JP2020054801A - Sorption material, specific substance capture system, and specific substance capture method - Google Patents
Sorption material, specific substance capture system, and specific substance capture method Download PDFInfo
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- JP2020054801A JP2020054801A JP2019162875A JP2019162875A JP2020054801A JP 2020054801 A JP2020054801 A JP 2020054801A JP 2019162875 A JP2019162875 A JP 2019162875A JP 2019162875 A JP2019162875 A JP 2019162875A JP 2020054801 A JP2020054801 A JP 2020054801A
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- JWHOQZUREKYPBY-UHFFFAOYSA-N rubonic acid Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(=O)C(C)(C)C5CC(=O)C34C)C2C1)C(=O)O JWHOQZUREKYPBY-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000003784 tall oil Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- UFDHBDMSHIXOKF-UHFFFAOYSA-N tetrahydrophthalic acid Natural products OC(=O)C1=C(C(O)=O)CCCC1 UFDHBDMSHIXOKF-UHFFFAOYSA-N 0.000 description 1
- YCGAZNXXGKTASZ-UHFFFAOYSA-N thiophene-2,5-dicarboxylic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)S1 YCGAZNXXGKTASZ-UHFFFAOYSA-N 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 239000002441 uremic toxin Substances 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 238000012982 x-ray structure analysis Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Separation Using Semi-Permeable Membranes (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- External Artificial Organs (AREA)
Abstract
Description
本発明は、血液等から特定物質を除去するための収着材料およびその収着材料を用いた特定物質捕捉システム、特定物質捕捉方法に関する。本発明は、特に、人工腎臓および人工透析における血液・血漿やバイオ生産物から、毒性物質や不純物を除去したり、有効成分を分離したりするための収着材料として有用である。 The present invention relates to a sorption material for removing a specific substance from blood or the like, a specific substance capture system using the sorption material, and a specific substance capture method. The present invention is particularly useful as a sorption material for removing toxic substances and impurities and separating active ingredients from blood / plasma and bioproducts in artificial kidney and artificial dialysis.
膜分離は、ある特定のカットオフ分子量未満の物質を除去する手法に用いられており、人工腎臓および人工透析において血液から毒性物質を除去する基本技術であるとともに、バイオ生産物を精製する基本技術でもあり、適切なカットオフ分子量を有する分離膜の選択により、除去されることが望まれる毒性物質の除去が実現される。しかし、タンパク質結合毒素に代表されるように、除去することが望まれる毒性物質が除去されることが望まれない物質と結合することにより分子量が増大すると、分離膜のカットオフ分子量を超えてしまい、適切に除去することができない場合がある。これを解決するための手法として、特許文献１には、透析精製プロセスと金属有機フレームワークを含む収着材による毒性物質除去プロセスを組み合わせたシステムが提案されている。 Membrane separation is used to remove substances below a certain cut-off molecular weight.It is a basic technique for removing toxic substances from blood in artificial kidney and dialysis, and a basic technique for purifying bioproducts. However, the selection of a separation membrane having an appropriate cut-off molecular weight achieves the removal of a toxic substance that is desired to be removed. However, when the molecular weight is increased by binding a toxic substance that is desired to be removed, such as a protein-bound toxin, to a substance that is not desired to be removed, the molecular weight exceeds the cut-off molecular weight of the separation membrane. , May not be properly removed. As a method for solving this, Patent Literature 1 proposes a system that combines a dialysis purification process and a toxic substance removal process using a sorbent containing a metal organic framework.
しかしながら、特許文献１に記載されたシステムでは、収着材が使用中に意図せずして分解すると、その分解物が生体内に入る血液等に混入するおそれがあり、人工腎臓および人工透析用途の場合はもちろん、医薬品ないし食品用途のバイオ生産物の精製に用いる場合も、生体に危害を加える可能性があるという課題がある。 However, in the system described in Patent Literature 1, if the sorbent is unintentionally decomposed during use, the decomposed product may be mixed into blood or the like entering a living body, and the sorbent is used for artificial kidney and artificial dialysis. In addition to the above case, there is a problem that there is a possibility of causing harm to the living body when used in the purification of bioproducts for pharmaceutical or food use.
上記事情に鑑み、本発明は、収着材料として用いる金属有機フレームワークの分解物が、血液やバイオ生産物等に混入するリスクを低減した収着材料および特定物質捕捉システムを提供することを目的とする。 In view of the above circumstances, an object of the present invention is to provide a sorbent material and a specific substance capturing system in which a decomposition product of a metal-organic framework used as a sorbent material has a reduced risk of being mixed into blood, bioproducts, and the like. And
本発明者らは、上記課題を解決するために鋭意検討した結果、収着材料に含まれる金属有機フレームワークを構成する中心金属およびリンカーの分子量を、これと併用する分離膜のカットオフ分子量未満とすることにより、上記課題を解決できることを見出した。 The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, the molecular weight of the central metal and the linker constituting the metal organic framework contained in the sorption material is less than the cut-off molecular weight of the separation membrane used together therewith. By doing so, it has been found that the above problem can be solved.
すなわち、本発明は以下のとおりである。
［１］
透析液、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉することのできる金属有機フレームワークを含む収着材料であって、
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、分離膜のカットオフ分子量未満である、収着材料。
［２］
前記特定物質は、毒素、毒性溶質、毒性小分子もしくは中分子、およびタンパク質結合毒素からなる群から選択される１種以上の毒性物質である、［１］記載の収着材料。
［３］
前記特定物質は、医薬的に有効な成分である、上記［１］記載の収着材料。
［４］
前記分離膜は、透析膜、限外ろ過膜、精密ろ過膜、イオン交換膜、ナノろ過膜、逆浸透膜、および正浸透膜からなる群から選択される１種以上である、上記［１］〜［３］のいずれかに記載の収着材料。
［５］
前記分離膜が、平膜または中空糸膜の形態である、上記［１］〜［４］のいずれかに記載の収着材料。
［６］
透析液、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉することのできる金属有機フレームワークを含む収着材料を備えた第１の手段と、
少なくとも前記金属有機フレームワークの分解物である中心金属およびリンカーを除去するための分離膜を備えた第２の手段と、
を有する特定物質捕捉システムであって、
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、前記分離膜のカットオフ分子量未満である、システム。
［７］
前記第１の手段と前記第２の手段が同一の装置内に存在する、上記［６］記載の特定物質捕捉システム。
［８］
前記第１の手段が前記第２の手段よりも前に配置されている、上記［６］または［７］記載の特定物質捕捉システム。
［９］
前記第１の手段が前記第２の手段よりも後に配置されている、上記［６］または［７］記載の特定物質捕捉システム。
［１０］
金属有機フレームワークを含む収着材料を用いて、透析液、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉する特定物質捕捉方法であって、
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、分離膜のカットオフ分子量未満である、方法。
［１１］
金属有機フレームワークを含む収着材料を用いて、透析液、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉する特定物質捕捉工程と、
前記金属有機フレームワークの分解物である中心金属およびリンカーを、分離膜を用いて除去する膜分離工程と、
を含む、上記［１０］記載の特定物質捕捉方法。
That is, the present invention is as follows.
[1]
A sorption material comprising a metal-organic framework capable of capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological method,
A sorbent material, wherein the molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
[2]
The sorption material according to [1], wherein the specific substance is at least one toxic substance selected from the group consisting of a toxin, a toxic solute, a toxic small or medium molecule, and a protein-bound toxin.
[3]
The sorption material according to the above [1], wherein the specific substance is a pharmaceutically active ingredient.
[4]
The above-mentioned [1], wherein the separation membrane is at least one selected from the group consisting of a dialysis membrane, an ultrafiltration membrane, a microfiltration membrane, an ion exchange membrane, a nanofiltration membrane, a reverse osmosis membrane, and a forward osmosis membrane. -The sorption material according to any one of [3].
[5]
The sorption material according to any one of the above [1] to [4], wherein the separation membrane is in the form of a flat membrane or a hollow fiber membrane.
[6]
First means comprising a sorption material comprising a metal-organic framework capable of capturing a specific substance from a liquid containing a dialysate, blood, plasma, or a crude product of a substance produced by biotechnological techniques When,
Second means comprising a separation membrane for removing at least a central metal and a linker which are decomposed products of the metal organic framework;
A specific substance capturing system having
The system wherein the molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
[7]
The specific substance capturing system according to the above [6], wherein the first means and the second means are present in the same device.
[8]
The specific substance capturing system according to the above [6] or [7], wherein the first means is arranged before the second means.
[9]
The specific substance capturing system according to the above [6] or [7], wherein the first means is disposed after the second means.
[10]
A specific substance capturing method for capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological technique using a sorption material including a metal organic framework. hand,
A method wherein the molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
[11]
A specific substance capturing step of capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological technique using a sorption material including a metal organic framework;
A membrane separation step of removing a central metal and a linker, which are decomposition products of the metal organic framework, using a separation membrane,
The method for capturing a specific substance according to the above [10], comprising:
本発明により、収着材料として用いる金属有機フレームワークが意図せず中心金属およびリンカーに分解したとしても、分離膜を用いた膜分離工程により、分離膜のカットオフ分子量未満の分子量を有した中心金属およびリンカーが適切に除去されるため、収着材料分解物の血液、血漿、ないしバイオ生産物等への混入を防止することができる。 According to the present invention, even when the metal organic framework used as the sorption material is unintentionally decomposed into the central metal and the linker, the center having a molecular weight less than the cut-off molecular weight of the separation membrane is obtained by the membrane separation step using the separation membrane. Since the metal and the linker are appropriately removed, it is possible to prevent the degradation product of the sorption material from being mixed into blood, plasma, bioproducts, and the like.
以下、本発明の実施の形態（以下、「本実施形態」という。）について詳細に説明するが、本発明はこれに限定されるものではなく、その要旨を逸脱しない範囲で様々な変形が可能である。 Hereinafter, an embodiment of the present invention (hereinafter, referred to as “the present embodiment”) will be described in detail, but the present invention is not limited thereto, and various modifications can be made without departing from the gist of the present invention. It is.
［収着材料］
本実施形態における収着材料は、
透析液、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉することのできる金属有機フレームワークを含む収着材料であって、
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、分離膜のカットオフ分子量未満である。
[Sorptive material]
The sorption material in the present embodiment is:
A sorption material comprising a metal-organic framework capable of capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological method,
The molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
本実施形態の収着材料は、中心金属が少なくとも１つの他の中心金属とリンカーを介して結合され、２次元ないし３次元網目構造を形成した多孔質構造を有する金属有機フレームワークであり、この収着材料と併用する分離膜のカットオフ分子量未満の分子量を有する中心金属とリンカーを組み合わせることにより得られる。
収着材料は、分離膜を用いた膜分離プロセスと組み合わせて使用される。すなわち、収着材料として用いる金属有機フレームワークが意図せずして中心金属およびリンカーに分解したとしても、金属有機フレームワークによる特定物質捕捉工程と併せて実施する膜分離工程により、分離膜のカットオフ分子量未満の分子量を有した中心金属およびリンカーが適切に除去されるため、収着材料の分解物である中心金属およびリンカーの血液、血漿、ないしバイオ生産物等への混入を防止することができる。そして、収着材料分解物の血液等への混入を防止することにより、分解物による生体毒性の発現やバイオ生産物のコンタミネーションを防ぐことができ、安全性向上に資することができる。
The sorption material of this embodiment is a metal-organic framework having a porous structure in which a central metal is bonded to at least one other central metal via a linker to form a two-dimensional or three-dimensional network. It is obtained by combining a linker with a central metal having a molecular weight less than the cutoff molecular weight of the separation membrane used in combination with the sorption material.
