JP2006296931A - Hollow fiber type blood purifying device and its manufacturing method - Google Patents
Hollow fiber type blood purifying device and its manufacturing method Download PDFInfo
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- JP2006296931A JP2006296931A JP2005126412A JP2005126412A JP2006296931A JP 2006296931 A JP2006296931 A JP 2006296931A JP 2005126412 A JP2005126412 A JP 2005126412A JP 2005126412 A JP2005126412 A JP 2005126412A JP 2006296931 A JP2006296931 A JP 2006296931A
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- hollow fiber
- blood purification
- blood
- fat
- membrane
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
- B01D63/021—Manufacturing thereof
- B01D63/0233—Manufacturing thereof forming the bundle
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D65/00—Accessories or auxiliary operations, in general, for separation processes or apparatus using semi-permeable membranes
- B01D65/02—Membrane cleaning or sterilisation ; Membrane regeneration
- B01D65/022—Membrane sterilisation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
- B01D63/021—Manufacturing thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2321/00—Details relating to membrane cleaning, regeneration, sterilization or to the prevention of fouling
- B01D2321/34—Details relating to membrane cleaning, regeneration, sterilization or to the prevention of fouling by radiation
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Manufacturing & Machinery (AREA)
- Apparatus For Disinfection Or Sterilisation (AREA)
- External Artificial Organs (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
Description
本発明は血液、血漿等の体液を透析、濾過透析、濾過等の原理により浄化する血液浄化療法に用いられる血液浄化装置およびその製造方法に関する。特に、脂溶性ビタミンを含有した中空糸膜を用いる血液浄化装置に関する。 The present invention relates to a blood purification apparatus used for blood purification therapy for purifying body fluids such as blood and plasma by the principle of dialysis, filtration dialysis, filtration, and the like, and a method for manufacturing the same. In particular, the present invention relates to a blood purification device using a hollow fiber membrane containing a fat-soluble vitamin.
近年、血液、血漿等の体液を浄化する血液浄化療法が普及し、各種疾患に罹患した患者の治療に応用されている。血液浄化療法に用いられる中空糸を用いた血液浄化装置を例示すると、例えば血液透析器、血液濾過透析器、血液濾過器、持続式血液濾過（透析）器、血漿分離器、血漿成分分離器、腹水濾過器、腹水濃縮器、人工肺、等が例示できる。これらの血液浄化装置は日々改良されており、特に血液適合性の観点からの改良が進められている。 In recent years, blood purification therapy for purifying body fluids such as blood and plasma has become widespread and applied to the treatment of patients suffering from various diseases. Examples of blood purification devices using hollow fibers used in blood purification therapy include, for example, hemodialyzers, hemofiltration dialysers, blood filters, continuous blood filtration (dialysis) devices, plasma separators, plasma component separators, Ascites filter, ascites concentrator, artificial lung, etc. can be exemplified. These blood purification apparatuses are improved every day, and in particular, improvements are being promoted from the viewpoint of blood compatibility.
血液透析を例にとって説明すると、長期透析患者では透析アミロイドーシス、動脈硬化など種々の合併症が見られ、その発症の一因として酸化ストレスの亢進が挙げられる。酸化ストレスとは酸化能が抗酸化能を上回った状態であり、透析患者では血液と透析膜の接触により活性化された白血球によるフリーラジカルの産生亢進や、ビタミンＣやビタミンＥなどの血中の抗酸化物質の減少により、酸化ストレスが亢進した状態となっている。 Taking hemodialysis as an example, various complications such as dialysis amyloidosis and arteriosclerosis are observed in long-term dialysis patients, and increased oxidative stress can be cited as a cause of the onset. Oxidative stress is a state in which the oxidative capacity exceeds the antioxidant capacity. In dialysis patients, the production of free radicals by leukocytes activated by contact between blood and the dialysis membrane is increased, and vitamin C, vitamin E, etc. Due to the decrease in antioxidants, oxidative stress is increased.
血液中にはスーパーオキシドジスムターゼ、尿酸、ビタミンＣ、ビタミンＥ、カロチノイドなどの種々の抗酸化物質があるが、透析患者の場合、血液中や赤血球膜のビタミンＥ濃度の低下が報告されている。ビタミンＥ濃度の低下が脂質などの酸化亢進や赤血球寿命の低下を引き起こし、透析患者の長期合併症である透析アミロイドーシス、動脈硬化性疾患、悪性腫瘍増加、貧血の原因となることが示唆されている。そのため、透析患者が受ける酸化ストレスを抑制することにより、患者のＱＯＬ（Ｑｕａｌｉｔｙ ｏｆ ｌｉｆｅ）や予後を改善する可能性が高いことが指摘されている。 There are various antioxidants such as superoxide dismutase, uric acid, vitamin C, vitamin E, and carotenoid in the blood, but in the case of dialysis patients, a decrease in vitamin E concentration in the blood and erythrocyte membrane has been reported. It has been suggested that a decrease in vitamin E concentration leads to increased oxidation of lipids and erythrocyte lifespan, leading to long-term complications in dialysis patients, such as dialysis amyloidosis, arteriosclerotic disease, increased malignancy, and anemia. . Therefore, it has been pointed out that suppressing oxidative stress experienced by dialysis patients has a high possibility of improving the patient's QOL (Quality of Life) and prognosis.
透析患者が受ける酸化ストレスを軽減する方法は幾つか考えられるが、その一つとして、抗酸化能を有する血液透析膜（血液透析器）を用いた血液透析方法が提案され、数多くの臨床例が報告されている。血液透析膜の主たる素材としては、樹脂としての汎用性、耐熱・耐放射線特性、生体適合性等の理由から、近年ではポリスルホン系高分子等の疎水性合成高分子が主流となっている。しかし、膜の血液接触面の疎水性が強すぎると血液凝固が起こるため、通常は親水性高分子とのポリマーブレンドや親水性高分子による表面改質により形成された膜が使用されている（特許文献１および２）。そして、このように内表面や膜全体を親水化した疎水性高分子膜において、脂溶性ビタミンを固定した中空糸膜が血液適合性により一層優れていることが知られている（特許文献３〜５）。 There are several ways to reduce the oxidative stress experienced by dialysis patients. One of them is a hemodialysis method using a hemodialysis membrane (hemodialyzer) with anti-oxidation ability. It has been reported. As a main material for hemodialysis membranes, hydrophobic synthetic polymers such as polysulfone polymers have become mainstream in recent years because of their versatility as a resin, heat resistance / radiation resistance, biocompatibility, and the like. However, since blood coagulation occurs when the hydrophobicity of the blood contact surface of the membrane is too strong, a membrane formed by polymer blending with a hydrophilic polymer or surface modification with a hydrophilic polymer is usually used ( Patent Documents 1 and 2). And in the hydrophobic polymer membrane which hydrophilized the inner surface and the whole membrane in this way, it is known that the hollow fiber membrane in which the fat-soluble vitamin is fixed is more excellent in blood compatibility (Patent Documents 3 to 3). 5).
これらの特許文献には、いずれも膜中の脂溶性ビタミンの含浸量が記載されており、例えば、特許文献３では１〜５０００ｍｇ／ｍ２（好ましくは１０〜１０００ｍｇ／ｍ２）、特許文献４では１〜１０００ｍｇ／ｍ３（好ましくは１０〜１００ｍｇ／ｍ３）、特許文献５では１〜１０００ｍｇ／ｍ２（好ましくは１０〜３００ｍｇ／ｍ２）という範囲が記載されている。 These patent documents all describe the impregnation amount of the fat-soluble vitamin in the membrane. For example, in Patent Document 3, 1 to 5000 mg / m 2 (preferably 10 to 1000 mg / m 2 ), Patent Document 4 1 to 1000 mg / m 3 (preferably 10 to 100 mg / m 3 ), and Patent Document 5 describes a range of 1 to 1000 mg / m 2 (preferably 10 to 300 mg / m 2 ).
しかしながら、本発明者らがこれらの特許文献に開示された条件について検討した結果、脂溶性ビタミンの含浸量が多くなるに従って、オートクレーブ（ＡＣ）滅菌した際に中空糸膜にクラック、すなわち大小を問わず亀裂が発生しやすくなることが判った。一般に、脂溶性ビタミンの含浸量が多いほど抗酸化能も高くなると思われるが、この知見は、実用に際し十分効果のある抗酸化能を発現させ得るために脂溶性ビタミンの含浸量を増やすと、中空糸膜がリークを起こす可能性が高くなることを示唆しており、実用上好ましくない領域があることを示している。 However, as a result of examination of the conditions disclosed in these patent documents by the present inventors, as the amount of the fat-soluble vitamin impregnated increases, the hollow fiber membrane is cracked, that is, whether the size is small or small when autoclaved (AC). It was found that cracks tend to occur. In general, it seems that the greater the amount of fat-soluble vitamin impregnated, the higher the antioxidant capacity, but this finding is that if the amount of fat-soluble vitamin impregnated is increased in order to develop an antioxidant capacity that is sufficiently effective in practical use, This suggests that there is a high possibility that the hollow fiber membrane will cause a leak, indicating that there is an unpreferable region for practical use.
また、脂溶性ビタミンの含浸量については、いずれも中空糸膜全体の量や表面からの抽出量で説明されるに留まり、膜構造中における分布については詳細な知見がなかった。このことは、中空糸膜全体として見れば十分高い含浸量であっても、実用に際して期待する効果効能が得られない可能性があることも示唆している。血液が接触する中空糸膜内表面近傍も同様に高い含浸量とは限らないからである。 In addition, the amount of fat-soluble vitamin impregnation was only explained by the amount of the entire hollow fiber membrane and the amount extracted from the surface, and there was no detailed knowledge about the distribution in the membrane structure. This also suggests that even if the amount of impregnation is sufficiently high as a whole of the hollow fiber membrane, there is a possibility that the effect and effect expected in practical use may not be obtained. This is because the vicinity of the inner surface of the hollow fiber membrane in contact with blood is not always high in impregnation.
以上述べたように、疎水性高分子と親水性高分子からなり、さらに脂溶性ビタミンを含有する中空糸膜を充填した血液浄化装置において、滅菌処理されていても中空糸膜がリークを起こす可能性が極めて低く、しかも効果効能を十分発揮できるように中空糸膜内表面近傍に脂溶性ビタミンを分布した中空糸膜が必要と考えられたが、そのような中空糸膜が充填された血液浄化装置はこれまで知られていなかった。
本発明は、上記問題点に鑑み、血液に対する抗酸化作用を確実に向上させ、また、脂溶性ビタミンの含有量が多くても滅菌による血液浄化用中空糸膜のクラックやリークがない血液浄化装置およびその製造方法を提供することを課題とする。 In view of the above problems, the present invention reliably improves the antioxidant effect on blood, and even if the content of fat-soluble vitamins is large, the blood purification device does not have cracks or leaks in the hollow fiber membrane for blood purification by sterilization. It is another object of the present invention to provide a manufacturing method thereof.
