WO2014129616A1 - Adsorbant pour administration par voie orale, médicament pour maladie rénale, et médicament pour maladie du foie - Google Patents

Adsorbant pour administration par voie orale, médicament pour maladie rénale, et médicament pour maladie du foie Download PDF

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WO2014129616A1
WO2014129616A1 PCT/JP2014/054263 JP2014054263W WO2014129616A1 WO 2014129616 A1 WO2014129616 A1 WO 2014129616A1 JP 2014054263 W JP2014054263 W JP 2014054263W WO 2014129616 A1 WO2014129616 A1 WO 2014129616A1
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activated carbon
spherical activated
bulk density
adsorbent
activation
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PCT/JP2014/054263
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English (en)
Japanese (ja)
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直弘 園部
尚志 若穂囲
恭弘 秋田
昌子 後藤
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株式会社クレハ
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • the present invention relates to an adsorbent for oral administration containing spherical activated carbon containing spherical activated carbon having different activation degrees (activation degrees).
  • the present invention also relates to a renal disease treatment or prevention agent, and a liver disease treatment or prevention agent comprising the above-mentioned adsorbent for oral administration as an active ingredient.
  • the adsorbent for oral administration according to the present invention has a high adsorbability for indoxyl sulfate, which is a toxic toxic substance (Toxin) in the body, and its precursor tryptophan in the presence of a high concentration of bile acid. Many toxic substances can be adsorbed during the residence period from ingestion to extracorporeal discharge.
  • Toxin toxic toxic substance
  • an oral adsorbent that can be taken orally and can treat renal or liver dysfunction has been developed and used (Patent Document 1).
  • the oral adsorbent consists of a porous spherical carbonaceous material (that is, spherical activated carbon) having a specific functional group, and is highly safe and stable to the living body. At the same time, it is toxic even in the presence of bile acids in the intestine.
  • Excellent selective adsorptive properties such as excellent adsorption of substances (ie ⁇ -aminoisobutyric acid, ⁇ -amino-n-butyric acid, dimethylamine, and octopamine) and less intestinal beneficial components such as digestive enzymes
  • substances ie ⁇ -aminoisobutyric acid, ⁇ -amino-n-butyric acid, dimethylamine, and octopamine
  • intestinal beneficial components such as digestive enzymes
  • the adsorbent described in Patent Document 1 was manufactured by preparing spherical activated carbon using pitches such as petroleum pitch as a carbon source, and then performing oxidation treatment and reduction treatment.
  • adsorbing toxic substances is a very important property, but especially in the intestinal environment, indoxyl sulfate, which is a toxic substance in chronic renal failure patients, and its precursors. It is important to adsorb and remove a certain tryptophan as quickly as possible. That is, a large amount of various substances are present in the human intestine, and in particular, a large amount of bile acid (15 mM) is present. Therefore, spherical activated carbon having an excellent ability to adsorb toxic substances in the small intestine where a large amount of bile acid is present is desirable.
  • An object of the present invention is to provide an adsorbent for oral administration capable of adsorbing a large amount of tryptophan or indoxyl sulfate in the presence of bile acid.
  • the present inventor has intensively developed an oral adsorbent capable of adsorbing and removing a large amount of harmful substances in the presence of a high concentration of bile acid, and has a low bulk density and a large specific surface area. It has been found that an oral adsorbent exhibiting an excellent adsorption ability even in the presence of bile acids can be obtained by the spherical activated carbon or the surface-modified spherical activated carbon. However, spherical activated carbon with a small bulk density has a drawback that the production cost is high because the carbonization yield is low.
  • activation distribution spherical activated carbon spherical activated carbons having different activation levels (which are distributed in activation levels) (hereinafter, sometimes referred to as “activation distribution spherical activated carbon”). It has been found that by using an adsorbent for oral administration, an adsorbent for oral administration showing further excellent adsorption ability can be obtained in the presence of bile acids.
  • the adsorbent for oral administration of the present invention has the same average bulk density and a conventionally known uniform bulk density spherical activated carbon, that is, a spherical activated carbon with no activation distribution (hereinafter referred to as “activation non-distributed spherical activated carbon”).
  • activation non-distributed spherical activated carbon a conventionally known uniform bulk density spherical activated carbon with no activation distribution
  • activation non-distributed spherical activated carbon a conventionally known uniform bulk density spherical activated carbon with no activation distribution
  • the average bulk density is 0.4 to 0.6 g / mL
  • the pore volume having a pore diameter of 1.5 to 2.0 nm determined by the SF method using the nitrogen adsorption method is expressed by the formula (1) y> 6 ⁇ 10 ⁇ 8 x 2 ⁇ 9 ⁇ 10 ⁇ 5 x + 0.0241 (1) [wherein y is a pore volume having a pore diameter of 1.5 to 2.0 nm determined by the SF method using a nitrogen adsorption method.
  • ML / g x represents a BET specific surface area (m 2 / g)]
  • spherical activated carbon an adsorbent for oral administration
  • the average bulk density is 0.4 to 0.6 g / mL, the spherical activated carbon having a bulk density exceeding the average bulk density is 5% by weight or more, and the spherical activated carbon having a bulk density less than the average bulk density is 5% by weight.
  • An adsorbent for oral administration comprising spherical activated carbon obtained by mixing, [3]
  • the spherical activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a surface unmodified spherical activated carbon having a total acidic group of less than 0.30 meq. [1] or [2 Or an adsorbent for oral administration, [4]
  • the surface-modified spherical activated carbon has a total acidic group of 0.30 meq / g to 1.20 meq / g and a total basic group of 0.20 meq / g to 0.9 meq / g.
  • Adsorbent for oral administration according to [5] An agent for treating or preventing renal disease, comprising as an active ingredient the adsorbent for oral administration according to any one of [1] to [4], or any one of [6] [1] to [4]
  • the present invention relates to an agent for treating or preventing liver diseases, which comprises an adsorbent for oral administration as an active ingredient.
  • a method for preventing or treating renal disease or liver disease comprising administering an effective amount of the adsorbent for oral administration according to any one of [1] to [4] to a subject to be treated for renal disease or liver disease, [9]
  • the average bulk density is 0.4 to 0.6 g / mL
  • the pore volume with a pore diameter of 1.5 to 2.0 nm determined by the SF method using the nitrogen adsorption method is expressed by the formula (1) y> 6 ⁇ 10 ⁇ 8 x 2 ⁇ 9 ⁇ 10 ⁇ 5 x + 0.0241 (1)
  • y represents the pore volume (mL / g) having a pore diameter of 1.5 to 2.0 nm determined by the SF method using the nitrogen adsorption method
  • x represents the BET specific surface area (m 2 / g).
  • the spherical activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a surface unmodified spherical activated carbon having a total acidic group of less than 0.30 meq [9] or [10].
  • the surface-modified spherical activated carbon has a total acidic group of 0.30 meq / g to 1.20 meq / g and a total basic group of 0.20 meq / g to 0.9 meq / g.
  • spherical activated carbon For the manufacture of a medicament for the prevention or treatment of kidney disease or liver disease, An average bulk density of 0.4 to 0.6 g / mL, 5% by weight or more of spherical activated carbon having a bulk density exceeding the average bulk density, and 5% by weight or more of spherical activated carbon having a bulk density less than the average bulk density.
  • the use of spherical activated carbon obtained by [15]
  • the spherical activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a surface non-modified spherical activated carbon having a total acidic group of less than 0.30 meq [13] or [14]
  • the surface-modified spherical activated carbon has a total acidic group of 0.30 meq / g to 1.20
  • spherical activated carbon For prevention or treatment of kidney disease or liver disease, An average bulk density of 0.4 to 0.6 g / mL, 5% by weight or more of spherical activated carbon having a bulk density exceeding the average bulk density, and 5% by weight or more of spherical activated carbon having a bulk density less than the average bulk density.
  • the use of spherical activated carbon obtained by [19]
  • the spherical activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a surface unmodified spherical activated carbon having a total acidic group of less than 0.30 meq.
  • the surface-modified spherical activated carbon has a total acidic group of 0.30 meq / g to 1.20 meq / g and a total basic group of 0.20 meq / g to 0.9 meq / g. [19] Use of the surface-modified spherical activated carbon described in Is disclosed.
  • the adsorbent for oral administration according to the present invention has a high ability to adsorb toxic substances in the presence of bile acids, it can adsorb toxic toxic substances very rapidly in the intestine. Therefore, it is effective as a therapeutic or preventive agent for renal diseases or a therapeutic or preventive agent for liver diseases.
  • the dose can be reduced over conventional adsorbents for oral administration.
  • the spherical activated carbon used in the adsorbent for oral administration according to the present invention can adsorb indoxyl sulfate and its precursor tryptophan at a high level in the presence of a high concentration of bile acid, and has a unit weight. Since a large amount of harmful substances can be adsorbed in the small intestine without increasing the hit volume, the volume taken by the patient can be reduced.
  • FIG. 3 is a graph showing the results of tryptophan adsorption tests of spherical activated carbons obtained in Examples 1 to 11 and Comparative Examples 1 to 5 in the presence of bile acids.
  • FIG. 6 is a graph showing the results of an indoxyl sulfate adsorption test in the presence of bile acids on the spherical activated carbon obtained in Examples 1 to 11 and Comparative Examples 1 to 5.
  • FIG. 5 is a graph showing the relationship between the BET specific surface area of the spherical activated carbon obtained in Examples 1 to 11 and Comparative Examples 1 to 5 and the pore volume having a pore diameter of 1.5 to 2.0 nm determined by the SF method. .
  • the adsorbent for oral administration of the present invention has an average bulk density of 0.4 to 0.6 g / mL, and a pore volume of 1.5 to 2.0 nm in pore diameter determined by the SF method based on the nitrogen adsorption method.
