JP2006096769A - Adsorbent for oral administration, agent for treating or preventing renal failure, and agent for treating or preventing hepatic failure - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an adsorbent for oral administration, exhibiting useful selective adsorption characteristics of little adsorptivity of internal useful materials and much adsorption properties of toxic substances. <P>SOLUTION: The adsorbent for the oral administration comprises a spherical activated carbon produced by using a thermosetting resin as a carbon source, and having 0.01-1 mm diameter, and ≥1,000 m<SP>2</SP>/g specific surface area obtained by the Langmuir adsorption equation, or a surface-treated spherical activated carbon produced by using a thermosetting resin as a carbon source, and having 0.01-1 mm diameter, ≥1,000 m<SP>2</SP>/g specific surface area obtained by the Langmuir adsorption equation, 0.40-1.00 meq/g total acidic groups and 0.40-1.10 meq/g total basic groups. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to an adsorbent for oral administration, which is produced by subjecting spherical activated carbon having a specific pore structure to further oxidation treatment and reduction treatment, and comprising surface-modified spherical activated carbon having the same specific pore structure. Furthermore, the present invention 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 selective adsorption property that it has a high adsorption performance for toxic toxic substances (Toxin) despite the low adsorption of beneficial components such as digestive enzymes in the body, Since it has a unique pore structure, the selective adsorption characteristics are remarkably improved as compared with conventional adsorbents for oral administration. Therefore, it is particularly effective as an adsorbent for oral administration for patients with liver and kidney diseases.

  Patients with deficient renal or hepatic functions cause encephalopathy such as uremia and disturbance of consciousness because harmful toxic substances accumulate in the body, such as in the blood, due to their organ dysfunction. Since the number of these patients tends to increase year by year, the development of organ substitute devices or therapeutic agents having a function of removing toxic substances from the body in place of these defective organs has become an important issue. At present, the removal method of toxic substances by hemodialysis is most popular as an artificial kidney. However, such a hemodialysis artificial kidney requires a special engineer from the viewpoint of safety management in order to use a special device, and the physical, mental and economic burden on the patient due to blood removal from the body is high. However, it is not always satisfactory.

In recent years, oral adsorbents that can be taken orally and can treat renal or liver dysfunction have attracted attention as means for solving these drawbacks. Specifically, the adsorbent described in JP-B-62-11611 (Patent Document 1) is composed of a porous spherical carbonaceous material having a specific functional group (hereinafter referred to as surface-modified spherical activated carbon). Highly safe and stable for the living body, and at the same time, it has excellent adsorptivity for toxic substances even in the presence of bile acids in the intestine, and it also has a beneficial selective adsorptive property that it absorbs less intestinal beneficial components such as digestive enzymes. In addition, it is widely used clinically, for example, for patients with hepatorenal dysfunction, as an oral therapeutic drug with few side effects such as constipation. In addition, the adsorbent described in the above Japanese Patent Publication No. 62-11611 (Patent Document 1) is obtained by carrying out oxidation treatment and reduction treatment after preparing spherical activated carbon using pitches such as petroleum pitch as a carbon source. It was manufactured.
Japanese Patent Publication No.62-11611

  The present inventor has prepared a spherical activated carbon from pitches and obtained an adsorbent for oral administration which exhibits a superior selective adsorptivity than an oral adsorbent made of a conventional porous spherical carbonaceous material obtained by oxidation and reduction. Surprisingly, the spherical activated carbon prepared using a thermosetting resin as a carbon source was found to be uremic in vivo even though it was in the state before the oxidation treatment and reduction treatment. It has been found that it has excellent selective adsorptivity with excellent adsorptivity of β-aminoisobutyric acid, which is considered to be one of the active substances, and has low adsorptivity to digestive enzymes (for example, α-amylase) which are beneficial substances. Furthermore, it has been found that the degree of selective adsorptivity is superior to that of the adsorbent described in Japanese Patent Publication No. 62-11611 (Patent Document 1). Since the spherical activated carbon prepared using a thermosetting resin as a carbon source exhibits excellent adsorptivity to β-aminoisobutyric acid, other toxic substances having the same molecular size, such as octopamine and α-aminobutyric acid, Furthermore, it is considered that it exhibits excellent adsorptivity to water-soluble basic and amphoteric substances such as toxic substances in kidney disease and their precursors such as dimethylamine, aspartic acid, or arginine.

  In the conventional porous spherical carbonaceous material, that is, the surface-modified spherical activated carbon used in the adsorbent described in JP-B-62-11611 (Patent Document 1), the spherical activated carbon prepared from pitches is further oxidized. In addition, the selective adsorption ability was introduced in the state of spherical activated carbon before performing the oxidation treatment and the reduction treatment because it was thought that the selective adsorption property was expressed by introducing the functional group after the reduction treatment. The above discovery by the inventor of the present invention and its ability to adsorb is superior to conventional adsorbents for oral administration is surprising.