The sorption material is used in combination with a membrane separation process using a separation membrane. That is, even if the metal organic framework used as the sorption material is unintentionally decomposed into the central metal and the linker, the separation of the separation membrane is performed by the membrane separation step performed in conjunction with the specific substance capturing step using the metal organic framework. Since the central metal and the linker having a molecular weight less than the off-molecular weight are appropriately removed, it is possible to prevent the central metal and the linker, which are decomposition products of the sorption material, from being mixed into blood, plasma, or bioproducts. it can. Then, by preventing the decomposition product of the sorption material from entering the blood or the like, it is possible to prevent biodegradation due to the decomposition product and contamination of the bioproduct, thereby contributing to improvement of safety.
本実施形態における金属有機フレームワークは、中心金属がリンカーにより結合されて一次元、二次元、または三次元構造となったハイブリッド材料である。金属有機フレームワークは、中心金属およびリンカーの設計次第で特定物質に対する高い選択性・吸着性を実現することができる。例えば、金属有機フレームワークのリンカーに様々な官能基を導入し、これにより捕捉する特定物質に対する親和性を調整することができる。 The metal organic framework in the present embodiment is a hybrid material in which a central metal is bonded by a linker to form a one-dimensional, two-dimensional, or three-dimensional structure. The metal organic framework can realize high selectivity and adsorptivity to a specific substance depending on the design of the central metal and the linker. For example, various functional groups can be introduced into the linker of the metal organic framework to adjust the affinity for a specific substance to be captured.
金属有機フレームワークは、それぞれの中心金属が少なくとも１つの他の中心金属に結合している複数の生体適合性金属と；隣接する中心金属を連結する複数の生体適合性リンカーと；複数の細孔とを含む。ここで、複数の中心金属は同一でも、異なっていてもよい。また、複数のリンカーについても同一でも、異なっていてもよい。また、金属有機フレームワーク中に存在する複数の細孔は、大きさが異なっていてもよいし、同一であってもよい。 The metal organic framework includes a plurality of biocompatible metals, each having a central metal bonded to at least one other central metal; a plurality of biocompatible linkers connecting adjacent central metals; and a plurality of pores. And Here, the plurality of central metals may be the same or different. Further, a plurality of linkers may be the same or different. Further, the plurality of pores existing in the metal organic framework may be different in size or may be the same.
本実施形態における収着材料である金属有機フレームワークは、中心金属およびリンカーを有し、反応条件に応じて、２次元または３次元網目構造として調製することができる。金属有機フレームワークの構造は、金属源、リンカーおよびモジュレータ（結晶成長速度調整剤）の選択ならびに反応条件（例えば、温度、ｐＨ、溶媒系、反応物質比および反応時間など）の選択により適宜調整することができ、用途に応じて所望の構造体を得ることができる。 The metal-organic framework that is the sorption material in the present embodiment has a central metal and a linker, and can be prepared as a two-dimensional or three-dimensional network structure depending on reaction conditions. The structure of the metal organic framework is appropriately adjusted by selecting a metal source, a linker and a modulator (crystal growth rate regulator) and selecting reaction conditions (eg, temperature, pH, solvent system, reactant ratio, reaction time, etc.). And a desired structure can be obtained depending on the application.
金属有機フレームワークとしては、それを構成する中心金属およびリンカーの分子量が、これと併用する分離膜のカットオフ分子量未満であれば特に限定されることはなく、用途に応じて様々なものを用いることができる。例えば、特表２０１０−５１２９３９号公報、特表２０１１−５１７３０９号公報、特表２０１５−５２９２５８号公報、H. Furukawa et al. "The Chemistry and Applications of Metal-Organic Frameworks" Science 341, 1230444 (2013)等に記載されたものを用いることができる。また、水分中で使用可能な金属有機フレームワークとしては、例えば、特開２０１６−１７９４３１号公報、特開２０１８−１０５８３５号公報、特開２０１８−１１８２１１号公報、特開２０１８−１１８９２９号公報、S. Li et al. "Water Purification: Adsorption over Metal-Organic Frameworks"Chin. J. Chem. 2016, 34, 175−185記載されたもの等を用いることができる。これらの中でも、透析液または血液（血漿）を精製するための用途においては、タンパク質結合毒素を選択的に除去可能な生体適合性の金属有機フレームワークが好ましく、例えば、ＵＳ２０１００２８６０２２Ａ１、ＵＳ８６９１７４８に記載されたもの等が挙げられる。 The metal organic framework is not particularly limited as long as the molecular weight of the central metal and the linker constituting the same is less than the cut-off molecular weight of the separation membrane used together therewith, and various ones are used depending on the application. be able to. For example, JP-T-2010-512939, JP-T-2011-517309, JP-T-2015-529258, H. Furukawa et al. "The Chemistry and Applications of Metal-Organic Frameworks" Science 341, 1230444 (2013). Etc. can be used. Examples of the metal organic framework usable in moisture include, for example, JP-A-2006-179431, JP-A-2018-105835, JP-A-2018-118211, JP-A-2018-118929, and S Li et al., "Water Purification: Adsorption over Metal-Organic Frameworks", Chin. J. Chem. 2016, 34, 175-185, and the like can be used. Among these, in applications for purifying a dialysate or blood (plasma), a biocompatible metal-organic framework capable of selectively removing a protein-bound toxin is preferable, and described in, for example, US20100028602A1 and US8691748. And the like.
［中心金属］
本実施形態において「中心金属」とは、金属イオンないし金属クラスターを指し、収着材料の用途や捕捉する特定物質に応じて最適なものが選択される。中心金属を構成する金属は、生体適合性の金属であれば特に限定されず、例えば、Ｌｉ、Ｎａ、Ｍｇ、Ｓｒ、Ｂａ、Ｃａ、Ｔｉ、Ｚｒ、Ｈｆ、Ｆｅ、Ｖ、Ｎｂ、Ｃｒ、Ｍｏ、Ｉｒ、Ｒｅ、Ｃｅ、Ｃｏ、Ｙ、Ｍｎ、Ｎｉ、Ｐｄ、Ｃｕ、Ａｌ、Ｓｉ、Ｚｎ、Ａｇ、Ｐｔ、Ａｕ、Ｍｏ、Ｗ、Ｒｕ、Ｏｓ、Ｓｂ、Ｃｅ等が挙げられ、透析液または血液（血漿）を精製するための用途においては、安全性の観点から、Ｆｅ、Ｔｉ、Ｍｇ、Ｚｒ、Ｈｆ、Ｃｅが好ましい。
[Center metal]
In the present embodiment, the “center metal” refers to a metal ion or a metal cluster, and an optimum one is selected according to the use of the sorption material and the specific substance to be captured. The metal constituting the central metal is not particularly limited as long as it is a biocompatible metal. For example, Li, Na, Mg, Sr, Ba, Ca, Ti, Zr, Hf, Fe, V, Nb, Cr, Mo , Ir, Re, Ce, Co, Y, Mn, Ni, Pd, Cu, Al, Si, Zn, Ag, Pt, Au, Mo, W, Ru, Os, Sb, Ce and the like. In applications for purifying blood (plasma), Fe, Ti, Mg, Zr, Hf, and Ce are preferred from the viewpoint of safety.
また、「金属クラスター」とは、金属原子が数個から十数個集まって、一つの化合物のような特定の構造単位をもった物質を意味する。金属クラスターには、金属同士が直接結合するものや、金属同士が他の原子や分子を介して結合しているもの等が挙げられる。 Further, the “metal cluster” refers to a substance having a specific structural unit such as one compound in which several to more than ten metal atoms are gathered. Examples of the metal cluster include those in which metals are directly bonded to each other and those in which metals are bonded via another atom or molecule.
［リンカー］
本実施形態において「リンカー」とは、上述した中心金属を架橋する配位子を指し、収着材料の用途や捕捉する特定物質に応じて最適なものが選択される。リンカーとしては、例えば、１〜２０個の炭素原子からなるアルキルまたはシクロアルキル基、１〜５個のフェニル環からなるアリール基、あるいは、１〜２０個の炭素原子を有するアルキルもしくはシクロアルキル基または１〜５個のフェニル環からなるアリール基からなるアルキルアミンまたはアリールアミンを含み、多座官能基が配位子の基礎構造に共有結合しているもの等が挙げられる。多座官能基としては、例えば、ＣＯ2Ｈ、ＣＳ2Ｈ、ＮＯ2、ＳＯ3Ｈ、Ｓｉ（ＯＨ）3、Ｇｅ（ＯＨ）3、Ｓｎ（ＯＨ）3、Ｓｉ（ＳＨ）4、Ｇｅ（ＳＨ）4、Ｓｎ（ＳＨ）4、ＰＯ3Ｈ、ＡｓＯ3Ｈ、ＡｓＯ4Ｈ、Ｐ（ＳＨ）3、Ａｓ（ＳＨ）3、ＣＨ（ＲＳＨ）2、Ｃ（ＲＳＨ）3、ＣＨ（ＲＮＨ2）2、Ｃ（ＲＮＨ2）3、ＣＨ（ＲＯＨ）2、Ｃ（ＲＯＨ）3、ＣＨ（ＲＣＮ）2、Ｃ（ＲＣＮ）3（ここで、Ｒは、１〜５個の炭素原子を有するアルキル基であるか、１〜２個のフェニル環からなるアリール基である）、ならびにＣＨ（ＳＨ）2、Ｃ（ＳＨ）3、ＣＨ（ＮＨ2）2、Ｃ（ＮＨ2）3、ＣＨ（ＯＨ）2、Ｃ（ＯＨ）3、ＣＨ（ＣＮ）2、およびＣ（ＣＮ）3等が挙げられる。上記の中でも、カルボン酸官能基を含むことが好ましい。また、いずれか１つ以上の炭素原子が、窒素、酸素、硫黄、硼素、リン、シリコンおよびアルミニウム原子等によって置換されていてもよい。
[Linker]
In the present embodiment, the “linker” refers to a ligand that bridges the central metal described above, and an optimal linker is selected according to the use of the sorption material and the specific substance to be captured. Examples of the linker include an alkyl or cycloalkyl group having 1 to 20 carbon atoms, an aryl group having 1 to 5 phenyl rings, or an alkyl or cycloalkyl group having 1 to 20 carbon atoms or Examples include alkylamines or arylamines comprising an aryl group consisting of 1 to 5 phenyl rings, in which a polydentate functional group is covalently bonded to the basic structure of the ligand. Examples of the polydentate functional group include CO 2 H, CS 2 H, NO 2 , SO 3 H, Si (OH) 3 , Ge (OH) 3 , Sn (OH) 3 , Si (SH) 4 , and Ge ( SH) 4, Sn (SH) 4, PO 3 H, AsO 3 H, AsO 4 H, P (SH) 3, As (SH) 3, CH (RSH) 2, C (RSH) 3, CH (RNH 2 ) 2 , C (RNH 2 ) 3 , CH (ROH) 2 , C (ROH) 3 , CH (RCN) 2 , C (RCN) 3 wherein R is an alkyl having 1 to 5 carbon atoms it is a group, a 1-2 aryl group consisting of phenyl ring), and CH (SH) 2, C ( SH) 3, CH (NH 2) 2, C (NH 2) 3, CH (OH ) 2 , C (OH) 3 , CH (CN) 2 , C (CN) 3 and the like. Among the above, it is preferable to include a carboxylic acid functional group. Further, any one or more carbon atoms may be replaced by nitrogen, oxygen, sulfur, boron, phosphorus, silicon, aluminum atoms and the like.
