent, the weaker the peak intensity P1 of the polymethoxyethyl methacrylate (PMEA)-derived peak (around 1735 cm −1 ) when ATR-IR is performed, and the smaller the amount of organic solvent. The peak intensity P2 of the peak derived from PMEA (in the vicinity of 1735 cm −1 ) becomes stronger.
ポリメトキシエチルメタクリレート（ＰＭＥＡ）の溶媒に対する溶解性は特異なものがある。例えば、ＰＭＥＡは１００％エタノール溶媒には溶解しないが、水／エタノール混合溶媒にはその混合比によって溶解する領域がある。そして、その溶解する領域内の混合比では、水の量が多いほど、ＰＭＥＡ由来のピーク（１７３５ｃｍ-1付近）のピーク強度Ｐ１は強くなる。 The solubility of polymethoxyethyl methacrylate (PMEA) in a solvent has a unique one. For example, PMEA does not dissolve in 100% ethanol solvent, but the water/ethanol mixed solvent has a region in which it dissolves depending on the mixing ratio. Then, in the mixing ratio in the dissolving region, the peak intensity P1 of the peak derived from PMEA (around 1735 cm −1 ) becomes stronger as the amount of water increases.
ポリスルホン系高分子とポリビニルピロリドンを含む分離膜表面に、ＰＭＥＡを含む被膜をコートした場合の、ＰＭＥＡ含有被膜の分離膜上での存在状態については、透水性能のひとつの指標であるＵＦＲを測定することで評価することが出来る。
ＰＭＥＡを含む被膜で分離膜をコートした場合には、そのポーラスな膜表面の穴径の変化が小さいので、透水性能の変化があまりなく製品設計が簡単である。これはＰＭＥＡを含む被膜が、分離膜表面に極薄膜状に付着し、穴をあまり塞がない状態で分離膜をコートするためであると考えられる。
When the coating film containing PMEA is coated on the surface of the separation membrane containing the polysulfone-based polymer and polyvinylpyrrolidone, the UFR, which is one index of water permeability, is measured for the presence state of the PMEA-containing coating on the separation membrane. It can be evaluated by that.
When the separation membrane is coated with a coating containing PMEA, the change in pore diameter of the porous membrane surface is small, so that the water permeability does not change so much and product design is simple. It is considered that this is because the coating film containing PMEA adheres to the surface of the separation membrane in an extremely thin film state and coats the separation membrane in a state in which the holes are not blocked so much.
本実施形態において、ポリメトキシエチルメタクリレート（ＰＭＥＡ）重合体の重量平均分子量は、例えば、実施例に記載するように、ゲルパーミエーションクロマトグラフィー（ＧＰＣ）などにより測定することができる。
本実施形態において、分離膜の表面にＰＭＥＡを含む被膜を設ける方法としては、例えば、ＰＭＥＡを分離膜製膜時の製膜（紡糸）原液に混合溶解して紡糸する方法、ＰＭＥＡを分離膜製膜時の中空内液に混合溶解して紡糸する方法、及びＰＭＥＡを溶解したコート液を分離膜にコーティングする方法等が好適に用いられる。
これらの方法の中でも、ＰＭＥＡの製膜原液及び中空内液に対する溶解性を考慮すると、分離膜にコート液をコーティングするコーティング方法が最も適していると思われる。
In the present embodiment, the weight average molecular weight of the polymethoxyethyl methacrylate (PMEA) polymer can be measured, for example, by gel permeation chromatography (GPC) as described in Examples.
In the present embodiment, as a method of providing a coating film containing PMEA on the surface of the separation membrane, for example, a method of mixing and dissolving PMEA in a stock solution (spinning) at the time of forming the separation membrane and spinning it, A method of mixing and dissolving in a hollow liquid at the time of membrane and spinning, and a method of coating a separation membrane with a coating liquid in which PMEA is dissolved are preferably used.
Among these methods, the coating method of coating the separation membrane with the coating solution seems to be most suitable in view of the solubility of PMEA in the membrane-forming stock solution and the hollow internal solution.
ＰＭＥＡを溶解したコート液を分離膜にコーティングする方法としては、分離膜に対し、好適には、分離膜を製膜し血液処理器に組み込んで成型した後に、分離膜表面に対し、コート液を通液して接触させることにより、被覆させることができる。 As a method for coating the separation membrane with the coating solution in which PMEA is dissolved, preferably, the separation membrane is formed into a membrane, incorporated into a blood processor, and molded, and then the coating solution is applied to the surface of the separation membrane. It can be coated by passing it through and bringing it into contact.
本実施形態の血液処理用分離膜は、例えば、酸素濃度１５％以上の雰囲気でも、放射線滅菌によって滅菌処理を施すことができる。すなわち、血液処理用分離膜に放射線滅菌を施す際に、脱酸素剤を用いたり、窒素などの不活性ガスに置換したりして、酸素濃度を低下させる必要がなく、大気下で放射線滅菌を施すことができる。 The separation membrane for blood treatment of the present embodiment can be sterilized by radiation sterilization even in an atmosphere having an oxygen concentration of 15% or more. That is, when performing radiation sterilization on a blood treatment separation membrane, it is not necessary to use a deoxidant or replace it with an inert gas such as nitrogen to reduce the oxygen concentration, and to perform radiation sterilization in the atmosphere. Can be given.
次に、血液処理器について説明する。
本実施形態の血液処理器は、本実施形態の血液処理用分離膜が組み込まれている血液処理器であって、血液透析、血液ろ過、血液ろ過透析、血液成分分画、酸素付与、及び血漿分離などの体外循環式の血液浄化療法に用いることができる。本実施形態の血液処理器は、その血液処理用分離膜に大気下で放射線滅菌を施した場合であっても、分離膜に含まれるポリビニルピロリドンとＰＭＥＡとの間で何等かの相互作用（分子同士の絡み合いによるアンカー効果等）による強固な結びつきを成しているため、ＰＭＥＡ含有被膜が剥がれること等がなく、血液適合性が非常に良好である。
Next, the blood processor will be described.
The blood processor of the present embodiment is a blood processor in which the separation membrane for blood processing of the present embodiment is incorporated, and is hemodialysis, hemofiltration, hemodiafiltration, blood component fractionation, oxygenation, and plasma. It can be used for extracorporeal blood purification therapy such as separation. In the blood treatment apparatus of the present embodiment, even if the separation membrane for blood treatment is subjected to radiation sterilization in the atmosphere, some interaction (molecules) between polyvinylpyrrolidone and PMEA contained in the separation membrane is Since a strong bond is formed due to the anchor effect due to the entanglement of each other), the PMEA-containing coating is not peeled off and the blood compatibility is very good.
血液処理器は、血液透析器、血液ろ過器、血液ろ過透析器等において好ましく用いられ、これらの持続的用途である、持続式血液透析器、持続式血液ろ過器、持続式血液ろ過透析器として用いることがより好適である。各用途に応じて、分離膜の寸法や分画性等の詳細仕様が決定される。 The blood processor is preferably used in a hemodialyzer, a hemofilter, a hemofilter dialyzer, etc., and is a continuous use of these, as a continuous hemodialyzer, a continuous hemofilter, a continuous hemofilter dialyzer. It is more preferable to use. Detailed specifications such as the size and fractionation of the separation membrane are determined according to each application.