  • y represents the pore volume (mL / g) having a pore diameter of 1.5 to 2.0 nm determined by the SF method using the nitrogen adsorption method
  • x represents the BET specific surface area (m 2 / g). It is characterized by including spherical activated carbon satisfying
  • the spherical activated carbon used as the adsorbent for oral administration according to the present invention has an activation degree distribution.
  • physical properties related to the progress of activation can include bulk density or BET specific surface area.
  • spherical activated carbons having activation distributions can be obtained by mixing spherical activated carbons having different bulk densities.
  • Spherical activated carbon having this activation distribution is superior in the amount of adsorption of tryptophan and indoxyl sulfate in the presence of bile acids, compared to spherical activated carbon (Comparative Examples 2 to 4) not having the same bulk density activation distribution. Yes. That is, the spherical activated carbon having the activation distribution is superior in the amount of adsorption of tryptophan and indoxyl sulfate in the presence of bile acid as compared with the spherical activated carbon having no activation distribution (FIGS. 1 and 2). As shown in FIGS.
  • the surface unmodified spherical activated carbon having no activation distribution manufactured in Comparative Examples 1 to 5 increases the amount of tryptophan or indoxyl sulfate adsorbed as the bulk density decreases. .
  • the spherical activated carbon used as the adsorbent for oral administration according to the present invention has an activation degree distribution. Therefore, the amount of tryptophan adsorbed in a solution containing 100 mg / L of tryptophan in the presence of bile acids of the surface unmodified spherical activated carbon obtained in Examples 1 to 11 is expressed by the formula (4). y> -23375x 4 + 44075x 3 -27926x 2 + 6155.3x-120.8 (4) (wherein y represents the amount of tryptophan adsorbed and x represents the bulk density) Meet.
  • the upper limit of the amount of spherical activated carbon tryptophan adsorbed used in the adsorbent for oral administration of the present invention is not particularly limited, but the formula (5) y ⁇ ⁇ 640x 2 + 150x + 210.2 (5) (wherein y represents the amount of tryptophan adsorbed and x represents the bulk density) Those satisfying these conditions are preferred.
  • the amount of indoxyl sulfate adsorbed in a solution containing 100 mg / L of indoxyl sulfate in the presence of bile acids of the surface unmodified spherical activated carbon obtained in Examples 1 to 11 is expressed by the formula (6).
  • y ′ > ⁇ 4416.7x 4 + 8950x 3 ⁇ 6020.8x 2 + 1401x ⁇ 25.8 (6) (wherein y ′ represents indoxyl sulfate adsorption amount and x represents bulk density) Meet.
  • the upper limit of the amount of adsorbed spherical activated carbon indoxyl sulfate used in the adsorbent for oral administration of the present invention is not particularly limited, but the formula (7) y ⁇ ⁇ 235x 2 + 131.5x + 34.8 (7) (wherein y represents the amount of adsorbed indoxyl sulfate and x represents the bulk density) Those satisfying these conditions are preferred.
  • the surface non-modified spherical activated carbons obtained in Examples 1 to 11 satisfy the above formulas (4) and / or (6), and have the surface modification having the activation degree distribution produced in Examples 12 to 14.
  • Spherical activated carbon also satisfies the above formula (4) and / or (6).
  • the bile acid that coexists when measuring the amount of adsorbed tryptophan and adsorbed indoxyl sulfate is not limited, but sodium cholate can be used.
  • the concentration of bile acid is not limited, but 6458 mg can be dissolved in 1000 mL of purified water. It should be noted that bile acids other than sodium cholate (for example, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate) and tryptophan adsorption amount and indoxyl at concentrations other than 0.645 w / v%.
  • the amount of sulfuric acid adsorption can be measured.
  • the spherical activated carbon used as the adsorbent for oral administration according to the present invention has an activation degree distribution.
  • the spherical activated carbon used for the adsorbent for oral administration of the present invention has a pore volume of 1.5 to 2.0 nm in pore diameter determined by the SF method based on the nitrogen adsorption method.
  • y represents the pore volume (mL / g) having a pore diameter of 1.5 to 2.0 nm determined by the SF method using the nitrogen adsorption method, and x represents the BET specific surface area (m 2 / g). ] Is satisfied.
  • the pore volume determined by the SF method with a pore diameter of 1.5 to 2.0 nm is a pore volume classified as a micropore.
  • the spherical activated carbon used as the adsorbent for oral administration according to the present invention forms micropores by activation. As the carbon material is activated, the unstructured portion of the carbon material is selectively decomposed and consumed, and the closed fine pores in the carbon structure (between the carbon crystal bodies) are released. Simple pores (micropores) are formed. That is, as the activation progresses, the closed hole becomes an open hole, which becomes a micropore. Such micropores are formed only by the progress of activation and serve as an index indicating the degree of progress of activation.
  • the BET specific surface area is also a physical property value reflecting micropores, it is a physical property related to the progress of activation. Therefore, the relationship between the pore volume of the pore diameter of 1.5 to 2.0 nm with respect to the BET specific surface area is a good indicator of the progress of activation.
  • the surface non-modified spherical activated carbon having no activation distribution manufactured in Comparative Examples 1 to 5 has a finer diameter with a pore diameter of 1.5 to 2.0 nm as the BET specific surface area increases. The pore volume increases synergistically.
  • the spherical activated carbon used as the adsorbent for oral administration according to the present invention has an activation degree distribution.
  • the pore volume of the pore diameter of 1.5 to 2.0 nm with respect to the BET specific surface area of the surface non-modified spherical activated carbon obtained in Examples 1 to 11 is expressed by the formula (1).
  • y represents the pore volume (mL / g) having a pore diameter of 1.5 to 2.0 nm determined by the SF method using the nitrogen adsorption method
  • x represents the BET specific surface area (m 2 / g).
  • the relational expression of the pore volume of the pore diameter of 1.5 to 2.0 nm with respect to the BET specific surface area, which is an index indicating the degree of progression of activation, is a quadratic function, it has the activation degree distribution in the present invention.
  • the spherical activated carbon that does not satisfy the formula (8) satisfies the formula (1). That is, the surface non-modified spherical activated carbon having a distribution in the activation degree used for the adsorbent for oral administration of the present invention is SF compared to the surface non-modified spherical activated carbon having no distribution in the activation degree.
  • the pore volume with a pore diameter of 1.5 to 2.0 nm required by the method is high (FIG. 3).
  • the surface-modified spherical activated carbon having the activation degree distribution produced in Examples 12 to 14 also satisfies the above formula (1).
  • “the spherical activated carbon has a distribution in activation degree” means that the spherical activated carbon satisfies the condition of the formula (1), and more specifically, the same BET specific surface area.
  • the pore volume having a pore diameter of 1.5 to 2.0 nm determined by the SF method is high.
  • a spherical activated carbon having an activation distribution can be obtained by mixing spherical activated carbon having no activation distribution.
  • the pore volume of the spherical activated carbon used in the present invention with a pore diameter of 1.5 to 2.0 nm is y> 6 ⁇ 10 ⁇ 8 x 2 ⁇ 9 ⁇ 10 ⁇ 5 x + 0.0241 (where y is the pore diameter) Represents a pore volume (mL / g) of 1.5 to 2.0 nm, and x represents a BET specific surface area (m 2 / g), and more preferably y> 6 ⁇ 10 ⁇ 8 x 2 ⁇ .
  • the upper limit of the pore volume with a pore diameter of 1.5 to 2.0 nm with respect to the BET specific surface area is not particularly limited, but y ⁇ 8 ⁇ 10 ⁇ 22 x 2 + 0.0001x ⁇ 0.1057 (wherein , Y represents a pore volume (mL / g) having a pore diameter of 1.5 to 2.0 nm, and x represents a BET specific surface area (m 2 / g).
  • a pore volume having a pore diameter of 1.5 to 2.0 nm can be measured by a nitrogen adsorption method, and includes a Saito-Foley method (hereinafter referred to as “SF method”), a Horverth-Kawazoe method, and Density. Although it can be analyzed by the Functional Theory method or the like, in the present invention, the pore volume obtained by the SF method for analysis is used assuming that the pore shape is cylindrical.
  • SF method Saito-Foley method
  • Horverth-Kawazoe method Horverth-Kawazoe method
  • Density Density
  • Surface non-modified spherical activated carbon is a porous body obtained by performing an activation treatment after heat-treating a carbon precursor, and is a spherical body that has not been subjected to surface modification treatment by oxidation treatment and reduction treatment after activation treatment.
  • the surface non-modified spherical activated carbon means a spherical activated carbon having a total acidic group of less than 0.30 meq / g.
  • the total acidic group is preferably 0.25 meq / g or less, more preferably 0.20 meq / g or less.
  • the surface-modified spherical activated carbon is obtained by heat-treating the carbon precursor, performing activation treatment, and then performing surface modification treatment by oxidation treatment, or surface modification treatment by oxidation treatment and reduction treatment. It is a porous body and can exhibit an appropriate interaction with acids and bases. From the viewpoint of the constitution of the functional group, the surface-modified spherical activated carbon means a spherical activated carbon having an acid point of 0.30 meq / g or more.
  • a surface-modified spherical activated carbon having a total acidic group of 0.30 to 1.20 meq / g and a total basic group of 0.20 to 0.9 meq / g is water-soluble such as DL- ⁇ -aminoisobutyric acid. It is preferable because of its high ability to adsorb sex toxins.
  • the total acidic group is preferably 0.30 to 1.00 meq / g
  • the total basic group is preferably 0.30 to 0.70 meq / g.
  • the average bulk density of the spherical activated carbon used in the present invention is 0.40 g / mL to 0.60 g / mL, more preferably 0.42 g / mL to 0.58 g / mL, and most preferably 0.45 g / mL. mL to 0.55 g / mL. If the bulk density exceeds 0.60 g / mL, the amount of adsorbed indoxyl sulfate and tryptophan decreases, which is not preferable.