In addition, the present inventor has demonstrated that the surface-modified spherical activated carbon prepared by further oxidizing and reducing the above-mentioned spherical activated carbon is capable of adsorbing β-aminoisobutyric acid, which is considered to be one of uremic substances in vivo. The beneficial selective adsorptivity, which is excellent and has a low adsorptivity to a beneficial substance such as a digestive enzyme (for example, α-amylase), is described in JP-B-62-11611 (Patent Document 1). It has been found that it is further improved than the adsorbent. Therefore, other toxic substances having the same molecular size as β-aminoisobutyric acid, such as octopamine and α-aminobutyric acid, toxic substances in kidney disease and their precursors dimethylamine, aspartic acid, arginine, etc. It is considered that water-soluble basic and amphoteric substances also exhibit better selective adsorption.
The present invention is based on these findings.

Therefore, the present invention is produced using a thermosetting resin as a carbon source, has a diameter of 0.01 to 1 mm, a specific surface area determined by Langmuir's adsorption formula is 1000 m ² / g or more, and has a total acidic group of 0. .40 meq / g to 1.00 meq / g, all basic groups are 0.40 meq / g to 1.10 meq / g, and the pore volume of pore diameter 20-1000 nm is 0.0185 mL / g or less. Further, the present invention relates to an adsorbent for oral administration characterized by comprising a surface-modified spherical activated carbon having a selective adsorption rate of β-aminoisobutyric acid or a substance having a molecular size equivalent to 4.0-amino acid.
A preferred adsorbent for oral administration according to the present invention comprises a surface-modified spherical activated carbon having a pore diameter of 20 to 15000 nm and a pore volume of 0.1 mL / g or less.
Another preferred oral adsorbent according to the present invention consists of surface-modified spherical activated carbon produced using phenolic resin as a carbon source.
A more preferred adsorbent for oral administration according to the present invention is a surface-modified spherical activated carbon produced using a thermosetting resin having a carbonization yield of 40% by weight or more by a heat treatment at 800 ° C. in a non-oxidizing gas atmosphere as a carbon source. Consists of.
Furthermore, the present invention also relates to an agent for treating or preventing renal diseases, an agent for treating or preventing liver diseases, and an agent for treating or preventing diseases related to uremic substances, comprising the aforementioned adsorbent for oral administration as an active ingredient.

  The adsorbent for oral administration according to the present invention is manufactured using a thermosetting resin as a carbon source and has a unique pore structure. Therefore, when it is taken orally, it absorbs beneficial components such as digestive enzymes in the body. In spite of the small amount of toxic toxic substances (Toxin), the selective adsorption property is excellent in the digestive system. Compared with conventional adsorbents for oral administration, the selective adsorption property is remarkable. improves.

  As described above, the surface-modified spherical activated carbon used as the adsorbent for oral administration of the present invention, instead of the pitches that have been used as the carbon source of the conventional adsorbent for oral administration, uses a thermosetting resin as the carbon source. It is characterized in that it is used, and in other respects, it can be prepared using operations substantially similar to conventional manufacturing methods using pitches.

The surface-modified spherical activated carbon used as the adsorbent for oral administration of the present invention can be produced, for example, by the following method.
First, a spherical activated carbon can be obtained by subjecting a spherical body made of a thermosetting resin to 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). Here, the spherical “activated carbon” is a porous body obtained by performing an activation treatment after heat treating a carbon precursor such as a spherical thermosetting resin, and is spherical and has a specific surface area of 100 m ² / g or more. Means something. In this invention, 1000 m < ² > / g or more is preferable.

In addition, when the spherical body made of a thermosetting resin is softened by heat treatment and deformed into a non-spherical shape, or the spherical bodies are fused, the infusibilization treatment is performed before the activation treatment. As described above, softening can be suppressed by performing an oxidation treatment at 150 ° C. to 400 ° C. in an atmosphere containing oxygen.
In addition, when a large amount of pyrolysis gas is generated when the thermosetting resin spheres are heat-treated, pre-baking may be appropriately performed before the activation operation to remove the pyrolysis products in advance. .

  According to what the present inventors have found, in the spherical activated carbon, when the total basic groups are 0.4 meq / g or more, further excellent adsorption performance can be obtained. The total basic group is more preferably 0.6 meq / g or more, and most preferably 0.7 meq / g or more.

  In order to further improve the selective adsorptivity of the spherical activated carbon, the spherical activated carbon thus obtained is subsequently subjected to an oxygen content of 0.1 to 50 vol% (preferably 1 to 30 vol%, particularly preferably 3 to 20 vol%). ) In an atmosphere of 300 to 800 ° C. (preferably 320 to 600 ° C.), and further in a non-oxidizing gas atmosphere at a temperature of 800 to 1200 ° C. (preferably 800 to 1000 ° C.). The surface-modified spherical activated carbon used as the adsorbent for oral administration of the present invention can be obtained by carrying out the reduction treatment by the above. Here, the surface-modified spherical activated carbon is a porous material obtained by subjecting the spherical activated carbon to the oxidation treatment and reduction treatment described above, and adds an acidic point and a basic point in a balanced manner to the spherical active surface. This improves the adsorption characteristics of toxic substances in the intestinal tract.

  The thermosetting resin sphere used as a starting material preferably has a particle size of about 0.02 to 1.5 mm.