カルボン酸官能基を含むリンカーとしては、例えば、メタン酸、エタン酸、プロパン酸、ブタン酸、吉草酸、カプロン酸、カプリル酸、カプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸、シクロヘキサンカルボン酸、フェニル酢酸、安息香酸、シュウ酸、マロン酸、コハク酸、グルタル酸、アジピン酸、ピメリン酸、スベリン酸、マレイン酸、フマル酸、フタル酸、イソフタル酸、テレフタル酸、２−アミノテレフタル酸、ヘミメリト酸、トリメリト酸、ピロメリト酸、トリメシン酸、２、６−ナフタレンジカルボン酸、４、４’−ビフェニルジカルボン酸、２、２’−ジメチルビフェニル−４、４’−ジカルボン酸、２、５−ジヒドロキシテレフタル酸、２、５−チオフェンジカルボン酸、テトラキス（４−カルボキシフェニル）ポルフィリン、テトラキス（４−カルボキシビフェニル）ポルフィリン、１、３、６、８−テトラキス（ｐ−カルボキシフェニル）ピレン、２、２’−ジヒドロビフェニル−３、３’、５、５’−テトラ（フェニル−４−カルボン酸）、４、４’−ジアミノ−３、３’、５、５’−テトラ（フェニル−４−カルボン酸）、４、４’−ジヒドロキシ−３、３’、５、５’−テトラ（フェニル−４−カルボン酸）、３、３’、５、５’−テトラカルボキシジフェニルメタン、１、３、５−トリス（４−カルボキシフェニル）−２、４、６−トリメチルベンゼン、無水コハク酸、無水マレイン酸、無水フタル酸、グリコール酸、乳酸、ヒドロキシ酪酸、マンデル酸、グリセリン酸、リンゴ酸、酒石酸、クエン酸およびアスコルビン酸が挙げられる。 Examples of the linker containing a carboxylic acid functional group include methane acid, ethanoic acid, propanoic acid, butanoic acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and oleic acid. , Linoleic acid, linolenic acid, cyclohexanecarboxylic acid, phenylacetic acid, benzoic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, maleic acid, fumaric acid, phthalic acid, isophthalic acid, Terephthalic acid, 2-aminoterephthalic acid, hemimellitic acid, trimellitic acid, pyromellitic acid, trimesic acid, 2,6-naphthalenedicarboxylic acid, 4,4′-biphenyldicarboxylic acid, 2,2′-dimethylbiphenyl-4,4 ′ Dicarboxylic acid, 2,5-dihydroxyterephthalic acid, 2,5-thiophene Rubonic acid, tetrakis (4-carboxyphenyl) porphyrin, tetrakis (4-carboxybiphenyl) porphyrin, 1,3,6,8-tetrakis (p-carboxyphenyl) pyrene, 2,2′-dihydrobiphenyl-3,3 ′ 5,5′-tetra (phenyl-4-carboxylic acid), 4,4′-diamino-3,3 ′, 5,5′-tetra (phenyl-4-carboxylic acid), 4,4′-dihydroxy- 3,3 ′, 5,5′-tetra (phenyl-4-carboxylic acid), 3,3 ′, 5,5′-tetracarboxydiphenylmethane, 1,3,5-tris (4-carboxyphenyl) -2, 4,6-trimethylbenzene, succinic anhydride, maleic anhydride, phthalic anhydride, glycolic acid, lactic acid, hydroxybutyric acid, mandelic acid, glyceric acid, malic acid, sake Acid, citric acid and ascorbic acid.
リンカーは、ポリカルボン酸であってもよく、例えば、不飽和脂肪族ジカルボン酸、飽和脂肪族ジカルボン酸、芳香族ジカルボン酸、不飽和環状ジカルボン酸、飽和環状ジカルボン酸、それらのヒドロキシ置換誘導体；不飽和脂肪族トリカルボン酸、飽和脂肪族トリカルボン酸、芳香族トリカルボン酸、不飽和環状トリカルボン酸、飽和環状トリカルボン酸、それらのヒドロキシ置換誘導体；などが挙げられる。これらのポリカルボン酸はいずれも、ヒドロキシ、ハロ、アルキル、アルコキシなどで置換されていてもよい。ポリカルボン酸の具体例としては、例えば、アコニット酸、アジピン酸、アゼライン酸、ブタンテトラカルボン酸二水素化物、ブタントリカルボン酸、クロレンド酸、シトラコン酸、ジシクロペンタジエン−マレイン酸付加物、ジエチレントリアミンペンタ酢酸、ジペンテンおよびマレイン酸の付加物、エチレンジアミン四酢酸（ＥＤＴＡ）、完全マレアート化ロジン、マレエート化トール油脂肪酸、フマル酸、グルタル酸、イソフタル酸、イタコン酸、アルコールに次いでカルボン酸に過酸化カリウムで酸化されるマレエート化ロジン、マレイン酸、リンゴ酸、メサコン酸、３−４カルボキシル基を導入するために反応させたビフェノールＡまたはビスフェノールＦ、シュウ酸、フタル酸、セバシン酸、コハク酸、酒石酸、テレフタル酸、テトラブロモフタル酸、テトラクロロフタル酸、テトラヒドロフタル酸、トリメリト酸、トリメシン酸、ならびにこれらの無水物等が挙げられる。 The linker may be a polycarboxylic acid, for example, an unsaturated aliphatic dicarboxylic acid, a saturated aliphatic dicarboxylic acid, an aromatic dicarboxylic acid, an unsaturated cyclic dicarboxylic acid, a saturated cyclic dicarboxylic acid, a hydroxy-substituted derivative thereof; And saturated aliphatic tricarboxylic acids, saturated aliphatic tricarboxylic acids, aromatic tricarboxylic acids, unsaturated cyclic tricarboxylic acids, saturated cyclic tricarboxylic acids, and hydroxy-substituted derivatives thereof. Any of these polycarboxylic acids may be substituted with hydroxy, halo, alkyl, alkoxy and the like. Specific examples of polycarboxylic acids include, for example, aconitic acid, adipic acid, azelaic acid, butanetetracarboxylic acid dihydride, butanetricarboxylic acid, chlorendic acid, citraconic acid, dicyclopentadiene-maleic acid adduct, diethylenetriaminepentaacetic acid Oxidation with potassium peroxide to adducts of dipentene and maleic acid, ethylenediaminetetraacetic acid (EDTA), fully maleated rosin, maleated tall oil fatty acids, fumaric acid, glutaric acid, isophthalic acid, itaconic acid, alcohol followed by carboxylic acid Maleated rosin, maleic acid, malic acid, mesaconic acid, biphenol A or bisphenol F reacted to introduce 3-4 carboxyl groups, oxalic acid, phthalic acid, sebacic acid, succinic acid, tartaric acid, terephthalic acid , Tiger bromo phthalic acid, tetrachlorophthalic acid, tetrahydrophthalic acid, trimellitic acid, trimesic acid, and the like anhydrides thereof.
リンカーとしては、具体的には、例えば、特表２０１１−５１７３０９号公報に記載されたもの等が挙げられるが、これらに限定されることはない。 Specific examples of the linker include, but are not limited to, those described in JP-T-2011-517309.
［分離膜］
本実施形態においては、金属有機フレームワークを構成する中心金属およびリンカーの分子量は、分離膜のカットオフ分子量未満である。ここで、「カットオフ分子量」とは、分離膜が特定の阻止率で阻止できる物質の最小の分子量を指し、「阻止率Ｒ」は、分離膜透過前の原液中の溶質濃度をＣｂ、分離膜透過後の透過液中の溶質濃度をＣｐとしたとき、Ｒ＝１−Ｃｐ／Ｃｂで求めることができる。
[Separation membrane]
In the present embodiment, the molecular weights of the central metal and the linker constituting the metal organic framework are less than the cut-off molecular weight of the separation membrane. Here, the “cut-off molecular weight” refers to the minimum molecular weight of a substance that the separation membrane can block at a specific rejection rate, and the “rejection rate R” is Cb, the solute concentration in the stock solution before passing through the separation membrane. Assuming that the solute concentration in the permeated liquid after permeation through the membrane is Cp, it can be determined by R = 1−Cp / Cb.
カットオフ分子量及び阻止率Ｒは、用途に応じて適宜設定すればよい。阻止率Ｒは、例えば、７０％以上であってもよく、７５％以上であってもよく、８０％以上であってもよく、８５％以上であってもよく、９０％以上であってもよく、９５％以上であってもよく、９９％以上であってもよく、９９．９％以上であってもよく、９９．９９％以上であってもよく、９９．９９９％以上であってもよく、９９．９９９９％以上であってもよく、１００％であってもよい。 The cut-off molecular weight and the rejection R may be set appropriately according to the application. The rejection R may be, for example, 70% or more, 75% or more, 80% or more, 85% or more, or 90% or more. 95% or more, 99% or more, 99.9% or more, 99.99% or more, 99.999% or more May be 99.9999% or more, and may be 100%.
また、中心金属が金属クラスターである場合、その分子量は金属クラスターを構成する金属自体の分子量を意味する。 Further, when the central metal is a metal cluster, the molecular weight means the molecular weight of the metal itself constituting the metal cluster.
本実施形態において「分離膜」とは、特定のカットオフ分子量未満の物質のみ透過できる膜のことを指し、人工腎臓および人工透析に用いられる透析膜やバイオ生産物の精製に用いられる分離膜を含む。分離膜は、そのカットオフ分子量が、併用する金属有機フレームワークの分解物である中心金属およびリンカーの分子量以上であれば、特に限定されることなく、様々な種類および形態のものを用いることができる。具体的には、透析膜、限外ろ過膜、精密ろ過膜、イオン交換膜、ナノろ過膜、逆浸透膜、および正浸透膜等が挙げられ、用途に応じて最適なものを選択して用いることができる。また、分離膜の形態も特に限定されず、平膜または中空糸膜等を用いることができる。 In the present embodiment, the `` separation membrane '' refers to a membrane that can only permeate a substance having a molecular weight less than a specific cut-off molecular weight, and refers to a dialysis membrane used for artificial kidney and artificial dialysis or a separation membrane used for purification of bioproducts. Including. The separation membrane is not particularly limited as long as its cut-off molecular weight is not less than the molecular weight of the central metal and the linker, which are decomposition products of the metal organic framework used in combination, and various types and forms can be used. it can. Specific examples include a dialysis membrane, an ultrafiltration membrane, a microfiltration membrane, an ion exchange membrane, a nanofiltration membrane, a reverse osmosis membrane, a forward osmosis membrane, and the like. be able to. The form of the separation membrane is not particularly limited, and a flat membrane or a hollow fiber membrane can be used.