本発明者らは、上記課題を解決するために鋭意研究した。その結果、疎水性高分子と親水性高分子からなり、さらに脂溶性ビタミンを含有する血液浄化用の中空糸膜を充填した血液浄化装置において、脂溶性ビタミンの膜全体の含有量と、膜内表面近傍の濃度、または滅菌条件を特定することで、従来技術の問題点が解決できることを見出した。具体的には、前記中空糸膜が７０ｍｇ／ｍ２以上３００ｍｇ／ｍ２以下の脂溶性ビタミンを含有し、このような中空糸膜を充填した血液浄化装置を放射線滅菌したもの、また、血液と直接接触する中空糸内表面近傍に存在する脂溶性ビタミン含有量が、中空糸内表面近傍に存在する前記疎水性高分子と親水性高分子の総量に対し２．５％以上３０．０％以下であるような中空糸膜を充填した血液浄化装置が、中空糸膜のリークを起こし難く、血液に対し優れた抗酸化作用を有することを見出した。
また、放射線滅菌により、中空糸膜中の親水性高分子が不完全に（適度に）架橋した、即ち部分架橋した構造をとるので、親水性高分子の溶出による孔径の変化を起こし難いことを見出し、これらを以って本発明を完成するに至った。
即ち本発明は以下を含む。
（１）疎水性高分子と親水性高分子よりなり、脂溶性ビタミンを含有する血液浄化用中空糸膜の複数本を容器に充填し、該中空糸膜の膜壁により血液側流路と濾液側流路に隔てて流路を形成する中空糸型血液浄化装置であって、前記血液浄化用中空糸膜は脂溶性ビタミンを膜面積換算で７０ｍｇ／ｍ２以上３００ｍｇ／ｍ２以下の範囲で含有し、かつ血液浄化装置は放射線滅菌されていることを特徴とする中空糸型血液浄化装置。
（２）疎水性高分子と親水性高分子よりなり、脂溶性ビタミンを含有する血液浄化用中空糸膜の複数本を容器に充填し、該中空糸膜の膜壁により血液側流路と濾液側流路に隔てて流路を形成する中空糸型血液浄化装置であって、前記血液浄化用中空糸膜の血液流路側表面に存在する脂溶性ビタミン含有量が、中空糸内表面近傍に存在する前記疎水性高分子と親水性高分子の総量に対し２．５％以上３０．０％以下の範囲であることを特徴とする中空糸型血液浄化装置。
（３）さらに、血液浄化用中空糸膜は脂溶性ビタミンを膜面積換算で７０ｍｇ／ｍ２以上３００ｍｇ／ｍ２以下の範囲で含有するものである、上記（２）に記載の中空糸型血液浄化装置。
（４）前記血液浄化用中空糸膜の血液流路側表面に存在する脂溶性ビタミン含有量が、中空糸内表面近傍に存在する前記疎水性高分子と親水性高分子の総量に対し２．５％以上３０．０％以下の範囲である上記（１）に記載の中空糸型血液浄化装置。
（５）さらに、該親水性高分子が部分架橋している上記（１）〜（４）の何れかに記載の中空糸型血液浄化装置。
（６）前記親水性高分子の含有量が総高分子量の１〜１８重量％であり、ジメチルアセトアミドに可溶性の親水性高分子量が総親水性高分子量の２５重量％以上９５重量％以下である上記（１）〜（５）のいずれかに記載の中空糸型血液浄化装置。
（７）前記疎水性高分子がポリスルホン系樹脂であり、前記親水性高分子がポリビニルピロリドンである上記（１）〜（６）の何れかに記載の中空糸型血液浄化装置。
（８）中空糸内表面近傍が、中空糸の血液側内表面から１〜５ｎｍの層である上記（１）〜（７）のいずれかに記載の中空糸型血液浄化装置。
（９）疎水性高分子と親水性高分子よりなる血液浄化用中空糸膜の複数本を容器に充填し、該中空糸膜の膜壁により血液側流路と濾液側流路に隔てて流路を形成する中空糸型血液浄化装置の製造方法において、該血液流路側に、脂溶性ビタミンを溶媒に溶解した脂溶性ビタミン溶液を通液し、次に余分な脂溶性ビタミン溶液を除去した後に溶媒を乾燥除去し、しかる後に血液浄化装置を放射線滅菌することを特徴とする中空糸型血液浄化装置の製造方法。
（１０）脂溶性ビタミンの溶媒がイソプロピルアルコールである上記（９）に記載の中空糸型血液浄化装置の製造方法。
（１１）乾燥後放射線滅菌をする前に、水系溶液で中空糸膜を湿潤化する上記（９）又は（１０）に記載の中空糸型血液浄化装置の製造方法。
（１２）放射線滅菌が、少なくとも中空糸膜に滅菌保護剤を付与した状態で滅菌するものである上記（９）〜（１１）の何れかに記載の中空糸型血液浄化装置の製造方法。
（１３）脂溶性ビタミン溶液の濃度が、０．２〜２．０％である上記（９）〜（１２）のいずれかに記載の中空糸型血液浄化装置の製造方法。
（１４）脂溶性ビタミン溶液の中空糸膜への通液が、中空糸膜の外表面に水を存在させた状態で行うものである、上記（９）〜（１３）のいずれかに記載の中空糸型血液浄化装置の製造方法。
The present inventors have intensively studied to solve the above problems. As a result, in a blood purification apparatus comprising a hydrophobic polymer and a hydrophilic polymer, and further filled with a hollow fiber membrane for blood purification containing fat-soluble vitamins, the content of the entire fat-soluble vitamin membrane, It has been found that the problems of the prior art can be solved by specifying the concentration near the surface or the sterilization conditions. Specifically, the hollow fiber membrane contains 70 mg / m 2 or more and 300 mg / m 2 or less of a fat-soluble vitamin, and a blood purification device filled with such a hollow fiber membrane is subjected to radiation sterilization, The fat-soluble vitamin content present in the vicinity of the inner surface of the hollow fiber that is in direct contact is 2.5% or more and 30.0% or less of the total amount of the hydrophobic polymer and the hydrophilic polymer present in the vicinity of the inner surface of the hollow fiber. It has been found that a blood purification apparatus filled with such a hollow fiber membrane hardly causes leakage of the hollow fiber membrane and has an excellent antioxidant effect on blood.
In addition, due to radiation sterilization, the hydrophilic polymer in the hollow fiber membrane is incompletely (moderately) crosslinked, that is, has a partially crosslinked structure, so that it is difficult to cause a change in pore size due to elution of the hydrophilic polymer. The present invention was completed with the headings and these.
That is, the present invention includes the following.
(1) A container is filled with a plurality of hollow fiber membranes for blood purification comprising a hydrophobic polymer and a hydrophilic polymer and containing a fat-soluble vitamin, and the blood-side flow path and the filtrate are filled by the membrane wall of the hollow fiber membrane. A hollow fiber type blood purification apparatus that forms a flow path separated from a side flow path, wherein the blood purification hollow fiber membrane is a fat-soluble vitamin in a range of 70 mg / m 2 or more and 300 mg / m 2 or less in terms of membrane area. A hollow-fiber blood purification apparatus containing the blood purification apparatus, wherein the blood purification apparatus is radiation sterilized.
(2) The container is filled with a plurality of hollow fiber membranes for blood purification comprising a hydrophobic polymer and a hydrophilic polymer and containing a fat-soluble vitamin, and the blood side channel and the filtrate are filled by the membrane wall of the hollow fiber membrane. A hollow-fiber blood purification apparatus that forms a flow channel separated from a side flow channel, wherein the fat-soluble vitamin content present on the blood flow channel side surface of the blood purification hollow fiber membrane is present in the vicinity of the inner surface of the hollow fiber A hollow fiber blood purification apparatus, wherein the content is in the range of 2.5% to 30.0% with respect to the total amount of the hydrophobic polymer and the hydrophilic polymer.
(3) Furthermore, the hollow fiber membrane for blood purification contains the fat-soluble vitamin in a range of 70 mg / m 2 or more and 300 mg / m 2 or less in terms of membrane area, and the hollow fiber blood according to (2) above Purification equipment.
(4) The fat-soluble vitamin content present on the blood flow path side surface of the blood purification hollow fiber membrane is 2.5 relative to the total amount of the hydrophobic polymer and hydrophilic polymer present in the vicinity of the hollow fiber inner surface. % To 30.0% of the hollow fiber blood purification device according to the above (1).
(5) The hollow fiber blood purification apparatus according to any one of (1) to (4), wherein the hydrophilic polymer is partially crosslinked.
(6) The content of the hydrophilic polymer is 1 to 18% by weight of the total high molecular weight, and the hydrophilic high molecular weight soluble in dimethylacetamide is 25 to 95% by weight of the total hydrophilic high molecular weight. The hollow fiber blood purification apparatus according to any one of (1) to (5) above.
(7) The hollow fiber blood purification apparatus according to any one of (1) to (6), wherein the hydrophobic polymer is a polysulfone resin, and the hydrophilic polymer is polyvinylpyrrolidone.
(8) The hollow fiber blood purification apparatus according to any one of (1) to (7), wherein the vicinity of the inner surface of the hollow fiber is a layer of 1 to 5 nm from the blood inner surface of the hollow fiber.
(9) A container is filled with a plurality of hollow fiber membranes for blood purification comprising a hydrophobic polymer and a hydrophilic polymer, and the membrane wall of the hollow fiber membrane separates the blood side channel and the filtrate side channel. In the method for producing a hollow fiber blood purification apparatus for forming a channel, after passing a fat-soluble vitamin solution in which a fat-soluble vitamin is dissolved in a solvent, and then removing the excess fat-soluble vitamin solution through the blood channel side A method for producing a hollow-fiber blood purification apparatus, comprising drying and removing the solvent, and then sterilizing the blood purification apparatus with radiation.
(10) The method for producing a hollow fiber blood purification apparatus according to (9), wherein the solvent of the fat-soluble vitamin is isopropyl alcohol.
(11) The method for producing a hollow fiber blood purification apparatus according to (9) or (10), wherein the hollow fiber membrane is wetted with an aqueous solution before radiation sterilization after drying.
(12) The method for producing a hollow fiber blood purification apparatus according to any one of the above (9) to (11), wherein the radiation sterilization is performed at least with a sterilization protective agent applied to the hollow fiber membrane.
(13) The method for producing a hollow fiber blood purification apparatus according to any one of (9) to (12), wherein the concentration of the fat-soluble vitamin solution is 0.2 to 2.0%.
(14) The fat-soluble vitamin solution is passed through the hollow fiber membrane in a state where water is present on the outer surface of the hollow fiber membrane, according to any one of (9) to (13) above. A method for producing a hollow fiber blood purification device.
本発明の血液浄化装置は、そこに充填された中空糸膜が血液に対して優れた抗酸化作用を示し、また、滅菌によるリークを起こすことが無い血液浄化装置である。また、該中空糸膜は血小板活性化を抑制しており、さらには膜中の疎水性高分子が部分架橋しているので膜成分の溶出の発生を抑制し、膜の孔径の変化を起こし難い。したがって、血液透析等に使われる血液浄化装置として優れた特性を持ち合わせている。 The blood purification apparatus of the present invention is a blood purification apparatus in which the hollow fiber membrane filled therein exhibits an excellent antioxidant effect on blood and does not cause leakage due to sterilization. In addition, the hollow fiber membrane suppresses platelet activation, and furthermore, since the hydrophobic polymer in the membrane is partially cross-linked, it suppresses the generation of membrane components and hardly changes the pore size of the membrane. . Therefore, it has excellent characteristics as a blood purification device used for hemodialysis and the like.
以下、本発明をさらに詳細に説明する。
本発明でいう疎水性高分子とは、水に溶解しないか或いは水に親和性を示さない合成または天然高分子を言い、例示すると、ポリスルホン、ポリエーテルスルホン、ポリアミド、ポリアリレート、ポリエーテルスルホン−ポリアリレートのポリマーアロイ、ポリメチルメタクリレート、ポリカーボネート、ポリエーテルエーテルケトン、ポリアリルエーテルケトン、セルローストリアセテート、セルロースジアセテートなどが挙げられる。中でも、ポリマーとしての組成の均一性から合成高分子が好ましく、特にポリスルホンは、血液浄化用途での好適な臨床実績が数多くあり、原料としての安定供給性に優れるため特に好ましい。本発明でいうポリスルホンには、芳香環の一部が化学修飾されたものの他に、ポリフェニルスルホンやポリアリルエーテルスルホン等のいわゆる類縁化合物も含まれる。
Hereinafter, the present invention will be described in more detail.
