JP2022028020A - Adsorbent for oral administration, and production method thereof - Google Patents
Adsorbent for oral administration, and production method thereof Download PDFInfo
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- JP2022028020A JP2022028020A JP2021207175A JP2021207175A JP2022028020A JP 2022028020 A JP2022028020 A JP 2022028020A JP 2021207175 A JP2021207175 A JP 2021207175A JP 2021207175 A JP2021207175 A JP 2021207175A JP 2022028020 A JP2022028020 A JP 2022028020A
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- adsorbent
- resin
- activated carbon
- oral administration
- carbon adsorbent
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Abstract
Description
本発明は、経口投与用吸着剤及びその製造方法に関し、特に、毒性物質の吸着速度を速めた経口投与用の吸着剤及びその製造方法に関する。 The present invention relates to an adsorbent for oral administration and a method for producing the same, and more particularly to an adsorbent for oral administration having an increased adsorption rate of toxic substances and a method for producing the same.
腎疾患または肝疾患の患者は、血液中に毒性物質が蓄積し、その結果として***や意識障害等の脳症を引き起こす。これらの患者数は年々増加する傾向にある。患者の治療には、毒性物質を体外へ除去する血液透析型の人工腎臓等が使用される。しかしながら、このような人工腎臓は、安全管理上から取り扱いに専門技術者を必要とし、また血液の体外への取り出しに際し、患者の肉体的、精神的、及び経済的負担を要することが問題視されており、必ずしも満足すべきものではない。 Patients with renal or liver disease accumulate toxic substances in their blood, resulting in encephalopathy such as uremia and impaired consciousness. The number of these patients tends to increase year by year. Hemodialysis-type artificial kidneys that remove toxic substances from the body are used to treat patients. However, such an artificial kidney requires a specialized technician for handling from the viewpoint of safety management, and it is regarded as a problem that it requires a physical, mental, and financial burden on the patient when removing blood from the body. It is not always satisfactory.
人工臓器に代わる方法として、経口により摂取し体内で毒性物質を吸着し、体外に排出する経口投与用吸着剤が開発されている（特許文献１、特許文献２等参照）。しかし、これらの吸着剤は、活性炭の吸着性能を利用した吸着剤であるため、除去すべき毒素の吸着容量や毒素の有用物質に対する選択吸着性が十分とはいえない。一般的に、活性炭の疎水性は高く、***の原因物質やその前駆物質に代表されるインドキシル硫酸、ＤＬ－β－アミノイソ酪酸、トリプトファン等の低分子量のイオン性有機化合物の吸着に適さないという問題点を内包している。 As an alternative method to artificial organs, an adsorbent for oral administration, which is taken orally, adsorbs toxic substances in the body, and is discharged to the outside of the body, has been developed (see Patent Document 1, Patent Document 2, etc.). However, since these adsorbents are adsorbents that utilize the adsorption performance of activated carbon, it cannot be said that the adsorption capacity of the toxin to be removed and the selective adsorption property of the toxin to useful substances are not sufficient. Generally, activated carbon has high hydrophobicity and is not suitable for adsorption of low molecular weight ionic organic compounds such as indoxyl sulfate, DL-β-aminoisobutyric acid, and tryptophan represented by the causative substance of uremia and its precursor. It contains the problem of.
そこで、活性炭吸着剤の問題点を改善するべく、原料物質として木質、石油系もしくは石炭系の各種ピッチ類等を使用し球状等の樹脂化合物を形成し、これらを原料とした活性炭からなる抗ネフローゼ症候群剤が報告されている（例えば、特許文献３参照）。前出の活性炭は、石油系炭化水素（ピッチ）等を原料物質とし、比較的粒径を均一にして、炭化、賦活により調製される。また、活性炭自体の粒径を比較的均一化するとともに、当該活性炭における細孔容積等の分布について調整を試みた経口投与用吸着剤が報告されている（特許文献４参照）。このように、薬用活性炭は、比較的粒径を均一にすることに伴い、腸内の流動性の悪さを改善し、同時に細孔を調整することにより当該活性炭の吸着性能の向上を図った。そこで、多くの軽度の慢性腎不全患者に服用されている。 Therefore, in order to improve the problem of the activated carbon adsorbent, various pitches of wood, petroleum or coal are used as the raw material to form a spherical resin compound, and the anti-nephrotic syndrome made of activated carbon using these as raw materials. Syndrome agents have been reported (see, for example, Patent Document 3). The above-mentioned activated carbon is prepared by carbonization and activation using petroleum-based hydrocarbons (pitch) or the like as a raw material and having a relatively uniform particle size. Further, an adsorbent for oral administration has been reported in which the particle size of the activated carbon itself is made relatively uniform and the distribution of the pore volume and the like in the activated carbon is adjusted (see Patent Document 4). As described above, the medicated activated carbon has improved the poor fluidity in the intestine as the particle size is relatively uniform, and at the same time, the adsorption performance of the activated carbon is improved by adjusting the pores. Therefore, it is taken by many patients with mild chronic renal failure.
薬用活性炭には、***の原因物質やその前駆物質に対する迅速かつ効率的な吸着が要求される。しかしながら、従来の薬用活性炭における細孔の調整は良好とはいえず、吸着性能も安定しなかった。そのため、一日当たりの服用量を多くしなければならない。特に、慢性腎不全患者は水分の摂取量を制限されていることから、少量の水分により嚥下することは患者にとって大変な苦痛となっていた。加えて、胃、小腸等の消化管においては、糖、タンパク質等の生理機能に不可欠な化合物及び腸壁より分泌される酵素等の種々物質の混在する環境である。その中において、***等の原因となる毒性物質、特には、窒素を含有する化合物を迅速に吸着し、そのまま便とともに体外に***する薬用の活性炭吸着剤が望まれていた。 Medicinal activated carbon is required to rapidly and efficiently adsorb the causative substance of uremia and its precursor. However, the adjustment of pores in the conventional medicated activated carbon was not good, and the adsorption performance was not stable. Therefore, the daily dose must be increased. In particular, since patients with chronic renal failure have limited water intake, swallowing with a small amount of water has been a great pain for the patients. In addition, in the digestive tract such as the stomach and small intestine, it is an environment in which compounds essential for physiological functions such as sugars and proteins and various substances such as enzymes secreted from the intestinal wall are mixed. Among them, a medicated activated carbon adsorbent that rapidly adsorbs toxic substances that cause uremia and the like, particularly nitrogen-containing compounds, and excretes them as they are with stool has been desired.
発明者は活性炭吸着剤の炭化前の原料、細孔の発達について精査した。その結果、活性炭の原料となる樹脂成分にフェノール樹脂を採用するとともに樹脂の組成を工夫することにより、樹脂炭化物由来の活性炭の細孔を好適に制御して、低分子量の含窒素化合物の迅速な吸着に好適な細孔分布を備えた活性炭を見出すに至った。 The inventor scrutinized the raw material of the activated carbon adsorbent before carbonization and the development of pores. As a result, by adopting a phenol resin as the resin component that is the raw material of the activated carbon and devising the composition of the resin, the pores of the activated carbon derived from the resin carbide can be appropriately controlled, and the low molecular weight nitrogen-containing compound can be rapidly controlled. We have found an activated carbon with a pore distribution suitable for adsorption.
本発明は、前記の点に鑑みなされたもので、フェノール樹脂に由来する活性炭において、フェノール樹脂中の樹脂組成を改良することにより、樹脂炭化物に生じる細孔中のマクロ孔の割合を高め、窒素を含有する低分子化合物を迅速に吸着可能な経口投与用吸着剤とその製造方法を提供する。 The present invention has been made in view of the above points. In activated carbon derived from a phenol resin, by improving the resin composition in the phenol resin, the proportion of macropores in the pores generated in the resin carbide is increased, and nitrogen is used. Provided are an adsorbent for oral administration capable of rapidly adsorbing a low molecular weight compound containing the above, and a method for producing the same.
すなわち、第１の発明は、ノボラック樹脂分とレゾール樹脂分を含有した複合フェノール樹脂の樹脂炭化物の活性炭吸着剤であって、前記活性炭吸着剤は粒状物ないし球状物であり、前記活性炭吸着剤の細孔直径７．５～１５０００ｎｍの範囲の水銀細孔容積値は０．２～０．５ｍＬ／ｇであり、前記活性炭吸着剤において、下記式（ｉ）にて示される細孔直径７．５～１５０００ｎｍの範囲の水銀細孔容積（ＶＭ）と細孔直径０．７～２．０ｎｍの範囲の窒素細孔容積（ＶＮ）との容積比（ＲＶ）は、０．２以上であり、前記活性炭吸着剤のＢＥＴ比表面積は８００ｍ２／ｇ以上であり、前記活性炭吸着剤の充填密度が０．３０～０．６０ｇ／ｍＬであることを特徴とする経口投与用吸着剤に係る。 That is, the first invention is an activated carbon adsorbent for a resin carbide of a composite phenol resin containing a novolak resin component and a resole resin component, wherein the activated carbon adsorbent is a granular substance or a spherical substance, and the activated carbon adsorbent is used. The mercury pore volume value in the range of the pore diameter of 7.5 to 15,000 nm is 0.2 to 0.5 mL / g, and the activated carbon adsorbent has a pore diameter of 7.5 represented by the following formula (i). The volume ratio ( RV ) between the mercury pore volume (VM) in the range of ~ 15000 nm and the nitrogen pore volume ( VN ) in the pore diameter range of 0.7 ~ 2.0 nm is 0.2 or more. The present invention relates to an adsorbent for oral administration, characterized in that the BET specific surface area of the activated carbon adsorbent is 800 m 2 / g or more, and the packing density of the activated carbon adsorbent is 0.30 to 0.60 g / mL. ..
第２の発明は、第１の発明において、前記複合フェノール樹脂の揮発分が５０％以下である経口投与用吸着剤に係る。 The second invention relates to the adsorbent for oral administration in which the volatile content of the composite phenol resin is 50% or less in the first invention.
第３の発明は、第２の発明において、前記活性炭吸着剤が、経口投与用腎疾患または経口投与用肝疾患のための治療剤または予防剤であることを特徴とする経口投与用吸着剤に係る。 A third aspect of the invention is an adsorbent for oral administration, wherein the activated carbon adsorbent is a therapeutic or prophylactic agent for a renal disease for oral administration or a liver disease for oral administration. Related.
第４の発明は、第１ないし３の発明に記載の経口投与用吸着剤の製造方法であって、フェノールと、ホルムアルデヒドと、酸性触媒とを混合しながら加熱してノボラック樹脂分を調製するノボラック樹脂合成工程と、フェノールと、ホルムアルデヒドと、塩基性触媒と、前記ノボラック樹脂生成工程により合成した前記ノボラック樹脂分とを混合しながら加熱して、レゾール樹脂分を合成するとともに前記ノボラック樹脂分も含有した複合フェノール樹脂を調製する複合フェノール樹脂調製工程と、前記複合フェノール樹脂を炭化して樹脂炭化物を得る炭化工程と、前記樹脂炭化物を賦活して活性炭吸着剤を得る賦活工程を有することを特徴とする経口投与用吸着剤の製造方法に係る。 The fourth invention is the method for producing an adsorbent for oral administration according to the first to third inventions, wherein a novolak resin component is prepared by heating while mixing phenol, formaldehyde, and an acidic catalyst. The resin synthesis step, phenol, formaldehyde, a basic catalyst, and the novolak resin component synthesized by the novolak resin production step are mixed and heated to synthesize a resol resin component and also contain the novolak resin component. It is characterized by having a composite phenol resin preparation step for preparing the compound phenol resin, a carbonization step for carbonizing the composite phenol resin to obtain a resin carbide, and an activation step for activating the resin carbide to obtain an activated carbon adsorbent. The present invention relates to a method for producing an adsorbent for oral administration.