分離膜としては、例えば、酒井清孝「人工透析膜の設計−透析カイネティクスより−」膜(MEMBRANE),14(1),31−44(1989)、酒井清孝「医療用膜の現状と将来展望」膜(MEMBRANE),30(4),185−191(2005)、酒井清孝「血液透析治療の歴史−装置工学的側面から見た−」膜(MEMBRANE),37(1),2−9(2012)、特開２０１５−２３１５２３号、特表２０１６−５２８２３３、特開２０１８−３８４２６、ＷＯ２００８／１５６１２４、ＷＯ２０１７／１２６４９６ Ａ１、ＷＯ２０１８／０３８２４８ Ａ１等に記載されたものを用いることができる。分離膜としては、より具体的には、例えば、ＡＰＳ、ＶＰＳ、ｋｆ−ｍ、ＫＦ（以上、すべて旭化成メディカル社製ダイアライザーの商品シリーズ名）、ＲＥＮＡＫ−ＰＳ、ｋｆ−ｍ、ＫＦ（以上、すべて川澄化学社製ダイアライザーの商品シリーズ名）、ＢＰ（ＪＭＳ社製ダイアライザーの商品シリーズ名）、Ｂ３、Ｂ１、ＢＫ、ＢＧ、ＮＦ、ＴＳ、ＣＳ、ＣＸ、ＮＶ（以上、すべて東レ社製ダイアライザーの商品シリーズ名）、ＦＬＸ、ＦＤＸ、ＦＤＹ、ＦＤＷ、ＦＤＺ、ＰＮ（以上、すべて日機装社製ダイアライザーの商品シリーズ名）、ＦＢ、ＰＥＳ（以上、すべてニプロ社製ダイアライザーの商品シリーズ名）、ＦＸ（フレゼニウス社製ダイアライザーの商品シリーズ名）、Ｈ１２（ガンブロ社製ダイアライザーの商品シリーズ名）等を用いることができる。 Examples of separation membranes include Kiyotaka Sakai, "Design of Artificial Dialysis Membrane-From Dialysis Kinetics-" Membrane (MEMBRANE), 14 (1), 31-44 (1989), Kiyotaka Sakai, "Present and Future of Medical Membrane" `` Membrane (MEMBRANE), 30 (4), 185-191 (2005), Kiyotaka Sakai `` History of hemodialysis treatment-from the viewpoint of device engineering-'' Membrane (MEMBRANE), 37 (1), 2-9 ( 2012), JP-A-2015-231523, JP-T-2006-528233, JP-A-2018-38426, WO2008 / 156124, WO2017 / 126496 A1, WO2018 / 038248 A1, and the like can be used. More specifically, examples of the separation membrane include APS, VPS, kf-m, and KF (all of which are product names of dialyzers manufactured by Asahi Kasei Medical Co., Ltd.), RENAK-PS, kf-m, and KF (all of which are all (Karasumi Chemical's dialyzer product series name), BP (JMS's dialyzer product series name), B3, B1, BK, BG, NF, TS, CS, CX, NV (all of which are Toray's dialyzer products) Series name), FLX, FDX, FDY, FDW, FDZ, PN (all are Nikkiso's dialyzer product series names), FB, PES (all are Nipro dialyzer product series names), FX (Fresenius Co., Ltd.) Dialyzer product series), H12 (Gambro dialyzer product series) Or the like can be used.
本実施形態の収着材料は、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉することのできる材料である。ここで、「生物工学的手法により製造された物質の粗生成物を含む液体」とは、所望の物質を分泌する生物等の培養上清、又は、所望の物質を産生した動物の血液ないし腹水培養液であって、所望の物質以外の夾雑物ないし溶媒を含む液体のことを指し、具体的には、遺伝子組み換えや細胞融合等の技術により改変した細胞ないし微生物の培養上清、あるいは、免疫した動物の血液ないし腹水培養液等が挙げられる。 The sorption material of the present embodiment is a material capable of capturing a specific substance from blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnology technique. Here, "liquid containing a crude product of a substance produced by a biotechnological technique" refers to a culture supernatant of an organism or the like that secretes a desired substance, or blood or ascites of an animal that has produced the desired substance. A culture solution, which is a liquid containing contaminants or a solvent other than a desired substance, specifically, a culture supernatant of cells or microorganisms modified by a technique such as gene recombination or cell fusion, or And blood or ascites culture of the isolated animal.
本実施形態において、「特定物質」には、収着材料を適用する対象に含まれる種々のものが含まれ、例えば、透析液や血液に適用する場合には、生体に悪影響を及ぼす毒性物質が挙げられ、バイオ生産物に適用する場合には、不純物もしくは有効成分等が挙げられるが、これらに限定されることはない。また、金属有機フレームワークによって捕捉される特定物質は、必ずしも１種である必要はなく、２種以上である場合も含まれる。 In the present embodiment, the “specific substance” includes various substances included in a target to which the sorbent material is applied.For example, when applied to a dialysate or blood, a toxic substance that adversely affects a living body is included. When applied to bioproducts, impurities, active ingredients, and the like can be mentioned, but are not limited thereto. In addition, the specific substance captured by the metal organic framework does not necessarily need to be one kind, and includes two or more kinds.
ここで、毒性物質としては、生体に悪影響のある物質であれば特に限定されることはないが、例えば、毒素、毒性溶質、毒性小分子もしくは中分子、およびタンパク質結合毒素からなる群から選択される１種以上であり、具体的には、カリウム、リン酸塩、尿素、尿酸、アンモニア、クレアチニン、パラクレジル硫酸、インドキシル硫酸、馬尿酸、３−カルボキシ−４−メチル−５−プロピル−２−フランプロパン酸（ＣＭＰＦ）、β２−ミクログロブリン（β２Ｍ）、ならびにビリルビンおよびパラアミノ馬尿酸などのアルブミン結合毒素等が挙げられる。また、毒性物質には、Vanholder R, et al, kidney Int, 63 (5): 1934−1943, 2003）のTable.1−3に記載された化合物等も含まれる。 Here, the toxic substance is not particularly limited as long as it is a substance that has an adverse effect on the living body, and for example, is selected from the group consisting of toxins, toxic solutes, toxic small or medium molecules, and protein-bound toxins. At least one of potassium, phosphate, urea, uric acid, ammonia, creatinine, paracresyl sulfate, indoxyl sulfate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2- Furanpropanoic acid (CMPF), β2-microglobulin (β2M), and albumin-binding toxins such as bilirubin and para-aminohippuric acid. Toxic substances also include the compounds described in Tables 1-3 of Vanholder R, et al, Kidney Int, 63 (5): 1934-1943, 2003).
また、不純物もしくは有効成分としては、特に限定されないが、バイオ生産物を精製して医薬品を得る場合には、医薬的に好ましくない不純物や、医薬的に有効な成分等が挙げられる。不純物の具体例としては、所望の物質を分泌する生物に由来する成分、所望の物質を分泌する生物の培養に用いた原料液に由来する夾雑成分、ウイルス等が挙げられ、医薬的に有効な成分の具体例としては、抗体医薬やタンパク・ペプチド医薬などのバイオ医薬品等が挙げられる。 The impurity or the active ingredient is not particularly limited. However, when a bioproduct is purified to obtain a drug, a pharmaceutically unfavorable impurity, a pharmaceutically effective ingredient and the like can be mentioned. Specific examples of impurities include components derived from organisms that secrete desired substances, contaminant components derived from raw material solutions used for culturing organisms that secrete desired substances, viruses, and the like, and are pharmaceutically effective. Specific examples of the components include biopharmaceuticals such as antibody drugs and protein / peptide drugs.
なお、本実施形態において「捕捉」とは、ある１種以上の特定物質を、種々の成分が含まれる溶液等から抜き出し保持することを意味し、「除去」、「分離」および「単離」等もこれに含まれる。 In this embodiment, “capture” means that one or more specific substances are extracted and held from a solution or the like containing various components, and “removed”, “separated”, and “isolated”. Etc. are also included in this.
［用途］
本実施形態の収着材料は、人工腎臓および人工透析用の収着材料や、バイオ生産物用の収着材料として特に有用であるが、これらの用途に限定されることはなく、様々な用途に用いることが可能である。具体的には、血液浄化療法、解毒治療、エンドトキシン吸着療法、活性炭吸着療法、ビリルビン吸着療法、血球吸着療法、あるいは、血漿吸着療法用の収着材料として用いることができる。
[Use]
The sorbent material of the present embodiment is particularly useful as a sorbent material for artificial kidney and artificial dialysis, and a sorbent material for bioproducts, but is not limited to these uses, and may be used in various applications. Can be used. Specifically, it can be used as a sorption material for blood purification therapy, detoxification therapy, endotoxin adsorption therapy, activated carbon adsorption therapy, bilirubin adsorption therapy, blood cell adsorption therapy, or plasma adsorption therapy.
バイオ生産物から不純物や毒性物質を分離するための収着材料として用いる場合には、例えば、バイオ医薬品を精製する際に、様々な膜による膜分離処理やクロマト工程を経て細胞や微生物の培養液から不純物を除去・分離することが一般的であるが、そのいずれかの工程間或いは工程中において、本実施形態の収着材料を用いて不純物や毒性物質を除去することができる。また、例えば、アフィニティ精製によってバイオ医薬品の有効成分を分離する場合には、本実施形態の収着材料を用いて特異的に有効成分を捕捉することができる。 When used as a sorption material to separate impurities and toxic substances from bio-products, for example, when purifying biopharmaceuticals, culture solutions of cells and microorganisms through various membrane separation processes and chromatographic processes It is common to remove and separate impurities from the sorbent material, but during or during any of the steps, the sorbent material of the present embodiment can be used to remove impurities and toxic substances. Further, for example, when an active ingredient of a biopharmaceutical is separated by affinity purification, the active ingredient can be specifically captured using the sorption material of the present embodiment.
［特定物質捕捉システム］
本実施形態における特定物質捕捉システムは、
透析液、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉することのできる金属有機フレームワークを含む収着材料を備えた第１の手段と、
少なくとも前記金属有機フレームワークの分解物である中心金属およびリンカーを除去するための分離膜を備えた第２の手段と、
を有する特定物質捕捉システムであって、
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、前記分離膜のカットオフ分子量未満である。
[Specific substance capture system]
The specific substance capturing system according to the present embodiment includes:
First means comprising a sorption material comprising a metal-organic framework capable of capturing a specific substance from a liquid containing a dialysate, blood, plasma, or a crude product of a substance produced by biotechnological techniques When,
Second means comprising a separation membrane for removing at least a central metal and a linker which are decomposed products of the metal organic framework;
A specific substance capturing system having
The molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
本実施形態における特定物質捕捉システムは、第１の手段により、血液やバイオ生産物等から特定物質を捕捉し、さらに、第１の手段に含まれる金属有機フレームワークが意図せず分解した場合でも、分解した中心金属およびリンカーが第２の手段により除去されるため、収着材料分解物の血液、血漿、ないしバイオ生産物への混入を防止することができる。 The specific substance capturing system according to the present embodiment captures a specific substance from blood, a bioproduct, or the like by the first means, and further, even when the metal organic framework included in the first means is unintentionally decomposed. Since the decomposed central metal and the linker are removed by the second means, it is possible to prevent the decomposed product of the sorption material from being mixed into blood, plasma or bioproducts.