The hydrophobic polymer as used in the present invention refers to a synthetic or natural polymer that does not dissolve in water or has no affinity for water. For example, polysulfone, polyethersulfone, polyamide, polyarylate, polyethersulfone- Examples thereof include polymer alloys of polyarylate, polymethyl methacrylate, polycarbonate, polyether ether ketone, polyallyl ether ketone, cellulose triacetate, and cellulose diacetate. Among them, a synthetic polymer is preferable from the uniformity of the composition as a polymer, and polysulfone is particularly preferable because it has many suitable clinical results in blood purification applications and is excellent in stable supply as a raw material. The polysulfone as used in the present invention includes so-called related compounds such as polyphenylsulfone and polyallylethersulfone, in addition to those in which a part of the aromatic ring is chemically modified.
親水性高分子とは、水に可溶であり、かつ物理的処理および／または化学的処理により架橋し、それにより水に対し不溶化し得る物質を言い、例示するとポリビニルピロリドン（ＰＶＰ）、ポリエチレングリコール（ＰＥＧ）、ポリプロピレングリコール（ＰＰＧ）、ハイドロキシプロピルセルロース（ＨＰＣ）、デンプン、ハイドロキシエチルスターチ（ＨＥＳ）等が挙げられる。中でも、ポリビニルピロリドンとポリエチレングリコールは中空糸膜の孔形成性が良いため好ましく、ポリビニルピロリドンが特に好ましい。
本発明でいう中空糸膜は、上記の疎水性高分子と親水性高分子とを含むが、それらの存在形態は特に限定されない。例えば、相溶性の高い成分同士がポリマーブレンドされたものや、疎水性高分子の膜基材に親水性高分子をグラフトしたものでもよい。あるいは、疎水性成分と親水性成分からなる共重合高分子を用いることもできる。その例としては、ＰＶＰとＰＳｆとのブロック共重合体やＰＥＧとＰＳｆとのブロック共重合体等が挙げられる。
The hydrophilic polymer refers to a substance that is soluble in water and can be crosslinked by physical treatment and / or chemical treatment, and thereby insolubilized in water. For example, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polypropylene glycol (PPG), hydroxypropyl cellulose (HPC), starch, hydroxyethyl starch (HES) and the like. Among them, polyvinyl pyrrolidone and polyethylene glycol are preferable because of good pore forming property of the hollow fiber membrane, and polyvinyl pyrrolidone is particularly preferable.
The hollow fiber membrane referred to in the present invention contains the above-described hydrophobic polymer and hydrophilic polymer, but their existence form is not particularly limited. For example, it may be a polymer blend of highly compatible components or a hydrophilic polymer grafted onto a hydrophobic polymer membrane substrate. Alternatively, a copolymerized polymer composed of a hydrophobic component and a hydrophilic component can be used. Examples thereof include a block copolymer of PVP and PSf, a block copolymer of PEG and PSf, and the like.
脂溶性ビタミンとは、一般に水に溶けにくく、アルコールや油脂に溶けるビタミンを言い、例示すると、ビタミンＡ、ビタミンＤ、ビタミンＥ、ビタミンＫおよびユビキノン等が挙げられるが、これらの中では、ビタミンＥが好適である。ビタミンＥとしては、α−トコフェロール、α−酢酸トコフェロール、α−ニコチン酸トコフェロール、β−トコフェロール、γ−トコフェロール、δ−トコフェロール等が挙げられる。中でもα−トコフェロールは生体内抗酸化作用、生体膜安定化作用、血小板凝集抑制作用 などの種々の生理作用を有するため、特に好ましい。 Fat-soluble vitamins generally refer to vitamins that are hardly soluble in water and soluble in alcohol and fats. Examples include vitamin A, vitamin D, vitamin E, vitamin K, and ubiquinone. Among these, vitamin E Is preferred. Examples of vitamin E include α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, β-tocopherol, γ-tocopherol, and δ-tocopherol. Among them, α-tocopherol is particularly preferable because it has various physiological functions such as in vivo antioxidant action, biological membrane stabilizing action, and platelet aggregation inhibitory action.
本発明でいう血液浄化用中空糸膜とは、血液透析器、血液濾過透析器、血液濾過器、持続式血液濾過（透析）器、血漿分離器、血漿成分分離器、腹水濾過器、腹水濃縮器、人工肺等に用いられる中空糸膜であり夫々の用途に適した孔径を持つ、疎水性高分子と親水性高分子からなり脂溶性ビタミンを含有する血液浄化用中空糸膜を言う。患者が受ける酸化ストレスは、体外循環治療の繰り返しや長期化によっても累積されることを考慮すると、高頻度かつ長期間にわたって実施される血液透析または血液濾過透析において、本発明を血液透析器や血液濾過透析器として用いることが好ましい。 The hollow fiber membrane for blood purification referred to in the present invention is a hemodialyzer, hemofiltration dialyzer, blood filter, continuous hemofiltration (dialysis) device, plasma separator, plasma component separator, ascites filter, ascites concentration This is a hollow fiber membrane for use in blood vessels, artificial lungs, etc., which has a pore size suitable for each use, and is composed of a hydrophobic polymer and a hydrophilic polymer and contains a fat-soluble vitamin and is used for blood purification. Considering that the oxidative stress experienced by patients is accumulated by repeated and prolonged extracorporeal circulation treatment, the present invention is applied to hemodialyzers and blood filters in hemodialysis or hemofiltration dialysis performed frequently and over a long period of time. It is preferable to use it as a filter dialyzer.
本発明の中空糸膜を充填した血液浄化装置における血液側流路とは、中空糸膜によって隔てられた中空糸膜内側の空間または中空糸膜外側と容器内側との間に形成される空間を言い、血液の流れる空間を言う。血液透析器等、中空糸膜の内腔部を血液が流れる場合は中空糸膜内面側の空間のことであるが、例えば人工肺のように中空糸膜の内腔をガスが流れる場合は、中空糸膜外側と容器内側との間に形成される空間のことをいう。 The blood flow path in the blood purification apparatus filled with the hollow fiber membrane of the present invention is a space inside the hollow fiber membrane or a space formed between the outside of the hollow fiber membrane and the inside of the container separated by the hollow fiber membrane. Says the space where blood flows. When blood flows through the lumen of the hollow fiber membrane, such as a hemodialyzer, it is a space on the inner side of the hollow fiber membrane, but when the gas flows through the lumen of the hollow fiber membrane, such as an artificial lung, The space formed between the outside of the hollow fiber membrane and the inside of the container.
本発明の中空糸膜を充填した血液浄化装置における濾液側流路とは、血液側流路と中空糸膜を隔てた空間であって、前記の血液側流路とは反対側の空間を言い、濾液や透析液の流れる空間を言う。血液透析器等、中空糸膜の内腔部を血液が流れる場合は中空糸膜外側と容器内側との間に形成される空間のことであるが、例えば人工肺のように中空糸膜の内腔をガスが流れる場合は、中空糸膜内側の空間のことをいう。 The filtrate side flow path in the blood purification apparatus filled with the hollow fiber membrane of the present invention is a space separating the blood side flow path and the hollow fiber membrane, and means a space opposite to the blood side flow path. The space where filtrate and dialysate flows. When blood flows through the hollow part of a hollow fiber membrane, such as a hemodialyzer, it is a space formed between the outer side of the hollow fiber membrane and the inner side of the container. When gas flows through the cavity, it means the space inside the hollow fiber membrane.
なお、以下の説明は全て、血液透析器のように中空糸膜の内腔部を血液が流れる場合を想定して説明するが、中空糸膜の内腔部に血液が流れない場合は、中空糸膜の内外を反対に読み替えるものとする。 In addition, all the following explanations are based on the assumption that blood flows through the lumen of the hollow fiber membrane as in a hemodialyzer, but when blood does not flow into the lumen of the hollow fiber membrane, The inside and outside of the thread membrane shall be read in reverse.
本発明の血液浄化装置に充填される血液浄化用中空糸膜は、脂溶性ビタミンを膜面積換算で７０ｍｇ／ｍ２以上３００ｍｇ／ｍ２以下の範囲で含有している必要がある。ここでいう膜面積とは濾過や透析に関与する中空糸膜の実効総内表面積のことであり、中空糸膜の平均内径、円周率、本数および有効長の積で示される。該脂溶性ビタミンが膜面積換算で７０ｍｇ／ｍ２より少ないと、脂溶性ビタミンの被覆にむらが生じやすいので、抗酸化能力に劣る。反対に、３００ｍｇ／ｍ２より多いと、膜全体の表面、例えば、中空糸内表面以外の血液が接触しない中空糸内部や中空糸外表面にも多量の脂溶性ビタミンが付着してしまうので、膜全体の疎水性が強まる。その結果、血液成分や濾過液あるいは透析液などの透過能力が低下するだけではなく、抗血栓性が低下し残血が発生する。
さらに、詳細は後述するが、滅菌時の熱履歴や熱水との接触により、該脂溶性ビタミンが局所凝集を起こして中空糸内にクラックが発生することがある。従って、より好ましい含有量の範囲は８０ｍｇ／ｍ２以上２５０ｍｇ／ｍ２以下であり、さらに好ましくは１００ｍｇ／ｍ２以上２００ｍｇ／ｍ２以下である。
Hollow fiber membrane for blood purification to be filled in the blood purification apparatus of the present invention is required to contain at 70 mg / m 2 or more 300 mg / m 2 or less in the range in the fat-soluble vitamins membrane area terms. The membrane area as used herein refers to the effective total inner surface area of the hollow fiber membrane involved in filtration and dialysis, and is indicated by the product of the average inner diameter, circumference ratio, number and effective length of the hollow fiber membrane. If the fat-soluble vitamin is less than 70 mg / m 2 in terms of membrane area, uneven coating of the fat-soluble vitamin is likely to occur, resulting in poor antioxidant ability. On the other hand, if it is more than 300 mg / m 2 , a large amount of fat-soluble vitamins adhere to the surface of the entire membrane, for example, the inside of the hollow fiber where the blood other than the inner surface of the hollow fiber does not contact or the outer surface of the hollow fiber. The entire membrane becomes more hydrophobic. As a result, not only the permeation ability of blood components, filtrate, dialysate, etc., but also antithrombogenicity decreases and residual blood is generated.
Furthermore, although mentioned later for details, this fat-soluble vitamin may raise | generate a local aggregation by the heat history at the time of sterilization, or contact with hot water, and a crack may generate | occur | produce in a hollow fiber. Therefore, the range of more preferable content is 80 mg / m 2 or more and 250 mg / m 2 or less, and further preferably 100 mg / m 2 or more and 200 mg / m 2 or less.
また、本発明においては、膜構造中の局所的な含有量を特定することが重要である。すなわち、脂溶性ビタミンの含有量は中空糸の濾液流路側よりも血液流路側、言い換えれば中空糸内表面近傍に多くすることが必要であり、中空糸内表面の近傍に存在する前記疎水性高分子と親水性高分子の総量に対し、血液流路側の脂溶性ビタミンは２．５％以上、３０．０％以下の範囲であることが必要である。その理由は、血液が接触する中空糸内表面に存在する脂溶性ビタミンが血液の酸化を抑制する効果をより高めるためと考えられる。中空糸内表面の抗酸化能を考慮すると、その含有量が高いほうが好ましく思われるが、必要以上に高いと前述のとおり内表面の疎水性が高くなりすぎて血液凝固系を刺激するおそれがある。反対に、低すぎると本来の効果を発揮し得ない。従って、より好ましくは３．５％以上、２５．０％以下の範囲であり、さらに好ましくは４．５％以上、２０．０％以下の範囲である。 In the present invention, it is important to specify the local content in the film structure. That is, the content of the fat-soluble vitamin needs to be increased on the blood channel side than the filtrate channel side of the hollow fiber, in other words, near the inner surface of the hollow fiber. The fat-soluble vitamin on the blood channel side needs to be in the range of 2.5% or more and 30.0% or less with respect to the total amount of molecules and hydrophilic polymer. The reason is considered to be that the fat-soluble vitamin present on the inner surface of the hollow fiber with which the blood comes into contact enhances the effect of suppressing blood oxidation. Considering the antioxidant capacity of the inner surface of the hollow fiber, it is preferable that the content is higher, but if it is higher than necessary, the hydrophobicity of the inner surface becomes too high as described above, which may irritate the blood coagulation system. . On the other hand, if it is too low, the original effect cannot be exhibited. Therefore, the range is more preferably 3.5% or more and 25.0% or less, and further preferably 4.5% or more and 20.0% or less.