  The thermosetting resin used as a starting material is a resin capable of forming a spherical body, and it is important that the heat treatment at 500 ° C. or lower does not melt or soften and does not cause shape deformation. . Further, any thermosetting resin that can avoid melt oxidation by so-called infusibilization treatment such as oxidation treatment can be used.

  The thermosetting 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 thermosetting resin is, the more preferable, and the preferred value of the yield by heat treatment at 800 ° C. in a non-oxidizing gas atmosphere is 40% by weight or more, more preferably 45% by weight or more.

  Specific examples of the thermosetting resin used as a starting material include phenolic resins such as novolak-type phenolic resins, resol-type phenolic resins, novolac-type alkylphenol resins, and resol-type alkylphenol resins. Furan resin, urea resin, melamine resin, or epoxy resin can also be used. As the thermosetting resin, a copolymer of divinylbenzene and styrene, acrylonitrile, acrylic acid, or methacrylic acid can be further used.

  Moreover, an ion exchange resin can also be used as said thermosetting resin. An ion exchange resin is generally made of a copolymer of divinylbenzene and styrene, acrylonitrile, acrylic acid, or methacrylic acid (that is, a thermosetting resin), and basically has a three-dimensional network skeleton. It has a structure in which an ion exchange group is bonded to a polymer matrix. Depending on the type of ion exchange group, the ion exchange resin may be 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, or a strong basic ion exchange having a quaternary ammonium salt. Resins, 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. In the present invention, it is particularly preferable to use a phenol resin as a starting material.

  The surface-modified spherical activated carbon used as the adsorbent for oral administration according to the present invention is produced by using the thermosetting resin as a raw material, for example, by the production method described above, and has a diameter of 0.01 to 1 mm. If the diameter of the surface-modified spherical activated carbon is less than 0.01 mm, the outer surface area of the surface-modified spherical activated carbon increases, and adsorption of beneficial substances such as digestive enzymes tends to occur. On the other hand, if the diameter exceeds 1 mm, the diffusion distance of the toxic substance to the inside of the surface-modified spherical activated carbon increases, and the adsorption rate decreases. The diameter is preferably 0.02 to 0.8 mm. In the present specification, the expression “diameter is D1 to Du” is a sieve in a particle size cumulative diagram prepared in accordance with JIS K 1474 (which will be described later in connection with the method of measuring the average particle size). It means that the sieve passing percentage (%) corresponding to the range of the mesh openings Dl to Du is 90% or more.

The surface-modified 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 Langmuir adsorption formula of 1000 m ² / g or more. A surface-modified spherical activated carbon having an SSA of less than 1000 m ² / g is not preferable because the adsorption performance of toxic substances is lowered. SSA is preferably 1000 m ² / g or more. Although 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.

Japanese Patent Publication No. Sho 62-11611 (Patent Document 1) discloses a surface having a pore volume of 100 to 75000 angstroms (that is, a pore volume of 20 to 15000 nm in pore diameter) of 0.1 to 1 mL / g. Although an adsorbent composed of modified spherical activated carbon is described, the surface modified spherical activated carbon used as the adsorbent for oral administration according to the present invention has a pore volume of 20 to 1000 nm and a pore volume of 0.0185 mL / g or less. It is.
In addition, in the surface-modified spherical activated carbon used as the adsorbent for oral administration according to the present invention, the pore volume with a pore diameter of 7.5 to 15000 nm is less than 0.25 mL / g from the viewpoint of obtaining more excellent selective adsorption. In particular, it is preferably 0.2 mL / g or less.

  In the surface-modified spherical activated carbon used as an adsorbent for oral administration according to the present invention (that is, a product produced by subjecting the spherical activated carbon to further oxidation treatment and reduction treatment), all the acidic groups are included in the functional group structure. 0.40 to 1.00 meq / g, and all basic groups are 0.40 to 1.10 meq / g. In the structure of the functional group, when the total acidic group is 0.40 to 1.00 meq / g and the total basic group satisfies the condition of 0.40 to 1.00 meq / g, the selective adsorption characteristic is improved. In particular, it is preferable because the adsorption ability of the toxic substance is increased. In the structure of the functional group, the total acidic group is preferably 0.40 to 0.90 meq / g, and the total basic group is preferably 0.40 to 1.00 meq / g.

When the adsorbent of the present invention is used as a therapeutic agent for liver and kidney disease, the constitution of the functional group is 0.40 to 1.00 meq / g for all acidic groups, 0.40 to 1.10 meq / g for all basic groups, The phenolic hydroxyl group is in the range of 0.20 to 0.70 meq / g and the carboxyl group is in the range of 0.15 meq / g or less, and the ratio of the total acidic group (a) to the total basic group (b) (a / b) is 0.40 to 2.5, and the relationship [(b + c) -d] of the total basic group (b), the phenolic hydroxyl group (c) and the carboxyl group (d) is 0.60 or more. It is preferable.
Each physical property value of the surface-modified spherical activated carbon used as an adsorbent for oral administration according to the present invention, that is, average particle diameter, specific surface area, pore volume, total acidic group, and total basic group is measured by the following method. To do.