第５の発明は、第４の発明において、下記式（ｉｉ）にて示される前記ノボラック樹脂分のフェノールの当量（ＰＮ）とホルムアルデヒドの当量（ＦＮ）との当量比（Ｒ１）が０．５～０．９である経口投与用吸着剤の製造方法に係る。 In the fifth invention, in the fourth invention, the equivalent ratio (R 1 ) of the phenol equivalent ( PN ) and the formaldehyde equivalent (F N ) of the novolak resin component represented by the following formula (ii) is The present invention relates to a method for producing an adsorbent for oral administration, which is 0.5 to 0.9.
第６の発明は、第４又は第５の発明において、下記式（ｉｉｉ）にて示される前記レゾール樹脂分のフェノールの当量（ＰＲ）とホルムアルデヒドの当量（ＦＲ）との当量比（Ｒ２）が１．１～１．８である経口投与用吸着剤の製造方法に係る。 The sixth invention is the equivalent ratio ( R ) of the equivalent of phenol ( PR ) and the equivalent of formaldehyde (FR) of the resol resin component represented by the following formula (iii) in the fourth or fifth invention. 2 ) relates to a method for producing an adsorbent for oral administration, wherein 2) is 1.1 to 1.8.
第７の発明は、第４ないし６の発明のいずれかにおいて、前記複合フェノール樹脂の揮発分が５０％以下である経口投与用吸着剤の製造方法に係る。 The seventh invention relates to any one of the fourth to sixth inventions, wherein the adsorbent for oral administration has a volatile content of 50% or less of the composite phenol resin.
第８の発明は、第４ないし７の発明のいずれかにおいて、前記複合フェノール樹脂調製工程中に乳化剤が添加される経口投与用吸着剤の製造方法に係る。 The eighth invention relates to the method for producing an adsorbent for oral administration to which an emulsifier is added during the composite phenol resin preparation step in any one of the fourth to seventh inventions.
第９の発明は、第４ないし８の発明のいずれかにおいて、前記複合フェノール樹脂が平均粒径２００～７００μｍの粒状物ないし球状物である経口投与用吸着剤の製造方法に係る。 A ninth aspect of the present invention relates to any one of the fourth to eighth inventions, wherein the composite phenol resin is a granular or spherical substance having an average particle size of 200 to 700 μm, and relates to a method for producing an adsorbent for oral administration.
第１０の発明は、第４ないし９の発明のいずれかにおいて、前記塩基性触媒が、アミン化合物である経口投与用吸着剤の製造方法に係る。 A tenth invention relates to a method for producing an adsorbent for oral administration in which the basic catalyst is an amine compound in any one of the fourth to ninth inventions.
第１の発明に係る経口投与用吸着剤によると、ノボラック樹脂分とレゾール樹脂分を含有した複合フェノール樹脂の樹脂炭化物の活性炭吸着剤であって、前記活性炭吸着剤は粒状物ないし球状物であり、前記活性炭吸着剤の細孔直径７．５～１５０００ｎｍの範囲の水銀細孔容積値は０．２～０．５ｍＬ／ｇであり、前記活性炭吸着剤において、下記式（ｉ）にて示される細孔直径７．５～１５０００ｎｍの範囲の水銀細孔容積（ＶＭ）と細孔直径０．７～２．０ｎｍの範囲の窒素細孔容積（ＶＮ）との容積比（ＲＶ）は、０．２以上であり、前記活性炭吸着剤のＢＥＴ比表面積は８００ｍ２／ｇ以上であり、前記活性炭吸着剤の充填密度が０．３０～０．６０ｇ／ｍＬであるため、フェノール樹脂に由来する活性炭において、フェノール樹脂中の樹脂組成を改良することにより樹脂炭化物に生じる細孔中のマクロ孔の割合を高めることができ、窒素を含有する低分子化合物を迅速に吸着可能な経口投与用吸着剤を得ることができる。 According to the adsorbent for oral administration according to the first invention, it is an activated carbon adsorbent of a resin carbide of a composite phenol resin containing a novolak resin component and a resole resin component, and the activated carbon adsorbent is a granular substance or a spherical substance. The mercury pore volume value in the range of the pore diameter of 7.5 to 15,000 nm of the activated carbon adsorbent is 0.2 to 0.5 mL / g, and is represented by the following formula (i) in the activated carbon adsorbent. The volume ratio ( RV ) between the mercury pore volume (VM) in the pore diameter range of 7.5 to 15,000 nm and the nitrogen pore volume ( VN ) in the pore diameter range of 0.7 to 2.0 nm is , 0.2 or more, the BET specific surface area of the activated carbon adsorbent is 800 m 2 / g or more, and the packing density of the activated carbon adsorbent is 0.30 to 0.60 g / mL, so that it is derived from a phenol resin. By improving the resin composition in the phenolic resin, the proportion of macropores in the pores generated in the resin carbide can be increased, and adsorption for oral administration can rapidly adsorb nitrogen-containing low molecular weight compounds. You can get the agent.
第２の発明に係る経口投与用吸着剤によると、第１の発明において、前記複合フェノール樹脂の揮発分が５０％以下であるため、揮発分の量が少なく活性炭吸着剤中の炭素量は増加し、より緻密な活性炭を得ることができる。 According to the adsorbent for oral administration according to the second invention, in the first invention, since the volatile content of the composite phenol resin is 50% or less, the amount of volatile content is small and the amount of carbon in the activated carbon adsorbent is increased. However, more dense activated carbon can be obtained.
第３の発明に係る経口投与用吸着剤によると、第１または２の発明において、前記活性炭吸着剤が、経口投与用腎疾患または経口投与用肝疾患のための治療剤または予防剤であるため、腎疾患または肝疾患の原因物質を選択的に吸着する効果が高く、治療剤または予防剤に相応しい。 According to the adsorbent for oral administration according to the third invention, in the first or second invention, the activated carbon adsorbent is a therapeutic agent or a preventive agent for a renal disease for oral administration or a liver disease for oral administration. , Has a high effect of selectively adsorbing the causative agent of renal disease or liver disease, and is suitable as a therapeutic agent or a preventive agent.
第４の発明に係る経口投与用吸着剤の製造方法によると、第１ないし３の発明に記載の経口投与用吸着剤の製造方法であって、フェノールと、ホルムアルデヒドと、酸性触媒とを混合しながら加熱してノボラック樹脂分を調製するノボラック樹脂合成工程と、フェノールと、ホルムアルデヒドと、塩基性触媒と、前記ノボラック樹脂生成工程により合成した前記ノボラック樹脂分とを混合しながら加熱して、レゾール樹脂分を合成するとともに前記ノボラック樹脂分も含有した複合フェノール樹脂を調製する複合フェノール樹脂調製工程と、前記複合フェノール樹脂を炭化して樹脂炭化物を得る炭化工程と、前記樹脂炭化物を賦活して活性炭吸着剤を得る賦活工程を有するため、フェノール樹脂中の樹脂組成を改良して樹脂炭化物に生じる細孔中のマクロ孔の割合を高めることができ、窒素を含有する低分子化合物を迅速に吸着可能な経口投与用吸着剤の製造方法を確立できる。 According to the method for producing an adsorbent for oral administration according to the fourth invention, the method for producing an adsorbent for oral administration according to the first to third inventions, in which phenol, formaldehyde, and an acidic catalyst are mixed. The resol resin is heated while mixing the novolak resin synthesis step of preparing the novolak resin component, phenol, formaldehyde, the basic catalyst, and the novolak resin component synthesized by the novolak resin production step. A composite phenol resin preparation step of synthesizing a component and preparing a composite phenol resin containing the novolak resin component, a carbonization step of carbonizing the composite phenol resin to obtain a resin carbide, and an activation of the resin carbide to adsorb active charcoal. Since it has an activation step for obtaining the agent, the resin composition in the phenol resin can be improved to increase the proportion of macropores in the pores generated in the resin carbide, and low molecular weight compounds containing nitrogen can be rapidly adsorbed. A method for producing an adsorbent for oral administration can be established.
第５の発明に係る経口投与用吸着剤の製造方法によると、第４の発明において、式（ｉｉ）にて示される前記ノボラック樹脂分のフェノールの当量（ＰＮ）とホルムアルデヒドの当量（ＦＮ）との当量比（Ｒ１）が０．５～０．９であるため、ノボラック樹脂分の合成に都合良い。 According to the method for producing an adsorbent for oral administration according to the fifth invention, in the fourth invention, the equivalent of phenol ( PN ) and the equivalent of formaldehyde ( FN ) of the novolak resin represented by the formula (ii). ) And the equivalent ratio (R 1 ) is 0.5 to 0.9, which is convenient for synthesizing the novolak resin component.
第６の発明に係る経口投与用吸着剤の製造方法によると、第４または第５の発明において、式（ｉｉｉ）にて示される前記レゾール樹脂分のフェノールの当量（ＰＲ）とホルムアルデヒドの当量（ＦＲ）との当量比（Ｒ２）が１．１～１．８であるため、レゾール樹脂分とノボラック樹脂分の量の割合は好ましくなる。 According to the method for producing an adsorbent for oral administration according to the sixth invention, in the fourth or fifth invention, the equivalent of phenol (PR) and the equivalent of formaldehyde of the resol resin represented by the formula (iii). Since the equivalent ratio ( R 2 ) to (FR) is 1.1 to 1.8, the ratio of the amount of the resol resin content to the amount of the novolak resin content is preferable.
第７の発明に係る経口投与用吸着剤の製造方法によると、第４ないし第６のいずれかの発明において、前記複合フェノール樹脂の揮発分が５０％以下であるため、揮発分の量が少なく活性炭吸着剤中の炭素量は増加し、より緻密な活性炭を得ることができる。 According to the method for producing an adsorbent for oral administration according to the seventh aspect of the invention, in any of the fourth to sixth inventions, the volatile content of the complex phenol resin is 50% or less, so that the amount of volatile matter is small. The amount of carbon in the activated carbon adsorbent increases, and more dense activated carbon can be obtained.
第８の発明に係る経口投与用吸着剤の製造方法によると、第４ないし第７のいずれかの発明において、前記複合フェノール樹脂調製工程中に乳化剤が添加されるため、反応液の表面張力は高まり、微小な液滴が生じて球状化は促進する。 According to the method for producing an adsorbent for oral administration according to the eighth aspect of the invention, in any of the fourth to seventh inventions, the emulsifier is added during the complex phenol resin preparation step, so that the surface tension of the reaction solution is high. It rises and produces fine droplets, which promotes spheroidization.
第９の発明に係る経口投与用吸着剤の製造方法によると、第４ないし第８のいずれかの発明において、前記複合フェノール樹脂が平均粒径２００～７００μｍの粒状物ないし球状物であるため、炭化の焼成に伴う体積減少を見越した大きさとなり、出来上がる活性炭吸着剤は経口投与の服用に適する大きさとなる。 According to the method for producing an adsorbent for oral administration according to the ninth aspect of the invention, in any of the fourth to eighth inventions, the composite phenol formaldehyde is a granular substance or a spherical substance having an average particle size of 200 to 700 μm. The size is expected to decrease in volume due to the firing of carbonization, and the resulting activated carbon adsorbent is of a size suitable for oral administration.
第１０の発明に係る経口投与用吸着剤の製造方法によると、第４ないし第９のいずれかの発明において、前記塩基性触媒が、アミン化合物であるため、安定した反応を得ることができる。 According to the method for producing an adsorbent for oral administration according to the tenth invention, in any of the fourth to ninth inventions, since the basic catalyst is an amine compound, a stable reaction can be obtained.