中空糸内表面近傍の脂溶性ビタミン存在量を測定する方法は、ＴＯＦ−ＳＩＭＳ（Ｔｉｍｅ−ｏｆ−Ｆｌｉｇｈｔ Ｓｅｃｏｎｄａｒｙ Ｉｏｎ Ｍａｓｓ Ｓｐｅｃｔｒｏｍｅｔｒｙ、時間飛行型二次イオン質量分析装置）が最適であり、以下にその妥当性を示す。 The most suitable method for measuring the abundance of fat-soluble vitamins near the inner surface of the hollow fiber is TOF-SIMS (Time-of-Flight Secondary Ion Mass Spectrometry). Showing gender.
ＴＯＦ−ＳＩＭＳは、固体試料の最表面の成分（原子、分子）およびその分布をｐｐｍオーダーの極微量オーダーにて捕らえることが可能な装置である。原理としては、高真空中で高速のイオンビーム（１次イオン）を固体試料表面にぶつけると、スパッタリング現象により、表面の構成成分がはじき飛ばされ、このとき発生する正または負の電荷を帯びたイオン（２次イオン）を電場によって一方向に飛ばして、一定距離離れた位置で検出するものである。特に、ＴＯＦ−ＳＩＭＳの場合は１次イオン照射量 が著しく少ないため、有機化合物は化学構造を保った状態でイオン化され、固体試料表面の最も外側で発生した２次イオンのみが、真空中へ飛び出す原理になっている。そのため、中空糸膜の最表面の情報を得ることが可能となる。さらに、イオンを検出する方法が、電子や光を検出する方法と比べて感度がよいため、ＴＯＦ−ＳＩＭＳは中空糸膜の表面に存在するｐｐｍオーダーの微量成分をも検出することができる長所も有する。このような点から、ＴＯＦ―ＳＩＭＳ法は、酸化ストレス等の血液適合性を確実に反映する中空糸内表面近傍、すなわち、中空糸膜内表面の極めて薄い層である１〜５ｎｍ付近に存在する脂溶性ビタミン存在量を適切に測定できる極めて有効な手法である。 TOF-SIMS is a device that can capture the components (atoms, molecules) on the outermost surface of a solid sample and the distribution thereof in the order of trace amounts on the order of ppm. As a principle, when a high-speed ion beam (primary ion) is struck against the surface of a solid sample in a high vacuum, the surface components are repelled by the sputtering phenomenon, and positive or negative charged ions are generated at this time. (Secondary ions) are scattered in one direction by an electric field and detected at a position separated by a certain distance. In particular, in the case of TOF-SIMS, the irradiation amount of primary ions is remarkably small, so that organic compounds are ionized while maintaining the chemical structure, and only secondary ions generated on the outermost surface of the solid sample jump out into the vacuum. It is the principle. Therefore, information on the outermost surface of the hollow fiber membrane can be obtained. Furthermore, since the method for detecting ions is more sensitive than the method for detecting electrons and light, TOF-SIMS also has the advantage of being able to detect trace components in the order of ppm present on the surface of the hollow fiber membrane. Have. From such points, the TOF-SIMS method exists in the vicinity of the inner surface of the hollow fiber that reliably reflects blood compatibility such as oxidative stress, that is, in the vicinity of 1 to 5 nm, which is an extremely thin layer on the inner surface of the hollow fiber membrane. This is an extremely effective technique that can appropriately measure the amount of fat-soluble vitamins.
本発明の血液浄化装置は、滅菌方法として放射線滅菌されていることが必要である。血液浄化装置に充填された中空糸膜において、脂溶性ビタミンの含有量が７０〜３００ｍｇ／ｍ２と多い場合、高温高湿条件を伴うオートクレーブ滅菌では脂溶性ビタミンが局所的凝集を起こすことにより、中空糸膜にクラックが発生する。これが原因となって血液リークが起こる可能性が高まる。また、ホルマリンやエチレンオキサイトガスのような薬剤（ガス）滅菌の場合には、薬剤の残留による副作用が問題となるため使用することができない。
一方、放射線滅菌では中空糸膜のリークの問題も起こらず、薬剤残留の問題もないばかりか、放射線の照射エネルギーによって親水性ポリマーが架橋することにより、親水性ポリマーの溶出を抑えることも可能となる。オートクレーブ滅菌や薬剤滅菌では親水性高分子の架橋が起こらず、親水性ポリマーの溶出を抑えることはできない。
The blood purification apparatus of the present invention must be sterilized by radiation as a sterilization method. In the hollow fiber membrane filled in the blood purification device, when the fat-soluble vitamin content is as high as 70 to 300 mg / m 2 , the fat-soluble vitamin causes local aggregation in autoclave sterilization with high temperature and high humidity conditions. Cracks occur in the hollow fiber membrane. This increases the possibility of blood leaks. Further, in the case of chemical (gas) sterilization such as formalin and ethylene oxide gas, it cannot be used because side effects due to residual chemicals are problematic.
On the other hand, radiation sterilization does not cause a problem of leakage of the hollow fiber membrane, there is no problem of drug residue, and it is possible to suppress the elution of the hydrophilic polymer by crosslinking the hydrophilic polymer by radiation irradiation energy. Become. In autoclave sterilization and drug sterilization, crosslinking of the hydrophilic polymer does not occur, and elution of the hydrophilic polymer cannot be suppressed.
本発明において、ジメチルアセトアミド（以下、ＤＭＡＣと称する）に可溶性の親水性高分子含有量は、総親水性高分子量の２５重量％以上９５重量％であることが好ましい。ＤＭＡＣに可溶性の親水性高分子含有量（％）が２５重量％未満であると、親水性高分子は強固に不溶化された状態で膜に存在し、親水性高分子溶出は極めて少ないが残血がひどくなる傾向にあり、９５重量％を越えると親水性高分子の溶出量増加が懸念される。そのための好ましい範囲は３５重量％以上９０重量％以下、更に好ましくは５０重量％以上８５重量％以下である。 In the present invention, the content of hydrophilic polymer soluble in dimethylacetamide (hereinafter referred to as DMAC) is preferably 25% by weight or more and 95% by weight of the total hydrophilic polymer weight. When the content (%) of the hydrophilic polymer soluble in DMAC is less than 25% by weight, the hydrophilic polymer exists in the membrane in a strongly insolubilized state, and the elution of the hydrophilic polymer is extremely small, but residual blood However, when the amount exceeds 95% by weight, there is a concern that the amount of hydrophilic polymer eluted may increase. A preferred range for this is 35% by weight or more and 90% by weight or less, more preferably 50% by weight or more and 85% by weight or less.
ＤＭＡＣ に可溶性の親水性高分子含有量とは、ＤＭＡＣに溶解する親水性高分子含有量の総親水性高分子量（もともと膜中に存在した親水性高分子の量）に対する割合の百分率であり、式（１）から算出される。
例えば、親水性高分子がポリビニルピロリドンの場合、次の方法で測定することができる。まず、総親水性高分子重量は、中空糸の元素分析により、その総窒素量から中空糸単位重量当たりの値を算出する。秤量した乾燥中空糸膜約１ｇにＤＭＡＣを５０ｍｌ加え、２５℃で５時間程度の充分な撹袢を行うと、ＤＭＡＣはポリスルホンおよび架橋不溶化していない親水性高分子を溶解するので、架橋によって不溶化した親水性高分子がゲル状の固形分として残る。この固形分を予め秤量したフィルターで濾過し、水洗した後、１０５℃で１６時間乾燥する。得られた固形分重量を測定することにより、中空糸単位重量当たりのＤＭＡＣに不溶性の親水性高分子重量を求めることができる。これらを上記数式に代入し、ＤＭＡＣに可溶性の親水性高分子含有量（％）を算出することができる。 For example, when the hydrophilic polymer is polyvinylpyrrolidone, it can be measured by the following method. First, the total hydrophilic polymer weight is calculated from the total nitrogen content by the elemental analysis of the hollow fiber based on the hollow fiber unit weight. When 50 ml of DMAC is added to about 1 g of the dry hollow fiber membrane weighed and sufficiently stirred at 25 ° C. for about 5 hours, DMAC dissolves polysulfone and the hydrophilic polymer that has not been cross-linked and insolubilized. The resulting hydrophilic polymer remains as a gel-like solid. The solid content is filtered through a pre-weighed filter, washed with water, and dried at 105 ° C. for 16 hours. By measuring the obtained solid content weight, the weight of the hydrophilic polymer insoluble in DMAC per unit weight of the hollow fiber can be determined. By substituting these into the above formula, the content (%) of hydrophilic polymer soluble in DMAC can be calculated.
一般に、中空糸膜製膜原液に添加した親水性高分子は膜が形成される過程ににおいてその一部が膜中に残存する。その残存率は親水性高分子の分子量や紡糸条件により変化するが、親水性高分子含有量が総高分子量、言い換えれば膜の乾燥重量の１〜１８重量％が良く、好ましくは２〜１５重量％、さらに好ましくは２〜１２重量％がよい。１重量％未満では、中空糸膜が十分な親水性を示さない傾向にあり、反対に１８重量％より多いと、膜表面の親水性が過度に高くなって乾燥時に中空糸外表面同士の固着が発生するため、成型上好ましくない。また、そのような膜を得ようとすると、製膜原液の粘性が高くなりすぎて安定紡糸が困難となる。
次に、本発明の血液浄化装置の製造方法について述べる。
Generally, a part of the hydrophilic polymer added to the hollow fiber membrane forming stock solution remains in the membrane in the process of forming the membrane. The residual ratio varies depending on the molecular weight of the hydrophilic polymer and the spinning conditions, but the hydrophilic polymer content is preferably the total polymer weight, in other words, 1 to 18% by weight of the dry weight of the membrane, preferably 2 to 15% by weight. %, More preferably 2 to 12% by weight. If the amount is less than 1% by weight, the hollow fiber membrane tends to not exhibit sufficient hydrophilicity. Conversely, if the amount is more than 18% by weight, the hydrophilicity of the membrane surface becomes excessively high, and the outer surfaces of the hollow fibers adhere to each other during drying. This is not preferable in terms of molding. Moreover, when trying to obtain such a membrane, the viscosity of the membrane-forming stock solution becomes too high, and stable spinning becomes difficult.
Next, the manufacturing method of the blood purification apparatus of this invention is described.
本発明の血液浄化装置の製造方法は、公知の方法によって、疎水性高分子と親水性高分子からなる血液浄化用中空糸膜の束を容器に充填し、一般的な中空糸膜型血液浄化装置の形状に組み立て、成型した後、脂溶性ビタミンの被覆工程および滅菌工程を順に経ることから構成される。その際、被覆工程と滅菌工程との間に、中空糸膜の湿潤化工程と滅菌保護剤の添加工程を加えることもできる。 The method for producing a blood purification apparatus of the present invention is a known hollow fiber membrane blood purification method in which a container is filled with a bundle of hollow fiber membranes for blood purification comprising a hydrophobic polymer and a hydrophilic polymer by a known method. After being assembled and molded into the shape of the device, it is composed of a fat-soluble vitamin coating step and a sterilization step in order. At that time, a step of wetting the hollow fiber membrane and a step of adding a sterilizing protective agent can be added between the coating step and the sterilization step.