第１の手段と第２の手段は、同一の装置内に存在していても、別々の装置内に存在していてもよい。また、各手段の順序についても特に限定されず。第１の手段が第２の手段よりも前に配置されていても、第１の手段が第２の手段よりも後に配置されていてもよい。例えば、本実施形態の特定物質捕捉システムを血液透析に用いる場合、第１の手段が第２の手段よりも後に配置されている場合には、収着材料分解物が一旦生体内に入った後、生体の血液排出口から排出された血液が第２の手段を通過することによって、収着材料分解物が適切に除去される。 The first means and the second means may be present in the same device, or may be present in different devices. The order of each means is not particularly limited. The first means may be arranged before the second means, or the first means may be arranged after the second means. For example, when the specific substance capturing system of the present embodiment is used for hemodialysis, when the first means is disposed after the second means, after the sorption material decomposed substance once enters the living body, When the blood discharged from the blood outlet of the living body passes through the second means, the decomposition product of the sorption material is appropriately removed.
［特定物質捕捉方法］
本実施形態における特定物質捕捉方法は、
金属有機フレームワークを含む収着材料を用いて、透析液、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉する特定物質捕捉方法であって、
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、分離膜のカットオフ分子量未満である。
本実施形態の特定物質捕捉方法により、収着材料として用いる金属有機フレームワークが意図せず中心金属およびリンカーに分解したとしても、分離膜を用いた膜分離工程により、分離膜のカットオフ分子量未満の分子量を有した中心金属およびリンカーが適切に除去されるため、収着材料分解物の血液、血漿、ないしバイオ生産物等への混入を防止することができる。
[Specific substance capture method]
The specific substance capturing method in the present embodiment,
A specific substance capturing method for capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological technique using a sorption material including a metal organic framework. hand,
The molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
According to the specific substance capturing method of the present embodiment, even if the metal organic framework used as the sorption material is unintentionally decomposed into the central metal and the linker, the cut-off molecular weight of the separation membrane is smaller than the cut-off molecular weight of the separation membrane using the separation membrane. Since the central metal and the linker having the molecular weight of 3 are appropriately removed, contamination of the decomposition product of the sorption material into blood, plasma, bioproducts, or the like can be prevented.
また、本実施形態における特定物質捕捉方法は、好ましくは、
金属有機フレームワークを含む収着材料を用いて、透析液、血液、血漿、または生物工学的手法により製造された物質の粗生成物を含む液体から、特定物質を捕捉する特定物質捕捉工程と、
前記金属有機フレームワークの分解物である中心金属およびリンカーを、分離膜を用いて除去する膜分離工程と、
を含む方法である。
ここで、上記方法には、特定物質捕捉工程における収着材料の分解物が一旦生体内に入った後、生体の血液排出口から排出された血液が膜分離工程を経ることによって、収着材料分解物が除去される態様も含まれる。
Further, the specific substance capturing method in the present embodiment, preferably,
A specific substance capturing step of capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological technique using a sorption material including a metal organic framework;
A membrane separation step of removing a central metal and a linker, which are decomposition products of the metal organic framework, using a separation membrane,
It is a method including.
Here, in the above method, after the decomposition product of the sorption material in the specific substance capturing step once enters the living body, the blood discharged from the blood outlet of the living body goes through the membrane separation step, An embodiment in which the decomposition product is removed is also included.
以下、実施例により本発明を詳細に説明するが、これらは本発明の範囲を実施例に制限することを意図したものではない。 Hereinafter, the present invention will be described in detail with reference to examples, but these are not intended to limit the scope of the present invention to the examples.
実施例及び比較例で製造した金属フレームワークの各物性の測定方法および評価方法は以下のとおりである。 The methods for measuring and evaluating the physical properties of the metal frameworks manufactured in the examples and comparative examples are as follows.
＜分子量＞
金属有機フレームワーク（１０ｍｇ）を１ｍｍｏｌ／ｌの水酸化ナトリウム水溶液（１０ｍｌ）に完全に溶解させる、もしくは硫酸水溶液（５ｍｌ）に完全に溶解させた後にジメチルスルホキシド溶液を加え１０ｍｌとし、液体クロマトグラフィ質量分析法によりリンカーの分子量を測定した。
<Molecular weight>
The metal organic framework (10 mg) was completely dissolved in a 1 mmol / l aqueous solution of sodium hydroxide (10 ml) or completely dissolved in an aqueous solution of sulfuric acid (5 ml), and then a dimethyl sulfoxide solution was added to make 10 ml. The molecular weight of the linker was measured by the method.
＜金属有機フレームワークによるＣＭＰＦまたは尿毒素の除去率評価＞
金属有機フレームワークによるＣＭＰＦまたは馬尿酸（いずれも代表的な尿毒素）の除去率評価は以下の方法により行った。容器中の金属有機フレームワーク（２．５ｍｇ）に、２０ｐｐｍのＣＭＰＦ水溶液（２．５ｍｌ）を加え、容器を２５℃で２４時間保持することにより、金属有機フレームワークにＣＭＰＦを吸着させた。その後、１０００ＲＣＦで１０分遠心し、上澄み液を回収した。そして、上澄み液中のＣＭＰＦ濃度を高速液体クロマトグラフィーにより測定し、金属有機フレームワーク非存在下でのＣＭＰＦ濃度と比較することで吸着除去率を算出した。除去率が７０％以上のものを◎、３０％以上７０％未満のものを○、３０％未満のものを△とした。同様の方法で馬尿酸除去率を算出した。
<Evaluation of removal rate of CMPF or uremic toxin by metal organic framework>
The following method was used to evaluate the removal rate of CMPF or hippuric acid (both typical urexins) by the metal organic framework. A 20 ppm aqueous solution of CMPF (2.5 ml) was added to the metal-organic framework (2.5 mg) in the container, and the container was kept at 25 ° C. for 24 hours to adsorb the CMPF to the metal-organic framework. Thereafter, the mixture was centrifuged at 1000 RCF for 10 minutes, and the supernatant was recovered. Then, the CMPF concentration in the supernatant was measured by high performance liquid chromatography, and the adsorption removal rate was calculated by comparing with the CMPF concentration in the absence of the metal organic framework. A sample having a removal rate of 70% or more was rated as ◎, a sample with a removal ratio of 30% or more and less than 70% was rated as ○, and a sample with a removal rate of less than 30% was rated as Δ. The hippuric acid removal rate was calculated in the same manner.
＜金属有機フレームワークの溶出量評価＞
金属有機フレームワーク１．５ｍｇを２．０ｍｌの５０ｍＭトリス緩衝液（イオン強度０．１５ｍｏｌ／ｌ）中に分散させ、３７℃で２４時間静置した。静置後のサンプルを１０００ＲＣＦで１０分遠心して得られた上澄み０．２ｍＬを透析器（Ｓｐｅｃｔｒｕｍ社製、Ｍｉｃｒｏ Ｆｌｏａｔ−Ａ−Ｌｙｚｅｒ、Ｆ２３５０５１；ＭＷＣＯ（カットオフ分子量）＝１，０００）に備え、１．０Ｌの５０ｍＭトリス緩衝液（イオン強度０．１５ｍｏｌ／ｌ）を用いて２４時間透析を行なった。透析終了後、上澄み中の金属濃度および配位子濃度を、各々ＩＣＰ発光分析測定および紫外可視吸収スペクトル測定より求めた。金属および配位子の濃度が１０ｐｐｍ以下を◎、２０ｐｐｍ以上５０ｐｐｍ以下を○、５０ｐｐｍ以上１００ｐｐｍ以下を△、１００ｐｐｍ以上を×とした。
<Evaluation of elution amount of metal organic framework>
1.5 mg of the metal-organic framework was dispersed in 2.0 ml of 50 mM Tris buffer (ionic strength: 0.15 mol / l) and allowed to stand at 37 ° C. for 24 hours. 0.2 ml of the supernatant obtained by centrifuging the sample after standing at 1000 RCF for 10 minutes was provided in a dialyzer (MicroFloat-A-Lyzer, F235051, manufactured by Spectrum); MWCO (cutoff molecular weight) = 1,000, Dialysis was performed for 24 hours using 1.0 L of 50 mM Tris buffer (ionic strength: 0.15 mol / l). After completion of the dialysis, the metal concentration and the ligand concentration in the supernatant were determined by ICP emission spectrometry and UV-visible absorption spectrometry, respectively. When the concentration of the metal and the ligand was 10 ppm or less, ◎, 20 ppm or more and 50 ppm or less, 、, 50 ppm or more to 100 ppm or less, and 100 ppm or more x.