  • the average bulk density means “bulk density of spherical activated carbon including spherical activated carbon having different activation degrees”.
  • the bulk density of spherical activated carbon obtained by mixing two or more spherical activated carbons having different bulk densities prepared by a conventional method can be referred to as an average bulk density.
  • the measurement method is not different from the usual bulk density measurement method.
  • the bulk density ⁇ B is a value obtained by dividing the dry weight W (g) of the spherical activated carbon when the container is filled with the spherical activated carbon by the volume V (mL) of the spherical activated carbon charged, Can be obtained from the following formula.
  • the bulk density of the spherical activated carbon is a good index indicating the degree of activation. That is, it shows that activation is progressing, so that a bulk density is small.
  • relatively small pores are formed at the initial stage of activation, and the pore diameter increases as the activation proceeds, resulting in a decrease in bulk density.
  • the manufacturing method of the spherical activated carbon used for the adsorbent for oral administration of this invention is not limited as long as it has activation distribution, it can manufacture, for example by the method of mixing the spherical activated carbon from which activation levels differ.
  • the spherical activated carbon used in the present invention can be produced by mixing two or more types of spherical activated carbon having no activation distribution prepared by a conventional method, that is, non-distributed spherical activated carbon. Therefore, the spherical activated carbon can be produced by mixing 5% by weight or more of spherical activated carbon having a bulk density exceeding the average bulk density and 5% by weight or more of spherical activated carbon having a bulk density less than the average bulk density. is there.
  • the activation reaction is a reaction that develops the pore structure of the carbon material and imparts pores, and the degree of activation is determined by the type and amount of raw materials, the type / composition / concentration of the activation reaction gas, the activation temperature, It can be controlled by the activation time. When the activation temperature, the activation time, and the concentration of the activation gas are activated so as to be uniform, the activation distribution does not occur.
  • the distributed spherical activated carbon used in the present invention can be prepared, for example, by mixing two or more non-distributed spherical activated carbons having different degrees of activation.
  • spherical activated carbon having a bulk density exceeding the average bulk density means a bulk density larger than the average bulk density of the distributed spherical activated carbon obtained by mixing two or more non-distributed spherical activated carbons having different bulk densities.
  • Means a spherical activated carbon having The difference between the bulk density of the spherical activated carbon exceeding the average bulk density and the average bulk density between the spherical activated carbon activated carbon of the present invention is not limited, but the lower limit is 0.0025 g / mL or more, preferably 0.8.
  • spherical activated carbon having a bulk density less than the average bulk density refers to an average bulk density of a distributed spherical activated carbon obtained by mixing two or more non-distributed spherical activated carbons having different bulk densities.
  • the difference between the bulk density of the spherical activated carbon less than the average bulk density and the average bulk density of the spherical activated carbon of the present invention is not limited, but the lower limit is 0.0025 g / mL or more, preferably 0.8. It is 005 g / mL or more, More preferably, it is 0.01 g / mL or more, More preferably, it is 0.02 g / mL, More preferably, it is 0.05 g / mL. Although an upper limit is not limited, it is 0.3 g / mL, Preferably it is 0.2 g / mL.
  • the distributed spherical activated carbon contains 5% by weight or more of spherical activated carbon having a bulk density exceeding the average bulk density, preferably 10% by weight or more, more preferably 15% by weight or more, and most preferably 20% by weight or more. Further, it contains 5% by weight or more of spherical activated carbon having a bulk density less than the average bulk density, preferably 10% by weight or more, more preferably 15% by weight or more, and most preferably 20% by weight or more.
  • the ratio of the amount of the spherical activated carbon having a bulk density exceeding the average bulk density and the amount of the spherical activated carbon having a bulk density less than the average bulk density is not particularly limited.
  • the ratio is suitably in the range of 1:99 to 99: 1.
  • it is preferably 20:80 to 80:20, more preferably 40:60 to 60:40, still more preferably 45:55 to 55:45, and most preferably 50: 50.
  • This mixing ratio is also applicable when three or more bulk density spherical activated carbons are mixed.
  • the distributed spherical activated carbon used in the present invention is a non-distributed spherical activated carbon having the same bulk density as the average bulk density in addition to the spherical activated carbon having a bulk density exceeding the average bulk density and the spherical activated carbon having a bulk density less than the average bulk density.
  • a non-distributed spherical activated carbon having a bulk density of 0.5 g / mL can be used to prepare a distributed spherical activity having an average bulk density of 0.5 g / mL.
  • the amount of the non-distributed spherical activated carbon added with the same bulk density is 90% by weight or less, preferably 80% by weight or less, more preferably 70% by weight or less based on the obtained distributed spherical activated carbon. Most preferably, it is 60% by weight or less.
  • the spherical activated carbon used for mixing is not limited, and the above-mentioned surface non-modified spherical activated carbon and surface modified spherical activated carbon can be used.
  • the effect of the present invention can be obtained by using a spherical activated carbon having a small bulk density as a “spherical activated carbon having a bulk density lower than the average bulk density”.
  • the bulk density of the surface non-modified spherical activated carbon used as “spherical activated carbon having a bulk density less than the average bulk density” is not limited, but is preferably 0.30 to 0.50 g / mL, and 0.30 to 0.46 g / mL. More preferred is mL.
  • the specific surface area of the surface non-modified spherical activated carbon is not limited, but the specific surface area determined by the BET method is preferably 1600 m 2 / g or more, and more preferably 2000 m 2 / g or more.
  • the pore volume of 20 to 10,000 nm of the surface unmodified spherical activated carbon is not limited, but is preferably 0.21 mL / g or less.
  • Spherical activated carbon having a micropore volume ratio (Vm) determined by the following formula is preferably 0.80 or more, and more preferably 1.0 or more. Further, the average particle diameter of the surface non-modified spherical activated carbon is not limited, but is preferably 50 to 200 ⁇ m.
  • the bulk density of the surface-modified spherical activated carbon used as “spherical activated carbon having a bulk density less than the average bulk density” is not limited, but is preferably 0.30 to 0.50 g / mL, and 0.30 to 0.46 g / mL. Is more preferable.
  • the specific surface area of the surface-modified spherical activated carbon is not limited, but the specific surface area determined by the BET method is preferably 1600 m 2 / g or more, and more preferably 1900 m 2 / g or more.
  • the pore volume of 20 to 10,000 nm of the surface unmodified spherical activated carbon is not limited, but is preferably 0.21 mL / g or less.
  • Spherical activated carbon having a micropore volume ratio (Vm) determined by the following formula is preferably 0.8 or more, and more preferably spherical activated carbon having a micropore volume ratio of 1.0 or more.
  • the average particle diameter of the surface non-modified spherical activated carbon is not limited, but is preferably 50 to 200 ⁇ m.
  • the specific surface area of the spherical activated carbon can be determined by the BET method or the Langmuir method.
  • the specific surface area of the spherical activated carbon used as the adsorbent for oral administration according to the present invention has a specific surface area (hereinafter sometimes abbreviated as “SSA”) determined by the BET method of 700 m 2 / g or more, more preferably 1200 m. 2 / g or more, particularly preferably 1600 m 2 / g or more, and most preferably 1900 m 2 / g or more.
  • SSA specific surface area
  • Spherical activated carbon with an SSA of less than 700 m 2 / g is not preferable because the adsorption performance of toxic substances in the presence of bile acids is reduced.
  • the upper limit of SSA is not particularly limited, SSA is preferably 3000 m 2 / g or less from the viewpoint of bulk density and strength.
  • the spherical activated carbon used for the adsorbent for oral administration of the present invention preferably has a pore volume of 20 to 10,000 nm in pore diameter of 0.21 mL / g or less, more preferably 0.20 mL / g or less, and still more preferably. Is 0.19 mL / g or less. If the pore volume with a pore diameter of 20 to 10,000 nm exceeds 0.21 mL / g, the amount of adsorption of useful substances such as digestive enzymes may increase, which is not preferable. Although a minimum is not specifically limited, 0.02 mL / g or more is preferable.
  • the spherical activated carbon used in the adsorbent for oral administration of the present invention has a pore volume of 7.5 to 15000 nm having a pore volume of 0.01 mL / g or more, preferably 0.05 mL / g or more, more preferably It is 0.08 mL / g or more, More preferably, it is 0.1 mL / g or more, Most preferably, it is 0.2 mL / g or more. Due to the large pore volume with a pore diameter of 7.5 to 15000 nm, the adsorption rate of toxic substances is excellent.
  • the upper limit of the pore volume having a pore diameter of 7.5 to 15000 nm is not particularly limited, but is preferably 1.0 mL / g or less. If the pore volume with a pore diameter of 7.5 to 15000 nm exceeds 1.0 mL / g, the amount of adsorption of useful substances such as digestive enzymes may increase, which is not preferable.
  • IUPAC defines pores of 2 nm or less as micropores, 2 to 50 nm as mesopores, and 50 nm or more as macropores.
  • the spherical activated carbon used as the adsorbent for oral administration according to the present invention mainly forms relatively small micropores by gas activation. The formation of the micropores reduces the density of the spherical activated carbon and increases the specific surface area, thereby increasing the adsorption performance of the toxic substance in the presence of bile acids.
  • the pore volume of micropores of 2 nm or less can be measured by a nitrogen adsorption method, and can be measured by the Saito-Foley method (hereinafter referred to as “SF method”), the Horverth-Kawazoe method, the Density Functional Theory method, or the like. In the present invention, it is assumed that the pore shape is cylindrical, and the pore volume obtained by the SF method for analysis is used.
  • SF method Saito-Foley method
  • micropore volume ratio When the micropore volume ratio is low, relatively large bile acid molecules cause pore occlusion, which is not preferable because adsorption of uremic substances and their precursors smaller than the molecular size is hindered. It is preferable because the micropore volume ratio is increased and relatively large bile acid molecules do not cause pore clogging and are excellent in adsorption of uremic substances having a smaller molecular size and their precursors.