（中空糸膜の準備〜組み立て・成型）
本発明においては、血液浄化用中空糸膜の製造方法は特に限定する必要はなく、前述の疎水性高分子と親水性高分子を含む中空糸膜であって、血液浄化に適した透過性能や膜構造を形成し得る方法を適宜利用すればよい。例えば、疎水性高分子と親水性高分子とを共通溶剤に溶解した製膜原料を用いて乾湿式紡糸する方法（国際公開第９８／５２６８３号パンフレット等）や、疎水性高分子の中空糸膜表面に親水性高分子を被覆する方法（特開平６−２３８１３９等）を例示することができる。
(Preparation of hollow fiber membranes-assembly and molding)
In the present invention, the method for producing the hollow fiber membrane for blood purification is not particularly limited, and is a hollow fiber membrane containing the above-described hydrophobic polymer and hydrophilic polymer, which has permeation performance suitable for blood purification, A method capable of forming a film structure may be appropriately used. For example, a method of dry-wet spinning using a film-forming raw material in which a hydrophobic polymer and a hydrophilic polymer are dissolved in a common solvent (International Publication No. 98/52683, etc.), a hollow fiber membrane of a hydrophobic polymer A method for coating the surface with a hydrophilic polymer (JP-A-6-238139, etc.) can be exemplified.
次に、前記のとおり製膜された中空糸膜を数千〜２万本程度に纏めた束を、例えば筒状の樹脂容器に充填し、該中空糸膜の膜壁により容器内を血液側流路と濾液側流路とに隔てるように組み立てられた血液浄化装置を準備する。具体的には、濾液または透析液の導入・導出用のノズルを設けた筒状の樹脂容器の両端部をウレタン等の包埋樹脂でポッティング加工し、包埋樹脂の硬化後に、両端部で各中空糸膜が開口するよう包埋樹脂を切断する。この両端部に血液導入（導出）用のノズルを有するヘッダーキャップを装填すれば血液浄化装置の形状を得ることができるが、これに限定する必要はなく、公知の組立技術を参照すればよい。 Next, a bundle of about several thousand to 20,000 hollow fiber membranes formed as described above is filled into, for example, a cylindrical resin container, and the inside of the container is blood sided by the membrane wall of the hollow fiber membrane. A blood purification apparatus assembled so as to be separated into a flow path and a filtrate side flow path is prepared. Specifically, both ends of a cylindrical resin container provided with nozzles for introducing / extracting filtrate or dialysate are potted with an embedding resin such as urethane, and after the embedding resin is cured, The embedding resin is cut so that the hollow fiber membrane opens. If a header cap having a blood introduction (lead-out) nozzle is loaded at both ends, the shape of the blood purification device can be obtained. However, the present invention is not limited to this, and a known assembly technique may be referred to.
（脂溶性ビタミンの被覆工程）
血液浄化装置の中空糸膜の内表面を被覆する場合を例に挙げて説明する。脂溶性ビタミン、脂溶性ビタミンの溶媒からなる脂溶性ビタミン溶液を作製し、これを中空糸膜の中空糸内腔部に流入することにより、脂溶性ビタミンを中空糸膜内表面に付着させる。流入方法は、例えば、循環ポンプを利用して、被覆用の脂溶性ビタミン溶液を血液浄化装置のヘッダーノズルから中空糸内腔部に導入する方法が簡便である。他には、ヘッダーキャップの装填前に包埋樹脂の切断面をビタミン溶液に浸漬し、これを吸い上げる方法、紡糸原液または紡糸芯液のいずれかまたは両方に脂溶性ビタミンを混入せしめる方法等が挙げられるが、適宜選択すればよい。
(Coating process of fat-soluble vitamins)
The case where the inner surface of the hollow fiber membrane of the blood purification apparatus is coated will be described as an example. A fat-soluble vitamin solution composed of a fat-soluble vitamin and a fat-soluble vitamin solvent is prepared, and the solution is poured into the hollow fiber lumen of the hollow fiber membrane, thereby attaching the fat-soluble vitamin to the inner surface of the hollow fiber membrane. As an inflow method, for example, a method of introducing a fat-soluble vitamin solution for coating into a hollow fiber lumen from a header nozzle of a blood purification device using a circulation pump is simple. Other methods include immersing the cut surface of the embedding resin in the vitamin solution before loading the header cap and sucking it up, or mixing fat-soluble vitamins in either or both of the spinning stock solution and the spinning core solution. However, it may be selected as appropriate.
このとき、中空糸膜の外表面および外表面近傍の膜厚部に水を存在させると、水に不溶あるいは難溶である脂溶性ビタミンは血液流路側に近い部分、すなわち中空糸内表面側に多く含有される。この脂溶性ビタミン溶液を所定時間、例えば、３０秒〜５分間、好ましくは４０〜１２０秒間、血液流路側に通液させることで中空糸膜内面に脂溶性ビタミンを充分なじませることが好ましい。 At this time, if water is present on the outer surface of the hollow fiber membrane and the film thickness portion in the vicinity of the outer surface, the fat-soluble vitamin that is insoluble or hardly soluble in water is located near the blood channel, that is, on the inner surface of the hollow fiber. Contains a lot. It is preferable that the fat-soluble vitamin is sufficiently infiltrated into the inner surface of the hollow fiber membrane by allowing the fat-soluble vitamin solution to flow through the blood channel side for a predetermined time, for example, 30 seconds to 5 minutes, preferably 40 to 120 seconds.
脂溶性ビタミン溶液に用いる溶媒としては、脂溶性ビタミンを溶解し基材を溶解しないものが好ましい。このような溶媒としては、たとえば、 メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノール、イソブタノール、ｓｅｃ− ブタノール、２−エチルヘキサノール等のアルコール類；ジエチルエーテル等のエーテル類；１，２，２−トリクロロ−１，２，２−トリフルオロエタン、トリクロロフルオロメタン、１，１，２，２−テトラクロロ−１，２−ジフルオロエタン等の塩化弗化炭化水素；弗化メチル、四弗化炭素、テトラフルオロエタン、テトラフルオロエチレン、パーフルオロメチルプロピルシクロヘキサン、パーフルオロブチルシクロヘキサン等のパーフルオロシクロアルカン類、パーフルオロデカン、パーフルオロメチルデカリン、パーフルオロアルキルテトラヒドロピラン等の弗化炭化水素；またはヘキサン、ヘプタン、デカン等の炭化水素等が挙げられる。溶媒は、これらの中から用いる基材の種類により適宜選択すればよいが、工業用生産に使用する場合は、安価であり、安全上沸点が高めのものが好ましく、さらに脂溶性ビタミンを多く含有するためには、より溶解力の高いものが好ましい。例えば、基材としてポリスルホンを、脂溶性ビタミンとしてビタミンＥを使用した場合その溶媒としてはイソプロパノールが好適に用いられる。 As a solvent used for the fat-soluble vitamin solution, a solvent that dissolves the fat-soluble vitamin and does not dissolve the base material is preferable. Examples of such solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol and 2-ethylhexanol; ethers such as diethyl ether; Chlorinated fluorinated hydrocarbons such as 2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane, 1,1,2,2-tetrachloro-1,2-difluoroethane; methyl fluoride, carbon tetrafluoride , Perfluorocycloalkanes such as tetrafluoroethane, tetrafluoroethylene, perfluoromethylpropylcyclohexane, perfluorobutylcyclohexane, fluorinated hydrocarbons such as perfluorodecane, perfluoromethyldecalin, perfluoroalkyltetrahydropyran; or Hexane, heptane, and hydrocarbons such as decane and the like. Solvents may be appropriately selected according to the type of substrate used from these, but when used for industrial production, those that are inexpensive, preferably have a high boiling point for safety, and further contain a large amount of fat-soluble vitamins. In order to do so, those having higher dissolving power are preferred. For example, when polysulfone is used as the base material and vitamin E is used as the fat-soluble vitamin, isopropanol is preferably used as the solvent.
これらの溶媒のうち、水溶性アルコールの溶媒に水を混和して用いると、脂溶性ビタミンの中空糸膜表面への付着がより促進される傾向にあるので好ましい。水との混和比率は、脂溶性ビタミンの溶解濃度により制限されるので、例えば５〜５０％（アルコール濃度として９５〜５０％）程度の範囲で、脂溶性ビタミンが析出しない程度に水を添加して用いると好ましい。 Among these solvents, it is preferable to mix water with a water-soluble alcohol solvent because it tends to promote the adhesion of fat-soluble vitamins to the hollow fiber membrane surface. Since the mixing ratio with water is limited by the dissolution concentration of the fat-soluble vitamin, water is added to such an extent that the fat-soluble vitamin does not precipitate, for example, in the range of about 5 to 50% (the alcohol concentration is 95 to 50%). And preferably used.
また、脂溶性ビタミン溶液中のビタミン濃度はその種類や溶媒組成によって適宜設定し得るものであるが、例えば、ビタミンＥを５０〜６０％のプロパノール水溶液に溶解して用いる際は、概ね０．２〜２．０％の範囲に調整してあれば良い。この範囲よりも濃度が低いと、抗酸化能を発揮するのに十分な被覆量が得られず、反対に、濃度が高いと被覆量が過剰となって被覆面の疎水性が強くなり、抗血栓性の低下につながる。 The vitamin concentration in the fat-soluble vitamin solution can be appropriately set depending on the type and solvent composition. For example, when vitamin E is dissolved in a 50-60% propanol aqueous solution, the concentration is approximately 0.2. It suffices if it is adjusted to a range of ~ 2.0%. If the concentration is lower than this range, it is not possible to obtain a coating amount sufficient to exert the antioxidant ability. On the contrary, if the concentration is high, the coating amount becomes excessive and the hydrophobicity of the coated surface becomes strong, and the It leads to a decrease in thrombosis.
溶液温度については、温度が高いほどビタミンの溶解度は高まるが、被覆工程で中空糸膜、容器、包埋樹脂等への影響を軽減するために、室温付近（１５〜３０℃）に調整すればよい。 As for the solution temperature, the higher the temperature, the higher the solubility of vitamins, but in order to reduce the influence on the hollow fiber membrane, container, embedding resin, etc. in the coating process, Good.
前記のとおり脂溶性ビタミン溶液を中空糸膜の内表面に接触させた後、自然落下あるいはエアフラッシュなどにより中空糸内腔部の脂溶性ビタミン溶液を排出する。しかる後、中空糸内腔部へ、例えば、空気、窒素、炭酸ガス等の乾燥気体を導入する等により被覆面を乾燥させ、脂溶性ビタミンの溶剤および水を乾燥除去すると同時に脂溶性ビタミンの皮膜を形成させる。導入する気体の温度は１０〜８０℃が好ましく、より好ましくは１５〜３０℃である。 As described above, after the fat-soluble vitamin solution is brought into contact with the inner surface of the hollow fiber membrane, the fat-soluble vitamin solution in the hollow fiber lumen is discharged by natural dropping or air flush. Thereafter, the coated surface is dried by, for example, introducing a dry gas such as air, nitrogen or carbon dioxide into the hollow fiber lumen, and the fat-soluble vitamin solvent and water are removed by drying. To form. The temperature of the introduced gas is preferably 10 to 80 ° C, more preferably 15 to 30 ° C.