本発明の経口投与用吸着剤は、出発原料をフェノール樹脂とし、特に、ノボラック樹脂とレゾール樹脂の両方を含有した複合フェノール樹脂を炭化して樹脂炭化物とし、これを賦活することにより生じた活性炭吸着剤である。はじめに、図１の工程図を用い経口投与用吸着剤の出発原料となる複合フェノール樹脂の合成工程から説明する。 The adsorbent for oral administration of the present invention uses a phenol resin as a starting material, and in particular, carbonizes a composite phenol resin containing both a novolak resin and a resole resin to form a resin charcoal, and activates the activated carbon adsorption. It is an agent. First, the process of synthesizing the composite phenol resin, which is the starting material of the adsorbent for oral administration, will be described with reference to the process diagram of FIG.
はじめにフェノール樹脂の原料となるフェノールにホルムアルデヒドが添加、混合され、両分子の架橋形成目的の酸性触媒が添加される。攪拌されながらの８０ないし１００℃の加熱により脱水縮合反応が進む。この段階でノボラック樹脂分が調製される（「ノボラック樹脂合成工程」）。なお、生成樹脂分は適宜洗浄される。 First, formaldehyde is added and mixed with phenol, which is a raw material for phenol resin, and an acidic catalyst for the purpose of forming crosslinks between both molecules is added. The dehydration condensation reaction proceeds by heating at 80 to 100 ° C. while stirring. At this stage, the novolak resin component is prepared (“novolak resin synthesis step”). The produced resin component is appropriately washed.
次に、ノボラック樹脂合成工程により合成したノボラック樹脂分と、フェノール及びホルムアルデヒドが追加混合される。さらに、新たに投入されたフェノールとホルムアルデヒドの架橋形成目的の塩基性触媒が添加される。これらは攪拌されながらの８０ないし１００℃の加熱により脱水縮合反応が進み、新たに投入されたフェノールからレゾール樹脂分が合成される。そこで、当該工程にて合成されたレゾール樹脂分とともに、先の工程にて合成されたノボラック樹脂分も含有する複合フェノール樹脂が調製される（「複合フェノール樹脂調製工程」）。なお、生成樹脂分は適宜洗浄される。 Next, the novolak resin component synthesized by the novolak resin synthesis step is additionally mixed with phenol and formaldehyde. Further, a newly introduced basic catalyst for the purpose of forming a crosslink between phenol and formaldehyde is added. The dehydration condensation reaction proceeds by heating these at 80 to 100 ° C. while stirring, and the resol resin component is synthesized from the newly added phenol. Therefore, a composite phenol resin containing the resol resin component synthesized in the relevant step and the novolak resin component synthesized in the previous step is prepared (“composite phenol resin preparation step”). The produced resin component is appropriately washed.
前述の両工程にて使用のフェノールに代えて、水酸基を有する芳香族化合物も用いられる。例えば、クレゾール（ｏ－、ｍ－、ｐ－位）、ｐ－フェニルフェノール、キシレノール（２，５－、３，５－）、レゾルシノール、各種ビスフェノール等が挙げられる。 Instead of the phenol used in both steps described above, an aromatic compound having a hydroxyl group is also used. For example, cresol (o-, m-, p-position), p-phenylphenol, xylenol (2,5-, 3,5-), resorcinol, various bisphenols and the like can be mentioned.
前述の両工程にて使用のホルムアルデヒドに代えて、次のアルデヒド化合物も用いられる。アセトアルデヒド、ベンズアルデヒド、グリオキサール、フルフラール等が挙げられる。 The following aldehyde compounds are also used in place of the formaldehyde used in both steps described above. Examples thereof include acetaldehyde, benzaldehyde, glyoxal and furfural.
ノボラック樹脂合成工程に使用した酸性触媒は、無機酸、有機酸である。実施例はシュウ酸である。これに加えて、ギ酸等のカルボン酸、マロン酸等のジカルボン酸、塩酸、硫酸、リン酸等が酸性触媒として挙げられる。 The acidic catalyst used in the novolak resin synthesis step is an inorganic acid or an organic acid. An example is oxalic acid. In addition to this, carboxylic acids such as formic acid, dicarboxylic acids such as malonic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned as acidic catalysts.
複合フェノール樹脂調製工程において、レゾール樹脂分の合成に使用される塩基性触媒にはアミン化合物が使用される。アミン化合物はレゾール樹脂分の合成に多用され、安定した反応を得る上で好適である。実施例では、ヘキサメチレンテトラミン（ヘキサミン、１，３，５，７－テトラアザアダマンタン）、トリエチレンテトラミン（Ｎ，Ｎ’－ジ（２－アミノエチル）エチレンジアミン）が使用される。これらに加えて、水酸化ナトリウム、水酸化マグネシウム、炭酸ナトリウム、アンモニア等も塩基性触媒として挙げられる。複合フェノール樹脂調製工程にて添加される塩基性触媒の量は、当該工程中の総仕込量の５ないし１５重量％である。添加量は塩基性触媒の種類等に依存する。 In the complex phenol resin preparation step, an amine compound is used as the basic catalyst used for the synthesis of the resole resin component. Amine compounds are often used in the synthesis of resole resin components and are suitable for obtaining stable reactions. In the examples, hexamethylenetetramine (hexamine, 1,3,5,7-tetraazaadamantane) and triethylenetetramine (N, N'-di (2-aminoethyl) ethylenediamine) are used. In addition to these, sodium hydroxide, magnesium hydroxide, sodium carbonate, ammonia and the like can also be mentioned as basic catalysts. The amount of the basic catalyst added in the composite phenol resin preparation step is 5 to 15% by weight of the total amount charged in the step. The amount added depends on the type of basic catalyst and the like.
ノボラック樹脂合成工程におけるノボラック樹脂分の合成促進と、未反応物の低減から原料物質量は当量比（モル換算量）により規定される。ノボラック樹脂分の合成時のフェノールの当量（ＰＮ）とホルムアルデヒドの当量（ＦＮ）との当量比（Ｒ１）の関係は、前出の式（ｉｉ）より、０．５ないし０．９の範囲である。後記の実施例においても当該範囲であればノボラック樹脂分の合成に都合良い。当量比Ｒ１が０．５を下回る場合、フェノールの量が過少であり、同当量比Ｒ１が０．９を上回る場合、相対的にフェノールの量が過剰である。 The amount of the raw material is defined by the equivalent ratio (molar equivalent amount) from the promotion of the synthesis of the novolak resin component in the novolak resin synthesis step and the reduction of unreacted substances. The relationship between the equivalent ratio (R 1 ) of the equivalent of phenol ( PN ) and the equivalent of formaldehyde (F N ) during the synthesis of novolak resin is 0.5 to 0.9 from the above formula (ii). Is the range of. Even in the examples described later, if it is within the above range, it is convenient for synthesizing the novolak resin component. When the equivalent ratio R 1 is less than 0.5, the amount of phenol is too small, and when the equivalent ratio R 1 is more than 0.9, the amount of phenol is relatively excessive.
複合フェノール樹脂調製工程におけるレゾール樹脂分の合成促進と、未反応物の低減から原料物質量も当量比（モル換算量）により規定される。レゾール樹脂分の合成時のフェノールの当量（ＰＲ）とホルムアルデヒドの当量（ＦＲ）との当量比（Ｒ２）の関係は、前出の式（ｉｉｉ）より、１．１ないし１．８の範囲、より好ましくは１．１ないし１．６の範囲である。当該範囲に収斂すると、レゾール樹脂分とノボラック樹脂分の量の割合は好ましくなる。当量比Ｒ２が１．１を下回る場合、フェノールの量が過少であり、同当量比Ｒ２が１．８を上回る場合、相対的にフェノールの量が過剰である。当該当量比Ｒ１及びＲ２の範囲は好適なエマルジョン形成等を加味した範囲であり、後記の実施例の検証に基づく。 The amount of raw material is also defined by the equivalent ratio (molar equivalent) from the promotion of synthesis of the resol resin component in the complex phenol resin preparation step and the reduction of unreacted substances. The relationship between the equivalent ratio ( R 2 ) of the equivalent of phenol ( PR ) and the equivalent of formaldehyde (FR) during the synthesis of the resole resin content is 1.1 to 1.8 from the above formula (iii). , More preferably in the range of 1.1 to 1.6. When it converges within this range, the ratio of the amount of the resole resin content and the amount of the novolak resin content becomes preferable. When the equivalent ratio R 2 is less than 1.1, the amount of phenol is too small, and when the equivalent ratio R 2 is more than 1.8, the amount of phenol is relatively excessive. The range of the corresponding equivalent ratios R 1 and R 2 is a range in which suitable emulsion formation and the like are taken into consideration, and is based on the verification of the examples described later.
複合フェノール樹脂は、炭化及び賦活を経て樹脂炭化物、最終的に経口投与用の活性炭吸着剤となる。それゆえ、活性炭吸着剤は、口腔、食道、胃、十二指腸、小腸、大腸と消化管内を円滑に流動しながら***等の原因物質を吸着して、便とともに肛門から***される。そうすると、抵抗の少ない粒径ないし球形は、各種の消化管内の円滑な流動の便宜から望ましい形状である。この点に鑑み、炭化前の樹脂の段階から粒状物ないし球状物であることが望ましい。 The complex phenolic resin undergoes carbonization and activation to become a resin carbide, and finally an activated carbon adsorbent for oral administration. Therefore, the activated carbon adsorbent adsorbs causative substances such as urinary poison while smoothly flowing in the oral cavity, esophagus, stomach, duodenum, small intestine, large intestine and gastrointestinal tract, and is excreted from the anus together with stool. Then, the particle size or sphere with low resistance is a desirable shape for the convenience of smooth flow in various gastrointestinal tracts. In view of this point, it is desirable that the resin is granular or spherical from the stage of the resin before carbonization.
そこで、複合フェノール樹脂調製工程においては乳化剤が添加される。同工程にて調製される複合フェノール樹脂は、乳化剤の作用による分散により粒状物ないし球状物になる。乳化剤として、ヒドロキシエチルセルロース、アラビアガム（アラビアゴム）等の水溶性の多糖類が使用される。乳化剤は炭化水素化合物であるため、以降の炭化に際しても余分な残分は生じにくい。乳化剤の添加量は、複合フェノール樹脂調製工程における総仕込量の０．１ないし１重量％である。乳化剤の種類、反応条件により適宜増減される。 Therefore, an emulsifier is added in the composite phenol resin preparation step. The composite phenol resin prepared in the same step becomes granular or spherical due to dispersion by the action of the emulsifier. As the emulsifier, water-soluble polysaccharides such as hydroxyethyl cellulose and gum arabic (gum arabic) are used. Since the emulsifier is a hydrocarbon compound, excess residue is unlikely to be generated during subsequent carbonization. The amount of the emulsifier added is 0.1 to 1% by weight of the total amount charged in the composite phenol resin preparation step. The dose may be adjusted according to the type of emulsifier and reaction conditions.
乳化剤が添加されているため、複合フェノール樹脂調製工程中の加熱と攪拌を通じてエマルジョン化が進み、反応液中に粒状物ないし球状物となった複合フェノール樹脂（複合フェノール樹脂粒子）が生じる。乳化剤の添加によりフェノール等を含む反応液の表面張力は高まり、微小な液滴が生じて球状化は促進すると考えられる。当該複合フェノール樹脂の望ましい大きさは、平均粒径２００ないし７００μｍの粒状物ないし球状物である。当該範囲の粒径は、次述の炭化の焼成に伴う体積減少を見越した大きさである。かつ、出来上がる活性炭吸着剤は経口投与の服用に適する大きさとなる。 Since the emulsifier is added, emulsification proceeds through heating and stirring during the complex phenol resin preparation step, and a complex phenol resin (composite phenol resin particles) in the form of granules or spheres is produced in the reaction solution. It is considered that the addition of the emulsifier increases the surface tension of the reaction solution containing phenol and the like, produces fine droplets, and promotes spheroidization. The desired size of the composite phenol resin is a granular substance or a spherical substance having an average particle size of 200 to 700 μm. The particle size in this range is a size in anticipation of a volume decrease due to the firing of carbonization described below. In addition, the resulting activated carbon adsorbent has a size suitable for oral administration.