  • the diameter of the spherical activated carbon used as the adsorbent for oral administration according to the present invention is not particularly limited, but is preferably 0.01 to 1 mm, more preferably 0.02 to 0.8 mm.
  • the diameter of the spherical activated carbon is less than 0.01 mm, the outer surface area of the spherical activated carbon increases, and adsorption of beneficial substances such as digestive enzymes tends to occur.
  • the diameter exceeds 1 mm the diffusion distance of the toxic substance into the spherical activated carbon increases, and the adsorption rate decreases, which is not preferable.
  • the average particle diameter means a particle diameter (Dv50) at a particle size accumulation ratio of 50% in a volume-based particle size accumulation diagram.
  • the range of the average particle diameter of the spherical activated carbon used as the adsorbent for oral administration according to the present invention is not particularly limited, but is 0.01 to 1 mm. If the average particle diameter of the spherical activated carbon is less than 0.01 mm, the outer surface area of the spherical activated carbon increases, and adsorption of beneficial substances such as digestive enzymes tends to occur.
  • the average particle diameter exceeds 1 mm, the diffusion distance of the toxic substance into the spherical activated carbon increases, and the adsorption rate decreases, which is not preferable.
  • the average particle diameter is preferably 0.02 to 0.8 mm, and the spherical activated carbon having an average particle diameter of 50 to 200 ⁇ m is particularly excellent in initial adsorption capacity, and within a general residence time in the upper small intestine, This is because toxic toxic substances in the living body can be adsorbed very quickly.
  • a more preferable range of the average particle diameter is 50 to 170 ⁇ m, and a further preferable range is 50 to 150 ⁇ m.
  • the spherical activated carbon used as the adsorbent for oral administration according to the present invention preferably has a narrow particle size distribution.
  • the ratio (D 4 / D 1 ) of the spherical activated carbon used as the adsorbent for oral administration according to the present invention is preferably 3 or less, more preferably 2 or less, still more preferably 1.5 or less.
  • D is the representative particle size of the measured particle size category
  • n is the number.
  • the total acidic group and total basic group of the spherical activated carbon used as the adsorbent for oral administration according to the present invention are not particularly limited. Especially in the case of a mixture of surface unmodified spherical activated carbon and surface modified spherical activated carbon, the amount of total acidic groups and total basic groups is not limited. However, when the spherical activated carbon is a surface non-modified spherical activated carbon, the total acidic group is preferably less than 0.30 meq / g.
  • the spherical activated carbon is a surface-modified spherical activated carbon
  • 0.30 meq / g or more is preferable
  • the total acidic group is 0.30 to 1.20 meq / g
  • the total basic group is 0.20 to More preferably, it is 0.9 meq / g.
  • Example 1 a steam atmosphere is set, the temperature is increased to 850 ° C. at a rate of 8 ° C. per minute, and the steam activation is performed by holding at 850 ° C. for 9 hours, but the activation distribution is not present. .
  • activated carbon having an activation distribution is excellent in the ability to adsorb toxic substances in the presence of a large amount of bile acids.
  • the activation distribution is not described at all, and it is clear from the description of the manufacture of the examples that the activation distribution is not generated.
  • Example 1 50 kg of a carbonaceous material is charged into a rotary furnace and activated in a 100% steam atmosphere at 950 ° C. for 13 hours, and non-distributed spherical activated carbons having different activation degrees are not mixed. It has no activation distribution.
  • activated carbon having an activation distribution is excellent in the ability to adsorb toxic substances in the presence of a large amount of bile acids.
  • the adsorbent for oral administration according to the present invention has such excellent effects is unknown at present, but it can also be estimated as follows.
  • the present invention is not limited to the following estimation.
  • Bile acid is a type of surfactant that helps absorb lipids that are difficult to dissolve in water. Therefore, in order for bile acids to form micelles of lipids, a concentration higher than the critical micelle concentration is necessary, and it exists in the human small intestine at a concentration of 15 mM at the time of satiety.
  • bile acids are sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, etc., which are medium molecules having a molecular weight of about 400 to 600.
  • the micelle size increases to several nanometers, compared to indoxyl sulfate and its precursor tryptophan, which are attracting attention as a toxic toxic substance (Toxin) in the body. Will be present in a large size.
  • an adsorbent for oral administration with a low bulk density, a large specific surface area, and a high pore volume with a pore diameter of 1.5 to 2.0 nm is effective.
  • the performance increases exponentially as the bulk density is lower, the specific surface area is higher, and the pore volume with a pore diameter of 1.5 to 2.0 nm is higher.
  • the spherical activated carbon of the present invention does not have an activation degree distribution at the same average bulk density by having an activation degree distribution in a specific bulk density range and a specific surface area range that exponentially improve adsorption capacity. Compared to spherical activated carbon, it is considered to have an excellent effect of adsorbing toxic substances in the presence of bile acids without increasing the volume of administration.
  • the spherical activated carbon used as the adsorbent for oral administration of the present invention can use any carbon-containing material as a carbon source.
  • the carbon-containing material that can be used for example, synthetic resin or pitch can be used.
  • the synthetic resin a heat-meltable resin or a heat-infusible resin can be used.
  • the heat-meltable resin is a resin that melts and decomposes as the temperature rises when an activation process is performed without performing an infusibilization process, and is a resin from which activated carbon cannot be obtained.
  • the activation treatment is performed after the infusibilization treatment is performed in advance, the activated carbon can be obtained.
  • the heat infusible resin is a resin that can be activated without obtaining melting, and can be activated without melting as the temperature rises, even if the activation treatment is performed.
  • the infusibilization treatment is, for example, an oxidation treatment at 150 ° C. to 400 ° C. in an atmosphere containing oxygen, as will be described later.
  • thermoplastic resin examples thereof include a crosslinked vinyl resin.
  • thermofusible resin is a thermosetting resin, and examples thereof include a phenol resin and a furan resin.
  • thermoplastic resins or thermosetting resins any thermoplastic resin or thermosetting resin capable of forming a spherical body can be used.
  • the above-mentioned infusibilization treatment is required, whereas when obtaining spherical activated carbon from an ion exchange resin produced by adding a functional group to the cross-linked vinyl resin. Does not require the infusibilization process described above.
  • cross-linked vinyl resin is modified from the heat-meltable resin to the heat-infusible resin by the functional group imparting treatment or the introduced functional group. That is, the crosslinked vinyl resin is included in the heat-meltable resin in the present specification, whereas the ion exchange resin is included in the heat-infusible resin in the present specification.
  • the carbon source of the spherical activated carbon used in the present invention is not particularly limited, but it is preferable to use a synthetic resin because it is easy to handle.
  • the synthetic resin include thermosetting resins (for example, phenol resins and furan resins) and ion exchange resins that are thermofusible resins; and thermoplastic resins (for example, cross-linked vinyl resins) that are thermomeltable resins. be able to.
  • the thermosetting resin tends to form a hollow in the spherical activated carbon, and has a risk of being pierced into the intestine when crushed because the strength is weak.
  • ion exchange resins contain sulfur, etc., care is required when used for oral administration. Therefore, it is more preferable to use a thermoplastic resin (for example, a cross-linked vinyl resin) as the carbon source of the spherical activated carbon.
  • a heat-meltable resin for example, a cross-linked vinyl resin
  • an operation substantially similar to a conventional manufacturing method using pitches can be used.
  • the spherical body made of a heat-meltable resin is softened by heat treatment and deformed into a non-spherical shape, or the spherical bodies are fused with each other.
  • Softening can be suppressed by performing oxidation treatment at 150 ° C. to 400 ° C. using As the oxidizing agent, O 2 or a mixed gas obtained by diluting these with air or nitrogen can be used.
  • the cross-linked vinyl resin that is a heat-meltable resin is softened and melted by heat treatment in a non-oxidizing gas atmosphere and the carbonization yield is less than 10%, but in an atmosphere containing oxygen as an infusible treatment,
  • a spherical carbonaceous material can be obtained with a high carbonization yield of 30% or more by performing an oxidation treatment at 150 ° C. to 400 ° C. without being softened or melted. Obtainable.
  • pre-baking is performed appropriately before performing activation operation to remove the pyrolysis products in advance. can do.
  • a spherical activated carbon can be obtained by activation treatment at a temperature of 700 to 1000 ° C. in an air stream having reactivity with carbon (for example, steam or carbon dioxide gas).
  • activated carbon means a porous body obtained by heat treatment of a carbon precursor such as a spherical heat-meltable resin and then activation treatment
  • spherical activated carbon means spherical The specific surface area is 100 m 2 / g or more.
  • the average particle diameter of the spherical body of the heat-meltable resin used as a starting material is not particularly limited, but is preferably about 0.02 to 1.5 mm, more preferably 50 ⁇ m to 800 ⁇ m, and further preferably 70 ⁇ m to 500 ⁇ m. .
  • the crosslinked vinyl resin used as a starting material for example, a spherical polymer obtained by emulsion polymerization, bulk polymerization or solution polymerization, or preferably a spherical polymer obtained by suspension polymerization can be used.
  • a spherical polymer obtained by emulsion polymerization, bulk polymerization or solution polymerization, or preferably a spherical polymer obtained by suspension polymerization can be used.
  • a spherical crosslinked vinyl resin having a diameter of 50 ⁇ m or more uniformly it is indispensable to previously form pores in the crosslinked vinyl resin. Formation of pores in the resin is possible by adding porogen during polymerization.
  • the surface area of the cross-linked vinyl resin necessary for infusibilizing the cross-linked vinyl resin uniformly is preferably 10 m 2 / g or more, more preferably 50 m 2 / g or more.