（中空糸膜の湿潤化工程）
脂溶性ビタミンの被覆を完了した中空糸膜は、滅菌前に水系溶液で湿潤化しておくと好ましい。水系溶液で中空糸膜を湿潤することにより中空糸膜が安定し、透水性能、透析性能、濾過性能等の性能の変化を起こすことが少なくなる。水系溶液で中空糸膜を湿潤化する方法は、容器に水系溶液を充填する方法、容器に水系溶液を充填した後排液する方法等がある。この中空糸膜の湿潤化工程は、以下に述べる滅菌保護剤の添加工程を兼ねることもできる。
(Wetting process of hollow fiber membrane)
The hollow fiber membrane that has been coated with the fat-soluble vitamin is preferably wetted with an aqueous solution before sterilization. Wetting the hollow fiber membrane with an aqueous solution stabilizes the hollow fiber membrane and reduces changes in performance such as water permeability, dialysis performance, and filtration performance. Methods for wetting the hollow fiber membrane with the aqueous solution include a method of filling the container with the aqueous solution, and a method of discharging after filling the container with the aqueous solution. This wetting step of the hollow fiber membrane can also serve as a step of adding a sterilizing protective agent described below.
（滅菌保護剤の添加工程）
前記の湿潤化にあたり、水系溶液として滅菌保護剤を含む水系溶液で湿潤化しておくとより好ましい。滅菌保護剤とは、後述する滅菌工程において照射される放射線エネルギーによって、中空糸膜の親水性高分子が著しく変性を受けないように保護するためのもので、有機化合物としては、一分子中に複数の水酸基や芳香環を有するラジカル捕捉剤である。具体的には、グリセリンやプロピレングリコール等の（多価）アルコール類、オリゴ糖や多糖等の水溶性糖類を例示できる。また、亜硫酸塩等の抗酸化作用を有する無機塩類も利用できる。
滅菌保護剤を中空糸膜に含浸させる方法は、滅菌保護剤を適当な溶媒に溶解して血液処理装置に導入する方法、例えば、水または生理的塩溶液に滅菌保護剤を溶解させて血液処理装置内部の空間に充填させる、または中空糸膜だけに含浸させる方法等が用いられる。血液処理装置内に滅菌保護剤が存在すると、以下に述べる放射線滅菌により血液処理装置、特に中空糸膜が変化を受けるのを抑制することができる。
滅菌保護剤を溶液状態にして用いる場合、滅菌保護剤の濃度は、血液処理装置の材質、抗酸化剤の種類および滅菌の条件によって最適な濃度が決定されるべきであるが、大体好ましくは０ ．００１ ％から１ ％、より好ましくは０ ．００５ ％から０ ．５ ％の濃度である。
(Sterile protective agent addition process)
In the above-mentioned wetting, it is more preferable to wet with an aqueous solution containing a sterilizing protective agent as an aqueous solution. The sterilization protective agent is for protecting the hydrophilic polymer of the hollow fiber membrane from being significantly modified by the radiation energy irradiated in the sterilization process described later. As an organic compound, It is a radical scavenger having a plurality of hydroxyl groups and aromatic rings. Specific examples include (polyhydric) alcohols such as glycerin and propylene glycol, and water-soluble saccharides such as oligosaccharides and polysaccharides. In addition, inorganic salts having an antioxidative action such as sulfites can also be used.
The method for impregnating the hollow fiber membrane with the sterilizing protective agent is a method of dissolving the sterilizing protective agent in an appropriate solvent and introducing it into the blood treatment apparatus, for example, dissolving the sterilizing protective agent in water or a physiological salt solution to treat the blood. A method of filling the space inside the apparatus or impregnating only the hollow fiber membrane is used. When a sterilization protective agent is present in the blood processing apparatus, it is possible to suppress changes in the blood processing apparatus, particularly the hollow fiber membrane, due to radiation sterilization described below.
When the sterilization protective agent is used in the form of a solution, the concentration of the sterilization protective agent should be determined by the material of the blood treatment apparatus, the type of the antioxidant and the sterilization conditions, but is preferably about 0. . 001% to 1%, more preferably 0. 005% to 0. The concentration is 5%.
（滅菌工程）
本発明で用いられる滅菌方法は、放射線滅菌法であることが必要である。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るが、中でも、対象物に対する照射エネルギーの透過性や処理効率の点から、ガンマ線を用いた放射線滅菌法が好んで用いられる。
放射線の照射線量は、ガンマ線の場合は通常５〜５０ｋＧｙであるが、本発明においては、１５〜２５ｋＧｙの比較的低い線量範囲で照射することが好ましい。このような条件下で放射線滅菌することにより、中空糸膜中の親水性高分子は部分架橋され、良好な血液適合性を維持したまま親水性高分子の溶出性を抑制することができる。より好ましくは、この照射線量の範囲で滅菌保護剤を併用することであり、その添加濃度の多少によりＤＭＡＣに可溶性の親水性高分子の含有量を制御しやすくなる。
(Sterilization process)
The sterilization method used in the present invention needs to be a radiation sterilization method. For the radiation sterilization method, an electron beam, gamma ray, X-ray or the like can be used. Among them, the radiation sterilization method using gamma ray is preferably used from the viewpoint of the permeability of irradiation energy to the object and the processing efficiency.
The irradiation dose of radiation is usually 5 to 50 kGy in the case of gamma rays, but in the present invention, irradiation is preferably performed in a relatively low dose range of 15 to 25 kGy. By performing radiation sterilization under such conditions, the hydrophilic polymer in the hollow fiber membrane is partially crosslinked, and the elution of the hydrophilic polymer can be suppressed while maintaining good blood compatibility. More preferably, a sterilization protective agent is used in combination within this irradiation dose range, and the content of the hydrophilic polymer soluble in DMAC can be easily controlled depending on the concentration of the addition.
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれに限定されるものではない。先ず、本実施例で用いた各種測定方法について説明する。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this. First, various measurement methods used in this example will be described.
（中空糸膜中の脂溶性ビタミン（ビタミンＥ）の総含有量）
血液浄化装置を分解して採取した血液浄化用中空糸膜を水洗した後、乾燥し、乾燥した中空糸膜重量を測定した後、その全量を細かく裁断し、４００mlのエタノールを加え、室温で６０分間、超音波振動を加えながらビタミンＥの抽出を行った。
定量操作は液体クロマトグラフ法により行ない、ビタミンＥ標準溶液のピーク面積から得た検量線を用いて、抽出液のビタミンＥ量を求めた。すなわち、高速液体クロマトグラフ装置(ＪＡＳＣＯ社製UV−２０７５ｐｌｕｓ ｉｎｔｅｌｌｉｇｅｎｔ ＵＶ／ＶＩＳ Ｄｅｔｅｃｔｅｒ、ＰＵ−２０８０ｐｌｕｓｉｎｔｅｌｌｉｇｅｎｔ ＨＰＬＣ ｐｕｍｐ、ＣＯ−２０６５ｐｌｕｓ ｉｎｔｅｌｌｉｇｅｎｔ ｃｏｌｕｍｎ ｏｖｅｎ、ＡＳ−２０５７ｐｌｕｓ ｉｎｔｅｌｌｉｇｅｎｔ ｓａｍｐｌｅｒ)に、カラム（Ｓｈｏｄｅｘ Ａｓａｈｉｐａｋ社製 ＯＤＰ−５０ ６Ｅ ｐａｃｋｅｄ ｃｏｌｕｍｎ ｆｏｒ ＨＰＬＣ）を取り付け、カラム温度４０℃において、移動相である高速液体クロマトグラフィー用メタノールを流量１ｍｌ／ｍｉｎで通液し、紫外部の吸収ピークの面積からビタミンＥ濃度を求めた。この濃度から、抽出効率を１００％として中空糸膜に含有されるビタミンＥ濃度を求めた。
(Total content of fat-soluble vitamin (vitamin E) in the hollow fiber membrane)
The hollow fiber membrane for blood purification collected by disassembling the blood purification apparatus was washed with water, dried, and the weight of the dried hollow fiber membrane was measured. Then, the whole amount was finely cut, 400 ml of ethanol was added, and 60 ml at room temperature was added. Vitamin E was extracted while applying ultrasonic vibration for a minute.
The quantitative operation was performed by liquid chromatography, and the amount of vitamin E in the extract was determined using a calibration curve obtained from the peak area of the vitamin E standard solution. That is, a high performance liquid chromatograph (JA-20, UV-2075 plus intelligent UV / VIS Detector, PU-2080 plus intelligent HPLC 50, CO-2065 plus intelligent DP, and AS-2057 plus intellh) 6E packed column for HPLC) was attached, and methanol for high-performance liquid chromatography as a mobile phase was passed at a flow rate of 1 ml / min at a column temperature of 40 ° C., and the vitamin E concentration was determined from the area of the absorption peak in the ultraviolet region. From this concentration, the concentration of vitamin E contained in the hollow fiber membrane was determined with an extraction efficiency of 100%.
（血液流路側（中空糸内表面近傍）に存在する脂溶性ビタミン（ビタミンＥ）含有量）
血液浄化装置を分解して採取した血液浄化用中空糸膜を水洗した後、凍結乾燥させた。乾燥した中空糸を軸方向に切開して内表面を露出させた状態にて、ＴＯＦ−ＳＩＭＳ装置（ＴＲＩＦＴIII，Ｐｈｙｓｉｃａｌ Ｅｌｅｃｔｒｏｎｉｃｓ社製）を用いて測定した。測定条件は、一次イオンＧａ＋、加速電圧１５ｋＶ、電流６００ｐＡ（ＤＣとして）、分析面積２００μm×２００μm、積算時間５ｍｉｎで行ない、検出器により、負イオン（Ｍａｓｓとして、ビタミンＥは１６３、ポリビニルピロリドンは２６、ポリスルホンは３２）を検出イオンとして検出した。本測定装置の特性上、測定深さは血液流路側を０とすると５ｎｍまでの深さに相当する。表面濃度算出方法は得られた試料の各成分のイオン強度を、プロトンのイオン強度IHを用い、式（２）、（３）、（４）、（５）、（６）、（７）に従い規格化して用いる。
(Fat-soluble vitamin (vitamin E) content present on the blood channel side (near the inner surface of the hollow fiber))
The blood purification hollow fiber membrane collected by disassembling the blood purification apparatus was washed with water and then freeze-dried. The measurement was performed using a TOF-SIMS apparatus (TRIFT III, manufactured by Physical Electronics) with the dried hollow fiber incised in the axial direction to expose the inner surface. The measurement conditions were as follows: primary ion Ga +, acceleration voltage 15 kV, current 600 pA (as DC), analysis area 200 μm × 200 μm, integration time 5 min, and negative ions (as mass, vitamin E 163, polyvinylpyrrolidone 26) Polysulfone was detected using 32) as a detection ion. Due to the characteristics of this measuring apparatus, the measurement depth corresponds to a depth of up to 5 nm when the blood flow path side is zero. In the surface concentration calculation method, the ionic strength of each component of the obtained sample is used as the ionic strength I H of the proton, and the equations (2), (3), (4), (5), (6), (7) Standardized according to the above.