一連の工程から調製された複合フェノール樹脂（ノボラック樹脂分及びレゾール樹脂分含有の複合フェノール樹脂粒子）は、適宜の洗浄と乾燥後、図２の工程図に示す工程を経て樹脂炭化物となる。複合フェノール樹脂は、円筒状レトルト電気炉等の焼成炉内に収容され、炉内を窒素、アルゴン、ヘリウム等の不活性雰囲気下とし、３００ないし１０００℃、好ましくは４５０ないし７００℃において１ないし２０時間かけて炭化され、樹脂炭化物となる（「炭化工程」）。 The composite phenol resin (composite phenol resin particles containing novolak resin component and resole resin component) prepared from a series of steps becomes a resin carbide through the steps shown in the process diagram of FIG. 2 after appropriate washing and drying. The composite phenol resin is housed in a firing furnace such as a cylindrical retort electric furnace, and the inside of the furnace is placed under an inert atmosphere such as nitrogen, argon, and helium at 300 to 1000 ° C, preferably 450 to 700 ° C. It is carbonized over time to become a resin carbide (“carbonation process”).
炭化工程の後、樹脂炭化物は、ロータリー式外熱炉等の加熱炉等に収容され、７５０ないし１０００℃、好ましくは８００ないし１０００℃、さらには８５０ないし９５０℃において水蒸気賦活される（「賦活工程」）。賦活時間は生産規模、設備等によるものの、０．５ないし５０時間である。あるいは、二酸化炭素等のガス賦活も用いられる。賦活後の活性炭吸着剤は、希塩酸によって洗浄される。希塩酸洗浄後の活性炭吸着剤は、例えば、ＪＩＳ Ｋ １４７４（２０１４）に準拠したｐＨの測定により、ｐＨ５ないし７になるまで水洗される。 After the carbonization step, the resin carbide is housed in a heating furnace such as a rotary external heating furnace and is steam activated at 750 to 1000 ° C., preferably 800 to 1000 ° C., and further at 850 to 950 ° C. (“Activation step”). "). The activation time is 0.5 to 50 hours, although it depends on the production scale and equipment. Alternatively, gas activation such as carbon dioxide is also used. The activated carbon adsorbent after activation is washed with dilute hydrochloric acid. The activated carbon adsorbent after washing with dilute hydrochloric acid is washed with water until the pH reaches 5 to 7, for example, by measuring the pH according to JIS K 1474 (2014).
希塩酸の洗浄後、必要により活性炭吸着剤は、酸素及び窒素の混合気体中において加熱処理、水洗浄され、灰分等の不純物が取り除かれる。加熱処理により残留する塩酸分等は取り除かれる。そして、各処理を経ることにより活性炭吸着剤の表面酸化物量は調整される。酸洗浄後、賦活済みの樹脂炭化物に対する加熱処理を通じて、活性炭吸着剤の表面酸化物量は増加する。当該処理時の酸素濃度は０．１ないし２１体積％である。また、加熱温度は１５０ないし１０００℃、好ましくは４００ないし８００℃であり、１５分ないし２時間である。 After washing with dilute hydrochloric acid, if necessary, the activated carbon adsorbent is heat-treated and washed with water in a mixed gas of oxygen and nitrogen to remove impurities such as ash. The residual hydrochloric acid and the like are removed by the heat treatment. Then, the amount of surface oxide of the activated carbon adsorbent is adjusted by going through each treatment. After pickling, the amount of surface oxide of the activated carbon adsorbent increases through heat treatment of the activated resin carbide. The oxygen concentration during the treatment is 0.1 to 21% by volume. The heating temperature is 150 to 1000 ° C, preferably 400 to 800 ° C, and is 15 minutes to 2 hours.
賦活処理後、または賦活処理に続く加熱処理後の樹脂炭化物（活性炭吸着剤）は、篩別により平均粒子径１５０ないし５００μｍの粒状物ないし球状物の活性炭に選別されるのがよい。粒子径の調整及び分別により、活性炭吸着剤の吸着速度の一定化と吸着能力の安定化が図られる。粒子径の範囲特に限定されるものではないが、前記の範囲とすると、患者（服用者）の嚥下を円滑にするとともに活性炭吸着材の表面積を確保することができる。また、粒子径が揃えられると、消化管内での吸着性能は安定することができる。しかも、粒子の硬さを維持して経口投与後（服用後）の消化管内でさらに粉化することも抑制される。ゆえに、経口投与用吸着剤の活性炭の形状は好ましくは球状物である。ただし、製造に起因する真球度のばらつき等も許容されるため、粒状物も含められる。 The resin carbide (activated carbon adsorbent) after the activation treatment or after the heat treatment following the activation treatment is preferably sorted into granular or spherical activated carbon having an average particle diameter of 150 to 500 μm by sieving. By adjusting and separating the particle size, the adsorption rate of the activated carbon adsorbent can be stabilized and the adsorption capacity can be stabilized. The range of the particle size is not particularly limited, but if it is within the above range, the patient (taker) can swallow smoothly and the surface area of the activated carbon adsorbent can be secured. In addition, if the particle sizes are the same, the adsorption performance in the digestive tract can be stabilized. Moreover, the hardness of the particles is maintained, and further powdering in the gastrointestinal tract after oral administration (after administration) is suppressed. Therefore, the shape of the activated carbon of the adsorbent for oral administration is preferably spherical. However, since variations in sphericity due to manufacturing are allowed, granules are also included.
既述のとおり、ノボラック樹脂合成工程及び複合フェノール樹脂調製工程を経て調製された複合フェノール樹脂は、ノボラック樹脂分とレゾール樹脂分の両方の異なる形質のフェノール樹脂を含有している。フェノール樹脂の内、ノボラック樹脂は熱可塑性樹脂であり、レゾール樹脂は熱硬化性樹脂である。従って、炭化工程の加熱温度に複合フェノール樹脂粒子が曝露された際、当該複合フェノール樹脂粒子中のノボラック樹脂分とレゾール樹脂分では耐熱性、溶融温度、揮発量等が互いに相違する。そうすると、焼成に伴う炭化は一様となるよりも、むしろ複合フェノール樹脂粒子の炭化は不均質に進行すると考えられる。炭化時の加熱焼成により複合フェノール樹脂粒子中から樹脂成分は揮発する。この揮発を通じて樹脂炭化物に割れ目、亀裂等が生じると予想される。このため、複合フェノール樹脂の樹脂炭化物由来の活性炭吸着剤には相対的にマクロ孔（およそ５０ｎｍ以上）が発達しやすくなると考えられる。 As described above, the composite phenol resin prepared through the novolak resin synthesis step and the composite phenol resin preparation step contains phenol resins having different traits of both the novolak resin content and the resole resin content. Of the phenolic resins, the novolak resin is a thermoplastic resin and the resol resin is a thermosetting resin. Therefore, when the composite phenol resin particles are exposed to the heating temperature of the carbonization step, the heat resistance, melting temperature, volatile amount, etc. of the novolak resin content and the resole resin content in the composite phenol resin particles are different from each other. Then, it is considered that the carbonization of the composite phenol resin particles proceeds inhomogeneously rather than being uniform in the carbonization associated with the firing. The resin component volatilizes from the composite phenol resin particles by heating and firing during carbonization. It is expected that cracks, cracks, etc. will occur in the resin carbide through this volatilization. Therefore, it is considered that macropores (about 50 nm or more) are relatively likely to develop in the activated carbon adsorbent derived from the resin carbide of the composite phenol resin.
そこで、複合フェノール樹脂（複合フェノール樹脂粒子）中に占めるノボラック樹脂分（前者）とレゾール樹脂分（後者）の割合は、４０（前者）：６０（後者）ないし６０（前者）：４０（後者）の重量比の範囲が望ましく、さらには、概ね同重量ずつの重量比がより好ましい。一方の樹脂成分の割合が過少となると、樹脂炭化物由来の活性炭には相対的にマクロ孔の発達状況が悪くなり、所望の細孔設計は難しくなる。また、形状維持等も難しくなる。 Therefore, the ratio of the novolak resin content (the former) and the resole resin content (the latter) to the composite phenol resin (composite phenol resin particles) is 40 (the former): 60 (the latter) to 60 (the former): 40 (the latter). The range of the weight ratio of is desirable, and more preferably, the weight ratio of about the same weight is more preferable. If the proportion of one of the resin components is too small, the development of macropores becomes relatively poor in the activated carbon derived from the resin carbide, and the desired pore design becomes difficult. In addition, it becomes difficult to maintain the shape.
複合フェノール樹脂（複合フェノール樹脂粒子）から炭化を経て樹脂炭化物となり、さらに賦活を経て活性炭吸着剤に至る過程において、自明ながら揮発分の重量は減少する。そのため、揮発分の量が少ないほど活性炭吸着剤中の炭素量は増加し、より緻密な活性炭を得ることができる。そこで、複合フェノール樹脂（複合フェノール樹脂粒子）の揮発分は、５０％以下に抑制される。 In the process from the composite phenol resin (composite phenol resin particles) to the resin carbide through carbonization and further to the activated carbon adsorbent through activation, the weight of the volatile matter is obviously reduced. Therefore, as the amount of volatile matter decreases, the amount of carbon in the activated carbon adsorbent increases, and more dense activated carbon can be obtained. Therefore, the volatile content of the composite phenol resin (composite phenol resin particles) is suppressed to 50% or less.
複合フェノール樹脂（複合フェノール樹脂粒子）は分子中に芳香環構造を有しているため、炭化率は高まる。さらに賦活により表面積の大きな活性炭吸着剤が生じる。賦活後の活性炭吸着剤は、従来の木質やヤシ殻、石油ピッチ等の活性炭と比較しても、細孔径は小さく充填密度は高い。そのため、比較的小さい分子量（分子量が数十ないし数百の範囲）のイオン性有機化合物の吸着に適する。また、複合フェノール樹脂は従来の活性炭原料の木質等と比較して窒素、リン、ナトリウム、マグネシウム等の灰分が少なく単位質量当たりの炭素の比率は高い。このため、不純物の少ない活性炭吸着剤を得ることができる。 Since the composite phenol resin (composite phenol resin particles) has an aromatic ring structure in the molecule, the carbonization rate is increased. Further, activation produces an activated carbon adsorbent having a large surface area. The activated carbon adsorbent after activation has a smaller pore diameter and a higher packing density than conventional activated carbon such as wood, coconut shell, and petroleum pitch. Therefore, it is suitable for adsorption of ionic organic compounds having a relatively small molecular weight (molecular weight in the range of tens to hundreds). Further, the composite phenol resin has a lower ash content such as nitrogen, phosphorus, sodium and magnesium as compared with the wood of the conventional activated carbon raw material, and the ratio of carbon per unit mass is high. Therefore, an activated carbon adsorbent with few impurities can be obtained.
前述の製造方法から得られた活性炭吸着剤には、後記する実施例に掲げる肝機能障害や腎機能障害の原因物質を極力速やかに吸着すること、また比較的少ない服用量で十分な吸着性能を発揮することが求められる。具備すべき性質の調和範囲を見いだすべく、活性炭吸着剤は、〔１〕水銀細孔容積値、〔２〕容積比、〔３〕ＢＥＴ比表面積の指標で規定される。そして、後記する実施例の傾向等から明らかなとおり、各指標の好適な範囲値が導出される。なお、以下に記載する前記活性炭の物性等の測定方法及び諸条件等は、実施例において詳述する。 The activated carbon adsorbent obtained from the above-mentioned production method adsorbs the causative substances of hepatic dysfunction and renal dysfunction listed in the examples below as quickly as possible, and has sufficient adsorption performance with a relatively small dose. It is required to demonstrate. The activated carbon adsorbent is defined by an index of [1] mercury pore volume value, [2] volume ratio, and [3] BET specific surface area in order to find a harmonized range of properties to be provided. Then, as is clear from the tendency of the examples described later, suitable range values of each index are derived. The method for measuring the physical properties of the activated carbon and various conditions described below will be described in detail in Examples.