(1) Average particle diameter For spherical activated carbon or surface-modified spherical activated carbon, a particle size cumulative diagram is prepared according to JIS K 1474. For the average particle diameter, in the particle size cumulative diagram, the horizontal line is drawn on the horizontal axis from the intersection of the vertical line at the 50% point on the horizontal axis and the particle size cumulative line to obtain the mesh size (mm) of the sieve indicated by the intersection. The average particle size.

ここで、ＭＡは窒素分子の断面積で０．１６２ｎｍ^２を用いた。 (2) Specific surface area (calculation method of specific surface area by Langmuir's formula)
Measure the gas adsorption amount of a spherical activated carbon sample or surface modified spherical activated carbon sample using a specific surface area measuring instrument (for example, “ASAP2010” manufactured by MICROMERITICS) by gas adsorption method, and calculate the specific surface area by Langmuir's formula Can do. Specifically, a sample activated carbon or surface-modified spherical activated carbon is filled in a sample tube, dried at 300 ° C. under reduced pressure, and the sample weight after drying is measured. Next, the sample tube is cooled to −196 ° C., nitrogen is introduced into the sample tube, and nitrogen is adsorbed on the spherical activated carbon sample or the surface-modified spherical activated carbon sample, and the relationship between nitrogen partial pressure and adsorption amount (adsorption isotherm) is obtained. taking measurement.
Langmuir plot is performed with the relative pressure of nitrogen as p and the adsorption amount at that time as v (cm ³ / g STP). That is, when the vertical axis is p / v, the horizontal axis is p, p is plotted in the range of 0.05 to 0.3, and the slope at that time is b (g / cm ³ ), the specific surface area S (unit) = M ² / g) is obtained by the following equation.

Here, MA were used 0.162Nm ² in cross-sectional area of nitrogen molecules.

(3) Pore volume by mercury porosimetry The pore volume can be measured using a mercury porosimeter (for example, “AUTOPORE 9200” manufactured by MICROMERITICS). Sample spherical activated carbon or surface modified spherical activated carbon is placed in a sample container and deaerated at a pressure of 2.67 Pa or less for 30 minutes. Next, mercury is introduced into the sample container, and gradually pressurized to pressurize mercury into the pores of the spherical activated carbon sample or the surface-modified spherical activated carbon sample (maximum pressure = 414 MPa). The pore volume distribution of the spherical activated carbon sample or the surface-modified spherical activated carbon sample is measured from the relationship between the pressure at this time and the intrusion amount of mercury using the following calculation formulas.
Specifically, the volume of mercury injected into the spherical activated carbon sample or the surface-modified spherical activated carbon sample from the pressure corresponding to the pore diameter of 22 μm (0.06 MPa) to the maximum pressure (414 MPa: equivalent to the pore diameter of 3 nm) is determined. taking measurement. The pore diameter is calculated when mercury is pressed into a cylindrical pore having a diameter (D) at a pressure (P), where the surface tension of mercury is “γ” and the contact angle between the mercury and the pore wall is “ θ ”, from the balance between the surface tension and the pressure acting on the pore cross section, the following formula:
−πDγcos θ = π (D / 2) ² · P
Holds. Therefore, D = (− 4γcos θ) / P
It becomes.
In this specification, the surface tension of mercury is 484 dyne / cm, the contact angle between mercury and carbon is 130 degrees, the pressure P is MPa, and the pore diameter D is expressed in μm.
D = 1.27 / P
To obtain the relationship between the pressure P and the pore diameter D. For example, the pore volume in the range of pore diameter of 20 to 1000 nm in the present invention corresponds to the volume of mercury injected from a mercury intrusion pressure of 1.27 MPa to 63.5 MPa, and a pore diameter of 7.5 to 15000 nm. The pore volume in the range of corresponds to the volume of mercury that is pressed from a mercury pressure of 0.085 MPa to 169 MPa.

(4) Total acidic groups Add 1 g of spherical activated carbon sample or surface modified spherical activated carbon sample pulverized to 200 mesh or less in 50 mL of 0.05N NaOH solution, shake for 48 hours, and then add spherical activated carbon sample or surface This is the consumption of NaOH determined by neutralizing titration after filtering the modified spherical activated carbon sample.

(5) Total basic group In 50 mL of 0.05N HCl solution, 1 g of spherical activated carbon sample or surface modified spherical activated carbon sample pulverized to 200 mesh or less was added and shaken for 24 hours. It is the consumption of HCl obtained by filtering the surface-modified spherical activated carbon sample and neutralizing titration.

  The surface-modified spherical activated carbon used as an adsorbent for oral administration according to the present invention is beneficial in spite of excellent adsorbability of toxic substances in liver disease aversion factor and kidney disease, as shown in Examples described later. Because it has excellent selective adsorption properties such as low adsorption to substances such as digestive enzymes, it is used as an adsorbent for oral administration for the treatment or prevention of renal diseases, or for oral administration for the treatment or prevention of liver diseases. It can be used as an adsorbent.

  Examples of 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 pathology of mild renal failure before dialysis and to improve pathology 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. In addition, it can be used for treatment of diseases caused by harmful substances existing in the body, that is, psychosis.