次に、本実施形態の血液処理器の製造方法について説明する。
本実施形態の血液処理用分離膜の製造方法は、少なくともポリスルホン系高分子とポリビニルピロリドンを含む分離膜を製膜する工程と、前記分離膜の表面に、ポリメトキシエチルアクリレート（ＰＭＥＡ）、水及び有機溶媒を含有するコート液をコーティングする工程と、を含む。
さらに、分離膜の水分含有率を１０質量％以下に乾燥する工程や、血液処理用分離膜を酸素濃度が１５％以上の雰囲気下で放射線滅菌する工程を含むこともできる。
Next, a method for manufacturing the blood processing device of this embodiment will be described.
The method for producing a separation membrane for blood treatment of the present embodiment comprises a step of forming a separation membrane containing at least a polysulfone-based polymer and polyvinylpyrrolidone, and polymethoxyethyl acrylate (PMEA), water, and water on the surface of the separation membrane. Coating with a coating liquid containing an organic solvent.
Furthermore, it is possible to include a step of drying the water content of the separation membrane to 10% by mass or less, and a step of sterilizing the blood treatment separation membrane with radiation in an atmosphere having an oxygen concentration of 15% or more.
分離膜は、少なくともポリスルホン系高分子とポリビニルピロリドンを含む製膜原液を用いて、通常の方法により製膜することにより用意することができる。
製膜原液としては、ポリスルホン高分子とポリビニルピロリドンを溶媒に溶解することによって調製することができる。
かかる溶媒としては、例えば、ジメチルアセトアミド、ジメチルスルホキシド、Ｎ−メチル−２−ピロリドン、ジメチルホルムアミド、スルホラン、及びジオキサンなどが挙げられる。
溶媒としては、１種を単独で用いてもよく、２種以上の混合溶媒を用いてもよい。
The separation membrane can be prepared by forming a membrane by a usual method using a membrane-forming stock solution containing at least a polysulfone-based polymer and polyvinylpyrrolidone.
The stock solution for film formation can be prepared by dissolving a polysulfone polymer and polyvinylpyrrolidone in a solvent.
Examples of such a solvent include dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, and dioxane.
As the solvent, one type may be used alone, or a mixed solvent of two or more types may be used.
製膜原液中のポリスルホン系高分子の濃度は、製膜可能で、かつ得られた膜が透過膜としての性能を有するような濃度の範囲であれば特に制限されないが、５〜３５質量％であることが好ましく、１０〜３０質量％であることがより好ましい。高い透水性能を達成する場合にはポリスルホン系樹脂濃度は低い方がよく、１０〜２５質量％であることがさらに好ましい。 The concentration of the polysulfone-based polymer in the membrane-forming undiluted solution is not particularly limited as long as it is within the concentration range such that the membrane can be formed and the obtained membrane has performance as a permeable membrane, but is 5 to 35% by mass. It is preferably present, and more preferably 10 to 30% by mass. In order to achieve high water permeability, the polysulfone resin concentration is preferably low, and more preferably 10 to 25% by mass.
製膜原液中のポリビニルピロリドン濃度に限定はないが、例えば、ポリスルホン系高分子に対するポリビニルピロリドンの比率（ポリビニルピロリドンの質量／ポリスチレン系高分子の質量）が好ましくは２７質量％以下、より好ましくは１８〜２７質量％、さらに好ましくは２０〜２７質量％となるように調整することが好ましい。
ポリスルホン系高分子に対するポリビニルピロリドンの比率を２７質量％以下とすることにより、ポリビニルピロリドンの溶出量を抑制することができる。また、好適には、１８質量％以上とすることにより、分離膜表面のポリビニルピロリドン濃度を好適な範囲に制御でき、タンパク質吸着を抑制する効果を高められ、血液適合性に優れた血液処理用分離膜とすることができる。
The concentration of polyvinylpyrrolidone in the film-forming stock solution is not limited, but for example, the ratio of polyvinylpyrrolidone to polysulfone-based polymer (mass of polyvinylpyrrolidone/mass of polystyrene-based polymer) is preferably 27% by mass or less, more preferably 18 It is preferable to adjust the content to be ~27% by mass, more preferably 20 to 27% by mass.
When the ratio of polyvinylpyrrolidone to the polysulfone-based polymer is 27% by mass or less, the elution amount of polyvinylpyrrolidone can be suppressed. Further, preferably, by setting it to 18% by mass or more, the concentration of polyvinylpyrrolidone on the surface of the separation membrane can be controlled within a suitable range, the effect of suppressing protein adsorption can be enhanced, and the separation for blood treatment is excellent in blood compatibility. It can be a membrane.
以上のような製膜原液を用いて、通常用いられている方法により平膜や中空糸膜の分離膜を製膜することができる。
中空糸膜の製造方法の一例を説明する。
チューブインオリフィス型の紡糸口金を用い、該紡糸口金のオリフィスからは製膜紡糸原液を、チューブからは該製膜紡糸原液を凝固させる為の中空内液を、同時に空中に吐出させる。中空内液としては、水や水を主体とした液体が使用でき、一般的には製膜紡糸原液に使った溶剤と水との混合溶液が好適に使用される。例えば、２０〜７０質量％のジメチルアセトアミド水溶液などが用いられる。
製膜紡糸原液吐出量と中空内液吐出量を調整することにより中空糸膜の内径と膜厚を所望の値に調整することができる。
A separation membrane such as a flat membrane or a hollow fiber membrane can be formed by a commonly used method using the above membrane-forming stock solution.
An example of the method for manufacturing the hollow fiber membrane will be described.
A tube-in-orifice type spinneret is used. From the orifice of the spinneret, a film-forming spinning solution is discharged from the tube, and a hollow liquid for coagulating the film-forming spinning solution is simultaneously discharged into the air. As the hollow internal liquid, water or a liquid containing water as a main component can be used, and generally, a mixed solution of the solvent used for the membrane-forming spinning solution and water is preferably used. For example, a 20 to 70 mass% dimethylacetamide aqueous solution or the like is used.
The inner diameter and the film thickness of the hollow fiber membrane can be adjusted to desired values by adjusting the discharge rate of the stock solution for membrane spinning and the discharge rate of the liquid inside the hollow fiber.
中空糸膜の内径は、特に限定はないが、血液処理用途においては一般に１７０〜２５０μｍであればよく、１８０〜２２０μｍであることが好ましい。透過膜としての物質移動抵抗による低分子量物の拡散除去の効率の観点から、中空糸膜の膜厚は５０μｍ以下であることが好ましい。
また強度の観点からは１０μｍ以上であることがより好ましい。
The inner diameter of the hollow fiber membrane is not particularly limited, but it is generally 170 to 250 μm, and preferably 180 to 220 μm in blood processing applications. The thickness of the hollow fiber membrane is preferably 50 μm or less from the viewpoint of the efficiency of diffusion and removal of low molecular weight substances due to the mass transfer resistance of the permeable membrane.
From the viewpoint of strength, it is more preferably 10 μm or more.
紡糸口金から中空内液とともに吐出された製膜紡糸原液は、エアーギャップ部を走行させられ、次いで、紡糸口金下部に設置された水を主体とする凝固浴中へ導入され、一定時間浸漬されて、その凝固が完了する。このとき、製膜紡糸原液吐出線速度と引取速度の比で表されるドラフトが１以下であることが好ましい。
なお、エアーギャップとは、紡糸口金と凝固浴との間の空間を意味し、製膜紡糸原液は紡糸口金から同時に吐出された中空内液中の水などの貧溶媒成分（ポリスルホン系高分子及びポリビニルピロリドンに対する貧溶媒成分）によって、内表面側から凝固が開始する。凝固開始時に平滑な分離膜表面を形成し、分離膜構造を安定にするためには、ドラフトは１以下が好ましく、より好ましくは０．９５以下である。
The film-forming spinning solution discharged from the spinneret together with the hollow inner solution is run through the air gap part, then introduced into a water-based coagulation bath installed under the spinneret, and immersed for a certain period of time. , Its solidification is complete. At this time, it is preferable that the draft represented by the ratio of the linear velocity of the film-forming spinning solution discharge and the take-up velocity is 1 or less.