そして、活性炭吸着剤は粒状物ないし球状物であり、その平均粒子径は特に規定されないが、１５０ないし５００μｍであることが望ましい。粒子自体の大きさが前記の範囲であると、マクロ孔等の細孔が適宜に発達し、選択吸着性の面から好ましい。また、表面積が適当となるため、吸着速度や強度の面からも好ましい。そこで、平均粒径は前記の範囲が好適となり、好ましくは１５０ないし５００μｍ、より好ましくは３００ないし４００μｍである。 The activated carbon adsorbent is a granular substance or a spherical substance, and the average particle diameter thereof is not particularly specified, but it is preferably 150 to 500 μm. When the size of the particles themselves is within the above range, pores such as macropores are appropriately developed, which is preferable from the viewpoint of selective adsorption. Further, since the surface area is appropriate, it is preferable from the viewpoint of adsorption rate and strength. Therefore, the average particle size is preferably in the above range, preferably 150 to 500 μm, and more preferably 300 to 400 μm.
本明細書及び実施例における活性炭吸着剤及び複合フェノール樹脂粒子の平均粒径はレーザー回折・散乱法によって求めた粒度分布における積算値５０％における粒径とした。 The average particle size of the activated carbon adsorbent and the composite phenol form resin particles in the present specification and Examples is the particle size at an integrated value of 50% in the particle size distribution obtained by the laser diffraction / scattering method.
〔１〕水銀細孔容積（ＶＭ）は活性炭のメソ孔ないしマクロ孔の大きな細孔を評価する指標である。そこで、細孔直径７．５ないし１５０００ｎｍの範囲の水銀細孔容積は０．２ないし０．５ｍＬ／ｇである。すなわち、マクロ孔側を発達させることにより、吸着対象物質は速く活性炭吸着剤の内部に取り込まれる。水銀細孔容積が０．２ｍＬ／ｇを下回る場合、マクロ孔は発達不足となる。水銀細孔容積０．５ｍＬ／ｇはフェノール樹脂由来の活性炭の上限と考えられる。従って、同値を上限とし、前記の水銀細孔容積の値の範囲とした。 [1] Mercury pore volume ( VM ) is an index for evaluating large pores of meso-pores or macropores of activated carbon. Therefore, the mercury pore volume in the pore diameter range of 7.5 to 15,000 nm is 0.2 to 0.5 mL / g. That is, by developing the macropore side, the substance to be adsorbed is quickly taken into the inside of the activated carbon adsorbent. If the mercury pore volume is less than 0.2 mL / g, the macropores are underdeveloped. The mercury pore volume of 0.5 mL / g is considered to be the upper limit of activated carbon derived from phenol resin. Therefore, the same value was set as the upper limit, and the range of the value of the mercury pore volume was set.
〔２〕容積比（ＲＶ）は、前掲の式（ｉ）にて示されるとおり０．２以上である。同式（ｉ）の容積比（ＲＶ）は、細孔直径７．５ないし１５０００ｎｍの範囲（マクロ孔）の水銀細孔容積（ＶＭ）を、細孔直径０．７ないし２．０ｎｍの範囲（ミクロ孔）の窒素細孔容積（ＶＨ）により除した商である。すなわち、ミクロ孔に比してマクロ孔の割合が高いことを示す指標である。活性炭のような吸着剤の場合、ミクロ孔、メソ孔、マクロ孔のいずれの細孔も存在している。その中で、いずれの範囲の細孔をより多く発達させるかにより、活性炭吸着剤の吸着対象、性能は変化する。本発明において所望される活性炭吸着剤は、***の原因物質やその前駆物質に代表されるインドキシル硫酸、アミノイソ酪酸、トリプトファン等の窒素を含有する低分子量のイオン性有機化合物の吸着を想定する。そして、本発明の活性炭吸着剤は、前記の吸着対象の分子を従前の活性炭吸着剤よりも速く吸着することである。 [2] The volume ratio ( RV ) is 0.2 or more as shown by the above-mentioned formula (i). The volume ratio ( RV ) of the same formula (i) is the mercury pore volume (VM) in the range of the pore diameter of 7.5 to 15,000 nm ( macropore ), and the pore diameter of 0.7 to 2.0 nm. It is a quotient divided by the nitrogen pore volume ( VH ) of the range (micropores). That is, it is an index showing that the ratio of macropores is higher than that of micropores. In the case of an adsorbent such as activated carbon, any of micropores, mesopores, and macropores is present. Among them, the adsorption target and performance of the activated carbon adsorbent change depending on which range of pores are developed more. The activated carbon adsorbent desired in the present invention assumes adsorption of low molecular weight ionic organic compounds containing nitrogen such as indoxyl sulfate, aminoisobutyric acid, and tryptophan represented by the causative substance of uremia and its precursor. .. The activated carbon adsorbent of the present invention is to adsorb the molecule to be adsorbed faster than the conventional activated carbon adsorbent.
マクロ孔側の割合が相対的に高められることにより、吸着対象は活性炭吸着剤内部へ容易に侵入できる。そして、吸着対象はマクロ孔に接続したミクロ孔に補足され、吸着は速く進む。通常、摂食から***までのうち、食物が消化により分解されて小腸内を流動する時間はおよそ６ないし１０時間と考えられる。つまり、小腸内を流動する間に経口投与用吸着剤（活性炭吸着剤）が目的の吸着対象である窒素を含有する低分子を吸着する必要がある。そこで、腸管内における効率良い吸着を勘案すると、短時間の吸着が望ましいといえる。このことから、活性炭吸着剤のマクロ孔側の細孔を多く発達させることには意味がある。後記の実施例に開示するように、容積比（ＲＶ）の数値が高まるほど、吸着速度は速まる。そこで、より詳細に見ると、容積比（ＲＶ）は０．２以上であれば優位差となり、さらには０．２７以上が好ましい。上限については、活性炭の構造上おそらく０．６付近と考えられる。 Since the ratio on the macropore side is relatively increased, the adsorption target can easily penetrate into the activated carbon adsorbent. Then, the adsorption target is captured by the micropores connected to the macropores, and the adsorption proceeds quickly. Usually, from feeding to excretion, it is considered that the time for food to be decomposed by digestion and flow in the small intestine is about 6 to 10 hours. That is, it is necessary for the adsorbent for oral administration (activated carbon adsorbent) to adsorb a small molecule containing nitrogen, which is the target adsorption target, while flowing in the small intestine. Therefore, considering efficient adsorption in the intestinal tract, it can be said that short-time adsorption is desirable. From this, it is meaningful to develop many pores on the macropore side of the activated carbon adsorbent. As disclosed in the examples below, the higher the value of the volume ratio ( RV ), the faster the adsorption rate. Therefore, when viewed in more detail, if the volume ratio ( RV ) is 0.2 or more, there is a dominant difference, and more preferably 0.27 or more. The upper limit is probably around 0.6 due to the structure of activated carbon.
〔３〕ＢＥＴ比表面積の８００ｍ２／ｇ以上とは、吸着性能の点から活性炭吸着剤として必要とされる下限であり、好ましくは１６００ｍ２／ｇ以上、より好ましくは１８００ｍ２／ｇ以上に規定される。７００ｍ２／ｇよりも小さくなると、毒性物質の吸着性能が低下すると考えられるためである。ＢＥＴ比表面積が３０００ｍ２／ｇを超える場合、充填密度が悪化することに加えて細孔容積が大きくなることから活性炭吸着剤自体の強度が悪化し易くなる。そこで、３０００ｍ２／ｇが上限と考えられる。 [3] The BET specific surface area of 800 m 2 / g or more is the lower limit required as an activated carbon adsorbent from the viewpoint of adsorption performance, and is preferably 1600 m 2 / g or more, more preferably 1800 m 2 / g or more. Will be done. This is because it is considered that the adsorption performance of toxic substances deteriorates when it becomes smaller than 700 m 2 / g. When the BET specific surface area exceeds 3000 m 2 / g, the strength of the activated carbon adsorbent itself tends to deteriorate because the packing density deteriorates and the pore volume increases. Therefore, 3000 m 2 / g is considered to be the upper limit.
これらの指標に加えて、〔４〕平均細孔直径も加えられる。そこで、平均細孔直径は１．７ないし２．０ｎｍの範囲である。活性炭吸着剤の平均細孔直径が当該範囲内に調整されることにより、分子量数十ないし数百の比較的低分子のイオン性有機化合物の吸着は良好となる。同時に、活性炭吸着剤は分子量数千ないし数万の酵素、多糖類等の生体に必要な高分子化合物の吸着を抑制できる。活性炭吸着剤の平均細孔直径が２．０ｎｍを越える場合、酵素、多糖類等の高分子を吸着する細孔が多く存在してしまうため好ましくない。また、活性炭の平均細孔直径が１．７ｎｍ未満であると、細孔容積自体が減少し、吸着力を低下させるおそれがある。 In addition to these indicators, [4] average pore diameter is also added. Therefore, the average pore diameter is in the range of 1.7 to 2.0 nm. By adjusting the average pore diameter of the activated carbon adsorbent within the range, the adsorption of relatively low molecular weight ionic organic compounds having a molecular weight of several tens to several hundreds becomes good. At the same time, the activated carbon adsorbent can suppress the adsorption of high molecular weight compounds necessary for living organisms such as enzymes and polysaccharides having a molecular weight of several thousand to tens of thousands. When the average pore diameter of the activated carbon adsorbent exceeds 2.0 nm, there are many pores that adsorb polymers such as enzymes and polysaccharides, which is not preferable. Further, if the average pore diameter of the activated carbon is less than 1.7 nm, the pore volume itself may decrease and the adsorptive power may decrease.
〔５〕充填密度については、０．３ないし０．６ｇ／ｍＬに規定される。充填密度が０．３ｇ／ｍＬ未満の場合、服用量が増加し経口投与時に嚥下し難くなる。充填密度が０．６ｇ／ｍＬを超える場合、フェノール樹脂由来の活性炭としての選択吸着性が伴わなくなる。このようなことから、充填密度は前記の範囲が好適となり、好ましくは０．３９ないし０．４５ｇ／ｍＬである。 [5] The packing density is specified as 0.3 to 0.6 g / mL. If the filling density is less than 0.3 g / mL, the dose will increase and it will be difficult to swallow during oral administration. When the packing density exceeds 0.6 g / mL, the selective adsorption property as the activated carbon derived from the phenol resin is not accompanied. Therefore, the packing density is preferably in the above range, preferably 0.39 to 0.45 g / mL.
前述の物性を具備する活性炭吸着剤は、経口投与を目的とした薬剤であって、腎疾患または肝疾患の治療剤または予防剤となる。活性炭吸着剤の表面に発達した細孔内に疾患、慢性症状の原因物質が吸着、保持され、体外へ排出されることにより、症状悪化は要請され、病態改善につながる。さらに、先天的あるいは後天的に代謝異常またはそのおそれのある場合、予め活性炭吸着剤を内服することにより、疾患、慢性症状の原因物質の体内濃度は下げられる。そこで、症状悪化を防ぐ予防としての服用も考えられる。 The activated carbon adsorbent having the above-mentioned physical characteristics is a drug intended for oral administration, and is a therapeutic or prophylactic agent for renal disease or liver disease. By adsorbing and retaining the causative substances of diseases and chronic symptoms in the pores developed on the surface of the activated carbon adsorbent and discharging them to the outside of the body, deterioration of the symptoms is requested, leading to improvement of the pathological condition. Furthermore, if there is a congenital or acquired metabolic disorder or a possibility of such abnormality, the concentration of the causative substance of the disease or chronic symptom in the body can be lowered by taking the activated carbon adsorbent in advance. Therefore, it may be taken as a preventive measure to prevent worsening of symptoms.