  Accordingly, when the adsorbent for oral administration according to the present invention is used as a therapeutic agent for renal diseases, the surface-modified spherical activated carbon is contained as an active ingredient. When the adsorbent for oral administration of the present invention is used as a therapeutic agent for kidney disease or a therapeutic agent for liver disease, 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, doses outside the following range may be appropriate depending on the medical condition, etc. In general, the oral dose for human subjects is from 1 to 20 g per day to 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. When taking as a capsule, an enteric capsule can be used as required in addition to normal gelatin. When used as a tablet, it is necessary that the tablet is unlocked into fine particles. Furthermore, 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.

EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.
In the following examples, the α-amylase adsorption test and the DL-β-aminoisobutyric acid adsorption test were performed by the following methods, and the selective adsorption rate was calculated by the following method.

(1) α-Amylase adsorption test After drying a spherical activated carbon sample or a surface-modified spherical activated carbon sample, 0.125 g of the dried sample is accurately weighed and placed in an Erlenmeyer flask with a stopper. On the other hand, 0.100 g of α-amylase (liquefied type) was accurately weighed and dissolved by adding a phosphate buffer solution of pH 7.4 to make exactly 1000 mL of the solution (stock solution) with the above stopper. Add exactly to the Erlenmeyer flask and shake at 37 ± 1 ° C for 3 hours. The contents of the flask are suction filtered with a membrane filter having a filter hole of 0.65 μm, about 20 mL of the first filtrate is removed, and about 10 mL of the next filtrate is taken as a sample solution.
On the other hand, the same operation is performed using a pH 7.4 phosphate buffer solution, and the filtrate is used as a correction solution. For the sample solution and the correction solution, the pH 7.4 phosphate buffer is used as a control, the test is performed by the absorbance measurement method, and the absorbance at a wavelength of 282 nm is measured. The difference between the absorbance of the sample solution and the absorbance of the correction solution is taken as the test absorbance.
The calibration curve was obtained by accurately dispensing the α-amylase stock solution into 0 mL, 25 mL, 50 mL, 75 mL, and 100 mL volumes into a volumetric flask, measuring up to 100 mL with pH 7.4 phosphate buffer, and measuring the absorbance at a wavelength of 282 nm. Created by measuring.
From the test absorbance and the calibration curve, α-amylase residual amount (mg / dL) was calculated.
In order to measure the dependency of the amount of the spherical activated carbon sample or the surface modified spherical activated carbon sample, the amount of the spherical activated carbon sample or the surface modified spherical activated carbon sample is set to 0.500 g, and the test absorbance is measured by the same method as above. The residual amount of α-amylase was calculated.

(2) DL-β-aminoisobutyric acid adsorption test After drying the spherical activated carbon sample or the surface-modified spherical activated carbon sample, accurately weigh 2.500 g of the dried sample into a conical stoppered Erlenmeyer flask. On the other hand, 0.100 g of DL-β-aminoisobutyric acid was accurately weighed and dissolved by adding a phosphate buffer solution of pH 7.4 to make exactly 1000 mL of the solution (stock solution) into the conical flask with a stopper. Add exactly and shake at 37 ± 1 ° C for 3 hours. The contents of the flask are suction filtered with a membrane filter having a filter hole of 0.65 μm, about 20 mL of the first filtrate is removed, and about 10 mL of the next filtrate is taken as a sample solution.
Take exactly 0.1 mL of the sample solution in a test tube, add exactly 5 mL of pH 8.0 phosphate buffer, mix, and then add 1 mL of 0.100 g of fluorescamine dissolved in 100 mL of nonaqueous titration acetone. After adding and mixing accurately, let stand for 15 minutes. This liquid is tested by a fluorometric method, and the fluorescence intensity is measured at an excitation wavelength of 390 nm and a fluorescence wavelength of 475 nm.
DL-β-aminoisobutyric acid stock solution is stirred with 100 mL of 0 mL, 15 mL, 50 mL, 75 mL, and 100 mL and pH 7.4 phosphate buffer, filtered, and 0.1 mL of filtrate is accurately added to the test tube. After adding 5 mL of phosphate buffer pH 8.0 accurately and mixing, 1 mL of a solution of 0.100 g of fluorescamine dissolved in 100 mL of non-aqueous titration was added and mixed. Let stand for 15 minutes. These liquids are tested by a fluorometric method, the fluorescence intensity is measured at an excitation wavelength of 390 nm and a fluorescence wavelength of 475 nm, and a calibration curve is created. Finally, the remaining amount of DL-β-aminoisobutyric acid (mg / dL) is calculated using the calibration curve.
In order to measure the dependency of the amount of the spherical activated carbon sample or the surface modified spherical activated carbon sample, the amount of the spherical activated carbon sample or the surface modified spherical activated carbon sample is set to 0.500 g, and the test fluorescence intensity is measured by the same method as described above. The residual amount of DL-β-aminoisobutyric acid was calculated.