The air gap means the space between the spinneret and the coagulation bath, and the film-forming spinning solution is a poor solvent component such as water in the hollow internal liquid discharged simultaneously from the spinneret (polysulfone-based polymer and Coagulation starts from the inner surface side due to the poor solvent component for polyvinylpyrrolidone). In order to form a smooth separation membrane surface at the start of solidification and stabilize the separation membrane structure, the draft is preferably 1 or less, more preferably 0.95 or less.
ついで熱水等による洗浄によって中空糸膜に残留している溶媒を除去した後、連続的に乾燥機内に導き、熱風などにより乾燥した中空糸膜を得ることができる。洗浄は不要なポリビニルピロリドンを除去するため、６０℃以上の熱水にて１２０秒以上実施することが好ましく、７０℃以上の熱水にて１５０秒以上洗浄することがより好ましい。 Then, the solvent remaining in the hollow fiber membrane is removed by washing with hot water or the like, and then the hollow fiber membrane can be continuously introduced into a dryer to obtain a dried hollow fiber membrane with hot air or the like. In order to remove unnecessary polyvinylpyrrolidone, the washing is preferably performed with hot water at 60° C. or higher for 120 seconds or more, and more preferably with hot water at 70° C. or higher for 150 seconds or more.
後工程においてウレタン樹脂で包埋するため、また、本実施の形態においては、ドライ状態で放射線滅菌を行うために、乾燥により分離膜の水分含有率を１０質量％以下とするのが好ましい。 In order to embed in a urethane resin in a subsequent step, and in this embodiment, in order to perform radiation sterilization in a dry state, it is preferable to set the water content of the separation membrane to 10% by mass or less by drying.
以上の工程を経て得られた中空糸膜は、所望の膜面積となるように、長さと本数を調整した束としてモジュール製造工程に供することができる。この工程では、中空糸膜は側面の両端部付近に２本のノズルを有する筒状容器に充填され、両端部がウレタン樹脂で包埋される。
次に両端の硬化したウレタン部分を切断して中空糸膜が開口（露出）した端部に加工する。この両端部に、液体導入（導出）用のノズルを有するヘッダーキャップを装填して血液処理器の形状に組み上げる。
以上のようにしてモジュールを組み立てた後、ＰＭＥＡを含むコート液を中空糸膜内に注入することにより、分離膜表面にポリビニルピロリドンを含む被膜を形成することもできる。
The hollow fiber membrane obtained through the above steps can be subjected to the module manufacturing step as a bundle of which the length and the number are adjusted so that the desired membrane area is obtained. In this step, the hollow fiber membrane is filled in a tubular container having two nozzles near both ends of the side surface, and both ends are embedded with urethane resin.
Next, the cured urethane portions on both ends are cut to form the ends where the hollow fiber membrane is opened (exposed). A header cap having a nozzle for introducing (outleting) a liquid is loaded on both ends thereof to be assembled into a blood processing device.
After assembling the module as described above, it is also possible to form a coating film containing polyvinylpyrrolidone on the surface of the separation membrane by injecting a coating solution containing PMEA into the hollow fiber membrane.
次に、分離膜の表面に、ＰＭＥＡを含む被膜を形成する方法について詳述する。
本実施形態においては、例えば、分離膜の表面に、ＰＭＥＡを含むコート液を塗布することによって、被膜を形成することができる。
Next, a method for forming a film containing PMEA on the surface of the separation film will be described in detail.
In this embodiment, for example, a coating film can be formed by applying a coating solution containing PMEA to the surface of the separation membrane.
コート液は、ポリスルホン系高分子を溶解しない溶媒であって、ＰＭＥＡを溶解する又は分散させることのできるものであれば特に限定されるものではないが、工程の安全性や、続く乾燥工程での取り扱いの良さから、水やアルコール水溶液が好ましい。沸点、毒性の観点から、水、エタノール水溶液、メタノール水溶液、及び、イソプロピルアルコール水溶液などが好適に用いられる。
なお、コート液の溶媒の種類、溶媒の組成については、前述したように被塗布基材である分離膜との関係も含めて考慮する必要がある。
The coating liquid is not particularly limited as long as it is a solvent that does not dissolve the polysulfone-based polymer and can dissolve or disperse PMEA. However, the safety of the process and the subsequent drying process From the viewpoint of easy handling, water or an aqueous alcohol solution is preferable. From the viewpoint of boiling point and toxicity, water, ethanol aqueous solution, methanol aqueous solution, isopropyl alcohol aqueous solution and the like are preferably used.
In addition, it is necessary to consider the type of solvent of the coating liquid and the composition of the solvent, including the relationship with the separation membrane that is the substrate to be coated, as described above.
コート液のＰＭＥＡの濃度に限定はないが、例えば、コート液の０．００１質量％〜１質量％とすることができ、０．００５質量％〜０．２質量％であることがより好ましい。
コート液の塗布方法に限定はないが、例えば、ノズルを有するヘッダーキャップより分離膜上に注入し、次いで、圧縮空気を用いて余分な溶液を除去する方法を採用することができる。
塗布後、乾燥を行うことが好ましく、乾燥方法に制限はないが、恒量となるまで減圧乾燥してもよいし、加熱乾燥してもよい。加熱乾燥の温度は、モジュールの部材が劣化しない温度であれば、工程の時間との兼ね合いだけなので、適宜設定すればよい。
The concentration of PMEA in the coating liquid is not limited, but can be, for example, 0.001% by mass to 1% by mass of the coating liquid, and more preferably 0.005% by mass to 0.2% by mass.
The method of applying the coating liquid is not limited, but, for example, a method of injecting the coating liquid onto the separation membrane from a header cap having a nozzle and then removing the excess solution using compressed air can be adopted.
Drying is preferably performed after coating, and the drying method is not limited, but may be dried under reduced pressure until it reaches a constant weight, or may be dried by heating. The temperature for heating and drying may be set as appropriate as long as it is a temperature at which the members of the module are not deteriorated, since it only depends on the process time.
以上のようにして得られたＰＭＥＡを分離膜表面に有する血液処理用分離膜には、放射線滅菌処理を施すことができる。放射線滅菌処理を行う雰囲気に限定はなく、酸素濃度１５％以上の雰囲気で、さらには大気下でも、分離膜の変性等を引き起こすことなく放射線滅菌を施すことができる。 The blood treatment separation membrane having the PMEA thus obtained on the surface of the separation membrane can be subjected to radiation sterilization treatment. The atmosphere in which the radiation sterilization treatment is performed is not limited, and the radiation sterilization can be performed in an atmosphere having an oxygen concentration of 15% or more, and even in the atmosphere without causing denaturation of the separation membrane.