腎疾患として、例えば、慢性腎不全、急性腎不全、慢性腎盂腎炎、急性腎盂腎炎、慢性腎炎、急性腎炎症候群、急性進行型腎炎症候群、慢性腎炎症候群、ネフローゼ症候群、腎硬化症、間質性腎炎、細尿管症、リポイドネフローゼ、糖尿病性腎症、腎血管性高血圧、高血圧症候群、あるいは前記の原疾患に伴う続発性腎疾患、さらに、透析前の軽度腎不全を挙げることができる。肝疾患として、例えば、劇症肝炎、慢性肝炎、ウイルス性肝炎、アルコール性肝炎、肝線維症、肝硬変、肝癌、自己免疫性肝炎、薬剤アレルギー性肝障害、原発性胆汁性肝硬変、振戦（しんせん）、脳症、代謝異常、機能異常を挙げることができる。 Examples of renal diseases include chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephritic syndrome, acute advanced nephritic syndrome, chronic nephritis syndrome, nephrotic syndrome, nephrotic syndrome, and interstitial nephritis. , Pyelonephritis, lipoid nephrotic syndrome, diabetic nephritis, renovascular hypertension, hypertension syndrome, or secondary renal disease associated with the primary disease, as well as mild renal failure before dialysis. Liver diseases include, for example, fulminant hepatitis, chronic hepatitis, viral hepatitis, alcoholic hepatitis, liver fibrosis, liver cirrhosis, liver cancer, autoimmune hepatitis, drug allergic liver disorder, primary biliary cirrhosis, and tremor. ), Encephalopathy, metabolic disorders, and dysfunction.
活性炭吸着剤を経口投与用吸着剤として使用する際の投与量は、年令、性別、体格または病状等に影響されるため一律の規定は難しい。しかし、一般にヒトを対象とする場合、活性炭吸着剤の重量換算で１日当り１～２０ｇ、２～４回の服用が想定される。活性炭吸着剤の経口投与用吸着剤は、散剤、顆粒剤、錠剤、糖衣錠、カプセル剤、懸濁剤、スティック剤、分包包装体、または乳剤等による形態、剤型で投与される。 When the activated carbon adsorbent is used as an adsorbent for oral administration, it is difficult to uniformly specify the dose because it is affected by age, gender, physique, medical condition, and the like. However, in general, when targeting humans, it is assumed that the activated carbon adsorbent is taken 1 to 20 g per day in terms of weight, 2 to 4 times. The adsorbent for oral administration of the activated carbon adsorbent is administered in the form or dosage form of powder, granule, tablet, sugar-coated tablet, capsule, suspension, stick, packaged package, emulsion or the like.
［ノボラック樹脂分の合成］
複合フェノール樹脂を調製するに際し、はじめに当量比（Ｒ１）の異なる３種類のノボラック樹脂分（Ｎｏｖ１，Ｎｏｖ２，Ｎｏｖ３）を合成した。実施例における「重量部」は「ｇ」と同義である。
[Synthesis of novolak resin]
In preparing the composite phenolic resin, first, three kinds of novolak resin components (Nov1, Nov2, Nov3) having different equivalent ratios ( R1 ) were synthesized. The "part by weight" in the examples is synonymous with "g".
・ノボラック樹脂分：Ｎｏｖ１
９０％フェノール１４００重量部、３７％ホルムアルデヒド（ホルマリン）７５３重量部、酸性触媒としてのシュウ酸６．５重量部を、攪拌機、還流冷却器を備えた２Ｌのセパラブルフラスコ内に投入して９０ないし１００℃で４時間反応した。反応終了後、反応容器内を減圧し、水分と及び未反応物を除去した。その後、９５℃まで昇温し、滴下漏斗により水を投入し低重合物を除去する操作を繰り返して洗浄した。こうして、「Ｎｏｖ１」のノボラック樹脂分を合成した。当該「Ｎｏｖ１」におけるフェノールの当量（ＰＮ）とホルムアルデヒドの当量（ＦＮ）との当量比（Ｒ１）は０．６９３であった。
-Novolak resin content: Nov1
1400 parts by weight of 90% phenol, 753 parts by weight of 37% formaldehyde (formalin), and 6.5 parts by weight of oxalic acid as an acidic catalyst are put into a 2 L separable flask equipped with a stirrer and a reflux condenser. The reaction was carried out at 100 ° C. for 4 hours. After completion of the reaction, the pressure inside the reaction vessel was reduced to remove water and unreacted substances. Then, the temperature was raised to 95 ° C., water was added using a dropping funnel, and the operation of removing the low polymer was repeated for washing. In this way, the novolak resin component of "Nov1" was synthesized. The equivalent ratio (R 1 ) of the equivalent of phenol ( PN) to the equivalent of formaldehyde (F N ) in the "Nov 1" was 0.693.
・ノボラック樹脂分：Ｎｏｖ２
反応原料を９０％フェノール１０８８重量部、３７％ホルムアルデヒド（ホルマリン）５００重量部、酸性触媒としてのシュウ酸４．９重量部に変更した以外は、Ｎｏｖ１と同様の条件下で反応して「Ｎｏｖ２」のノボラック樹脂分を合成した。当該「Ｎｏｖ２」におけるフェノールの当量（ＰＮ）とホルムアルデヒドの当量（ＦＮ）との当量比（Ｒ１）は０．５９２であった。
-Novolak resin content: Nov2
The reaction was carried out under the same conditions as Nov1 except that the reaction raw material was changed to 1088 parts by weight of 90% phenol, 500 parts by weight of 37% formaldehyde (formalin), and 4.9 parts by weight of oxalic acid as an acidic catalyst. Novolak resin content was synthesized. The equivalent ratio (R 1 ) of the equivalent of phenol ( PN) to the equivalent of formaldehyde (F N ) in the "Nov 2" was 0.592.
・ノボラック樹脂分：Ｎｏｖ３
反応原料を９０％フェノール１２００重量部、３７％ホルムアルデヒド（ホルマリン）８３８重量部、酸性触媒としてのシュウ酸５．４重量部に変更した以外は、Ｎｏｖ１と同様の条件下で反応して「Ｎｏｖ３」のノボラック樹脂分を合成した。当該「Ｎｏｖ３」におけるフェノールの当量（ＰＮ）とホルムアルデヒドの当量（ＦＮ）との当量比（Ｒ１）は０．９００であった。
-Novolak resin content: Nov3
The reaction was carried out under the same conditions as Nov1 except that the reaction raw material was changed to 1200 parts by weight of 90% phenol, 838 parts by weight of 37% formaldehyde (formalin), and 5.4 parts by weight of oxalic acid as an acidic catalyst. Novolak resin content was synthesized. The equivalent ratio (R 1 ) of the equivalent of phenol ( PN) to the equivalent of formaldehyde (F N ) in the "Nov 3" was 0.900.
［複合フェノール樹脂の調製（レゾール樹脂分の合成）］
ノボラック樹脂分（Ｎｏｖ１，Ｎｏｖ２，Ｎｏｖ３）のいずれかを含有するとともに、新たにレゾール樹脂分も合成して双方のフェノール樹脂を含有する複合フェノール樹脂（粒子）（実施例１ないし５）を調製した。
[Preparation of composite phenol resin (synthesis of resole resin)]
A composite phenol resin (particles) (Examples 1 to 5) containing any of the novolak resin components (Nov1, Nov2, Nov3) and also newly synthesizing a resole resin component to contain both phenol resins was prepared. ..
・複合フェノール樹脂：実施例１
ノボラック樹脂分（Ｎｏｖ１）１０８重量部、９０％フェノール１２０重量部、３７％ホルムアルデヒド（ホルマリン）１４０重量部、乳化剤としてのヒドロキシエチルセルロース１．６２重量部、水１４８重量部を、攪拌機、還流冷却器を備えた１Ｌのセパラブルフラスコ内に投入して７０℃で溶解した。次に、塩基性触媒としてのヘキサメチレンテトラミン３７．８重量部、水５６．７重量部を同セパラブルフラスコ内に投入し８０ないし９０℃を維持しながら３時間加熱して反応を進めた。その後、９５℃以上に加熱し４時間還流してレゾール樹脂分の合成とともに実施例１の複合フェノール樹脂を調製した。
-Composite phenolic resin: Example 1
108 parts by weight of novolak resin (Nov1), 120 parts by weight of 90% phenol, 140 parts by weight of 37% formaldehyde (formalin), 1.62 parts by weight of hydroxyethyl cellulose as an emulsifier, 148 parts by weight of water, a stirrer and a reflux cooler. It was put into a 1 L separable flask provided and melted at 70 ° C. Next, 37.8 parts by weight of hexamethylenetetramine and 56.7 parts by weight of water as a basic catalyst were placed in the same separable flask and heated for 3 hours while maintaining 80 to 90 ° C. to proceed with the reaction. Then, the compound phenol resin of Example 1 was prepared by heating to 95 ° C. or higher and refluxing for 4 hours to synthesize the resole resin component.
・複合フェノール樹脂：実施例２ないし５
実施例２ないし５の複合フェノール樹脂の調製に際しては、後出の表１に記載のノボラック樹脂分（Ｎｏｖ１，２，３）と量を選択するとともに、同表１に記載の反応原料、乳化剤、塩基性触媒の量を使用した。実施例２ないし５は、前述の実施例１と同様の条件により反応を行い調製した。実施例１ないし５の複合フェノール樹脂は、乳化剤により調製の工程を通じて粒状ないし球状となった。表１の平均粒子径が参照される。
-Composite phenolic resin: Examples 2 to 5
In the preparation of the composite phenolic resin of Examples 2 to 5, the novolak resin content (Nov1, 2, 3) and the amount shown in Table 1 below are selected, and the reaction raw materials, emulsifiers and emulsifiers shown in Table 1 below are selected. The amount of basic catalyst used. Examples 2 to 5 were prepared by carrying out a reaction under the same conditions as in Example 1 described above. The composite phenolic resins of Examples 1 to 5 became granular or spherical through the preparation step with an emulsifier. The average particle size in Table 1 is referenced.
・比較例１，２
比較例１及び２は、ノボラック樹脂分を含まずレゾール樹脂分のみのフェノール樹脂とした。比較例１では、９０％フェノール２００重量部、３７％ホルムアルデヒド（ホルマリン）２３３重量部、乳化剤としてのヒドロキシエチルセルロース０．６３重量部、水１００重量部を、攪拌機、還流冷却器を備えた１Ｌのセパラブルフラスコ内に投入して６０℃で溶解した。次に、塩基性触媒としてのヘキサメチレンテトラミン１６．２重量部、水１６．２重量部を同セパラブルフラスコ内に投入し８０ないし９０℃を維持しながら３時間加熱して反応を進めた。その後、９５℃以上に加熱し４時間還流してレゾール樹脂分を合成し比較例１を得た。
-Comparative examples 1 and 2
In Comparative Examples 1 and 2, a phenol resin containing only a resol resin and not containing a novolak resin was used. In Comparative Example 1, 200 parts by weight of 90% phenol, 233 parts by weight of 37% formaldehyde (formalin), 0.63 parts by weight of hydroxyethyl cellulose as an emulsifier, 100 parts by weight of water, 1 L of separa equipped with a stirrer and a reflux condenser It was put into a bull flask and melted at 60 ° C. Next, 16.2 parts by weight of hexamethylenetetramine and 16.2 parts by weight of water as a basic catalyst were placed in the same separable flask and heated for 3 hours while maintaining 80 to 90 ° C. to proceed with the reaction. Then, the mixture was heated to 95 ° C. or higher and refluxed for 4 hours to synthesize a resole resin component to obtain Comparative Example 1.