  • a crosslinked vinyl resin is prepared by suspension polymerization
  • an organic phase containing a vinyl monomer, a crosslinking agent, a porogen and a polymerization initiator is added to an aqueous dispersion medium containing a dispersion stabilizer, and mixed by stirring.
  • a spherical crosslinked vinyl resin can be prepared.
  • any vinyl monomer that can be molded into a spherical shape can be used.
  • an aromatic vinyl monomer such as styrene, or a styrene derivative substituted with vinyl group hydrogen or phenyl group hydrogen.
  • a compound in which a heterocyclic or polycyclic compound is bonded to a vinyl group instead of a phenyl group can be used.
  • aromatic vinyl monomers include ⁇ - or ⁇ -methylstyrene, ⁇ - or ⁇ -ethylstyrene, methoxystyrene, phenylstyrene, or chlorostyrene, or o-, m-, or p-methylstyrene, ethylstyrene, methoxystyrene, methylsilylstyrene, hydroxystyrene, chlorostyrene, cyanostyrene, nitrostyrene, aminostyrene, carboxystyrene, sulfoxystyrene, sodium styrenesulfonate, or vinylpyridine , Vinyl thiophene, vinyl pyrrolidone, vinyl naphthalene, vinyl anthracene, or vinyl biphenyl.
  • Aliphatic vinyl monomers can also be used. Specifically, for example, vinyl esters such as ethylene, propylene, isobutylene, diisobutylene, vinyl chloride, acrylic acid ester, methacrylic acid ester, vinyl acetate, vinyl Vinyl ketones such as methyl ketone and vinyl ethyl ketone, vinyl aldehydes such as acrolein and methacrolein, vinyl ethers such as vinyl methyl ether or vinyl ethyl ether, vinyl nitriles such as acrylonitrile, ethyl acrylonitrile, diphenyl acrylonitrile and chloroacrylonitrile There can be mentioned.
  • vinyl esters such as ethylene, propylene, isobutylene, diisobutylene, vinyl chloride, acrylic acid ester, methacrylic acid ester, vinyl acetate, vinyl Vinyl ketones such as methyl ketone and vinyl ethyl ketone, vinyl aldehydes such as
  • any crosslinking agent that can be used for crosslinking of the above-mentioned vinyl monomers can be used.
  • crosslinking agents examples include polyvinyl aromatic hydrocarbons (eg, divinylbenzene), glycol trimethacrylate (eg, ethylene glycol dimethacrylate), or polyvinyl hydrocarbons (eg, trivinylcyclohexane). is there. Divinylbenzene is most preferred because of its excellent thermal decomposition characteristics.
  • Suitable porogens include alkanols having 4 to 10 carbon atoms (eg, n-butanol, sec-butanol, 2-ethylhexanol, decanol, or 4-methyl-2-pentanol), having at least 7 carbon atoms.
  • Alkyl esters eg, n-hexyl acetate, 2-ethylhexyl acetate, methyl oleate, dibutyl sebacate, dibutyl adipate, or dibutyl carbonate
  • alkyl ketones having 4 to 10 carbon atoms eg, dibutyl ketone
  • methyl isobutyl ketone or alkyl carboxylic acids (eg, heptanoic acid)
  • aromatic hydrocarbons eg, toluene, xylene, or benzene
  • higher saturated aliphatic hydrocarbons eg, hexane, heptane, or isooctane
  • Cycloaliphatic hydrocarbons eg If, cyclohexane
  • the polymerization initiator is not particularly limited, and those generally used in this field can be used, but an oil-soluble polymerization initiator that is soluble in the polymerizable monomer is preferable.
  • the polymerization initiator include dialkyl peroxide, diacyl peroxide, peroxyester, peroxydicarbonate, and azo compound.
  • dialkyl peroxides such as methyl ethyl peroxide, di-t-butyl peroxide, dicumyl peroxide; isobutyl peroxide, benzoyl peroxide, 2,4-dichlorobenzoyl peroxide, 3, Diacyl peroxide such as 5,5-trimethylhexanoyl peroxide; t-butyl peroxypivalate, t-hexyl peroxypivalate, t-butyl peroxyneodecanoate, t-hexylperoxyneodecanoate 1-cyclohexyl-1-methylethylperoxyneodecanoate, 1,1,3,3-tetramethylbutylperoxyneodecanoate, cumylperoxyneodecanoate, ( ⁇ , ⁇ -bis-neo Decanoyl peroxy) diisopropylbenzene -Oxyester; bis (4-
  • thermofusible resin for example, thermosetting resin or ion exchange resin
  • a conventional production method using pitches Substantially similar operations can be used. For example, first, a spherical body made of a heat infusible resin is activated at a temperature of 700 to 1000 ° C. in an air stream reactive with carbon (for example, steam or carbon dioxide) to obtain a spherical activated carbon. be able to.
  • the thermal decomposition product can be removed in advance.
  • the average particle diameter of the spherical body of the heat infusible resin used as a starting material is not particularly limited, but is preferably about 0.02 to 1.5 mm, more preferably 50 ⁇ m to 800 ⁇ m, and further 70 ⁇ m to 500 ⁇ m. preferable.
  • the heat infusible resin used as a starting material is a material capable of forming a spherical body, and it is important that it does not melt or soften during heat treatment at 500 ° C. or lower and does not cause shape deformation. .
  • the heat infusible resin used as a starting material desirably has a high carbonization yield by heat treatment. When the carbonization yield is low, the strength as the spherical activated carbon becomes weak. In addition, since unnecessary pores are formed, the bulk density of the spherical activated carbon is lowered, and the specific surface area per volume is lowered, so that the administration volume is increased and oral administration becomes difficult. Therefore, the higher the carbonization yield of the heat infusible resin, the better.
  • the preferable value of the yield by heat treatment at 800 ° C. in a non-oxidizing gas atmosphere is 30% by weight or more, more preferably 35% by weight or more. is there.
  • thermosetting resin used as a starting material examples include phenol resins, such as novolac type phenol resins, resol type phenol resins, novolac type alkyl phenol resins, or resole type alkyl phenol resins, and others.
  • furan resin, urea resin, melamine resin, epoxy resin and the like can be used.
  • thermosetting resin a copolymer of divinylbenzene and styrene, acrylonitrile, acrylic acid, or methacrylic acid can be further used.
  • an ion exchange resin can be used as the heat infusible resin.
  • An ion exchange resin is generally composed of a copolymer of divinylbenzene and styrene, acrylonitrile, acrylic acid, or methacrylic acid (that is, a cross-linked vinyl resin that is a heat-meltable resin), and is basically three-dimensional. It has a structure in which an ion exchange group is bonded to a copolymer matrix having a network skeleton.
  • the ion exchange resin is a strongly acidic ion exchange resin having a sulfonic acid group, a weak acid ion exchange resin having a carboxylic acid group or a sulfonic acid group, and a strong basic ion exchange having a quaternary ammonium salt.
  • Resins broadly divided into weakly basic ion exchange resins having primary or tertiary amines, and other special resins include so-called hybrid ion exchange resins having both acid and base ion exchange groups. In the invention, all these ion exchange resins can be used as raw materials.
  • activation treatment is carried out at a temperature of 700 to 1000 ° C. in an air stream (for example, steam or carbon dioxide gas) having reactivity with carbon.
  • an air stream for example, steam or carbon dioxide gas
  • surface-modified spherical activated carbon can be obtained by subjecting the surface non-modified spherical activated carbon only to oxidation or oxidation and reduction treatment.
  • the physical properties of the spherical activated carbon (for example, average particle diameter, pore volume, particle size distribution, specific surface area, etc.) Can be controlled in various ways.
  • the average particle size and particle size distribution of the resin depend on the size of the droplets in the aqueous phase, and the size of the droplets depends on the amount of the suspending agent, the number of rotations of stirring, the shape of the stirring blades, or the aqueous phase. It can be controlled by the monomer ratio (the ratio of the amount of water and the amount of monomer).
  • the droplet can be made smaller, if the rotation speed of stirring is increased, the droplet can be made smaller, and if the amount of the monomer in the aqueous phase is decreased, the droplet is reduced.
  • This is preferable from the standpoint of not only controlling the coalescence but also facilitating heat removal from the polymerization heat.
  • the monomer ratio is too small, the amount of monomer per batch decreases, and the resulting synthetic resin. The amount is reduced, which is not preferable from the viewpoint of productivity.
  • the pore volume and specific surface area can be controlled mainly by the amount and type of porogen when the controlled pore diameter is 10 nm or more, and when the controlled pore diameter is 10 nm or less, It can control by the activation conditions by water vapor
  • the microstructure of the surface-modified spherical activated carbon can be controlled by the type of resin, the type and amount of the crosslinking agent, the infusibilizing conditions, the firing conditions, and / or the activation temperature.
  • a surface non-modified spherical activated carbon is obtained by activation treatment at a temperature of 700 to 1000 ° C. in an air stream having reactivity with carbon (for example, steam or carbon dioxide gas).
  • carbon for example, steam or carbon dioxide gas
  • the surface-modified spherical activated carbon that can be used as the adsorbent for oral administration of the present invention can be obtained by subjecting the surface non-modified spherical activated carbon only to oxidation or oxidation and reduction treatment.
  • the bulk density can be controlled by the activation conditions. For example, it is possible to reduce the bulk density by increasing the activation time, increasing the activation temperature, or increasing the concentration of the air stream having reactivity with carbon. It is.
  • pitch When pitch is used as the carbon source for the preparation of the spherical activated carbon used as the adsorbent for oral administration of the present invention, it can be prepared, for example, by the following method. To a pitch such as petroleum pitch or coal pitch, a bicyclic or tricyclic aromatic compound having a boiling point of 200 ° C. or higher or a mixture thereof is added as an additive, mixed by heating, and then molded to obtain a pitch molded body. The size of the pitch formed body can be controlled by the nozzle diameter at the time of extrusion molding or the pulverizing conditions of the pitch formed body. The smaller the volume of the pitch formed body, the smaller the spherical pitch can be made, and the spherical activated carbon having a smaller particle diameter can be obtained.