各成分の規格化イオン強度（規格化値I163(ViE)、I26(PVP)、I32(psf)）と純粋な各試料の規格化イオン強度（規格化値I163(ViE)100%、I26(PVP)100%、I32(psf)100%）から各成分濃度（CViE、CPVP、Cpsf）を式（８）、（９）、(10)により求める。
（血液の抗酸化能指標であるグルタチオンペルオキシターゼ（Ｇｐｘ）の試験方法）
血液浄化装置を分解して採取した血液浄化用中空糸膜３００本を有効長９ｃｍ（膜面積０．０１６ｍ２）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成した。このミニモジュールを注射用蒸留水（大塚製薬株式会社、大塚注射用蒸留水）で洗浄後、生理食塩水（大塚製薬株式会社、大塚生食注）２５ｍｌを中空糸内腔に流して洗浄し、蒸留水と置換した（以下、プライミングと称す）。その後、ミニモジュールを遠心チューブ内に立てた状態で遠心脱水（１０００ｒｐｍ×５ｍｉｎ）し、脱水したモジュールを恒温槽に並べて３７℃で加温した。一方、バットに氷を入れ、血液回収用の遠心管を氷冷しておいた。
ブランク用の血液として、ヘパリン加人血を約５ｍｌ採取し、血清採取用の容器に約３．０ｍｌを入れ良く攪拌し、３０分放置後、遠心分離（３０００ｒｐｍ×１０ｍｉｎ）した。得られた血清をＧＰｘ測定用に０．５ｍｌずつマイクロチューブに入れた。
試験用の血液として、ヘパリン加人血をミニモジュールの中空糸内腔部に吸い上げた状態でホールドし、３７℃の恒温漕に入れて反応を開始した。それと同時に、ブランク用の血液３．５ｍｌを３７℃の恒温漕に入れて反応を開始する。反応終了後、別のバットで氷冷しておいた遠心管にミニモジュールを移し入れ、キャップを外して、遠心分離し（５００ｒｐｍ×３ｍｉｎ、４℃）、ホールドした血液を遠心管に回収した。回収した血液はブランク同様、血清採取用の容器に約３．０ｍｌを入れ良く攪拌し、３０分放置後、遠心分離（３０００ｒｐｍ×１０ｍｉｎ）した。得られた血清をＧＰｘ用に０．５ｍｌずつマイクロチューブに入れ、これらの検体中のＧｐｘ測定を検査業者（ＳＲＬ株式会社）に外注した。
Ｇｐｘの測定方法は以下のとおりである。すなわち、反応試薬として、第一試薬と第二試薬を使用する。第一試薬は、０．２５Ｍ Ｐｏｔａｓｓｉｕｍ ｐｈｏｓｐｈａｔｅ ｂｕｆｆｅｒ、ｐＨ７．０（０．２５ｍＭ ＥＤＴＡ、２．５ｍＭ ＮａＮ３）、１０ｍＭ グルタチオン水溶液、２．５ｍＭ ＮＡＤＰＨ ｉｎ ０．１％ＮａＨＣＯ３、５０μｇ／ｍｌ（１２０Ｕ／ｍｇ）ＧＲｉｎｐｈｏｓｐａｔｅ ｂｕｆｆｅｒ、ｐＨ７．０（０．２５ｍＭ ＥＤＴＡ，２．５ｍＭ ＮａＮ３）を使用時に当量混和し、蒸留水で２倍に希釈して用い、第二試薬は、２０ｍＭ Ｈ２Ｏ２水溶液である。検体の血清２０μｌに第一試薬を３２０μｌ混和し、３７℃で１０分反応させ、その後、第二試薬を２０μｌ加え、３４０ｎｍで吸光度を１分間測定する。ブランクは、２０μｌ蒸留水に第一試薬を３２０μｌ混和し、３７℃で１０分反応させ、その後、第二試薬を２０μｌ加え、３４０ｎｍで１分間吸光度を測定する。１分間当たりの吸光度変化量からブランクの変化量を差し引き、これにファクターを乗じ、活性測定値（μｌ ＮＡＤＰＨ／ｍｉｎ／ｌ）とする。ファクター（Ｆ）は、ＮＡＤＰＨの３４０ｎｍでのモル吸光度係数：６．３（ｃｍ２／μｍｏｌ）、検体量０．０２ｍｌ、キュベットの底面積：０．２５ｃｍ２より、下記式により算出される。
Ｆ＝（１／モル吸光度係数）×（１／光路長）×１０３
＝（１／６．３）×（０．２５／０．０２）×１０３
≒１９８４
本方法では、Ｇｐｘの低下能（％）として表記されるが、この低下能が小さいほど抗酸化能に優れることを意味する。
(Test method for glutathione peroxidase (Gpx), an index of blood antioxidant capacity)
300 hollow fiber membranes for blood purification collected by disassembling the blood purification apparatus were processed with silicon so that the effective length was 9 cm (membrane area 0.016 m 2 ), and mini-modules were produced. After washing this mini module with distilled water for injection (Otsuka Pharmaceutical Co., Ltd., Otsuka Injection distilled water), 25 ml of physiological saline (Otsuka Pharmaceutical Co., Ltd., Otsuka raw food injection) is poured into the hollow fiber lumen and washed. Replaced with water (hereinafter referred to as priming). Then, the spin-drying | dehydration (1000 rpm * 5min) was carried out in the state which stood the mini module in the centrifuge tube, the dehydrated module was put in the thermostat, and it heated at 37 degreeC. On the other hand, ice was put in the vat and the centrifuge tube for blood collection was ice-cooled.
About 5 ml of heparinized human blood was collected as blank blood, about 3.0 ml was placed in a serum collection container, stirred well, allowed to stand for 30 minutes, and then centrifuged (3000 rpm × 10 min). 0.5 ml of the obtained serum was put into a microtube for GPx measurement.
As test blood, heparin-added blood was held in a state where it was sucked into the hollow fiber lumen of the mini-module, and placed in a constant temperature bath at 37 ° C. to initiate the reaction. At the same time, 3.5 ml of blank blood is placed in a constant temperature bath at 37 ° C. to start the reaction. After completion of the reaction, the mini-module was transferred to a centrifuge tube that had been ice-cooled with another vat, the cap was removed, and centrifugation was performed (500 rpm × 3 min, 4 ° C.), and the held blood was collected in the centrifuge tube. Like the blank, about 3.0 ml of the collected blood was placed in a serum collection container, stirred well, allowed to stand for 30 minutes, and then centrifuged (3000 rpm × 10 min). 0.5 ml of the obtained serum was put into a microtube for GPx, and Gpx measurement in these samples was outsourced to a testing company (SRL Co., Ltd.).
The measuring method of Gpx is as follows. That is, the first reagent and the second reagent are used as reaction reagents. The first reagent was 0.25M Potassium phosphate buffer, pH 7.0 (0.25 mM EDTA, 2.5 mM NaN 3 ), 10 mM glutathione aqueous solution, 2.5 mM NADPH in 0.1% NaHCO 3 , 50 μg / ml (120 U / ml mg) GRinphosphate buffer, pH 7.0 (0.25 mM EDTA, 2.5 mM NaN 3 ) is mixed at an equivalent amount when used, diluted two-fold with distilled water, and the second reagent is 20 mM H 2 O 2 aqueous solution. is there. 320 μl of the first reagent is mixed with 20 μl of the serum of the specimen and reacted at 37 ° C. for 10 minutes. Then, 20 μl of the second reagent is added, and the absorbance is measured at 340 nm for 1 minute. As for the blank, 320 μl of the first reagent is mixed with 20 μl of distilled water, reacted at 37 ° C. for 10 minutes, then 20 μl of the second reagent is added, and the absorbance is measured at 340 nm for 1 minute. The amount of change in the blank is subtracted from the amount of change in absorbance per minute, and this is multiplied by a factor to obtain the measured activity (μl NADPH / min / l). The factor (F) is calculated by the following equation from the molar absorbance coefficient of NADPH at 340 nm: 6.3 (cm 2 / μmol), the sample amount 0.02 ml, and the bottom area of the cuvette: 0.25 cm 2 .
F = (1 / molar absorbance coefficient) × (1 / optical path length) × 10 3
= (1 / 6.3) × (0.25 / 0.02) × 10 3
≒ 1984
In this method, it is expressed as Gpx reduction ability (%), and the smaller the reduction ability, the better the antioxidant ability.
（血小板活性化指標である乳酸脱水素酵素（ＬＤＨ）の試験方法）
血液浄化装置を分解して採取した血液浄化用中空糸膜５６本を有効長１５ｃｍ（膜面積５０ｍｍ２）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成した。このミニモジュールに対し、生理食塩水（大塚製薬株式会社、大塚生食注）１０ｍｌを中空糸内側に流し洗浄した（以下、プライミングと称す）。その後、ヘパリン加人血を７ｍｌシリンジポンプにセットして、１．４４ｍｌ/ｍｉｎの流速でミニモジュール内に通血した後、生理食塩水によりミニモジュールの内側を１０ｍｌ、外側を１０ｍｌ洗浄した。
洗浄したミニモジュールから長さ１４ｃｍの中空糸膜を２８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。次に、燐酸緩衝溶液（ＰＢＳ）（和光純薬工業（株）製）にＴｒｉｔｏｎＸ−１００（ナカライテスク社製）を溶解して得た０．５容量ＴｒｉｔｏｎＸ−１００／ＰＢＳ溶液をＬＤＨ測定用のスピッツ管に０．５ｍｌ添加後、超音波処理を６０分行って中空糸膜に付着した細胞（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ＮａＤＨ溶液０.３ｍｌを加えて反応させ、直ちにその０．５ｍｌを分取して３４０ｎｍの吸光度を測定した。残液をさらに３７℃で１時間反応させた後に３４０ｎｍの吸光度を測定し、反応直後からの吸光度の減少を測定した。同様に血液と反応させていない膜についても吸光度を測定し、下記式（１１）により吸光度の差を算出した。本方法では、この減少率が大きいほどＬＤＨ活性が高い、すなわち血小板活性化が大きいことを意味する。
Δ３４０ｎｍ＝（サンプル反応直後吸光度−サンプル６０分後吸光度）−（ブランク反応直後吸光度−ブランク６０分後吸光度） （１１）
(Test method for lactate dehydrogenase (LDH), an indicator of platelet activation)
Both ends of the 56 blood purification hollow fiber membranes collected by disassembling the blood purification apparatus were processed with silicon so as to have an effective length of 15 cm (membrane area 50 mm 2 ), thereby producing a mini module. To this mini module, 10 ml of physiological saline (Otsuka Pharmaceutical Co., Ltd., Otsuka raw food injection) was poured inside the hollow fiber and washed (hereinafter referred to as priming). Thereafter, heparin-added blood was set in a 7 ml syringe pump and passed through the mini module at a flow rate of 1.44 ml / min, and then 10 ml of the inside of the mini module and 10 ml of the outside were washed with physiological saline.
After collecting 28 hollow fiber membranes having a length of 14 cm from the cleaned minimodule, they were chopped and put into a Spitz tube for LDH measurement to obtain a measurement sample. Next, 0.5 volume Triton X-100 / PBS solution obtained by dissolving Triton X-100 (manufactured by Nacalai Tesque) in phosphate buffer solution (PBS) (manufactured by Wako Pure Chemical Industries, Ltd.) was used for LDH measurement. After adding 0.5 ml to the Spitz tube, ultrasonic treatment was performed for 60 minutes to destroy cells (mainly platelets) adhering to the hollow fiber membrane, and LDH in the cells was extracted. 0.05 ml of this extract was taken, and further reacted with 2.7 ml of 0.6 mM sodium pyruvate solution and 0.3 ml of 1.277 mg / ml NaDH solution, and 0.5 ml of the extract was immediately taken. The absorbance at 340 nm was measured. The remaining solution was further reacted at 37 ° C. for 1 hour, and then the absorbance at 340 nm was measured, and the decrease in absorbance immediately after the reaction was measured. Similarly, the absorbance of the membrane not reacted with blood was also measured, and the difference in absorbance was calculated by the following formula (11). In this method, the larger the decrease rate, the higher the LDH activity, that is, the greater the platelet activation.