(3) Selective adsorption rate The amount of residual α-amylase in the α-amylase adsorption test when the amount of spherical activated carbon sample or surface modified spherical activated carbon sample used is 0.500 g, and similarly, the spherical activated carbon sample or surface modified spherical Based on the respective data of the residual amount of DL-β-aminoisobutyric acid in the DL-β-aminoisobutyric acid adsorption test when the amount of the activated carbon sample used is 0.500 g, the following calculation formula:
A = (10−Tr) / (10−Ur)
(Here, A is the selective adsorption rate, Tr is the residual amount of DL-β-aminoisobutyric acid, and Ur is the residual amount of α-amylase)
Calculated from

<< Reference Example 1 >>
Spherical phenol resin (particle size = 10 to 700 μm: trade name “Highly Functional True Spherical Resin Marilyn HF500 Type”; manufactured by Gunei Chemical Co., Ltd.) is sieved with a sieve having an opening of 250 μm, and fine powder is removed. After adding 150 g of spherical phenol resin from which fine powder has been removed to a quartz vertical reaction tube with a mesh pan, the temperature is raised to 350 ° C. in a nitrogen gas flow for 1.5 hours, and further to 900 ° C. in 6 hours. Holding at 1 ° C. for 1 hour, 68.1 g of a spherical carbonaceous material was obtained. Thereafter, activation treatment was performed at 900 ° C. in a mixed gas atmosphere of nitrogen gas (3 NL / min) and water vapor (2.5 NL / min). When the packing density of the spherical activated carbon decreased to 0.5 mL / g, the activation treatment was terminated, and 29.9 g of spherical activated carbon (yield 19.9 wt%) was obtained.
The characteristics of the obtained spherical activated carbon are shown in Tables 1 and 2.
Calculated from

<< Reference Example 2 >>
Instead of the phenol resin (manufactured by Gunei Chemical Co., Ltd.) used in Reference Example 1, a spherical phenol resin (average particle size = 700 μm: product name “phenol resin spherical cured product ACS series PR-ACS” manufactured by Sumitomo Bakelite Co., Ltd. Except for using -2-50C "), the method described in Reference Example 1 was repeated to obtain spherical activated carbon. The yield was 26.5%.
The characteristics of the obtained spherical activated carbon are shown in Tables 1 and 2.
Calculated from

Example 1
The spherical activated carbon obtained in Reference Example 1 was further oxidized in a fluidized bed in a mixed gas atmosphere of nitrogen and oxygen having an oxygen concentration of 18.5 vol% at 470 ° C. for 3 hours and 15 minutes, and then in a fluidized bed Reduction treatment was performed at 900 ° C. for 17 minutes in a gas atmosphere to obtain surface-modified spherical activated carbon.
The characteristics of the obtained surface-modified spherical activated carbon are shown in Tables 1 and 2.
Calculated from

Example 2
A surface-modified spherical activated carbon was obtained by repeating the method described in Example 1 except that the spherical activated carbon obtained in Reference Example 2 was used as a starting material.
The characteristics of the obtained surface-modified spherical activated carbon are shown in Tables 1 and 2.
Calculated from

<< Reference Example 3 >>
The method described in Example 1 was used except that an ion exchange resin (styrene type; effective diameter = 0.50 to 0.65 mm: trade name “Amberlite 15WET”; manufactured by Organo Corporation) was used instead of the phenol resin. Repeatedly, a surface modified spherical activated carbon was obtained.
The characteristics of the obtained surface-modified spherical activated carbon are shown in Tables 1 and 2.
Moreover, the scanning electron micrograph (50 times) which shows the surface structure of the obtained surface modification spherical activated carbon is shown in FIG. Furthermore, the scanning electron micrograph (200 times) which shows the cross-sectional structure of the obtained surface modification spherical activated carbon is shown in FIG.

<< Comparative Example 1 >>
68 kg of petroleum-based pitch (softening point = 210 ° C .; quinoline insoluble content = 1 wt% or less; H / C atomic ratio = 0.63) and 32 kg of naphthalene are charged into a pressure-resistant container having an internal volume of 300 L with a stirring blade. After melt mixing at 180 ° C., the mixture was cooled to 80 to 90 ° C. and extruded to obtain a string-like molded body. Next, the string-like molded body was crushed so that the ratio of diameter to length was about 1-2.
The crushed material was put into an aqueous solution in which 0.23% by weight of polyvinyl alcohol (degree of saponification = 88%) was dissolved and heated to 93 ° C., and spheroidized by stirring and dispersing. Was replaced by water and cooled at 20 ° C. for 3 hours to solidify the pitch and precipitate naphthalene crystals to obtain a spherical pitch formed body slurry.
After most of the water was removed by filtration, naphthalene in the pitch formed body was extracted and removed with about 6 times the weight of n-hexane of the spherical pitch formed body. The porous spherical pitch obtained in this way was heated to 235 ° C. through heated air using a fluidized bed, and then oxidized by holding at 235 ° C. for 1 hour, so that it was infusible to heat. A porous spherical oxide pitch was obtained. The resulting porous spherical oxide pitch had an oxygen content of 14% by weight.
Subsequently, the porous spherical oxidation pitch was activated using a fluidized bed in a nitrogen gas atmosphere containing 50 vol% of water vapor at 900 ° C. for 170 minutes to obtain spherical activated carbon, which was further treated in a fluidized bed with an oxygen concentration of 18 Oxidation treatment was performed at 470 ° C. for 3 hours and 15 minutes in a mixed gas atmosphere of nitrogen and oxygen of 5 vol%, and then the reduction treatment was performed in a fluidized bed at 900 ° C. for 17 minutes in a nitrogen gas atmosphere. Activated carbon was obtained.
The characteristics of the obtained surface-modified spherical activated carbon are shown in Tables 1 and 2.
A scanning electron micrograph (50 times) showing the surface structure of the obtained surface-modified spherical activated carbon is shown in FIG. Furthermore, the scanning electron micrograph (200 times) which shows the cross-sectional structure of the obtained surface modification spherical activated carbon is shown in FIG.