放射線滅菌法には、電子線、ガンマ線、エックス線等を用いることができ、いずれを用いてもよい。放射線の照射線量は、電子線やガンマ線の場合は、通常１５〜５０Ｋｇｙであり、２０〜４０Ｋｇｙの線量範囲で照射することが好ましい。このような放射線滅菌等の滅菌工程を経て、血液処理器として完成する。 Electron beams, gamma rays, X-rays and the like can be used in the radiation sterilization method, and any of them may be used. The irradiation dose of radiation is usually 15 to 50 Kgy in the case of electron beam or gamma ray, and it is preferable to irradiate in the dose range of 20 to 40 Kgy. Through such a sterilization process such as radiation sterilization, a blood processor is completed.
以下に実施例及び比較例を示し、本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
（１）赤外ＡＴＲ（全反射法）測定
サンプルの手順は以下のようにした。
中空糸形状分離膜の内表面を蒸留水で１．５ｍ2あたり１００ｍｌ／ｍｉｎで５分間洗浄することによりプライミングを行った。プライミング後の血液処理器を分解してサンプリングした中空糸を剃刀で開き中空糸分離膜表面を上向きにしてその部分にプリズムを圧しあて赤外ＡＴＲ測定を行った。（６５０ｃｍ-1〜４０００ｃｍ-1）
ＰＭＥＡ由来の１７３５ｃｍ-1付近のエステル基−Ｏ−Ｃ＝Ｏの赤外吸収ピークのピーク強度面積（１７１５ｃｍ-1と１７５５ｃｍ-1をベースラインとしたピーク面積）をＰ１、ポリスルホン由来の１５９５ｃｍ-1付近のＣ＝Ｃの赤外吸収ピークのピーク強度面積（１５５５ｃｍ-1と１６２０ｃｍ-1をベースラインとしたピーク面積）をＰ２とし、Ｐ１／Ｐ２の比から分離膜表面のＰＭＥＡの存在量を測定した。
The present invention will be specifically described below with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.
(1) Infrared ATR (total reflection method) measurement The sample procedure was as follows.
Priming was performed by washing the inner surface of the hollow fiber shape separation membrane with distilled water at 100 ml/min for 5 minutes per 1.5 m 2 . After priming, the blood processor was disassembled and the hollow fibers sampled were opened with a razor, the surface of the hollow fiber separation membrane was faced upward, and a prism was pressed against that portion for infrared ATR measurement. (650 cm -1 to 4000 cm -1 )
The peak intensity area (peak area with 1715 cm −1 and 1755 cm −1 as a baseline) of infrared absorption peak of ester group —O—C═O near 1735 cm −1 derived from PMEA is P1, and 1595 cm −1 derived from polysulfone. The peak intensity area (peak area with 1555 cm −1 and 1620 cm −1 as a baseline) of the infrared absorption peak of C=C in the vicinity is defined as P2, and the amount of PMEA present on the surface of the separation membrane is measured from the ratio of P1/P2. did.
（２）熱分解ガスクロマトグラフ質量分析
以下の装置を用いて、以下の条件にて熱分解ガスクロマトグラフ質量分析を行った。
装置名 Ａｇｉｌｅｎｔ ５９７３Ｎ−ＭＳＤ（アジレント製）
熱分解装置名 ダブルショットパイロライザーＰｙ−２０２０ｉＤ（フロンティア・ラボ製）
カラム名 ＨＰ−５ＭＳ
カラム概要 長さ３０ｍ、内径０．２５ｍｍ、膜厚０．２５μｍ、フェニルメチルシロキサン膜
熱分解温度／時間 ６００°Ｃ ０秒
熱分解装置インターフェース温度 ３２０°Ｃ
ＧＣインジェクション温度 ３２０°Ｃ
ＧＣオーブン初期温度／保持時間 ４０°Ｃ／３分
ＧＣオーブン昇温速度 １０°Ｃ／分
ＧＣオーブン到達温度／保持時間 ３００°Ｃ／０分
ＭＳトランスファーライン温度 ３００°Ｃ
ＭＳイオン化源温度 ２３０°Ｃ
ＭＳ四重極温度 １５０°Ｃ
ＭＳイオン化電圧／電流 ７０ｅＶ／３５μＡ
ＭＳスキャン範囲 ２９−５５０
(2) Pyrolysis gas chromatograph mass spectrometry Pyrolysis gas chromatograph mass spectrometry was performed using the following apparatus under the following conditions.
Device name Agilent 5973N-MSD (manufactured by Agilent)
Pyrolysis device name Double shot pyrolyzer Py-2020iD (manufactured by Frontier Lab)
Column name HP-5MS
Column overview Length 30m, inner diameter 0.25mm, film thickness 0.25μm, phenylmethylsiloxane membrane Pyrolysis temperature/hour 600°C 0 seconds Pyrolysis device interface temperature 320°C
GC injection temperature 320°C
GC oven initial temperature/holding time 40°C/3 minutes GC oven temperature raising rate 10°C/minute GC oven temperature reached/holding time 300°C/0 minutes MS transfer line temperature 300°C
MS ionization source temperature 230°C
MS quadrupole temperature 150°C
MS ionization voltage/current 70 eV/35 μA
MS scan range 29-550
（３）ＵＦＲ（ｍｌ／Ｈｒ・ｍｍＨｇ）の測定
血液処理器の血液側入り口（ｂｉｎ）から血液側出口（ｂｏｕｔ）へ元液（Ｕｒｅａ＝１０００ｐｐｍ，ＶＢ−１２（ビタミンＢ１２）＝１０ｐｐｍ／純水）を１００ｍｌ／ｍｉｎで流し、透析液側入り口（ｄｉｎ）から透析液側出口（ｄｏｕｔ）へ、純水を元液と交差する方向に５００ｍｌ／ｍｉｎで流した。
ＵＦＲは以下の式で表される。
ＵＦＲ（ｍｌ／Ｈｒ・ｍｍＨｇ）
＝｛ｂｉｎの流量（ｍｌ／ｍｉｎ）×６０（ｍｉｎ／Ｈｒ）×ＵＦＲ係数｝／ＴＭＰ
＝｛１００×６０×ＵＦＲ係数｝／ＴＭＰ
ここで、ＵＦＲ係数はUFＲ測定値を算出する場合の基準圧力である。また、ＴＭＰ（ｍｍＨｇ）は血液側出口（ｂｏｕｔ）部をストップさせた時に血液処理用分離膜にかかる圧力であって、以下の式で表される。
ＴＭＰ＝｛（Ｐｂｉｎ＋Ｐｂｏｕｔ）−（Ｐｄｉｎ＋Ｐｄｏｕｔ）｝／２
(3) Measurement of UFR (ml/Hr·mmHg) From the blood side inlet (bin) to the blood side outlet (bout) of the blood processor, the original solution (Urea=1000 ppm, VB-12 (vitamin B12)=10 ppm/pure water) ) At a flow rate of 100 ml/min, and pure water was flowed from the dialysate side inlet (din) to the dialysate side outlet (dout) at a rate of 500 ml/min in a direction intersecting with the original solution.
UFR is represented by the following formula.
UFR (ml/Hr·mmHg)
={bin flow rate (ml/min)×60 (min/Hr)×UFR coefficient}/TMP
={100×60×UFR coefficient}/TMP
Here, the UFR coefficient is a reference pressure when calculating the UFR measurement value. Further, TMP (mmHg) is a pressure applied to the blood treatment separation membrane when the blood side outlet (bout) portion is stopped, and is represented by the following formula.