Δ340 nm = (absorbance immediately after sample reaction−absorbance after 60 minutes of sample) − (absorbance immediately after blank reaction−absorbance after 60 minutes of blank) (11)
〔実施例１〕
ポリスルホン（ソルベイ社製Ｐ−１７００）１８．０重量％、ポリビニルピロリドン（ＢＡＳＦ社製 Ｋ９０、重量平均分子量１，２００，０００）４．３重量％を、Ｎ，Ｎ−ジメチルアセトアミド７７．７重量％に溶解して均一な溶液とした。ここで、製膜原液中のポリスルホンに対するポリビニルピロリドンの混和比率は２３．９重量％であった。この製膜原液を６０℃に保ち、Ｎ，Ｎ−ジメチルアセトアミド３０重量％と水７０重量％の混合溶液からなる内部液とともに、２重環状紡口から吐出させ、０．９６ｍのエアギャップを通過させて７５℃の水からなる凝固浴へ浸漬し、８０ｍ／分にて巻き取った。この時、紡口から凝固浴までを円筒状の筒で囲み、筒の中に水蒸気を含んだ窒素ガスを流しながら、筒の中の湿度を５４．５％、温度を５１℃にコントロールした。紡速に対するエアギャップの比率は、０．０１２ｍ／（ｍ／分）であった。巻き取った糸束を切断後、束の切断面上方から８０℃の熱水シャワーを２時間かけて洗浄することにより膜中の残溶剤を除去し、該膜をさらに乾燥することにより含水量が１％未満の乾燥膜を得た。さらに、該乾燥膜を、液体の導入および導出用の２本のノズルを有する筒状容器に充填して両端部をウレタン樹脂で包埋後、硬化したウレタン部分を切断して中空糸膜が開口した端部に加工した。この両端部に血液導入（導出）用のノズルを有するヘッダーキャップを装填し血液浄化装置の形状に組み上げた。
次に、イソプロパノール５７ｗｔ％の水溶液にビタミンＥを０．２３ｗｔ％溶解した被覆溶液を、血液浄化装置の血液導入ノズルから中空糸膜の内腔部に５２秒通液してビタミンＥを接触させた。さらにエアフラッシュして内腔部の残液を除去した後、２４℃の乾燥空気を３０分間通気して溶媒を乾燥除去することにより、ビタミンＥを被覆した。湿潤化工程として、滅菌保護剤であるピロ亜硫酸ナトリウムを０．０６％含み、さらにｐＨ調整のための炭酸ナトリウムを０．０３％含む水溶液を血液浄化装置の血液側流路と濾液側流路に充填し、各ノズルを密栓した状態でγ線を２５ｋＧｙ照射滅菌することにより、本発明の血液浄化装置を得た。
得られた血液浄化装置内の中空糸膜のビタミンＥ含有量を測定した結果、７１．２mg／m２であった。
[Example 1]
18.0% by weight of polysulfone (P-1700 manufactured by Solvay), 4.3% by weight of polyvinylpyrrolidone (K90 manufactured by BASF, weight average molecular weight 1,200,000), 77.7% by weight of N, N-dimethylacetamide To a uniform solution. Here, the mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane forming stock solution was 23.9% by weight. This film-forming stock solution is kept at 60 ° C. and discharged from the double annular nozzle together with an internal solution composed of a mixed solution of 30% by weight of N, N-dimethylacetamide and 70% by weight of water, and passes through an air gap of 0.96 m. Then, it was immersed in a coagulation bath made of water at 75 ° C. and wound up at 80 m / min. At this time, the area from the spinning nozzle to the coagulation bath was surrounded by a cylindrical tube, and while the nitrogen gas containing water vapor was passed through the tube, the humidity in the tube was controlled to 54.5% and the temperature was controlled to 51 ° C. The ratio of the air gap to the spinning speed was 0.012 m / (m / min). After cutting the wound yarn bundle, the remaining solvent in the film is removed by washing with hot water shower at 80 ° C. for 2 hours from above the cut surface of the bundle, and the water content is increased by further drying the film. A dry film of less than 1% was obtained. Further, the dried membrane is filled into a cylindrical container having two nozzles for introducing and discharging liquid, both ends are embedded with urethane resin, and then the cured urethane portion is cut to open the hollow fiber membrane. Processed to the end. A header cap having a blood introduction (lead-out) nozzle was loaded at both ends, and assembled into the shape of a blood purification apparatus.
Next, a coating solution obtained by dissolving 0.23 wt% of vitamin E in an aqueous solution of isopropanol 57 wt% was passed through the lumen of the hollow fiber membrane for 52 seconds from the blood introduction nozzle of the blood purification device to contact vitamin E. . Furthermore, after removing the residual liquid in the lumen by air flushing, vitamin E was coated by ventilating dry air at 24 ° C. for 30 minutes to dry and remove the solvent. As the wetting step, an aqueous solution containing 0.06% of sodium pyrosulfite as a sterilizing protective agent and 0.03% of sodium carbonate for pH adjustment is added to the blood side flow path and the filtrate side flow path of the blood purification apparatus. The blood purification apparatus of the present invention was obtained by filling and sterilizing γ rays with 25 kGy with each nozzle sealed.
It was 71.2 mg / m < 2 > as a result of measuring vitamin E content of the hollow fiber membrane in the obtained blood purification apparatus.
〔実施例２〕
ビタミンＥを０．５ｗｔ％溶解した被覆溶液を用いた以外は、実施例１と同様の方法により血液浄化装置を得た。得られた血液浄化装置内の中空糸膜のビタミンＥ含有量を測定した結果、１４８．９mg／m２であった。
[Example 2]
A blood purification apparatus was obtained by the same method as in Example 1 except that a coating solution in which 0.5 wt% of vitamin E was dissolved was used. It was 148.9 mg / m < 2 > as a result of measuring vitamin E content of the hollow fiber membrane in the obtained blood purification apparatus.
〔実施例３〕
ビタミンＥを１．０ｗｔ％溶解した被覆溶液を用いた以外は、実施例１と同様の方法により血液浄化装置を得た。得られた血液浄化装置内の中空糸膜のビタミンＥ含有量を測定した結果、２８２．２mg／m２であった。
Example 3
A blood purification apparatus was obtained by the same method as in Example 1 except that a coating solution in which 1.0 wt% of vitamin E was dissolved was used. As a result of measuring the vitamin E content of the hollow fiber membrane in the obtained blood purification apparatus, it was 282.2 mg / m 2 .
〔比較例１〕
ビタミンＥを０．２ｗｔ％溶解した被覆溶液を用いた以外は、実施例１と同様の方法により血液浄化装置を得た。得られた血液浄化装置内の中空糸膜のビタミンＥ含有量を測定した結果、６２．８mg／m２であった。
[Comparative Example 1]
A blood purification apparatus was obtained by the same method as in Example 1 except that a coating solution in which 0.2 wt% of vitamin E was dissolved was used. As a result of measuring the vitamin E content of the hollow fiber membrane in the obtained blood purification apparatus, it was 62.8 mg / m 2 .
〔比較例２〕
ビタミンＥを１．２ｗｔ％溶解した被覆溶液を用いた以外は、実施例１と同様の方法により血液浄化装置を得た。得られた血液浄化装置内の中空糸膜のビタミンＥ含有量を測定した結果、３５２．１mg／m２であった。
[Comparative Example 2]
A blood purification apparatus was obtained by the same method as in Example 1 except that a coating solution in which 1.2 wt% of vitamin E was dissolved was used. As a result of measuring vitamin E content of the hollow fiber membrane in the obtained blood purification apparatus, it was 352.1 mg / m 2 .
〔比較例３〕
γ線照射滅菌の代わりに１２１℃で1時間のオートクレーブ滅菌（ＡＣ）を行った以外は、実施例１と同様の方法により血液浄化装置を得た。得られた血液浄化装置内の中空糸膜のビタミンＥ含有量を測定した結果、７０．３mg／m２であった。
[Comparative Example 3]
A blood purification apparatus was obtained in the same manner as in Example 1 except that autoclave sterilization (AC) was performed at 121 ° C. for 1 hour instead of γ-ray irradiation sterilization. As a result of measuring the vitamin E content of the hollow fiber membrane in the obtained blood purification apparatus, it was 70.3 mg / m 2 .
〔比較例４〕
ビタミンＥを１．０ｗｔ％溶解した被覆溶液を用いたこと、およびγ線照射滅菌の代わりに１２１℃で1時間のオートクレーブ滅菌を行った以外は、実施例１と同様の方法により血液浄化装置を得た。得られた血液浄化装置内の中空糸膜のビタミンＥ含有量を測定した結果、３０２．６mg／m２であった。
また、これらの実施例および比較例について、内表面ビタミンＥの存在量、ＤＭＡＣ可溶性のＰＶＰ量、抗酸化能、リーク率、および血小板活性化の測定も行ったので、その結果も表1に示す。
[Comparative Example 4]
A blood purification apparatus was prepared in the same manner as in Example 1 except that a coating solution in which 1.0 wt% of vitamin E was used was used, and autoclave sterilization was performed at 121 ° C. for 1 hour instead of γ-ray irradiation sterilization. Obtained. It was 302.6 mg / m < 2 > as a result of measuring vitamin E content of the hollow fiber membrane in the obtained blood purification apparatus.
Further, for these examples and comparative examples, the abundance of inner surface vitamin E, the amount of DMAC-soluble PVP, the antioxidant capacity, the leak rate, and the platelet activation were also measured, and the results are also shown in Table 1. .
本発明血液浄化装置は、血液浄化療法に於いて必要な本来の機能に加え、血液に対する高い抗酸化能力を示す。また、充填されている中空糸のリークがなく、さらには、優れた血液適合性を併せ持っているので、各種疾患に罹患した患者に対する血液浄化療法用の血液浄化装置として有用である。
また、かかる特性を有することから、リユース（使用後の装置を洗浄して再使用すること）の分野においても有用となるものである。
The blood purification apparatus of the present invention exhibits a high antioxidant capacity for blood in addition to the essential functions required in blood purification therapy. In addition, since there is no leakage of the filled hollow fiber and it has excellent blood compatibility, it is useful as a blood purification device for blood purification therapy for patients suffering from various diseases.
Further, since it has such characteristics, it is useful in the field of reuse (cleaning and reusing a used device).
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6080461A (en) * | 1983-10-07 | 1985-05-08 | テルモ株式会社 | Production of articifial organ |
| JPH0966225A (en) * | 1995-06-22 | 1997-03-11 | Terumo Corp | Production of hollow fiber membrane, hollow fiber membrane and dialyser |
| JPH10244000A (en) * | 1997-03-07 | 1998-09-14 | Terumo Corp | Hollow fiber membrane type body fluid purification device and its production |
| JPH11347117A (en) * | 1998-06-09 | 1999-12-21 | Terumo Corp | Hollow fiber membrane and hollow fiber membrane type artificial kidney |
| WO2004018085A1 (en) * | 2002-08-21 | 2004-03-04 | Toray Industries, Inc. | Modified substrate and process for producing modified substrate |
-
2005
- 2005-04-25 JP JP2005126412A patent/JP4845417B2/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6080461A (en) * | 1983-10-07 | 1985-05-08 | テルモ株式会社 | Production of articifial organ |
| JPH0966225A (en) * | 1995-06-22 | 1997-03-11 | Terumo Corp | Production of hollow fiber membrane, hollow fiber membrane and dialyser |
| JPH10244000A (en) * | 1997-03-07 | 1998-09-14 | Terumo Corp | Hollow fiber membrane type body fluid purification device and its production |
| JPH11347117A (en) * | 1998-06-09 | 1999-12-21 | Terumo Corp | Hollow fiber membrane and hollow fiber membrane type artificial kidney |
| WO2004018085A1 (en) * | 2002-08-21 | 2004-03-04 | Toray Industries, Inc. | Modified substrate and process for producing modified substrate |
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