比較例２は、反応原料等を表２に記載の量に変更した。量の変更以外は比較例１と同様の条件により反応を行い合成した。比較例１及び２の樹脂も乳化剤の作用により調製の工程を通じて粒状ないし球状となった。表２の平均粒子径が参照される。 In Comparative Example 2, the reaction raw materials and the like were changed to the amounts shown in Table 2. The reaction was carried out under the same conditions as in Comparative Example 1 except that the amount was changed, and the cells were synthesized. The resins of Comparative Examples 1 and 2 also became granular or spherical through the preparation process due to the action of the emulsifier. Refer to the average particle size in Table 2.
［活性炭吸着剤の調製］
実施例１ないし５の複合フェノール樹脂と比較例１及び２のフェノール樹脂について、それぞれを円筒状のレトルト電気炉に収容し炉内を窒素により充たした後、６００℃まで１００℃／１時間で昇温し、６００℃を１時間維持して炉内のフェノール樹脂を炭化した。その後、フェノール樹脂の炭化物を９００℃に加熱し炉内に水蒸気を注入して９００℃で１時間維持して賦活した。賦活後、０．１％塩酸水溶液で洗浄して各実施例及び比較例の活性炭吸着剤を得た。
[Preparation of activated carbon adsorbent]
The composite phenolic resins of Examples 1 to 5 and the phenolic resins of Comparative Examples 1 and 2 were each housed in a cylindrical retort electric furnace, the inside of the furnace was filled with nitrogen, and then the temperature was raised to 600 ° C. in 100 ° C./1 hour. It was warmed and maintained at 600 ° C. for 1 hour to carbonize the phenolic resin in the furnace. Then, the carbide of the phenol resin was heated to 900 ° C., steam was injected into the furnace, and the mixture was maintained at 900 ° C. for 1 hour for activation. After activation, it was washed with a 0.1% aqueous hydrochloric acid solution to obtain activated carbon adsorbents of each Example and Comparative Example.
洗浄後の活性炭吸着剤について、ＪＩＳ Ｋ １４７４（２０１４）に記載の方法でｐＨを測定し、おおむねｐＨ５ないし７になるまで水洗した。水洗後の活性炭吸着剤をロータリー式外熱炉により窒素雰囲気中において６００℃で２時間加熱して、各実施例及び比較例に対応する活性炭吸着剤を得た。 The pH of the activated carbon adsorbent after washing was measured by the method described in JIS K 1474 (2014), and the mixture was washed with water until the pH became approximately 5 to 7. The activated carbon adsorbent after washing with water was heated at 600 ° C. for 2 hours in a nitrogen atmosphere in a rotary external heating furnace to obtain activated carbon adsorbents corresponding to each Example and Comparative Example.
［測定項目・測定方法］
実施例の複合フェノール樹脂及び比較例のフェノール樹脂、並びに実施例及び比較例の活性炭吸着剤に関し、揮発分（％）、ノボラック・レゾール重量比、平均粒子径（μｍ）、収率（％）、充填密度（ｇ／ｍＬ）、ＢＥＴ比表面積（ｍ２／ｇ）、平均細孔直径（ｎｍ）、水銀細孔容積（ＶＭ）（ｍＬ／ｇ）、窒素細孔容積（ＶＨ）、容積比（ＲＶ）を測定した。結果は表１及び２である。表２は関連する項目のみを表記した。
[Measurement items / measurement methods]
Volatile content (%), novolak-resole weight ratio, average particle size (μm), yield (%), with respect to the composite phenol resin of Examples and the phenol resin of Comparative Examples, and the activated carbon adsorbents of Examples and Comparative Examples. Filling density (g / mL), BET specific surface area (m 2 / g), average pore diameter (nm), mercury pore volume (VM) (mL / g), nitrogen pore volume (VH ) , volume The ratio ( RV ) was measured. The results are shown in Tables 1 and 2. Table 2 shows only related items.
〔揮発分〕
実施例の複合フェノール樹脂と比較例のフェノール樹脂の揮発分（％）の測定は、前述の「活性炭吸着剤の調製」において、当初の樹脂の重量と窒素雰囲気中での炭化後の重量を測定し、両者から炭化の前後の重量変化を求めた。樹脂は炭化すると重量は減少する。そこで当該重量減少は揮発による減少量とし、当初の樹脂重量からの割合とした。
[Vaporized content]
In the measurement of the volatile content (%) of the composite phenol resin of the example and the phenol resin of the comparative example, the weight of the initial resin and the weight after carbonization in a nitrogen atmosphere were measured in the above-mentioned "preparation of activated carbon adsorbent". Then, the weight change before and after carbonization was obtained from both. When the resin is carbonized, its weight decreases. Therefore, the weight reduction was taken as the amount of reduction due to volatilization, and was taken as the ratio from the initial resin weight.
〔ノボラック・レゾール重量比〕
ノボラック・レゾール重量比は、実施例の複合フェノール樹脂中に含有されたノボラック樹脂分とレゾール樹脂分の互いの重量を反応量から算定した比率である。
[Novolak / Resol weight ratio]
The novolak-resole weight ratio is a ratio calculated from the reaction amount by the mutual weight of the novolak resin content and the resol resin content contained in the composite phenol resin of the example.
〔平均粒径〕
実施例の複合フェノール樹脂及び比較例のフェノール樹脂、並びに活性炭吸着剤の平均粒子径（μｍ）は、株式会社島津製作所製のレーザー光散乱式粒度分布測定装置（ＳＡＬＤ３０００Ｓ）を使用して測定し、レーザー回折・散乱法によって求めた粒度分布における積算値５０％における粒径とした。
[Average particle size]
The average particle size (μm) of the composite phenol resin of the example, the phenol resin of the comparative example, and the activated charcoal adsorbent was measured using a laser light scattering type particle size distribution measuring device (SALD3000S) manufactured by Shimadzu Corporation. The particle size was set at an integrated value of 50% in the particle size distribution obtained by the laser diffraction / scattering method.
〔収率〕
収率（％）は、炭化前の樹脂段階の重量と、炭化、賦活、洗浄、篩別を終えて最終的に分取した活性炭吸着剤の重量を計測して減少量を求めた。そして、当初の樹脂重量からの割合とした。
〔yield〕
The yield (%) was determined by measuring the weight of the resin stage before carbonization and the weight of the activated carbon adsorbent finally separated after carbonization, activation, washing and sieving. Then, the ratio was taken from the initial resin weight.
〔充填密度〕
実施例及び比較例の活性炭吸着剤の充填密度（ｇ／ｍＬ）は、ＪＩＳ Ｋ １４７４（２０１４）に準拠して測定した。
[Filling density]
The packing densities (g / mL) of the activated carbon adsorbents of Examples and Comparative Examples were measured according to JIS K 1474 (2014).
〔ＢＥＴ比表面積〕
実施例及び比較例の活性炭吸着剤のＢＥＴ比表面積（ｍ２／ｇ）は、７７Ｋにおける窒素吸着等温線を日本ベル株式会社製，ＢＥＬＳＯＲＰ ｍｉｎｉにより測定し、ＢＥＴ法により求めた。
[BET specific surface area]
The BET specific surface area (m 2 / g) of the activated carbon adsorbents of Examples and Comparative Examples was determined by the BET method by measuring the nitrogen adsorption isotherm at 77K with BELSORP mini manufactured by Nippon Bell Co., Ltd.
〔平均細孔直径〕
実施例及び比較例の活性炭吸着剤の平均細孔直径（ｎｍ）は、細孔の形状を円筒形と仮定し、細孔容積（ｍＬ／ｇ）及び比表面積（ｍ２／ｇ）の値を用いて下記の（ｉｖ）式より求めた。
[Average pore diameter]
For the average pore diameter (nm) of the activated carbon adsorbents of Examples and Comparative Examples, the pore shape is assumed to be cylindrical, and the values of pore volume (mL / g) and specific surface area (m 2 / g) are used. It was obtained from the following equation (iv) using.
〔水銀細孔容積（ＶＭ）〕
実施例及び比較例の活性炭吸着剤の水銀細孔容積（ＶＭ）は、株式会社島津製作所製，オートポア９５００を使用し、接触角１３０°、表面張力４８４ダイン／ｃｍ（４．８４ｍＮ／ｍ）に設定し、細孔直径７．５ないし１５０００ｎｍの水銀圧入法による細孔容積値（ｍＬ／ｇ）を求めた。
[Mercury pore volume ( VM )]
For the mercury pore volume (VM) of the activated carbon adsorbents of Examples and Comparative Examples, Autopore 9500 manufactured by Shimadzu Corporation was used, the contact angle was 130 °, and the surface tension was 484 dynes / cm (4.84 mN / m). The pore volume value (mL / g) was determined by the mercury intrusion method having a pore diameter of 7.5 to 15,000 nm.
〔窒素細孔容積（ＶＨ）〕
実施例及び比較例の活性炭吸着剤の窒素細孔容積（ＶＨ）は、Ｇｕｒｖｉｔｓｃｈの法則を適用し、日本ベル株式会社製ＢＥＬＳＯＲＰｍｉｎｉを使用し、相対圧０．９５３における液体窒素換算した窒素吸着量（Ｖａｄｓ）を（ｖ）式から液体状態の窒素体積（ＶＨ）に換算して求めた。同方法は細孔直径０．７ないし２．０ｎｍの範囲を対象とした。（ｖ）式において、Ｍｇは吸着質の分子量（窒素：２８．０２０）、ρｇ（ｇ／ｃｍ３）は吸着質の密度（窒素：０．８０８）である。
[Nitrogen pore volume ( VH )]
For the nitrogen pore volume ( VH ) of the activated carbon adsorbents of Examples and Comparative Examples, the nitrogen adsorption amount converted to liquid nitrogen at a relative pressure of 0.953 using BELSORPmini manufactured by Nippon Bell Co., Ltd., applying Gurvitsch's law. (V ads ) was obtained by converting from the equation (v) into the nitrogen volume (V H ) in the liquid state. The method targeted a pore diameter range of 0.7 to 2.0 nm. In equation (v), Mg is the molecular weight of the adsorbent (nitrogen: 28.020), and ρ g ( g / cm 3 ) is the density of the adsorbent (nitrogen: 0.808).
〔容積比（ＲＶ）〕
容積比（ＲＶ）は、前出の式（ｉ）のとおり、水銀細孔容積（ＶＭ）を窒素細孔容積（ＶＨ）により除した商とした。
[Volume ratio ( RV )]
The volume ratio ( RV ) was the quotient obtained by dividing the mercury pore volume (VM) by the nitrogen pore volume ( VH ) as in the above formula (i).
［物性値に関する考察］
実施例１ないし５の複合フェノール樹脂の結果より、ノボラック樹脂分の合成段階において、フェノールの当量（ＰＮ）とホルムアルデヒドの当量（ＦＮ）との当量比（Ｒ１）は０．５ないし０．９範囲からの合成を確認した。実施例の複合フェノール樹脂の揮発分は、比較例のフェノール樹脂（レゾール樹脂分単独）よりも少ない。しかも、平均粒子径も総じて大きい傾向にある。実施例５については、投入量の増加と反応容器の大きさよりエマルジョン粒子の形成が左右されたと考える。
[Consideration on physical property values]
From the results of the composite phenol resins of Examples 1 to 5, the equivalent ratio (R 1 ) between the equivalent of phenol ( PN ) and the equivalent of formaldehyde (F N ) was 0.5 to 0 at the stage of synthesizing the novolak resin component. The synthesis from the 9.9 range was confirmed. The volatile content of the composite phenol resin of the examples is smaller than that of the phenol resin of the comparative example (resole resin content alone). Moreover, the average particle size tends to be large as a whole. In Example 5, it is considered that the formation of emulsion particles was influenced by the increase in the input amount and the size of the reaction vessel.