TMP={(Pbin+Pbout)-(Pdin+Pdout)}/2
（４）接触角の測定
中空糸形状分離膜の内表面を蒸留水で１．５ｍ2あたり１００ｍｌ／ｍｉｎで５分間洗浄することによりプライミングを行った。プライミング後の血液処理器を分解してサンプリングした中空糸を剃刀で開き、中空糸分離膜表面を上向きにして接触角を測定した。
次いで、１．５ｍ2あたり１００ｍｌ／ｍｉｎで５分間洗浄するプライミングを５回繰り返し、中空糸分離膜表面の接触角の変化の有無を確認した。
(4) Measurement of contact angle Priming was carried out by washing the inner surface of the hollow fiber shape separation membrane with distilled water for 5 minutes at 100 ml/min per 1.5 m 2 . The blood processing device after priming was disassembled and the hollow fiber sampled was opened with a razor, and the contact angle was measured with the surface of the hollow fiber separation membrane facing upward.
Then, priming of washing at 100 ml/min for 5 minutes per 1.5 m 2 was repeated 5 times to confirm whether or not the contact angle on the surface of the hollow fiber separation membrane changed.
（５）ＰＭＥＡ（ポリメトキシエチルアクリレート）の作製
２−メトキシエチルアクリレート１５ｇを１，４−ジオキサン６０ｇ中でアゾビスイソブチロニトリル（０．１重量％）を開始剤として、窒素バブリングしながら７５℃で１０時間重合を行った。重合反応終了後、得られた重合溶液をｎ−ヘキサンに滴下し、生成物を沈殿させ、単離した。得られた生成物をテトラヒドロフランに溶解し、さらに２回ｎ−ヘキサンを用いて精製を行った。精製物を一昼夜減圧乾燥した。無色透明で水飴状のポリマーが得られた。収量（収率）は１２．３ｇ（８２．０％）であった。
得られたポリマー構造は、１Ｈ−ＮＭＲによって確認した。
また、ＧＰＣの分子量分析の結果から、その数平均分子量（Ｍｎ）は２０，０００であり、分子量分布（Ｍｗ／Ｍｎ）は２．４であった。
(5) Preparation of PMEA (polymethoxyethyl acrylate) 15 g of 2-methoxyethyl acrylate was used in 60 g of 1,4-dioxane with azobisisobutyronitrile (0.1% by weight) as an initiator while bubbling nitrogen to 75. Polymerization was carried out at 10°C for 10 hours. After the completion of the polymerization reaction, the obtained polymerization solution was added dropwise to n-hexane to precipitate the product and isolate it. The obtained product was dissolved in tetrahydrofuran and further purified twice using n-hexane. The purified product was dried under reduced pressure overnight. A colorless and transparent starch syrup-like polymer was obtained. The amount (yield) was 12.3 g (82.0%).
The obtained polymer structure was confirmed by 1H-NMR.
Moreover, the number average molecular weight (Mn) was 20,000 and the molecular weight distribution (Mw/Mn) was 2.4 from the result of the molecular weight analysis of GPC.
（６）ＰＭＥＡの溶媒との溶解性の確認
コート液を作製するため、ＰＭＥＡの溶媒との溶解性を確認した。結果を以下の表に示す。エタノール／水系とメタノール／水系とでは、ＰＭＥＡの溶解性に違いがあることがわかった。
(6) Confirmation of Solubility of PMEA with Solvent To prepare a coating liquid, the solubility of PMEA with a solvent was confirmed. The results are shown in the table below. It was found that there is a difference in the solubility of PMEA between the ethanol/water system and the methanol/water system.
（７）血液適合性 乳酸脱水酵素（ＬＤＨ）活性の測定と残血本数
分離膜の血液適合性は、膜表面への血小板の付着性で評価し、膜に付着した血小板に含まれる乳酸脱水素酵素（ＬＤＨ）の活性を指標として定量化した。
生理食塩水（大塚生食注、大塚製薬株式会社）にて血液処理器を洗浄することにより、プライミングを行った。プライミング後の血液処理器を分解して採取した分離膜を有効長１５ｃｍ、膜内表面の面積が５×１０-3ｍ2となるように両端をシリコンで加工し、ミニモジュールを作製した。このミニモジュールに対し、生理食塩水１０ｍｌを中空糸内側に流し洗浄した。
その後、ヘパリン加人血１５ｍｌ（ヘパリン１０００ＩＵ／Ｌ）を１．３ｍｌ／ｍｉｎの流速で上記作製したミニモジュールに３７℃で４時間循環させた。生理食塩水によりミニモジュールの内側を１０ｍｌ、外側を１０ｍｌでそれぞれ洗浄した。洗浄したミニモジュールから長さ７ｃｍの中空糸膜を全体の半数本採取後、これを細断してＬＤＨ測定用のスピッツ管に入れたものを測定用試料とした。またミニモジュール中の中空糸に残血（血液が中空糸の中で凝固したもの）が何本発生しているかを目視で判断した。
次に、燐酸緩衝溶液（ＰＢＳ）（和光純薬工業株式会社）にＴｒｉｔｏｎＸ−１００（ナカライテスク株式会社）を溶解して得た０．５容量％のＴｒｉｔｏｎＸ−１００／ＰＢＳ溶液をＬＤＨ測定用のスピッツ管に０．５ｍｌ添加後、振とう処理を６０分行って分離膜に付着した細胞（主に血小板）を破壊し、細胞中のＬＤＨを抽出した。この抽出液を０．０５ｍｌ分取し、さらに０．６ｍＭのピルビン酸ナトリウム溶液２．７ｍｌ、１．２７７ｍｇ／ｍｌのニコチンアミドアデニンジヌクレオチド（ＮＡＤＨ）溶液０．３ｍｌを加えて３７℃で１時間反応させた後にその３４０ｎｍの吸光度を測定した。
同様に血液と反応させていない分離膜（ブランク）についても同様に吸光度を測定し、下記式により吸光度の差△Ａｂｓ（３４０ｎｍ）／Ｈｒを算出した。
△Ａｂｓ（３４０ｎｍ）／Ｈｒ
＝［ブランク（血液非接触膜）の１Ｈｒ後のＡｂｓ（３４０ｎｍ）］−［サンプル（血液接触膜）の１Ｈｒ後のＡｂｓ（３４０ｎｍ）］
そして、ポリスルホン系高分子とポリビニルピロリドンを含有する分離膜単体（今回は比較例1）についても同様にコントロールサンプルとして△Ａｂｓ（３４０ｎｍ）／Ｈｒを測定し、その値を１００とした場合の比例値を算出した。
本方法では、この比例値を各サンプルのＬＤＨ活性とした。ＬＤＨ活性が高いと、膜表面への血小板の付着量が多く、血液適合性が低いことを意味する。尚、測定は３回行い、その平均値として記載した。
血液適合性が優れる分離膜としては、ＬＤＨ活性が５以下のものが好ましく、ＬＤＨ活性が２以下のものは血液適合性が非常に優れると判断できる。
(7) Blood compatibility Measurement of lactate dehydrogenase (LDH) activity and residual blood count The blood compatibility of the separation membrane was evaluated by the adhesion of platelets to the membrane surface, and lactate dehydrogenation contained in the platelets attached to the membrane. The activity of the enzyme (LDH) was quantified as an index.
Priming was performed by washing the blood processor with a physiological saline solution (Otsuka raw food injection, Otsuka Pharmaceutical Co., Ltd.). The separation membrane collected by disassembling the blood processing device after priming was processed with silicon at both ends so that the effective length was 15 cm and the area of the inner surface of the membrane was 5×10 −3 m 2 , to produce a mini module. The mini module was washed by pouring 10 ml of physiological saline into the hollow fiber.