<< Comparative Example 2 >>
Spherical activated carbon was obtained by repeating the method described in Comparative Example 1 except that the spherical activated carbon was not oxidized and reduced.
The characteristics of the obtained spherical activated carbon are shown in Tables 1 and 2.

ここで、ＭＡは窒素分子の断面積で０．１６２ｎｍ^２を用いた。 The “pore volume (Hg pore)” shown in Table 1 corresponds to the pore volume in the range of pore diameters of 20 to 1000 nm determined by mercury porosimetry.
“SSA (BET type)” described in Table 1 above is a specific surface area measurement value described as a reference, and was measured by the following method.
Similarly to the measurement of the specific surface area by Langmuir's equation, nitrogen is adsorbed on the spherical activated carbon sample or the surface-modified spherical activated carbon sample at -196 ° C., 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). That is, p / (v (1-p)) is plotted on the vertical axis, p is plotted on the horizontal axis, and p is plotted in the range of 0.05 to 0.3, and the slope b (unit = g / cm ^{3) at} that time is plotted. ) And the intercept c (unit = g / cm ³ ), the specific surface area S (unit = m ² / g) is determined by the following equation.

Here, MA were used 0.162Nm ² in cross-sectional area of nitrogen molecules.

<< Pharmacological effect confirmation test 1: Kidney disease improvement action >>
Using a renal failure model rat prepared by extracting 3/4 of the kidney, a pharmacological effect confirmation test for renal failure by administration of the oral adsorbent of the present invention was performed. As a sample, the adsorbent for oral administration obtained in Reference Example 1 and Example 1 was used. In the confirmation test, the control group (6 animals; hereinafter referred to as the C1 group) and the adsorbent administration group for oral administration in Reference Example 1 (6 animals) were prepared so that there was no bias between the groups after 6 weeks from the preparation of the model rats. (Hereinafter referred to as P1 group) and adsorbent administration group for oral administration of Example 1 (6 animals; hereinafter referred to as given P2 group).
Each group was fed a powdered feed. The amount of food fed to each group was determined based on the average amount of food consumed for 2-3 days in group C1. For the P1 group and the P2 group, 5 wt% of an adsorbent for oral administration was additionally mixed with the powdered feed similar to the C1 group. At 8 weeks after the start of the administration of the adsorbent for oral administration, serum creatinine, urea nitrogen, urine creatinine, creatinine clearance, and protein excretion were measured. The same experiment was performed on normal rats (6 animals) from which kidneys were not removed (normal group).
The results are shown in FIGS. The serum creatinine (FIG. 5) and urea nitrogen (FIG. 6) were significantly lower in the P1 group and the P2 group than in the C1 group after 8 weeks from the start of administration. A decrease in creatinine clearance (FIG. 7), which is an index of renal function, was observed in the C1 group, and a significant suppression was observed in the P1 and P2 groups against the decrease observed in the C1 group. On the other hand, the amount of protein excretion (FIG. 8), which is an index of tubular function, was observed to increase in the C1 group, but the increase was significantly suppressed in the P1 and P2 groups. Similar results were obtained for creatinine in urine.
From the above results, it was revealed that the oral adsorbent of the present invention can suppress or improve the progression of chronic renal failure and prevent and maintain the decrease in renal function.