  • a pitch such as petroleum pitch or coal pitch
  • a bicyclic or tricyclic aromatic compound having a boiling point of 200 ° C. or higher or a mixture thereof is added as an additive, mixed by heating, and then molded to obtain
  • the pitch molded body is dispersed in hot water at 50 to 120 ° C. with stirring, granulated to form a microsphere, and then cooled to obtain a spherical pitch molded body.
  • the average particle diameter of the spherical pitch molded body is not particularly limited, but is preferably about 0.02 to 1.5 mm, more preferably 60 to 350 ⁇ m, and further preferably 60 to 300 ⁇ m.
  • the additive is extracted and removed from the spherical pitch molded body with a solvent having low solubility with respect to pitch and high solubility with respect to the additive, and the resulting porous pitch is oxidized using an oxidizing agent.
  • porous pitch is infusible with respect to the obtained heat and further processed in an air stream reactive with carbon, for example, steam or carbon dioxide, at a temperature of 800 to 1000 ° C.
  • carbon for example, steam or carbon dioxide
  • a spherical activated carbon can be obtained.
  • the temperature at which naphthalene and pitch are spun is increased, the amount of polyvinyl alcohol is increased, or the cooling step is performed in a short time. It is preferable to perform such control.
  • aromatic additive The purpose of the aromatic additive described above is to make the molded body porous by extracting and removing the additive from the pitch-formed body after molding, and to facilitate structural control and firing of the carbonaceous material by subsequent oxidation. It is in.
  • additives are selected from, for example, one or a mixture of two or more aromatic compounds such as naphthalene, methylnaphthalene, phenylnaphthalene, benzylnaphthalene, methylanthracene, phenanthrene, or biphenyl.
  • the amount added to the pitch is preferably in the range of 10 to 50 parts by weight with respect to 100 parts by weight of the pitch.
  • the pitch and additive are mixed in a molten state by heating in order to achieve uniform mixing. Molding may be performed in a molten state, or may be performed by a method such as pulverizing the mixture after cooling, but the method of extruding the mixed pitch into a thread form in the molten state and then cutting or pulverizing the mixture at equal intervals is used. This is preferable because the distribution can be controlled in a narrower range.
  • the particle diameter can be controlled by the nozzle diameter at the time of extruding the mixing pitch, and a small mixture molded body can be obtained by using a thin nozzle.
  • Solvents for extracting and removing the additive from the mixture of pitch and additive include aliphatic hydrocarbons such as butane, pentane, hexane, or heptane, mixtures mainly composed of aliphatic hydrocarbons such as naphtha or kerosene, methanol, Aliphatic alcohols such as ethanol, propanol or butanol are preferred.
  • the additive By extracting the additive from the pitch and additive mixture molded body with such a solvent, the additive can be removed from the molded body while maintaining the shape of the molded body. At this time, it is presumed that a through hole for the additive is formed in the molded body, and a pitch molded body having uniform porosity is obtained. The resulting pitch-formed body showing porosity is then infusibilized, that is, insoluble to heat by an oxidation treatment using an oxidizing agent, preferably at a temperature of 150 ° C. to 400 ° C. An infusible pitch molded body is used.
  • the oxidizing agent O 2 or a mixed gas obtained by diluting these with air or nitrogen can be used.
  • the pore volume is controlled by controlling the amount, type and precipitation conditions within the pitch of the aromatic additive. be able to.
  • the pitch used as a starting material has a high carbonization yield by heat treatment.
  • the carbonization yield is low, the strength as the spherical activated carbon becomes weak.
  • the bulk density of the spherical activated carbon is lowered, and the specific surface area per volume is lowered, so that the administration volume is increased and oral administration becomes difficult. Therefore, the higher the carbonization yield of the pitch, the better.
  • the preferred yield value by heat treatment at 800 ° C. in a non-oxidizing gas atmosphere is 50% by weight or more, more preferably 60% by weight or more.
  • the surface non-modified spherical activated carbon By performing heat treatment resin, heat infusible resin, or pitch as a carbon source, the surface non-modified spherical activated carbon having the desired pores obtained by oxidation treatment alone, or oxidation treatment and reduction treatment, The surface-modified spherical activated carbon used in the present invention can be obtained.
  • the oxidation treatment is performed under an atmosphere having an oxygen content of 0.1 to 50% by volume, preferably 1 to 30% by volume, particularly preferably 3 to 20% by volume, at a temperature of 300 to 800 ° C., preferably 320 to 600 ° C. be able to.
  • the reduction treatment can be performed in a non-oxidizing gas atmosphere at a temperature of 800 to 1200 ° C., preferably 800 to 1000 ° C.
  • the atmosphere inert to carbon means nitrogen, argon, helium alone, or a mixed system thereof.
  • the surface-modified spherical activated carbon is a porous body obtained by subjecting the spherical activated carbon to the oxidation treatment alone or the oxidation treatment and reduction treatment.
  • the adsorption characteristics of toxic substances in the upper small intestinal tract are improved by adding acid points and basic points in a balanced manner to the surface of the spherical activated carbon.
  • the specificity for the toxic substance to be adsorbed can be improved by subjecting the spherical activated carbon to oxidation treatment and reduction treatment.
  • Each physical property value of the spherical activated carbon used as the adsorbent for oral administration according to the present invention is measured by the following methods.
  • Average particle diameter (Dv50) Using a laser diffraction particle size distribution analyzer (Shimadzu Corporation: SALAD-3000S), a volume-based particle size cumulative diagram was prepared, and the particle size at a particle size cumulative rate of 50% was defined as the average particle size (Dv50).
  • Specific surface area (calculation method of specific surface area by BET method)
  • the specific surface area can be calculated by the following formula by measuring the gas adsorption amount of the spherical activated carbon sample using a specific surface area measuring instrument (for example, “ASAP2010” or “ASAP2020” manufactured by MICROMERITICS) by gas adsorption method.
  • a spherical activated carbon as a sample is filled in a sample tube, dried under reduced pressure at 350 ° C., and the weight of the sample after drying is measured.
  • the sample tube is cooled to ⁇ 196 ° C.
  • nitrogen is introduced into the sample tube, nitrogen is adsorbed on the spherical activated carbon sample, and the relationship between nitrogen partial pressure and adsorption amount (adsorption isotherm) is measured.
  • BET plotting is performed with the relative pressure of nitrogen as p and the adsorption amount at that time as v (cm 3 / g STP).
  • Specific surface area (calculation method of specific surface area by Langmuir's formula)
  • the specific surface area can be calculated by Langmuir's equation by measuring the amount of gas adsorbed on the spherical activated carbon sample using a specific surface area measuring instrument (for example, “ASAP2010” or “ASAP2020” manufactured by MICROMERITICS). Specifically, a spherical activated carbon as a sample is filled in a sample tube, dried under reduced pressure at 350 ° C., and the weight of the sample after drying is measured.
  • a specific surface area measuring instrument for example, “ASAP2010” or “ASAP2020” manufactured by MICROMERITICS.
  • the sample tube is cooled to ⁇ 196 ° C.
  • nitrogen is introduced into the sample tube
  • nitrogen is adsorbed on the spherical activated carbon sample
  • the relationship between nitrogen partial pressure and adsorption amount is measured.
  • MA were used 0.162Nm 2 in cross sectional area of nitrogen molecules.
  • Pore volume by mercury porosimetry The pore volume can be measured using a mercury porosimeter (for example, “AUTOPORE 9200” manufactured by MICROMERITICS).
  • Spherical activated carbon as a sample is put in a sample container and deaerated at a pressure of 2.67 Pa or less for 30 minutes.
  • the volume of mercury injected into the spherical activated carbon sample from a pressure corresponding to a pore diameter of 21 ⁇ m (0.06 MPa) to a maximum pressure (414 MPa: corresponding to a pore diameter of 3 nm) is measured.
  • D ( ⁇ 4 ⁇ cos ⁇ ) / P It becomes.
  • the surface tension of mercury is 484 dyne / cm
  • the contact angle between mercury and carbon is 130 degrees
  • the pressure P is MPa
  • the pore diameter D is expressed in ⁇ m.
  • D 1.24 / P
  • the pore volume in the range of pore diameters of 20 to 10000 nm corresponds to the volume of mercury that is injected from a mercury intrusion pressure of 0.124 MPa to 62 MPa.
  • the pore volume in the range of the pore diameter of 7.5 to 15000 nm corresponds to the volume of mercury that is injected from a mercury intrusion pressure of 0.083 MPa to 165 MPa.
  • the pore volume in the range of the pore diameter of 3 to 20 nm corresponds to the volume of mercury that is pressed from a mercury pressure of 413 MPa to 62 MPa.
  • the spherical activated carbon used as the adsorbent for oral administration of the present invention has a very small particle size, the gap between the sample particles filled in the sample container is also reduced. Therefore, in the pore volume measurement operation by the mercury intrusion method, there is a stage in which mercury is intruded into the interparticle voids, and in the intrusion stage, pores having a pore diameter of 8000 to 15000 nm exist. Behaves like The presence of pores having a pore diameter of 8000 to 15000 nm in the spherical activated carbon used as the adsorbent for oral administration of the present invention can be confirmed, for example, by observation with an electron microscope.
  • pore volume in the range of pore diameter of 20 to 15000 nm” or “pore volume in the range of pore diameter of 7.5 to 15000 nm” includes mercury injected into the interparticle void. The amount is also included.
  • Total acidic group 1 g of spherical activated carbon sample material was added to 50 mL of 0.05N NaOH solution, and using an 8-shaped shaker (“TRIPLE SHAKER NR-80” manufactured by Taitec Corporation), This is the consumption of NaOH determined by neutralization titration after shaking the surface modified spherical activated carbon sample after shaking for 48 hours at 37 ° C. with a figure 8 shake, amplitude 3 cm, 76 cycles / min.