実施例１ないし５の活性炭吸着剤によると、水銀細孔容積（ＶＭ）は比較例よりも有意に大きく、同時に、容積比（ＲＶ）も大きい。すなわち、相対的にマクロ孔は多く発達したことを確認した。なお、ミクロ孔自体も窒素細孔容積（ＶＨ）の測定から、比較例と同等の数値である。それゆえ、ミクロ孔が減少していないことも確認した。 According to the activated carbon adsorbents of Examples 1 to 5, the mercury pore volume ( VM ) is significantly larger than that of the comparative example, and at the same time, the volume ratio ( RV ) is also large. That is, it was confirmed that relatively many macropores were developed. It should be noted that the micropores themselves have the same numerical values as the comparative examples from the measurement of the nitrogen pore volume ( VH ). Therefore, it was also confirmed that the micropores did not decrease.
実施例と比較例は何れもフェノール樹脂に起因する活性炭吸着剤であり、炭化焼成、賦活の条件は同一である。これにもかかわらず、実施例のマクロ孔の発達は顕著である。実施例は熱硬化性のレゾール樹脂分に加えて熱可塑性のノボラック樹脂分も含有する性状である。実施例の活性炭吸着剤のマクロ孔がより多く発達した原因として、複合フェノール樹脂に対する炭化焼成時において、樹脂成分の熱膨張（膨張率の相違）、揮発条件の相違等が複合的に重なり合い、活性炭表面の細孔に留まらず、活性炭の粒子内部に侵入する深さの細孔が生じたと推察する。 Both Examples and Comparative Examples are activated carbon adsorbents derived from phenol resin, and the conditions for carbonization firing and activation are the same. Nevertheless, the development of macropores in the examples is remarkable. Examples are properties that contain a thermoplastic novolak resin component in addition to a thermosetting resole resin component. The cause of the development of more macropores in the activated carbon adsorbent of the example is that the thermal expansion (difference in expansion rate) of the resin component, the difference in volatile conditions, etc., overlap in a complex manner during carbonization and firing of the composite phenol resin, and the activated carbon is activated carbon. It is presumed that not only the pores on the surface but also the pores with a depth that penetrates into the particles of activated carbon were generated.
また、実施例１ないし５の複合フェノール樹脂は、ノボラック・レゾール重量比を前者５０：後者５０の同重量を目標とした合成例である。このように双方の重量割合の揃った実施例ではマクロ孔の発達に有利に作用した。そこで、合成時の重量変動等を勘案して４０：６０ないし６０：４０の重量比の範囲を妥当と考える。 Further, the composite phenolic resins of Examples 1 to 5 are synthetic examples in which the novolak-resole weight ratio is the same as the former 50: the latter 50. In this way, in the examples in which the weight ratios of both were the same, it had an advantageous effect on the development of macropores. Therefore, the range of the weight ratio of 40:60 to 60:40 is considered to be appropriate in consideration of the weight fluctuation at the time of synthesis.
［吸着性能評価］
前述のとおり、実施例の複合フェノール樹脂の炭化、賦活の工程を経て調製した活性炭吸着剤はマクロ孔の相体割合が大きい。この点を踏まえ、発明者は、***等の原因となり得る窒素を含有する化合物に対する吸着性能の良否を検討した。そこで、含窒素低分子化合物から「インドール、インドール酢酸、インドキシル硫酸、及びトリプトファン」の４種類の物質を選択し、実施例１ないし５と、比較例１及び２の活性炭吸着剤について、当該４種の分子の吸着率（％）を経時的（１，２，３，２４時間経過時点）に測定した。これと併せて、２４時間経過時点の吸着率の半分量の吸着率となる経過時間も求めた。吸着率の結果は表３ないし表６である。
[Evaluation of adsorption performance]
As described above, the activated carbon adsorbent prepared through the steps of carbonization and activation of the composite phenol resin of the example has a large phase ratio of macropores. Based on this point, the inventor examined the quality of adsorption performance for nitrogen-containing compounds that can cause uremia and the like. Therefore, four kinds of substances "indole, indole acetic acid, indoxyl sulfate, and tryptophan" were selected from the nitrogen-containing low molecular weight compounds, and the activated carbon adsorbents of Examples 1 to 5 and Comparative Examples 1 and 2 were referred to as the 4th. The adsorption rate (%) of the seed molecule was measured over time (after 1, 2, 3, 24 hours). At the same time, the elapsed time, which is half the adsorption rate at the time of 24 hours, was also determined. The results of the adsorption rate are shown in Tables 3 to 6.
インドール、インドール酢酸、インドキシル硫酸、及びトリプトファンの４種類の吸収率については、ｐＨ７．４のリン酸緩衝液に前記の物質をそれぞれ溶解して１０ｍｇ／ｄＬの濃度の標準溶液を調製した。各物質の標準溶液を溶出試験用ベッセルに５００ｍＬずつ注ぎ３７℃に調温した。そして、各実施例及び比較例の活性炭吸着剤を０．１ｇずつ投入して、攪拌しながら経時的に分取した。分取試料の２７９ｎｍの吸光度を測定して、標準溶液の吸光度の差から吸着率（％）を算出した。 For the absorption rates of the four types of indole, indole acetic acid, indoxyl sulfate, and tryptophan, the above substances were dissolved in a phosphate buffer solution having a pH of 7.4 to prepare a standard solution having a concentration of 10 mg / dL. A standard solution of each substance was poured into a vessel for elution test by 500 mL each, and the temperature was adjusted to 37 ° C. Then, 0.1 g of the activated carbon adsorbents of each Example and Comparative Example were added, and the mixture was separated over time while stirring. The absorbance at 279 nm of the sample was measured, and the adsorption rate (%) was calculated from the difference in the absorbance of the standard solution.
［吸着性能の結果・考察］
実施例１ないし５の活性炭吸着剤は、吸着性能評価に供した４種類の含窒素化合物の何れについて、どの時点においても、比較例１及び２よりも高い吸着性能を発揮した。特に、初期段階において迅速に吸着性能を発現した。吸着速度（時間）の指標からも明らかである。この結果より、実際の投与後の消化管内においても迅速な吸着が進み、体外への***が期待できる。そこで、活性炭吸着剤は腎機能、肝機能障害等の治療、予防に有効な経口投与用吸着剤となり得る。
[Results / discussion of adsorption performance]
The activated carbon adsorbents of Examples 1 to 5 exhibited higher adsorption performance than Comparative Examples 1 and 2 at any time point for any of the four nitrogen-containing compounds used for the adsorption performance evaluation. In particular, the adsorption performance was rapidly developed in the initial stage. It is also clear from the index of adsorption rate (time). From this result, rapid adsorption proceeds even in the gastrointestinal tract after the actual administration, and excretion to the outside of the body can be expected. Therefore, the activated carbon adsorbent can be an effective oral adsorbent for the treatment and prevention of renal function, liver dysfunction and the like.
本発明の経口投与用吸着剤は、経口投与により消化器官に達し、***、腎機能、肝機能障害等の原因となる窒素を含有する化合物を迅速に吸着できることから、治療剤または予防剤として有望である。また本発明の経口投与用吸着剤の製造方法は、活性炭吸着剤におけるマクロ孔を効率良く発達できることから、吸収速度の高い活性炭を得ることができる。
The adsorbent for oral administration of the present invention reaches the digestive organs by oral administration and can rapidly adsorb nitrogen-containing compounds that cause uremia, renal function, hepatic dysfunction, etc., and thus can be used as a therapeutic or prophylactic agent. Promising. Further, in the method for producing an adsorbent for oral administration of the present invention, since macropores in the activated carbon adsorbent can be efficiently developed, activated carbon having a high absorption rate can be obtained.
Claims (10)
前記活性炭吸着剤は粒状物ないし球状物であり、
前記活性炭吸着剤の細孔直径７．５～１５０００ｎｍの範囲の水銀細孔容積値は０．２～０．５ｍＬ／ｇであり、
前記活性炭吸着剤において、下記式（ｉ）にて示される細孔直径７．５～１５０００ｎｍの範囲の水銀細孔容積（ＶＭ）と細孔直径０．７～２．０ｎｍの範囲の窒素細孔容積（ＶＮ）との容積比（ＲＶ）は、０．２以上であり、
前記活性炭吸着剤のＢＥＴ比表面積は８００ｍ２／ｇ以上であり、
前記活性炭吸着剤の充填密度が０．３０～０．６０ｇ／ｍＬである
ことを特徴とする経口投与用吸着剤。
The activated carbon adsorbent is a granular substance or a spherical substance, and is
The mercury pore volume value in the range of the pore diameter of 7.5 to 15,000 nm of the activated carbon adsorbent is 0.2 to 0.5 mL / g.
In the activated carbon adsorbent, the mercury pore volume ( VM ) in the pore diameter range of 7.5 to 15,000 nm and the nitrogen fine particle in the pore diameter range of 0.7 to 2.0 nm represented by the following formula (i). The volume ratio ( RV ) with the hole volume ( VN ) is 0.2 or more.
The BET specific surface area of the activated carbon adsorbent is 800 m 2 / g or more.
An adsorbent for oral administration, wherein the activated carbon adsorbent has a filling density of 0.30 to 0.60 g / mL.
フェノールと、ホルムアルデヒドと、酸性触媒とを混合しながら加熱してノボラック樹脂分を調製するノボラック樹脂合成工程と、
フェノールと、ホルムアルデヒドと、塩基性触媒と、前記ノボラック樹脂生成工程により合成した前記ノボラック樹脂分とを混合しながら加熱して、レゾール樹脂分を合成するとともに前記ノボラック樹脂分も含有した複合フェノール樹脂を調製する複合フェノール樹脂調製工程と、
前記複合フェノール樹脂を炭化して樹脂炭化物を得る炭化工程と、
前記樹脂炭化物を賦活して活性炭吸着剤を得る賦活工程を有する
ことを特徴とする経口投与用吸着剤の製造方法。 The method for producing an adsorbent for oral administration according to any one of claims 1 to 3.
A novolak resin synthesis step that prepares a novolak resin component by heating while mixing phenol, formaldehyde, and an acidic catalyst.
A composite phenol resin containing phenol, formaldehyde, a basic catalyst, and the novolak resin synthesized in the novolak resin production step while being mixed and heated to synthesize a resole resin and also containing the novolak resin. Complex phenol resin preparation process to prepare and
A carbonization step of carbonizing the composite phenol resin to obtain a resin carbide, and
A method for producing an adsorbent for oral administration, which comprises an activation step of activating the resin carbide to obtain an activated carbon adsorbent.
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| JP2001114852A (en) * | 1999-10-18 | 2001-04-24 | Gun Ei Chem Ind Co Ltd | Method for producing globular phenol resin |
| JP2006117523A (en) * | 2002-06-03 | 2006-05-11 | Sanyo Chem Ind Ltd | Porous carbon material |
| JP2011037749A (en) * | 2009-08-10 | 2011-02-24 | Mylan Seiyaku Ltd | Orally administered adsorbent having excellent adsorption property |
| JP2011083758A (en) * | 2009-10-15 | 2011-04-28 | Chan Sieh Enterprises Co Ltd | Spherical active carbon and method for production thereof |
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| JP2001114852A (en) * | 1999-10-18 | 2001-04-24 | Gun Ei Chem Ind Co Ltd | Method for producing globular phenol resin |
| JP2006117523A (en) * | 2002-06-03 | 2006-05-11 | Sanyo Chem Ind Ltd | Porous carbon material |
| JP2011037749A (en) * | 2009-08-10 | 2011-02-24 | Mylan Seiyaku Ltd | Orally administered adsorbent having excellent adsorption property |
| JP2011083758A (en) * | 2009-10-15 | 2011-04-28 | Chan Sieh Enterprises Co Ltd | Spherical active carbon and method for production thereof |
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