<< Pharmacological effect confirmation test 2: Liver disease improvement action >>
Using a carbon tetrachloride-induced liver disease model rat, a test for confirming the pharmacological effect on liver disease by the administration of the oral adsorbent of the present invention was performed. As a sample, the adsorbent for oral administration obtained in Reference Example 1 and Example 1 was used.
Specifically, Sprague-Dauley rats (manufactured by CLEA Japan; male 7-week-old) and carbon tetrachloride in an amount of 12 mg / kg, twice a week until the end of this pharmacological effect confirmation test Subcutaneous administration was continued (for about 4 months). 2 months after the start of administration of carbon tetrachloride, since a decrease in liver function was confirmed, a control group (6 animals; hereinafter referred to as group C2), reference example so that the disease state was not biased between groups It was divided into 1 adsorbent administration group for oral administration (6 animals; hereinafter referred to as Q1 group) and 1 adsorbent administration group for oral administration in Example 1 (6 animals; hereinafter referred to as Q2 group).
Each group was fed a powdered feed. The amount of food fed to each group was determined based on the average amount of food consumed for 2-3 days in group C2. For the Q1 group and the Q2 group, 5 wt% of an adsorbent for oral administration was additionally mixed in the same powdered feed as in the C2 group and administered for 2 months after grouping. The same experiment was performed for normal rats not administered with carbon tetrachloride (normal group).
ICG (Indocyanine green), GOT (glutamic-oxaloacetic transaminase), GPT, and GPT for about 2 months from the start of administration of the adsorbent for oral administration to completion of the administration experiment (Glutamic-pyruvic transaminase; glutamate-pyruvate transaminase) was measured. The results two months after the start of administration of the adsorbent for oral administration are shown in FIG. 9 (ICG), FIG. 10 (GOT), and FIG. 11 (GPT). When the ICG test reflecting liver parenchymal function was compared, both the Q1 group and the Q2 group showed significantly lower values than the C2 group. Furthermore, in the GOT and GPT, which are the deviating enzymes, both the Q1 group and the Q2 group showed significantly lower values than the C2 group.
From the above results, it was revealed that the oral administration adsorbent of the present invention can improve the decrease in liver function.

The adsorbent for oral administration according to the present invention is manufactured using a thermosetting resin as a carbon source and has a unique pore structure. Therefore, when it is taken orally, it absorbs beneficial components such as digestive enzymes in the body. In spite of the small amount of toxic toxic substances (Toxin), the selective adsorption property is excellent in the digestive system. Compared with conventional adsorbents for oral administration, the selective adsorption property is remarkable. improves.
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.
Examples of 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. In addition, it can be used for treatment of diseases caused by harmful substances existing in the body, that is, psychosis.
As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.

It is a scanning electron micrograph (50 times) which shows the surface structure of the surface modification spherical activated carbon which uses an ion exchange resin as a carbon source. It is a scanning electron micrograph (200 times) which shows the cross-sectional structure of the surface modification spherical activated carbon which uses an ion exchange resin as a carbon source. It is a scanning electron micrograph (50 times) which shows the surface structure of the surface modification spherical activated carbon by a conventional method. It is a scanning electron micrograph (200 times) which shows the cross-sectional structure of the surface modification spherical activated carbon by a conventional method. It is a graph which shows the result of having investigated the effect to the serum creatinine by the adsorbent for oral administration of this invention. It is a graph which shows the result of having investigated the effect to blood urea nitrogen by the adsorbent for oral administration of this invention. It is a graph which shows the result of having investigated the effect on the creatinine clearance by the adsorbent for oral administration of the present invention. It is a graph which shows the result of having investigated the effect on the urinary protein excretion amount by the adsorbent for oral administration of the present invention. It is a graph which shows the result of having investigated the effect on ICG (Indocyanine green: indocyanine green) by the adsorbent for oral administration of this invention. It is a graph which shows the result of having investigated the effect on GOT (glutamic-oxaloacetic transaminase; glutamic acid-oxaloacetic transaminase) by the adsorbent for oral administration of this invention. It is a graph which shows the result of having investigated the effect on GPT (glutamic-pyruvic transaminase; glutamic acid-pyruvate transaminase) by the adsorbent for oral administration of this invention.

Claims (11)

It is manufactured using a thermosetting resin as a carbon source, and is made of spherical activated carbon having a diameter of 0.01 to 1 mm and a specific surface area determined by Langmuir adsorption formula of 1000 m ² / g or more. Adsorbent for administration.   The adsorbent for oral administration according to claim 1, comprising spherical activated carbon having a total basic group of 0.40 meq / g or more. Manufactured using a thermosetting resin as a carbon source, the diameter is 0.01 to 1 mm, the specific surface area determined by Langmuir's adsorption formula is 1000 m ² / g or more, and the total acidic groups are 0.40 to 1.00 meq. / G, and consists of surface-modified spherical activated carbon having a total basic group of 0.40 to 1.10 meq / g.   A therapeutic or prophylactic agent for renal diseases, comprising as an active ingredient the adsorbent for oral administration according to any one of claims 1 to 3.   The liver disease treatment or prevention agent which uses the adsorption agent for oral administration as described in any one of Claims 1-3 as an active ingredient.   An agent for treating or preventing renal disease, comprising the adsorbent for oral administration according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier or diluent.   The liver disease treatment or prevention agent containing the adsorption agent for oral administration as described in any one of Claims 1-3, and a pharmacologically acceptable carrier or diluent.   A method for treating or preventing renal disease, comprising administering an effective amount of the adsorbent for oral administration according to any one of claims 1 to 3 to a patient in need of treatment or prevention of renal disease.   A method for treating or preventing liver disease, comprising administering an effective amount of the adsorbent for oral administration according to any one of claims 1 to 3 to a patient in need of treatment or prevention of liver disease.   Use of the adsorbent for oral administration according to any one of claims 1 to 3 for the manufacture of an agent for treating or preventing a renal disease.   Use of the adsorbent for oral administration according to any one of claims 1 to 3 for the manufacture of an agent for treating or preventing a liver disease.

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