＜金属塩と有機配位子の略称＞
（金属塩）
ＺｒＣｌ4：塩化ジルコニウム（Ｚｉｒｃｏｎｉｕｍ（ＩＶ） Ｃｈｌｏｒｉｄｅ）
ＨｆＣｌ4：塩化ジルコニウム（Ｈａｆｎｉｕｍ（ＩＶ） Ｃｈｌｏｒｉｄｅ）
ＺｒＯＣｌ2・８Ｈ2Ｏ：オキシ塩化ジルコニウム・８水和物（Ｚｉｒｃｏｎｉｕｍ（ＩＶ） ｏｘｙｃｈｌｏｒｉｄｅ ｏｃｔａｈｙｄｒａｔｅ）
ＨｆＯＣｌ2・８Ｈ2Ｏ：オキシ塩化ハフニウム・８水和物（Ｈａｆｎｉｕｍ（ＩＶ） ｏｘｙｃｈｌｏｒｉｄｅ ｏｃｔａｈｙｄｒａｔｅ）
<Abbreviation of metal salt and organic ligand>
(Metal salt)
ZrCl 4 : Zirconium (IV) Chloride
HfCl 4 : zirconium chloride (Hafnium (IV) Chloride)
ZrOCl 2 · 8H 2 O: Zirconium oxychloride octahydrate (Zirconium (IV) oxychloride octahydrate)
HfOCl 2 · 8H 2 O: oxychloride hafnium octahydrate (Hafnium (IV) oxychloride octahydrate)
（有機配位子）
ＢＤＣ：テレフタル酸（Ｔｅｒｅｐｈｔｈａｌｉｃ ａｃｉｄ）
ＢＤＣ−ＮＨ2：２−アミノテレフタル酸（２−Ａｍｉｎｏｔｅｒｅｐｈｔｈａｌｉｃ ａｃｉｄ）
ＢＤＣ−（ＣＯＯＨ）2：ピロメリト酸（Ｐｙｒｏｍｅｌｌｉｔｉｃ ａｃｉｄ）
ＮＤＣ：２、６−ナフタレンジカルボン酸（２，６−Ｎａｐｈｔｈａｌｅｎｅｄｉｃａｒｂｏｘｙｌｉｃ ａｃｉｄ）
ＢＰＤＣ：４、４’−ビフェニルジカルボン酸（４，４’−Ｂｉｐｈｅｎｙｌｄｉｃａｒｂｏｘｙｌｉｃ ａｃｉｄ）
Ｍｅ2ＢＰＤＣ：２、２’−ジメチルビフェニル−４、４'−ジカルボン酸（２，２’−ｄｉｍｅｔｈｙｌｂｉｐｈｅｎｙｌ−４，４’−ｄｉｃａｒｂｏｘｙｌｉｃ ａｃｉｄ）
ＢＤＣ−（ＯＨ）2：２、５−ジヒドロキシテレフタル酸（２，５−Ｄｉｈｙｄｒｏｘｙｔｅｒｅｐｈｔｈａｌｉｃ ａｃｉｄ）
ＴＤＣ：２、５−チオフェンジカルボン酸（２，５−Ｔｈｉｏｐｈｅｎｅｄｉｃａｒｂｏｘｙｌｉｃ ａｃｉｄ）
ＴＣＰＰ：テトラキス（４−カルボキシフェニル）ポルフィリン（Ｔｅｔｒａｋｉｓ（４−ｃａｒｂｏｘｙｐｈｅｎｙｌ）ｐｏｒｐｈｙｒｉｎ））
ＴＣＢＰ：テトラキス（４−カルボキシビフェニル）ポルフィリン（Ｔｅｔｒａｋｉｓ（４−ｃａｒｂｏｘｙｂｉｐｈｅｎｙｌ）ｐｏｒｐｈｙｒｉｎ））
Ｈ4ＴＢＡＰｙ：１、３、６、８−テトラキス（ｐ−カルボキシフェニル）ピレン（１，３，６，８−ｔｅｔｒａｋｉｓ（ｐ−ｂｅｎｚｏｉｃ ａｃｉｄ）ｐｙｒｅｎｅ
Ｈ4ＴＰＣＢ：２、２’−ジヒドロビフェニル−３、３'、５、５'−テトラ（フェニル−４−カルボン酸）（２，２’−ｄｉｈｙｄｒｏｂｉｐｈｅｎｙｌ−３，３’，５，５’−ｔｅｔｒａ（ｐｈｅｎｙｌ−４−ｃａｒｂｏｘｙｌｉｃ ａｃｉｄ））
４、４’−ＮＨ2−Ｈ4ＴＰＣＢ：４、４’−ジアミノ−３、３'、５、５'−テトラ（フェニル−４−カルボン酸）（４，４’−ｄｉａｍｉｎｏ−ｂｉｐｈｅｎｙｌ−３，３’，５，５’−ｔｅｔｒａ（ｐｈｅｎｙｌ−４−ｃａｒｂｏｘｙｌｉｃ ａｃｉｄ））
４、４’−ＯＨ−Ｈ4ＴＰＣＢ：４、４’−ジヒドロキシ−３、３'、５、５'−テトラ（フェニル−４−カルボン酸）（４，４’−ｄｉｈｙｄｒｏｘｙ−ｂｉｐｈｅｎｙｌ−３，３’，５，５’−ｔｅｔｒａ（ｐｈｅｎｙｌ−４−ｃａｒｂｏｘｙｌｉｃ ａｃｉｄ））
Ｈ4ＭＤＩＰ：３、３’、５、５’−テトラカルボキシジフェニルメタン（３，３’，５，５’−ｔｅｔｒａｃａｒｂｏｘｙｄｉｐｈｅｎｙｌｍｅｔｈａｎｅ）
ＴＭＴＡ：１、３、５−トリス（４−カルボキシフェニル）−２、４、６−トリメチルベンゼン（１，３，５−ｔｒｉｓ（４−ｃａｒｂｏｘｙｐｈｅｎｙｌ）−２，４，６−ｔｒｉｍｅｔｈｙｌｂｅｎｚｅｎｅ）
(Organic ligand)
BDC: Terephthalic acid
BDC-NH 2: 2- aminoterephthalate (2-Aminoterephthalic acid)
BDC- (COOH) 2 : pyromellitic acid
NDC: 2,6-Naphthalenedicarboxylic acid
BPDC: 4,4'-biphenyldicarboxylic acid (4,4'-biphenyldicarboxyliccarboxylic acid)
Me 2 BPDC: 2,2′-dimethylbiphenyl-4,4′-dicarboxylic acid (2,2′-dimethylbiphenyl-4,4′-dicarboxylic acid)
BDC- (OH) 2 : 2,5-dihydroxyterephthalic acid (2,5-Dihydroxyterephthalic acid)
TDC: 2,5-Thiophenedicarboxylic acid
TCPP: Tetrakis (4-carboxyphenyl) porphyrin
TCBP: Tetrakis (4-carboxybiphenyl) porphyrin)
H 4 TBAPy: 1,3,6,8- tetrakis (p- carboxyphenyl) pyrene (1,3,6,8-tetrakis (p-benzoic acid) pyrene
H 4 TPCB: 2,2'-dihydro-3,3 ', 5,5'-tetra (phenyl-4-carboxylic acid) (2,2'-dihydrobiphenyl-3,3' , 5,5'-tetra (Phenyl-4-carboxylic acid))
4,4'-NH 2 -H 4 TPCB: 4,4'- diamino-3,3 ', 5,5'-tetra (phenyl-4-carboxylic acid) (4,4'-diamino-biphenyl- 3, 3 ', 5,5'-tetra (phenyl-4-carboxylic acid))
4,4'-OH-H 4 TPCB: 4,4'- dihydroxy-3,3 ', 5,5'-tetra (phenyl-4-carboxylic acid) (4,4'-dihydroxy-biphenyl- 3,3 ', 5,5'-tetra (phenyl-4-carboxylic acid))
H 4 MDIP: 3,3 ', 5,5'- tetracarboxylic diphenylmethane (3,3', 5,5'-tetracarboxydiphenylmethane)
TMTA: 1,3,5-tris (4-carboxyphenyl) -2,4,6-trimethylbenzene (1,3,5-tris (4-carboxyphenyl) -2,4,6-trimethylbenzene)
＜金属有機フレームワークの合成＞
金属有機フレームワークを以下の実施例および比較例に示す通りに作成した。
<Synthesis of metal organic framework>
Metal organic frameworks were made as shown in the following examples and comparative examples.
（実施例１−１−１）
密閉式ガラス容器にＺｒＣｌ4（１２５ｍｇ）、ＢＤＣ（１２３ｍｇ）、ジメチルホルムアミド（ＤＭＦ、１５ｍｌ）を加え室温で十分に溶解させた。続いて、１２ｍｍｏｌ／ｌの塩酸（１．０ｍｌ）を加えた後、室温まで空冷させた。得られた前記反応溶液を８０℃の防爆オーブンで２４時間反応させた。反応終了後、得られた固体をジメチルスルホキシド（ＤＭＳＯ、１５ｍｌ）で計３回洗浄を行い、再度ＤＭＳＯ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、８０℃の防爆オーブンで２４時間反応させた。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、８０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-1-1)
ZrCl 4 (125 mg), BDC (123 mg), and dimethylformamide (DMF, 15 ml) were added to a closed glass container and sufficiently dissolved at room temperature. Subsequently, 12 mmol / l hydrochloric acid (1.0 ml) was added, and the mixture was air-cooled to room temperature. The obtained reaction solution was reacted in an explosion-proof oven at 80 ° C. for 24 hours. After the completion of the reaction, the obtained solid was washed with dimethyl sulfoxide (DMSO, 15 ml) three times in total, dispersed again in DMSO (20 ml), and 12 mmol / l hydrochloric acid (0.5 mL) was added. In an explosion-proof oven for 24 hours. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 80 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１−２）
ＢＤＣ（１２３ｍｇ）からＢＤＣ−ＮＨ2（１３５ｍｇ）に変更した以外は実施例１−１−１と同様に合成した。
(Example 1-1-2)
Synthesized in the same manner as in Example 1-1-1 except that BDC (123 mg) was changed to BDC-NH 2 (135 mg).
（実施例１−１−３）
ＢＤＣ（１２３ｍｇ）からＢＤＣ−（ＣＯＯＨ）2（１９０ｍｇ）に変更した以外は実施例１−１−１と同様に合成した。
(Example 1-1-3)
Synthesis was performed in the same manner as in Example 1-1-1 except that BDC (123 mg) was changed to BDC- (COOH) 2 (190 mg).
（実施例１−２）
ＢＤＣ（１２３ｍｇ）からＢＰＤＣ（９０ｍｇ）に変更した以外は実施例１−１−１と同様に合成した。
(Example 1-2)
Synthesis was performed in the same manner as in Example 1-1-1 except that BDC (123 mg) was changed to BPDC (90 mg).
（実施例１−３）
ＢＤＣ（１２３ｍｇ）からＮＤＣ（８０ｍｇ）に変更した以外は実施例１−１−１と同様に合成した。
(Example 1-3)
Synthesis was performed in the same manner as in Example 1-1-1 except that BDC (123 mg) was changed to NDC (80 mg).
（実施例１−４）
ＢＤＣ（１２３ｍｇ）からＢＤＣ−（ＯＨ）2（１３５ｍｇ）に変更した以外は実施例１−１−１と同様に合成した。
(Example 1-4)
Synthesis was performed in the same manner as in Example 1-1-1 except that BDC (123 mg) was changed to BDC- (OH) 2 (135 mg).