  • TriPLE SHAKER NR-80 manufactured by Taitec Corporation
  • the adsorbent for oral administration of the present invention contains the spherical activated carbon as an active ingredient, it may be composed of only spherical activated carbon, and may contain a pharmaceutically acceptable additive in addition to the spherical activated carbon.
  • additives include excipients, disintegrants, surfactants, binders, lubricants, acidulants, foaming agents, sweeteners, fragrances, colorants, stabilizers, and flavoring agents. be able to.
  • Examples of the dosage form when the adsorbent for oral administration is made of spherical activated carbon include powders, granules, capsules, and packaged packages.
  • the adsorbent for oral administration contains spherical activated carbon and additives
  • examples of the dosage form include powders, granules, tablets, dragees, capsules, suspensions, sticks, sachets, and emulsions. Can be mentioned.
  • Adsorbent for oral administration for the treatment or prevention of kidney disease or liver disease The spherical activated carbon used as the adsorbent for oral administration of the present invention is excellent in adsorbability of toxic substances in liver disease aversion factor and kidney disease. Therefore, it can be used as an adsorbent for oral administration for the treatment or prevention of renal diseases, or as an adsorbent for oral administration for the treatment or prevention of liver diseases.
  • renal diseases include chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephritic syndrome, acute progressive nephritic syndrome, chronic nephritic syndrome, nephrotic syndrome, nephrosclerosis, interstitial Nephritis, ureteropathy, lipoid nephrosis, diabetic nephropathy, renovascular hypertension, or hypertension syndrome, or secondary kidney disease associated with the above-mentioned primary disease, further, mild renal failure before dialysis, It can also be used to improve the condition of mild renal failure before dialysis and to improve the condition during dialysis ("clinical nephrology" Asakura Shoten, Nishio Honda, Kenkichi Ogura, Kiyoshi Kurokawa, 1990 edition and "Nephrology” medical bookstore (See Teruo Omae and Satoshi Fujimi, 1981 edition).
  • 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, vibration Mental, encephalopathy, metabolic abnormalities, or functional abnormalities can be mentioned.
  • it can be used for treatment of diseases caused by harmful substances existing in the body, that is, psychosis.
  • the adsorbent for oral administration according to the present invention contains the spherical activated carbon as an active ingredient when used as a therapeutic agent for kidney diseases.
  • the dosage depends on whether the subject of administration is a human or other animal, and varies depending on age, individual difference. In some cases, dosages outside the following range may be appropriate depending on the medical condition, etc.
  • the oral dosage for human subjects is 1 to 20 g per day, 3 to 4 times. It can be taken separately and further increased or decreased depending on the symptoms.
  • the dosage form can be powders, granules, tablets, dragees, capsules, suspensions, sticks, sachets or emulsions.
  • an enteric capsule can be used as required in addition to normal gelatin.
  • a tablet it is necessary that the tablet is unlocked into fine particles.
  • it can also be used in the form of a composite agent blended with other chemicals such as an aluminum gel and an electrolyte regulator such as silicaxate.
  • the spherical activated carbon having an activation distribution can be used as a renal disease treatment or prevention agent, or a liver disease treatment or prevention agent in the form of a mixture mixed with conventionally known spherical activated carbon having no distribution of activation.
  • spherical activated carbon having an activation distribution and a conventionally known spherical activated carbon having no distribution of activation can be used in combination as a renal disease treatment or prevention agent, or a liver disease treatment or prevention agent.
  • the spherical activated carbon used in the adsorbent for oral administration according to the present invention can be used in a method for preventing or treating kidney disease or liver disease. Therefore, the method for treating renal disease or liver disease according to the present invention is characterized in that the adsorbent for oral administration containing the spherical activated carbon is administered to a subject to be treated for renal disease or liver disease in an effective amount. .
  • the administration route, dosage, and administration interval of the spherical activated carbon can be appropriately determined according to the type of illness, the patient's age, sex, weight, symptom level, or administration method.
  • Spherical activated carbon for use in a method for treating kidney disease or liver disease
  • the spherical activated carbon used in the adsorbent for oral administration according to the present invention can be used in a method for preventing or treating kidney disease or liver disease.
  • the spherical activated carbon of the present invention is for use in a method for preventing or treating kidney disease or liver disease.
  • the amount of spherical activated carbon used in the prevention or treatment can be appropriately determined according to the type of illness, the age, sex, weight, symptom level, or administration method of the patient.
  • spherical activated carbon for the treatment of renal disease or liver disease for the manufacture of a medicament for treatment
  • the spherical activated carbon used in the adsorbent for oral administration according to the present invention is used for the manufacture of a medicament for the prevention or treatment of renal disease or liver disease.
  • Can be used. Therefore, the use of the present invention is the use of spherical activated carbon for the manufacture of a medicament for the prevention or treatment of kidney disease or liver disease.
  • the content of the spherical activated carbon in the preventive or therapeutic drug can be appropriately determined according to the type of disease, the age, sex, weight, symptom level, or administration method of the patient.
  • spherical activated carbon for treatment of renal disease or liver disease
  • the spherical activated carbon used for the adsorbent for oral administration according to the present invention can be used for the treatment of renal disease or liver disease. Therefore, the use of the present invention is the use of spherical activated carbon for the prevention or treatment of kidney disease or liver disease.
  • the fee for use in the prevention or treatment of the spherical activated carbon can be appropriately determined according to the type of illness, the age, sex, weight, symptom level, or administration method of the patient.
  • Comparative Example 1 >> 4800 g of deionized water, 7.2 g of methylcellulose, and 1.0 g of sodium nitrite are placed in a 10 L polymerization can. 481 g of styrene and 57% divinylbenzene (57% divinylbenzene and 43% ethylvinylbenzene) 1119 g, 2,2′-azobis (2,4-dimethylvaleronitrile) 9.3 g, and 560 g of hexane as a porogen were added as appropriate, the inside of the system was replaced with nitrogen gas, and the two-phase system was stirred at 140 rpm. After being heated to 55 ° C., it was kept for 20 hours.
  • the obtained resin was filtered, and hexane was removed from the resin by distillation under reduced pressure, and then dried under reduced pressure at 90 ° C. for 12 hours to obtain a spherical porous synthetic resin having an average particle size of 246 ⁇ m.
  • the specific surface area of the porous synthetic resin was about 240 m 2 / g.
  • the obtained spherical porous synthetic resin was charged into a reactor equipped with a sieve pan and subjected to infusibilization treatment in a vertical tubular furnace.
  • the infusible condition was that dry air was flowed from the lower part of the reaction tube to the upper part, and after heating up to 190 ° C., the temperature was raised from 190 ° C.
  • Comparative Example 2 In the comparative example 1, instead of performing the activation treatment until the bulk density becomes 0.70 g / mL, the operation of the comparative example 1 is repeated except that the activation treatment is performed until the bulk density is 0.60 g / mL. Activated carbon was obtained.
  • Comparative Example 3 In the comparative example 1, instead of performing the activation treatment until the bulk density becomes 0.70 g / mL, the operation of the comparative example 1 is repeated except that the activation treatment is performed until the bulk density is 0.50 g / mL. Activated carbon was obtained.
  • Comparative Example 4 In Comparative Example 1, instead of performing the activation treatment until the bulk density reaches 0.70 g / mL, the operation of Comparative Example 1 is repeated except that the activation treatment is performed until the bulk density is 0.40 g / mL. Activated carbon was obtained.
  • Comparative Example 5 In the comparative example 1, instead of performing the activation treatment until the bulk density becomes 0.70 g / mL, the operation of the comparative example 1 is repeated except that the activation treatment is performed until the bulk density becomes 0.30 g / mL. Activated carbon was obtained.
  • Comparative Example 6 >> 4800 g of deionized water, 7.2 g of methylcellulose, and 1.0 g of sodium nitrite are placed in a 10 L polymerization can. 481 g of styrene and 57% divinylbenzene (57% divinylbenzene and 43% ethylvinylbenzene) 1119 g, 2,2′-azobis (2,4-dimethylvaleronitrile) 9.3 g, and 560 g of hexane as a porogen were added as appropriate, the inside of the system was replaced with nitrogen gas, and the two-phase system was stirred at 140 rpm. After being heated to 55 ° C., it was kept for 20 hours.
  • the obtained resin was filtered, and hexane was removed from the resin by distillation under reduced pressure, and then dried under reduced pressure at 90 ° C. for 12 hours to obtain a spherical porous synthetic resin having an average particle size of 246 ⁇ m.
  • the specific surface area of the porous synthetic resin was about 240 m 2 / g.
  • the obtained spherical porous synthetic resin was charged into a reactor equipped with a sieve pan and subjected to infusibilization treatment in a vertical tubular furnace.
  • the infusible condition was that dry air was flowed from the lower part of the reaction tube to the upper part, and after heating up to 190 ° C., the temperature was raised from 190 ° C.
  • a spherical porous oxide resin After firing a spherical porous oxidized resin at 850 ° C. in a nitrogen atmosphere, batch activation by a fluidized bed using a tank reactor in a nitrogen gas atmosphere containing water vapor at 850 ° C. has a bulk density of 0.63 g / It carried out until it became mL, and obtained the spherical activated carbon.
  • the obtained spherical activated carbon was further oxidized in a fluidized bed at 470 ° C. in air for 3 hours, and then reduced in a fluidized bed at 900 ° C. for 17 minutes in a nitrogen gas atmosphere to obtain a surface-modified spherical activated carbon. .
  • the bulk density of the obtained surface-modified spherical activated carbon was 0.60 g / mL.