Then, 15 ml of heparinized blood (1000 IU/L of heparin) was circulated at 37° C. for 4 hours in the mini-module prepared above at a flow rate of 1.3 ml/min. The inside of the mini module was washed with 10 ml and the outside was washed with 10 ml with physiological saline. A 7 cm-long hollow fiber membrane was collected from the washed mini-module, half of the whole was cut into small pieces, and the pieces were placed in a Spitz tube for LDH measurement to obtain a measurement sample. Further, it was visually determined how many residual blood (blood coagulated in the hollow fiber) was generated in the hollow fiber in the mini-module.
Next, 0.5 volume% of Triton X-100/PBS solution obtained by dissolving Triton X-100 (Nacalai Tesque, Inc.) in a phosphate buffer solution (PBS) (Wako Pure Chemical Industries, Ltd.) was used for LDH measurement. After adding 0.5 ml to the Spitz tube, shaking treatment was performed for 60 minutes to destroy cells (mainly platelets) attached to the separation membrane, and extract LDH in the cells. 0.05 ml of this extract was taken, 2.7 ml of 0.6 mM sodium pyruvate solution and 0.3 ml of 1.277 mg/ml nicotinamide adenine dinucleotide (NADH) solution were added, and the mixture was kept at 37° C. for 1 hour. After the reaction, the absorbance at 340 nm was measured.
Similarly, the absorbance was similarly measured for the separation membrane (blank) that was not reacted with blood, and the absorbance difference ΔAbs (340 nm)/Hr was calculated by the following formula.
ΔAbs (340 nm)/Hr
= [Abs (340 nm) after 1 Hr of blank (blood non-contact membrane)]-[Abs (340 nm) after 1 Hr of sample (blood contact membrane)]
Then, for the separation membrane simple substance containing the polysulfone-based polymer and polyvinylpyrrolidone (Comparative Example 1 this time), ΔAbs (340 nm)/Hr was similarly measured as a control sample, and the proportional value when the value was set to 100 Was calculated.
In this method, this proportional value was used as the LDH activity of each sample. A high LDH activity means that the amount of platelets attached to the membrane surface is large and blood compatibility is low. The measurement was performed 3 times and the average value was shown.
As the separation membrane having excellent blood compatibility, those having LDH activity of 5 or less are preferable, and those having LDH activity of 2 or less can be judged to have very excellent blood compatibility.
（実施例１）
製膜紡糸原液は、ジメチルアセトアミド（キシダ化学社製、試薬特級）７９質量部にポリスルホン（ソルベイ社製、Ｐ−１７００）１７質量部及びポリビニルピロリドン（ビーエーエスエフ社製、Ｋ−９０）４質量部を溶解して作製した。
中空内液は、ジメチルアセトアミド６０質量％水溶液を使用した。
チューブインオリフィス型の紡糸口金から、製膜紡糸原液及び中空内液を吐出させた。吐出時の製膜紡糸原液の温度は４０℃とした。吐出した製膜紡糸原液をフードで覆った落下部を経て水よりなる６０℃の凝固浴に浸漬して凝固させた。紡糸速度は３０ｍ／分とした。
凝固後、水洗、乾燥を行って中空形状分離膜を得た。水洗温度は９０℃、水洗時間は１８０秒とした。なお、乾燥後の膜厚が３５μｍ、内径が１８５μｍとなるように製膜紡糸原液及び中空内液の吐出量を調整した。
得られた中空糸分離膜を血液処理器に組み込んで成型し、有効面積１．５ｍ2のモジュールを組み上げた。次いでＰＭＥＡ（Ｍｎ２０，０００，Ｍｗ／Ｍｎ２．４）０．１ｇをエタノール４０ｇ／水６０ｇの水溶液（１００ｇ）中に溶解させ、コート液を作製した。組み立てたモジュールを垂直に把持しその上部からコート液を流速１００ｍｌ／ｍｉｎ流し分離膜表面にコート液を接触させた。
コート液接触後、０．１ＫＭｐａのエアーでモジュール内のコート液を吹き飛ばし、真空乾燥機内にモジュールを入れて３５℃１５時間真空乾燥させ、大気雰囲気下、２５Ｋｇｙでガンマ線滅菌を実施し血液処理器を得た。
得られた血液処理器に対して血液適合性試験を実施した結果、ＬＤＨ活性は１．３、残血本数は０であった。
(Example 1)
The film-forming spinning solution is composed of 79 parts by mass of dimethylacetamide (manufactured by Kishida Chemical Co., Ltd., special grade reagent), 17 parts by mass of polysulfone (P-1700 manufactured by Solvay Co., Ltd.) and 4 parts by mass of polyvinylpyrrolidone (K-90 manufactured by BSF). Was prepared by dissolving.
A 60% by mass dimethylacetamide aqueous solution was used as the hollow internal liquid.
From the tube-in-orifice type spinneret, the stock solution for film formation and the hollow internal solution were discharged. The temperature of the stock solution for film formation during discharge was 40°C. The discharged film-forming spinning solution was immersed in a coagulation bath of water at 60° C. through a dropping part covered with a hood to coagulate it. The spinning speed was 30 m/min.
After coagulation, washing with water and drying were performed to obtain a hollow separation membrane. The washing temperature was 90° C. and the washing time was 180 seconds. The amounts of the stock solution for membrane spinning and the liquid in the hollow space were adjusted so that the film thickness after drying was 35 μm and the inner diameter was 185 μm.
The obtained hollow fiber separation membrane was incorporated into a blood treatment device and molded, and a module having an effective area of 1.5 m 2 was assembled. Next, 0.1 g of PMEA (Mn 20,000, Mw/Mn 2.4) was dissolved in an aqueous solution (100 g) of 40 g of ethanol/60 g of water to prepare a coating liquid. The assembled module was vertically held, and the coating liquid was caused to flow from the upper portion at a flow rate of 100 ml/min to bring the coating liquid into contact with the surface of the separation membrane.
After contact with the coating solution, blow the coating solution in the module with 0.1 KMpa air, put the module in the vacuum dryer and vacuum dry at 35°C for 15 hours. Obtained.
As a result of performing a blood compatibility test on the obtained blood treatment device, LDH activity was 1.3 and residual blood count was 0.
この試料について赤外ＡＴＲ測定を行った。その赤外吸収曲線を図１に示す。
ＰＭＥＡ由来の赤外吸収（１７３５ｃｍ-1付近）のエステル基（−Ｏ−Ｃ＝Ｏ）ピークを確認した。
また、赤外吸収（１７３５ｃｍ-1付近）ピーク強度面積Ｐ１と赤外吸収（１５９５ｃｍ-1付近）ピーク強度面積Ｐ２の比Ｐ１／Ｐ２は０．１１５であった。
Infrared ATR measurement was performed on this sample. The infrared absorption curve is shown in FIG.
An ester group (—O—C═O) peak of infrared absorption (around 1735 cm −1 ) derived from PMEA was confirmed.
The ratio P1/P2 of the infrared absorption (in the vicinity of 1735 cm −1 ) peak intensity area P1 and the infrared absorption (in the vicinity of 1595 cm −1 ) peak intensity area P2 was 0.115.