（実施例１−５）
密閉式ガラス容器に（８０ｍｇ）、ギ酸（１０ｍｌ）、ＢＴＣ（５０ｍｇ）、ＤＭＦ（１０ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１００℃の防爆オーブンで５日間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により白色固体を回収した。得られた固体を再度ＤＭＦ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、得られた固体をＤＭＳＯ（１５ｍｌ）で計３回洗浄を行い、再度ＤＭＳＯ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、８０℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により白色固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１５０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-5)
(80 mg), formic acid (10 ml), BTC (50 mg), and DMF (10 ml) were added to a closed glass container and dissolved sufficiently at room temperature. The resulting solution was reacted in an explosion-proof oven at 100 ° C. for 5 days. . After the completion of the reaction, the vessel was air-cooled to room temperature, and a white solid was recovered by centrifugation. The obtained solid was dispersed again in DMF (20 ml), and after adding 12 mmol / l hydrochloric acid (0.5 mL), the mixture was reacted in an explosion-proof oven at 100 ° C. for 24 hours. After the completion of the reaction, the obtained solid was washed with DMSO (15 ml) three times in total, dispersed again in DMSO (20 ml), and 12 mmol / l hydrochloric acid (0.5 mL) was added. For 24 hours. After completion of the reaction, a white solid was recovered from the resulting solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 150 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−６）
密閉式ガラス容器にＺｒＣｌ4（２３０ｍｇ）、ＴＤＣ（２５８ｍｇ）、ＤＭＦ（２５ｍｌ）、酢酸（１１ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで３日間反応させた。反応終了後、得られた固体をＤＭＳＯ（１５ｍｌ）で計３回洗浄を行い、再度ＤＭＳＯ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、容器を室温まで空冷し、遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１００℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-6)
ZrCl 4 (230 mg), TDC (258 mg), DMF (25 ml), and acetic acid (11 ml) were added to a closed glass container and dissolved sufficiently at room temperature. The resulting solution was reacted in an explosion-proof oven at 120 ° C. for 3 days. I let it. After the completion of the reaction, the obtained solid was washed with DMSO (15 ml) three times in total, dispersed again in DMSO (20 ml), and 12 mmol / l hydrochloric acid (0.5 mL) was added. For 24 hours. After the completion of the reaction, the vessel was air-cooled to room temperature, and the solid was recovered by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 100 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−７）
密閉式ガラス容器にＺｒＣｌ4（２００ｍｇ）、ＢＰＤＣ−（ＣＨ3）2（１００ｍｇ）、ＤＭＦ（２０ｍｌ）、トリフルオロ酢酸（１ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで３日間反応させた。反応終了後、得られた固体をＤＭＳＯ（１５ｍｌ）で計３回洗浄を行い、再度ＤＭＳＯ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（１．０ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、容器を室温まで空冷し、遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１００℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-7)
ZrCl 4 (200 mg), BPDC- (CH 3 ) 2 (100 mg), DMF (20 ml), and trifluoroacetic acid (1 ml) were added to a closed glass container, and the mixture was dissolved sufficiently at room temperature. The reaction was carried out for 3 days in an explosion-proof oven at ℃. After the completion of the reaction, the obtained solid was washed with DMSO (15 ml) three times in total, dispersed again in DMSO (20 ml), and 12 mmol / l hydrochloric acid (1.0 mL) was added. For 24 hours. After the completion of the reaction, the vessel was air-cooled to room temperature, and the solid was recovered by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 100 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−８）
密閉式ガラス容器に（３８ｍｇ）、ＴＣＰＰ（７ｍｇ）、ギ酸（７ｍｌ）、ＤＭＦ（１０ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１３０℃の防爆オーブンで５日間反応させた。反応終了後、得られた固体をＤＭＳＯ（１５ｍｌ）で計３回洗浄を行い、再度ＤＭＳＯ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、容器を室温まで空冷し、遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１２０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-8)
After adding (38 mg), TCPP (7 mg), formic acid (7 ml) and DMF (10 ml) to a closed glass container and sufficiently dissolving at room temperature, the resulting solution was reacted in an explosion-proof oven at 130 ° C. for 5 days. . After the completion of the reaction, the obtained solid was washed with DMSO (15 ml) three times in total, dispersed again in DMSO (20 ml), and 12 mmol / l hydrochloric acid (0.5 mL) was added. For 24 hours. After the completion of the reaction, the vessel was air-cooled to room temperature, and the solid was recovered by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 120 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−９）
密閉式ガラス容器にＺｒＣｌ4（３０ｍｇ）、ＴＣＰＰ（１０ｍｇ）、安息香酸（４００ｍｇ）、ＤＭＦ（２ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで２４時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体を再度ＤＭＳＯ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１２０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-9)
ZrCl 4 (30 mg), TCPP (10 mg), benzoic acid (400 mg), and DMF (2 ml) were added to a closed glass container and dissolved sufficiently at room temperature, and the resulting solution was placed in a 120 ° C. explosion-proof oven for 24 hours. Reacted. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was dispersed again in DMSO (20 ml), and after adding 12 mmol / l hydrochloric acid (0.5 mL), the mixture was reacted in an explosion-proof oven at 100 ° C. for 24 hours. After completion of the reaction, a solid was recovered from the obtained solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 120 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１０）
密閉式ガラス容器に（２００ｍｇ）、安息香酸（３ｇ）、ＤＭＦ（１６ｍｌ）を加え室温で十分に溶解させた後、トリフルオロ酢酸（１６０μｌ）、Ｈ4ＴＢＡＰｙ（８０ｍｇ）を加え、十分溶解させた。得られた溶液を１２０℃の防爆オーブンで２４時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体を再度ＤＭＳＯ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（１ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１２０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-10)
(200 mg), benzoic acid (3 g), and DMF (16 ml) were added to a closed glass container and dissolved sufficiently at room temperature. Then, trifluoroacetic acid (160 μl) and H 4 TBAPy (80 mg) were added and dissolved sufficiently. . The obtained solution was reacted in an explosion-proof oven at 120 ° C. for 24 hours. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was dispersed again in DMSO (20 ml), and after adding 12 mmol / l hydrochloric acid (1 mL), the mixture was reacted in an explosion-proof oven at 100 ° C. for 24 hours. After completion of the reaction, a solid was recovered from the obtained solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 120 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１１）
密閉式ガラス容器に（１００ｍｇ）、１−アミノ安息香酸（３ｇ）、ＤＭＦ（８ｍｌ）を加え室温で十分に溶解させた後、Ｈ4ＴＢＡＰｙ（４０ｍｇ）を加え、十分溶解させた。得られた溶液を１２０℃の防爆オーブンで２４時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体を再度ＤＭＳＯ（２０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（１ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１２０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-11)
(100 mg), 1-aminobenzoic acid (3 g) and DMF (8 ml) were added to a closed glass container, and the mixture was sufficiently dissolved at room temperature. Then, H 4 TBAPy (40 mg) was added and sufficiently dissolved. The obtained solution was reacted in an explosion-proof oven at 120 ° C. for 24 hours. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was dispersed again in DMSO (20 ml), and after adding 12 mmol / l hydrochloric acid (1 mL), the mixture was reacted in an explosion-proof oven at 100 ° C. for 24 hours. After completion of the reaction, a solid was recovered from the obtained solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 120 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１２）
密閉式ガラス容器にＺｒＣｌ4（２０ｍｇ）、ＴＰＣＢ（１０ｍｇ）、安息香酸（７００ｍｇ）、ＤＭＦ（３ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで２４時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体を再度ＤＭＳＯ（１０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、８０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-12)
ZrCl 4 (20 mg), TPCB (10 mg), benzoic acid (700 mg), DMF (3 ml) were added to a closed glass container, and the mixture was sufficiently dissolved at room temperature. Reacted. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was dispersed again in DMSO (10 ml), and after adding 12 mmol / l hydrochloric acid (0.5 mL), the mixture was reacted in an explosion-proof oven at 100 ° C. for 24 hours. After completion of the reaction, a solid was recovered from the obtained solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 80 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１３）
密閉式ガラス容器にＺｒＣｌ4（２０ｍｇ）、４、４’−ＯＨ−ＴＰＣＢ（１０ｍｇ）、安息香酸（５００ｍｇ）、ＤＭＦ（２ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで４８時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体を再度ＤＭＳＯ（１０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、８０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-13)
ZrCl 4 (20 mg), 4,4′-OH-TPCB (10 mg), benzoic acid (500 mg), DMF (2 ml) were added to a closed glass container, and the mixture was dissolved sufficiently at room temperature. The reaction was carried out for 48 hours in an explosion-proof oven at ℃. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was dispersed again in DMSO (10 ml), and after adding 12 mmol / l hydrochloric acid (0.5 mL), the mixture was reacted in an explosion-proof oven at 100 ° C. for 24 hours. After completion of the reaction, a solid was recovered from the obtained solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 80 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１４）
密閉式ガラス容器にＺｒＣｌ4（２０ｍｇ）、４、４’−ＯＨ−ＴＰＣＢ（１０ｍｇ）、安息香酸（５００ｍｇ）、ＤＭＦ（２ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで４８時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体を再度ＤＭＳＯ（１０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（０．５ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、８０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-14)
ZrCl 4 (20 mg), 4,4′-OH-TPCB (10 mg), benzoic acid (500 mg), DMF (2 ml) were added to a closed glass container, and the mixture was dissolved sufficiently at room temperature. The reaction was carried out for 48 hours in an explosion-proof oven at ℃. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was dispersed again in DMSO (10 ml), and after adding 12 mmol / l hydrochloric acid (0.5 mL), the mixture was reacted in an explosion-proof oven at 100 ° C. for 24 hours. After completion of the reaction, a solid was recovered from the obtained solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 80 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１５）
密閉式反応容器にＨ4ＭＤＩＰ（２００ｍｇ）、ギ酸（１２ｍｌ）、無水酢酸（１５ｍｌ）を加え１２０℃で十分に溶解させた後、得られた溶液にＺｒＣｌ4（４００ｍｇ）を加え、１２０℃の防爆オーブンで７２時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体を再度ＤＭＳＯ（５０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（４ｍＬ）を加えた後、８０℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、８０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-15)
After adding H 4 MDIP (200 mg), formic acid (12 ml), and acetic anhydride (15 ml) to a closed reaction vessel and sufficiently dissolving at 120 ° C., ZrCl 4 (400 mg) was added to the obtained solution, and the mixture was heated at 120 ° C. The reaction was performed in an explosion-proof oven for 72 hours. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was dispersed again in DMSO (50 ml), and after adding 12 mmol / l hydrochloric acid (4 mL), the mixture was reacted in an explosion-proof oven at 80 ° C. for 24 hours. After completion of the reaction, a solid was recovered from the obtained solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 80 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１６）
密閉式ガラス容器にＺｒＣｌ4（２００ｍｇ）、Ｍｅ2−ＢＰＤＣ（１００ｍｇ）、ＤＭＦ（２０ｍｌ）、トリフルオロ酢酸（１ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで３日間反応させた。反応終了後、得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１００℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-16)
After adding ZrCl 4 (200 mg), Me 2 -BPDC (100 mg), DMF (20 ml) and trifluoroacetic acid (1 ml) to a closed glass container and sufficiently dissolving at room temperature, the obtained solution was explosion-proof at 120 ° C. The reaction was performed in an oven for 3 days. After completion of the reaction, the obtained solid was washed and centrifuged with DMF (15 ml) three times in total and acetone (15 ml) in total three times to remove unreacted raw materials. Subsequently, drying was performed at 100 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１７）
密閉式ガラス容器にＺｒＣｌ4（２３０ｍｇ）、ＴＤＣ（１１０ｍｇ）、ＤＭＦ（１０ｍｌ）、Ｎ−メチルピロリドン（１０ｍｌ）、酢酸（７ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで２日間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１００℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-17)
ZrCl 4 (230 mg), TDC (110 mg), DMF (10 ml), N-methylpyrrolidone (10 ml), and acetic acid (7 ml) were added to a closed glass container, and the mixture was sufficiently dissolved at room temperature. The reaction was carried out for 2 days in an explosion-proof oven at ℃. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 100 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例１−１８）
密閉式ガラス容器にＺｒＣｌ4（２３０ｍｇ）、ＴＤＣ（１７２ｍｇ）、ＤＭＦ（５０ｍｌ）、酢酸（３ｍｌ）を加え室温で十分に溶解させた後、得られた溶液を１２０℃の防爆オーブンで１２時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１００℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 1-18)
ZrCl 4 (230 mg), TDC (172 mg), DMF (50 ml), and acetic acid (3 ml) were added to a closed glass container and dissolved sufficiently at room temperature. The resulting solution was reacted in an explosion-proof oven at 120 ° C. for 12 hours. I let it. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 100 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（比較例１−１）
密閉式反応容器にＴＣＢＰ（１２０ｍｇ）、安息香酸（１．４ｇ）、ＤＭＦ（８ｍｌ）を加え８０℃で十分に溶解させた後、得られた溶液にＺｒＣｌ4（８０ｍｇ）を加え、１２０℃の防爆オーブンで７２時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体を再度ＤＭＳＯ（５０ｍｌ）に分散させ、１２ｍｍｏｌ／ｌの塩酸（１．０ｍＬ）を加えた後、１００℃の防爆オーブンで２４時間反応させた。反応終了後、得られた溶液から遠心分離により固体を回収した。得られた固体は、ＤＭＦ（１５ｍｌ）で計３回、アセトン（１５ｍｌ）で計３回洗浄および遠心分離を行い、未反応原料を除去した。続いて、１２０℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Comparative Example 1-1)
TCBP (120 mg), benzoic acid (1.4 g) and DMF (8 ml) were added to a closed reaction vessel and dissolved sufficiently at 80 ° C. After that, ZrCl 4 (80 mg) was added to the obtained solution, and the mixture was heated at 120 ° C. The reaction was performed in an explosion-proof oven for 72 hours. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was again dispersed in DMSO (50 ml), and after adding 12 mmol / l hydrochloric acid (1.0 mL), the mixture was reacted in an explosion-proof oven at 100 ° C. for 24 hours. After completion of the reaction, a solid was recovered from the obtained solution by centrifugation. The obtained solid was washed and centrifuged three times in total with DMF (15 ml) and three times in acetone (15 ml) to remove unreacted raw materials. Subsequently, drying was performed at 120 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例２−１−１）
ＺｒＣｌ4（１２５ｍｇ）から塩化ハフニウム（１８０ｍｇ）に変更した以外は実施例１−１−１と同様に合成した。
(Example 2-1-1)
Synthesis was performed in the same manner as in Example 1-1-1 except that ZrCl 4 (125 mg) was changed to hafnium chloride (180 mg).