  • Comparative Example 7 In the comparative example 6, instead of performing the activation treatment until the bulk density becomes 0.63 g / mL, by repeating the operation of the comparative example 6 except that the activation treatment is performed until the bulk density is 0.48 g / mL, the surface is obtained. A modified spherical activated carbon was obtained. The bulk density of the obtained surface-modified spherical activated carbon was 0.50 g / mL.
  • Comparative Example 8 In the comparative example 6, instead of performing the activation treatment until the bulk density becomes 0.63 g / mL, by repeating the operation of the comparative example 6 except that the activation treatment is performed until the bulk density is 0.37 g / mL, the surface is obtained. A modified spherical activated carbon was obtained. The bulk density of the obtained surface-modified spherical activated carbon was 0.40 g / mL.
  • Reference Example 1 Put spherical phenolic resin (trade name “Industrial Phenol Resin Resin Top (Marilyn HF-100, Manufacture No. 60303); manufactured by Gunei Chemical Co., Ltd.”) into a quartz vertical reaction tube with an eye plate and run under nitrogen gas flow The temperature was raised to 300 ° C. in 5 hours, raised to 700 ° C. in 2 hours, and held for 30 minutes. Thereafter, activation treatment was performed at 850 ° C. in a nitrogen gas atmosphere further containing water vapor to a bulk density of 0.40 g / mL to obtain spherical activated carbon.
  • spherical phenolic resin trade name “Industrial Phenol Resin Resin Top (Marilyn HF-100, Manufacture No. 60303); manufactured by Gunei Chemical Co., Ltd.”
  • Example 1 The spherical activated carbons of Comparative Examples 1, 3, and 5 were mixed at a weight ratio of 5: 90: 5 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Example 2 The spherical activated carbons of Comparative Examples 1, 3, and 5 were mixed at a weight ratio of 10:80:10 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Example 3 The spherical activated carbons of Comparative Examples 1 and 5 were mixed at a weight ratio of 50:50 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Example 4 The spherical activated carbons of Comparative Examples 2 to 4 were mixed at a weight ratio of 15:70:15 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Example 5 The spherical activated carbons of Comparative Examples 2 to 4 were mixed at a weight ratio of 30:40:30 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Example 6 The spherical activated carbons of Comparative Examples 2 and 4 were mixed at a weight ratio of 50:50 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Example 7 The spherical activated carbons of Comparative Examples 1 to 5 were mixed at a weight ratio of 20: 20: 20: 20: 20 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Example 8 The spherical activated carbons of Comparative Examples 1 to 3 were mixed at a weight ratio of 15:70:15 to obtain spherical activated carbon having an average bulk density of 0.60 g / mL.
  • Example 9 The spherical activated carbons of Comparative Examples 1 and 5 were mixed at a weight ratio of 75:25 to obtain spherical activated carbon having an average bulk density of 0.60 g / mL.
  • Example 10 The spherical activated carbons of Comparative Examples 3 to 5 were mixed at a weight ratio of 15:70:15 to obtain spherical activated carbon having an average bulk density of 0.40 g / mL.
  • Example 11 The spherical activated carbons of Comparative Examples 1 and 5 were mixed at a weight ratio of 25:75 to obtain spherical activated carbon having an average bulk density of 0.40 g / mL.
  • Example 12 The spherical activated carbons of Comparative Examples 6 to 8 were mixed at a weight ratio of 15:70:15 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Example 13 Spherical activated carbon having an average bulk density of 0.50 g / mL was obtained by mixing the spherical activated carbons of Comparative Examples 6 to 8 at a weight ratio of 30:40:30.
  • Example 14 The spherical activated carbons of Comparative Examples 6 and 8 were mixed at a weight ratio of 50:50 to obtain spherical activated carbon having an average bulk density of 0.50 g / mL.
  • Pore volume The micropore pore volume of the various spherical activated carbons obtained in the examples and comparative examples was determined by the SF method using the nitrogen adsorption method. The pore volume with a diameter of 7.5 to 150,000 nm and the pore volume with a pore diameter of 3 to 20 nm were determined by the mercury intrusion method.
  • Total acidic group 1 g of spherical activated carbon sample is added to 50 mL of 0.05 N NaOH solution, and 8 parts of shaker (“TRIPLE SHAKER NR-80” manufactured by Taitec Co., Ltd.) is used. This is the consumption of NaOH determined by neutralization titration after filtering the surface-modified spherical activated carbon sample after shaking for 48 hours at 37 ° C. with an amplitude of 3 cm and an amplitude of 76 cycles / min.
  • shaker (“TRIPLE SHAKER NR-80” manufactured by Taitec Co., Ltd.)
  • Total basic groups 1 g of spherical activated carbon sample was added to 50 mL of 0.05 normal HCl solution, and using an 8-shaped shaker (“TRIPLE SHAKER NR-80” manufactured by Taitec Corporation), This is the consumption amount of HCl determined by neutralization titration after shaking the surface modified spherical activated carbon sample after shaking for 24 hours at 37 ° C. with a figure 8 shake, amplitude 3 cm, 76 cycles / min.
  • TriPLE SHAKER NR-80 manufactured by Taitec Corporation
  • a sample solution was obtained.
  • the calibration curve was prepared by accurately dispensing an indoxyl potassium sulfate stock solution into volumetric flasks in amounts of 0 mL, 25 mL, 50 mL, 75 mL, and 100 mL, and measuring up to 100 mL with pH 7.4 phosphate buffer.
  • Tryptophan adsorption test With respect to the various spherical activated carbons and surface-modified spherical activated carbons obtained in Examples 1 to 14 and Comparative Examples 1 to 8, tryptophan adsorption tests were carried out by the following method. After the sample was dried, 0.01 g of the dried sample was weighed and taken into a 50 mL screw mouth sample bottle. On the other hand, 100 mg of tryptophan and 6458 mg of sodium cholate were accurately weighed and dissolved by adding a phosphate buffer solution of PH 7.4 to make exactly 1000 mL (tryptophan stock solution) 50 mL of the above 50 mL screw mouth.
  • the mixture was shaken for 2 hours using a mix rotor (“Mix Rotor Variable VMR-5R” manufactured by As One Co., Ltd.) at 10 rpm and 37 ⁇ 1 ° C.
  • the contents of the screw mouth sample bottle after shaking are suction filtered through a membrane filter having a filter hole of 0.65 ⁇ m, and about 20 mL of the first filtrate is removed, and about 10 mL of the next filtrate is diluted with acetonitrile.
  • a sample solution of acetonitrile 1: 1 was used.
  • the adsorbent for oral administration of the present invention can be used as an adsorbent for oral administration for the treatment or prevention of kidney disease, or as an adsorbent for treatment or prevention of liver disease.
  • renal diseases include chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephritic syndrome, acute progressive nephritic syndrome, chronic nephritic syndrome, nephrotic syndrome, nephrosclerosis, interstitial Nephritis, ureteropathy, lipoid nephrosis, diabetic nephropathy, renovascular hypertension, or hypertension syndrome, or secondary kidney disease associated with the above-mentioned primary disease, further, mild renal failure before dialysis, It can also be used to improve the condition of mild renal failure before dialysis and to improve the condition during dialysis ("clinical nephrology" Asakura Shoten
  • 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, vibration Mental, encephalopathy, metabolic abnormalities, or functional abnormalities can be mentioned.
  • it can be used for treatment of diseases caused by harmful substances existing in the body, that is, psychosis.
  • this invention was demonstrated along the specific aspect, the deformation

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Abstract

L'invention a pour objectif de fournir un adsorbant pour administration par voie orale permettant d'adsorber en grande quantité un tryptophane ou un indoxyle sulfate, en présence d'un acide biliaire. L'objectif de l'invention peut être atteint à l'aide de cet adsorbant pour administration par voie orale qui est caractéristique en ce qu'il contient un charbon actif sphérique qui présente une masse volumique apparente moyenne de 0,4 à 0,6g/mL, et un volume des pores de diamètre compris entre 1,5 et 2,0nm obtenu selon un procédé SF à l'aide d'un procédé d'adsorption d'azote, satisfaisant la formule (1) y＞6×10-8x2-9×10-5x＋0,0241 [Dans la formule, y représente le volume des pores (mL/g) de diamètre compris entre 1,5 et 2,0nm obtenu selon un procédé SF à l'aide du procédé d'adsorption d'azote, et x représente une surface spécifique BET (m2/g)].
PCT/JP2014/054263 2013-02-22 2014-02-24 Adsorbant pour administration par voie orale, médicament pour maladie rénale, et médicament pour maladie du foie WO2014129616A1 (fr)

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CN115253762A (zh) * 2022-08-27 2022-11-01 西畔(北京)信息技术有限责任公司 一种活性炭口服丸、制备装置及制备方法

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JP7499054B2 (ja) 2020-04-03 2024-06-13 フタムラ化学株式会社 経口投与用錠剤型吸着剤

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WO2005094844A1 (fr) * 2004-04-02 2005-10-13 Kureha Corporation Adsorbant pour administration orale, préventif ou remède pour une maladie rénale et préventif ou remède pour une maladie hépatique
WO2005094845A1 (fr) * 2004-04-02 2005-10-13 Kureha Corporation Vis
WO2010086985A1 (fr) * 2009-01-29 2010-08-05 旭有機材工業株式会社 Adsorbant pour administration orale

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WO2005094844A1 (fr) * 2004-04-02 2005-10-13 Kureha Corporation Adsorbant pour administration orale, préventif ou remède pour une maladie rénale et préventif ou remède pour une maladie hépatique
WO2005094845A1 (fr) * 2004-04-02 2005-10-13 Kureha Corporation Vis
WO2010086985A1 (fr) * 2009-01-29 2010-08-05 旭有機材工業株式会社 Adsorbant pour administration orale

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Publication number Priority date Publication date Assignee Title
CN115253762A (zh) * 2022-08-27 2022-11-01 西畔(北京)信息技术有限责任公司 一种活性炭口服丸、制备装置及制备方法

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