この試料について熱分解ガスクロマトグラフ質量分析を行った。
その結果を図４に示す。また、対照として、ＰＭＥＡについて熱分解ガスクロマトグラフ質量分析を行った結果を図２に示す。
ＰＭＥＡの熱分解物のクロマトグラムのピークはＲＴ１．７ｍｉｎにあるところ（図２）、同様の痕跡がこの試料にも見られた（図４）。そして、マススペクトルの検索結果（図５）から、このピークは２−メトキシエタノールのものであることが解った。２−メトキシエタノールはＰＭＥＡの（側鎖部分の）熱分解物が加水分解したものであると考えられるので、このことから、実施例１の分離膜表面にはＰＭＥＡが存在していることが確認できた。なお、後述（比較例１）するが、ＰＭＥＡをコートしていない分離膜についても同様に熱分解ガスクロマトグラフ質量分析したところ（図３）、ＲＴ１．７ｍｉｎにピークの痕跡は見られなかった。
This sample was subjected to pyrolysis gas chromatograph mass spectrometry.
The result is shown in FIG. In addition, as a control, the result of the thermal decomposition gas chromatograph mass spectrometry of PMEA is shown in FIG.
The peak of the chromatogram of the thermal decomposition product of PMEA was at RT 1.7 min (Fig. 2), and similar traces were also found in this sample (Fig. 4). From the mass spectrum search results (FIG. 5), it was found that this peak was of 2-methoxyethanol. Since 2-methoxyethanol is considered to be a hydrolyzate of the thermal decomposition product (of the side chain portion) of PMEA, it was confirmed from this that PMEA was present on the surface of the separation membrane of Example 1. did it. As will be described later (Comparative Example 1), when a separation membrane not coated with PMEA was subjected to the same pyrolysis gas chromatograph mass spectrometry (FIG. 3), no trace of a peak was observed at RT 1.7 min.
この試料について接触角の測定を実施した。
その結果を以下の表に示す。
接触角は６０°程度で、プライミングを繰り返しても接触角に変化は見られなかった。
The contact angle of this sample was measured.
The results are shown in the table below.
The contact angle was about 60°, and the contact angle did not change even after repeated priming.
この試料についてＵＦＲ（ｍｌ／Ｈｒ・ｍｍＨｇ）を測定したところ、ＵＦＲ＝４７７（ｍｌ／Ｈｒ・ｍｍＨｇ）であった。 When the UFR (ml/Hr·mmHg) of this sample was measured, it was UFR=477 (ml/Hr·mmHg).
（比較例１）
分離膜にコート液を接触させない以外は実施例１と同様にして、有効面積１．５ｍ2のモジュールを組み上げた。これについて血液適合性試験を実施した結果、ＬＤＨ活性は１００、残血本数は６であった。
この試料について赤外ＡＴＲ測定を行ったが、その吸収曲線では赤外吸収（１７３５ｃｍ-1付近）ピークは見られなかった。
この試料について行った熱分解ガスクロマトグラフ質量分析の結果を図３に示す。ＰＭＥＡ由来の２−メトキシエタノールは確認できなかった。
実施例１と同様に接触角の測定を行った。結果を以下の表に示す。接触角は７０°程度で、プライミングを繰り返しても接触角に変化は見られなかった。
(Comparative Example 1)
A module having an effective area of 1.5 m 2 was assembled in the same manner as in Example 1 except that the coating solution was not brought into contact with the separation membrane. As a result of performing a blood compatibility test on this, the LDH activity was 100 and the number of residual blood was 6.
Infrared ATR measurement was performed on this sample, but no infrared absorption (around 1735 cm −1 ) peak was found in its absorption curve.
The result of the pyrolysis gas chromatograph mass spectrometry performed on this sample is shown in FIG. 2-Methoxyethanol derived from PMEA could not be confirmed.
The contact angle was measured in the same manner as in Example 1. The results are shown in the table below. The contact angle was about 70°, and the contact angle did not change even after repeated priming.
（比較例２）
実施例１の製膜紡糸原液にポリビニルピロリドンを加えないこと以外は実施例１と同様にして分離膜を製膜し、これを血液処理器に組み込んで実施例１と同様に成型し、ＰＭＥＡをコートしたものについて血液適合性試験を実施したところ、ＬＤＨ活性は２７、残血本数は３本であった。
また、この試料について接触角を測定した。結果を以下の表に示す。接触角はプライミングを繰り返すことにより疎水性へ変化した。ＰＭＥＡの分離膜表面への固定化が不安定であったと考えられる。
(Comparative example 2)
A separation membrane was formed in the same manner as in Example 1 except that polyvinylpyrrolidone was not added to the membrane-spinning stock solution of Example 1, and this was incorporated into a blood processor and molded in the same manner as in Example 1 to prepare PMEA. When the blood compatibility test was performed on the coated product, the LDH activity was 27 and the number of residual blood was 3.
Further, the contact angle of this sample was measured. The results are shown in the table below. The contact angle changed to hydrophobic by repeating priming. It is considered that the immobilization of PMEA on the surface of the separation membrane was unstable.
（実施例２〜５，比較例３）
実施例１と同様にして中空糸分離膜を製膜し、これを血液処理器に組み込んで成型し、有効面積１．５ｍ2のモジュールを組み上げた。
次いで、コート液のＰＭＥＡ濃度と水と有機溶媒（エタノール）の混合比を表１のとおり変化させた以外は実施例１と同様にして、血液処理器を作製し、ＬＤＨ活性、残血本数、赤外吸収ピーク比を測定した。
結果を以下の表１にしめす。
ＰＭＥＡ濃度を増加させるとＬＤＨ活性は若干改善されるが大差は見られなかった。
一方、混合溶媒比（ＥＴＯＨ／Ｈ2Ｏ）を変化させると、有機溶媒の量が多くなるにつれ、ピーク比（Ｐ１／Ｐ２）は小さくなる、すなわち分離膜表面のＰＭＥＡの存在量が少なくなる傾向にあり、また、ＬＤＨ活性は大きくなる、すなわち血液適合性が低下する傾向にある。但し、ＬＤＨ活性はいずれも通常市販品が有する値の範疇にある。
(Examples 2 to 5, Comparative Example 3)
A hollow fiber separation membrane was formed in the same manner as in Example 1, and the hollow fiber separation membrane was incorporated into a blood treatment device and molded to form a module having an effective area of 1.5 m 2 .
Then, a blood processor was prepared in the same manner as in Example 1 except that the PMEA concentration of the coating liquid and the mixing ratio of water and the organic solvent (ethanol) were changed as shown in Table 1. LDH activity, residual blood count, The infrared absorption peak ratio was measured.
The results are shown in Table 1 below.
LDH activity was slightly improved with increasing PMEA concentration, but no significant difference was observed.
On the other hand, when the mixed solvent ratio (ETOH/H 2 O) is changed, the peak ratio (P1/P2) decreases as the amount of organic solvent increases, that is, the amount of PMEA existing on the surface of the separation membrane tends to decrease. In addition, LDH activity tends to increase, that is, blood compatibility tends to decrease. However, the LDH activities are all within the range of values usually possessed by commercial products.
実施例１と同様に実施例２〜５および比較例３の試料について、熱分解ガスクロマトグラフ質量分析で解析した。全ての試料について、ＰＭＥＡの熱分解物のピークであるＲＴ１．７ｍｉｎのピークが確認され、マススペクトルの検索結果からこのピークは２−メトキシエタノールであることが解った。このことから実施例２〜５および比較例３においても膜表面にＰＭＥＡが存在していることが確認できた。 Similar to Example 1, the samples of Examples 2 to 5 and Comparative Example 3 were analyzed by pyrolysis gas chromatograph mass spectrometry. A peak at RT 1.7 min, which is the peak of the pyrolyzed product of PMEA, was confirmed for all the samples, and it was found from the mass spectrum search results that this peak was 2-methoxyethanol. From this, it was confirmed that PMEA was present on the film surface in Examples 2 to 5 and Comparative Example 3 as well.