（実施例２−１−２）
ＺｒＣｌ4（１２５ｍｇ）から塩化ハフニウム（１８０ｍｇ）に変更した以外は実施例１−１−２と同様に合成した。
(Example 2-1-2)
It was synthesized in the same manner as in Example 1-1-2, except that ZrCl 4 (125 mg) was changed to hafnium chloride (180 mg).
（実施例２−１−３）
ＺｒＣｌ4（１２５ｍｇ）から塩化ハフニウム（１８０ｍｇ）に変更した以外は実施例１−１−３と同様に合成した。
(Example 2-1-3)
Synthesis was performed in the same manner as in Example 1-1-3, except that ZrCl 4 (125 mg) was changed to hafnium chloride (180 mg).
（実施例２−２）
ＺｒＣｌ4（１２５ｍｇ）から塩化ハフニウム（１８０ｍｇ）に変更した以外は実施例１−２と同様に合成した。
(Example 2-2)
Synthesis was performed in the same manner as in Example 1-2 except that ZrCl 4 (125 mg) was changed to hafnium chloride (180 mg).
（実施例２−３）
ＺｒＣｌ4（１２５ｍｇ）から塩化ハフニウム（１８０ｍｇ）に変更した以外は実施例１−３と同様に合成した。
(Example 2-3)
Synthesis was performed in the same manner as in Example 1-3, except that ZrCl 4 (125 mg) was changed to hafnium chloride (180 mg).
（実施例２−４）
ＺｒＣｌ4（１２５ｍｇ）から塩化ハフニウム（１８０ｍｇ）に変更した以外は実施例１−４と同様に合成した。
(Example 2-4)
Synthesis was performed in the same manner as in Example 1-4 except that ZrCl 4 (125 mg) was changed to hafnium chloride (180 mg).
（実施例２−５）
オキシ塩化ジルコニウム（８０ｍｇ）からＨｆＯＣｌ２・８Ｈ２Ｏ（１５０ｍｇ）に変更した以外は実施例１−５と同様に合成した。
(Example 2-5)
Synthesis was performed in the same manner as in Example 1-5, except that zirconium oxychloride (80 mg) was changed to HfOCl2.8H2O (150 mg).
（実施例２−６）
ＺｒＣｌ4（２３０ｍｇ）からＨｆＯＣｌ２・８Ｈ２Ｏ（３５０ｍｇ）に変更した以外は実施例１−６と同様に合成した。
(Example 2-6)
Synthesis was carried out in the same manner as in Example 1-6, except that ZrCl 4 (230 mg) was changed to HfOCl2.8H2O (350 mg).
（実施例２−７）
ＺｒＣｌ4（２００ｍｇ）から塩化ハフニウム（３００ｍｇ）に変更した以外は実施例１−８と同様に合成した。
(Example 2-7)
Synthesis was performed in the same manner as in Example 1-8, except that ZrCl 4 (200 mg) was changed to hafnium chloride (300 mg).
（実施例２−８）
ＺｒＯＣｌ2・８Ｈ2Ｏ（３８ｍｇ）からＨｆＯＣｌ２・８Ｈ２Ｏ（５０ｍｇ）に変更した以外は実施例１−７と同様に合成した。
(Example 2-8)
Was changed from ZrOCl 2 · 8H 2 O (38mg ) in HfOCl2 · 8H2O (50mg) was synthesized in the same manner as in Example 1-7.
（実施例２−９）
ＺｒＣｌ4（３０ｍｇ）から塩化ハフニウム（４０ｍｇ）に変更した以外は実施例１−９と同様に合成した。
(Example 2-9)
Synthesis was performed in the same manner as in Example 1-9, except that ZrCl 4 (30 mg) was changed to hafnium chloride (40 mg).
（実施例２−１０）
ＺｒＯＣｌ2・８Ｈ2Ｏ（２００ｍｇ）からＨｆＯＣｌ２・８Ｈ２Ｏ（２４０ｍｇ）に変更した以外は実施例１−１０と同様に合成した。
(Example 2-10)
Except for changing ZrOCl 2 · 8H 2 from O (200 mg) in HfOCl2 · 8H2O (240mg) was synthesized in the same manner as in Example 1-10.
（実施例２−１１）
ＺｒＯＣｌ2・８Ｈ2Ｏ（１００ｍｇ）からＨｆＯＣｌ２・８Ｈ２Ｏ（１５０ｍｇ）に変更した以外は実施例１−１１と同様に合成した。
(Example 2-11)
Except for changing ZrOCl 2 · 8H 2 from O (100 mg) in HfOCl2 · 8H2O (150mg) was synthesized in the same manner as in Example 1-11.
（実施例２−１２）
ＺｒＣｌ4（２０ｍｇ）から塩化ハフニウム（３０ｍｇ）に変更した以外は実施例１−１２と同様に合成した。
(Example 2-12)
Synthesis was performed in the same manner as in Example 1-12, except that ZrCl 4 (20 mg) was changed to hafnium chloride (30 mg).
（実施例２−１３）
ＺｒＣｌ4（２０ｍｇ）から塩化ハフニウム（３０ｍｇ）に変更した以外は実施例１−１３と同様に合成した。
(Example 2-13)
Synthesis was performed in the same manner as in Example 1-13, except that ZrCl 4 (20 mg) was changed to hafnium chloride (30 mg).
（実施例２−１４）
ＺｒＣｌ4（２０ｍｇ）から塩化ハフニウム（３０ｍｇ）に変更した以外は実施例１−１２と同様に合成した。
(Example 2-14)
Synthesis was performed in the same manner as in Example 1-12, except that ZrCl 4 (20 mg) was changed to hafnium chloride (30 mg).
（実施例２−１５）
ＺｒＣｌ4（４００ｍｇ）から塩化ハフニウム（６００ｍｇ）に変更した以外は実施例１−１５と同様に合成した。
(Example 2-15)
Synthesis was performed in the same manner as in Example 1-15, except that ZrCl 4 (400 mg) was changed to hafnium chloride (600 mg).
（実施例３−１）
密閉式ガラス容器に鉄（粉末、１１０ｍｇ）、ＢＴＣ（２８０ｍｇ）、硝酸（１５．６Ｍ、８０μｌ）、水（１０ｍｌ）を加え９５℃の防爆オーブンで２４時間反応させた。反応終了後、容器を室温まで空冷した後、遠心分離により固体を回収した。得られた固体は、水（１５ｍｌ）で計５回洗浄後、６０℃の防爆オーブンで加熱した。加熱終了後、容器を室温まで空冷下後、ＤＭＦ（１５ｍｌ）で計５回、エタノール（１５ｍｌ）で計３回洗浄を行った。および遠心分離を行い、未反応原料を除去した。続いて、１００℃、２ｍｍＨｇの条件下で２４時間乾燥を行い、金属有機フレームワークを得た。
(Example 3-1)
Iron (powder, 110 mg), BTC (280 mg), nitric acid (15.6 M, 80 μl), and water (10 ml) were added to a closed glass container, and reacted in an explosion-proof oven at 95 ° C. for 24 hours. After completion of the reaction, the vessel was air-cooled to room temperature, and then a solid was recovered by centrifugation. The obtained solid was washed with water (15 ml) five times in total, and then heated in an explosion-proof oven at 60 ° C. After the heating was completed, the vessel was air-cooled to room temperature, and washed with DMF (15 ml) five times in total and ethanol (15 ml) three times in total. And centrifugation was performed to remove unreacted raw materials. Subsequently, drying was performed at 100 ° C. and 2 mmHg for 24 hours to obtain a metal organic framework.
（実施例３−２）
鉄（粉末、１１０ｍｇ）をクロム（粉末、１００ｍｇ）に変更した以外は実施例３−１と同様に合成した。
(Example 3-2)
Synthesis was performed in the same manner as in Example 3-1 except that iron (powder, 110 mg) was changed to chromium (powder, 100 mg).
（実施例３−３）
鉄（粉末、１１０ｍｇ）をアルミニウム（粉末、１００ｍｇ）に変更した以外は実施例３−１と同様に合成した。
(Example 3-3)
Synthesis was performed in the same manner as in Example 3-1 except that iron (powder, 110 mg) was changed to aluminum (powder, 100 mg).
得られた金属有機フレームワークの単結晶Ｘ線構造解析を行ったところ、いずれも、Ｚｒ、ＨｆまたはＦｅが３または６個集合してなる金属クラスターとリンカーとから構成されていることが確認された。それぞれの金属有機フレームワークの中心金属の金属原子数を表１〜３に示す。 When a single crystal X-ray structure analysis of the obtained metal organic framework was performed, it was confirmed that each of the metal organic frameworks was composed of a metal cluster composed of three or six Zr, Hf or Fe and a linker. Was. Tables 1 to 3 show the number of metal atoms of the central metal of each metal organic framework.
金属有機フレームワークの評価結果を表１〜３に示す。 Tables 1 to 3 show the evaluation results of the metal organic framework.
中心金属とリンカーの分子量が１，０００未満である実施例１−１−１、１−１−２、１−１−３、１−２〜１−１８、実施例２−１−１、２−１−２、２−１−３、２−２〜２−１５、および、実施例３−１〜３−３を備えた第一の手段と、透析膜（カットオフ分子量：５００−１０００）を備えた第二の手段と、を有するシステム中では、いずれも金属有機フレームワークの溶出量が１０ｐｐｍ以下に抑えられていた。
Claims (11)
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、分離膜のカットオフ分子量未満である、収着材料。 A sorption material comprising a metal-organic framework capable of capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological method,
A sorbent material, wherein the molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
少なくとも前記金属有機フレームワークの分解物である中心金属およびリンカーを除去するための分離膜を備えた第２の手段と、
を有する特定物質捕捉システムであって、
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、前記分離膜のカットオフ分子量未満である、システム。 First means comprising a sorption material comprising a metal-organic framework capable of capturing a specific substance from a liquid containing a dialysate, blood, plasma, or a crude product of a substance produced by biotechnological techniques When,
Second means comprising a separation membrane for removing at least a central metal and a linker which are decomposed products of the metal organic framework;
A specific substance capturing system having
The system wherein the molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
前記金属有機フレームワークを構成する中心金属およびリンカーの分子量が、分離膜のカットオフ分子量未満である、方法。 A specific substance capturing method for capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological technique using a sorption material including a metal organic framework. hand,
A method wherein the molecular weight of the central metal and the linker constituting the metal organic framework is less than the cut-off molecular weight of the separation membrane.
前記金属有機フレームワークの分解物である中心金属およびリンカーを、分離膜を用いて除去する膜分離工程と、
を含む、請求項１０記載の特定物質捕捉方法。 A specific substance capturing step of capturing a specific substance from a dialysate, blood, plasma, or a liquid containing a crude product of a substance manufactured by a biotechnological technique using a sorption material including a metal organic framework;
A membrane separation step of removing a central metal and a linker, which are decomposition products of the metal organic framework, using a separation membrane,
The method for capturing a specific substance according to claim 10, comprising:
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