（実施例６〜７）
製膜紡糸原液に関し、ジメチルアセトアミド（キシダ化学社製、試薬特級）７９質量部に対するポリスルホン（ソルベイ社製、Ｐ−１７００）の量とポリビニルピロリドン（ビーエーエスエフ社製、Ｋ−９０）の量を以下の表に示すように変化させた以外は実施例１と同様にして中空糸分離膜を製膜し、血液処理器に組み込んでＰＭＥＡをコートしてＬＤＨ活性を測定した。
結果を以下の表に示す。製膜原液組成を変更してもＬＤＨ活性は小さく血液適合性は良好であった。
(Examples 6 to 7)
Regarding the membrane-forming spinning solution, the amount of polysulfone (P-1700 manufactured by Solvay Co., Ltd.) and the amount of polyvinylpyrrolidone (K-90 manufactured by BSF Corporation) with respect to 79 parts by mass of dimethylacetamide (Kesida Chemical Co., Ltd., special grade reagent) are as follows. A hollow fiber separation membrane was formed in the same manner as in Example 1 except that the changes were made as shown in Table 1, and the hollow fiber separation membrane was incorporated into a blood processor, coated with PMEA, and the LDH activity was measured.
The results are shown in the table below. Even if the composition of the stock solution for film formation was changed, the LDH activity was small and the blood compatibility was good.
（比較例４）
市販品ＣＸ−２１Ｕ（東レ製）について同様に血液適合性試験を実施しＬＤＨ活性と残血本数を測定したところ、そのＬＤＨ活性は６６．２、残血本数は４であった
残血が発生している言うことは、血液適合性は劣ると考えられる。
なお、ここでは、ＬＤＨ活性測定に使用するＨＦとしては残血糸を含まないものを選択している。
(Comparative Example 4)
When the blood compatibility test was similarly performed on the commercial product CX-21U (manufactured by Toray) and the LDH activity and the number of residual blood were measured, the LDH activity was 66.2 and the number of residual blood was 4, residual blood occurred. What is said is that blood compatibility is considered to be poor.
Here, as the HF used for measuring the LDH activity, one that does not contain residual blood thread is selected.
本発明の血液処理用分離膜及びその膜を組み込んだ血液処理器は、大気下、ドライ状態で放射線滅菌され、ドライ状態で供される血液処理用分離膜でありながら、非常に良好な血液適合性を発現すると言う効果を奏し、血液透析、血液ろ過、血液ろ過透析、血液成分分画、酸素付与、及び血漿分離などの体外循環療法において好適に用いることができる。 INDUSTRIAL APPLICABILITY The blood treatment separation membrane of the present invention and the blood treatment device incorporating the membrane are excellent in blood compatibility even though they are blood treatment separation membranes that are radiation-sterilized in the dry state under the atmosphere and provided in the dry state. It has an effect of expressing sex and can be suitably used in extracorporeal circulation therapy such as hemodialysis, hemofiltration, hemodiafiltration, blood component fractionation, oxygenation, and plasma separation.
Claims (4)
前記分離膜の表面に、ポリメトキシエチルアクリレート（ＰＭＥＡ）、水及び有機溶媒を含有するコート液をコーティングする工程と、
を有する血液処理用分離膜の製造方法であって、
前記分離膜の水分含有率が１０質量％以下の条件下、及び酸素濃度が１５％以上の雰囲気下で放射線滅菌した後の前記血液処理用分離膜の表面に対して全反射赤外吸収測定（ＡＴＲ−ＩＲ）を実施したときの赤外吸収曲線において、１７３５ｃｍ-1付近の赤外吸収ピークのピーク強度（Ｐ１）と１５９５ｃｍ-1付近の赤外吸収ピークのピーク強度（Ｐ２）の比（Ｐ１／Ｐ２）が０．０５以上である、製造方法。 A step of forming a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone,
Coating the surface of the separation membrane with a coating liquid containing polymethoxyethyl acrylate (PMEA), water and an organic solvent;
A method for producing a separation membrane for blood treatment, comprising:
Total reflection infrared absorption measurement on the surface of the separation membrane for blood treatment after radiation sterilization under conditions where the water content of the separation membrane is 10% by mass or less and in an atmosphere with an oxygen concentration of 15% or more ( in the infrared absorption curve when ATR-IR) was performed, the ratio of the 1735 cm -1 infrared absorption peak of a peak intensity in the vicinity (P1) and peak intensity of the infrared absorption peak near 1595cm -1 (P2) (P1 /P2) is 0.05 or more.
前記分離膜の表面に、ポリメトキシエチルアクリレート（ＰＭＥＡ）、水及び有機溶媒を含有するコート液をコーティングする工程と、
コーティングされた前記分離膜を、前記分離膜の水分含有率が１０質量％以下の条件下、及び酸素濃度が１５％以上の雰囲気下で放射線滅菌する工程と、
を有する血液処理用分離膜の製造方法。 A step of forming a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone,
Coating the surface of the separation membrane with a coating liquid containing polymethoxyethyl acrylate (PMEA), water and an organic solvent;
Radiation sterilizing the coated separation membrane under conditions where the water content of the separation membrane is 10% by mass or less and in an atmosphere with an oxygen concentration of 15% or more;
A method for producing a separation membrane for blood treatment, comprising:
分離膜はポリスルホン系高分子とポリビニルピロリドンを含む製膜原液を用いて製膜され、
該製膜原液中のポリスルホン系高分子に対するポリビニルピロリドンの比率（ポリビニルピロリドン／ポリスルホン系高分子）が２７質量％以下である、
請求項１〜３のいずれか一項に記載の血液処理用分離膜の製造方法。 In the step of forming the separation membrane,
The separation membrane is formed using a membrane-forming stock solution containing a polysulfone-based polymer and polyvinylpyrrolidone,
The ratio of polyvinylpyrrolidone to polysulfone-based polymer in the stock solution for film formation (polyvinylpyrrolidone/polysulfone-based polymer) is 27 mass% or less.
Manufacturing method of a blood treatment separation membrane according to any one of claims 1-3.
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| JP3908839B2 (en) * | 1997-10-09 | 2007-04-25 | テルモ株式会社 | Hollow fiber membrane external blood perfusion oxygenator |
| JP4754400B2 (en) * | 2006-04-27 | 2011-08-24 | 旭化成クラレメディカル株式会社 | Blood purification membrane and method for producing the same |
| KR101525642B1 (en) * | 2008-03-31 | 2015-06-03 | 도레이 카부시키가이샤 | Separation membrane, method of producing the same and separation membrane module using the separation membrane |
| JP5872465B2 (en) * | 2009-07-15 | 2016-03-01 | テクニカル ユニバーシティ オブ デンマーク | Polymer coatings containing methoxyethyl acrylate units synthesized by surface-initiated atom transfer radical polymerization |
| EP2495025A1 (en) * | 2011-03-04 | 2012-09-05 | Fresenius Medical Care Deutschland GmbH | Filter for the removal of micro-vesicles from biological fluids, methods and devices using such a filter |
| EP2859904A4 (en) * | 2012-06-11 | 2015-07-22 | Asahi Kasei Medical Co Ltd | Separation membrane for blood treatment and blood treatment device having same membrane incorporated therein |
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