JP7438897B2 - Tablet type adsorbent for oral administration - Google Patents

Description

The present invention relates to a tablet-shaped adsorbent for oral administration, and particularly to a tablet-shaped adsorbent for oral administration using activated carbon as an adsorbent, which has excellent adsorption performance for toxic substances.

In patients with kidney or liver disease, toxic substances accumulate in the blood, resulting in encephalopathy such as uremia and impaired consciousness. The number of these patients tends to increase every year. For patient treatment, hemodialysis-type artificial kidneys and the like are used to remove toxic substances from the body. However, such artificial kidneys require specialized technicians to handle them for safety reasons, and the physical, mental, and financial burden placed on patients when removing blood from the body has been seen as a problem. However, the results are not necessarily satisfactory.

As an alternative to artificial organs, an adsorbent for oral administration has been developed that is ingested orally, adsorbs toxic substances within the body, and excretes them from the body (see Patent Document 1, Patent Document 2, etc.). Anti-nephrotic syndrome drugs have been reported that use petroleum-based hydrocarbons (pitch) as a raw material, adjust the particle size to be relatively uniform, carbonize it, and activate it (for example, see Patent Document 3). . In addition, an adsorbent for oral administration has been reported in which the particle size of the activated carbon itself is made relatively uniform and the distribution of pore volume and the like in the activated carbon is adjusted (see Patent Document 4). In this way, medicinal activated carbon improves poor fluidity in the intestines by making the particle size relatively uniform, and at the same time, by adjusting the pores, the adsorption performance of the activated carbon can be improved. planned. Therefore, it is taken by many patients with mild chronic renal failure.

Medicinal activated carbon is required to quickly and efficiently adsorb uremia-causing substances and their precursors. However, with existing medicinal activated carbon, it is difficult to reduce the particle size while keeping the shape spherical. In addition, the pores of conventional medicated activated carbon cannot be said to be well adjusted, and the adsorption performance is not necessarily sufficient, so the daily dose must be increased. In particular, patients with chronic renal failure have limited water intake, and swallowing small amounts of water is extremely painful for patients.

A tablet-shaped composition for oral administration that is easy to take has been proposed using medicinal activated carbon in the form of a tablet (see, for example, Patent Document 5). Medicinal activated charcoal requires a large dose, so the volume is large, and since activated charcoal does not dissolve in water, fine-grained charcoal leaves a feeling of discomfort in the oral cavity, making it not easy to take. In addition, if the capsule type is used, a dead volume is created, which increases the volume to be taken and makes it difficult to swallow.

Although the aforementioned tablet-shaped composition for oral administration is intended to reduce the burden on patients when taking it, the binder tends to block the pores on the activated carbon surface, resulting in a decrease in adsorption performance. Dosage may need to be increased. Therefore, in the end, the burden of taking the drug may not change much, or the burden may even increase.

Patent No. 3835698 Japanese Patent Application Publication No. 2008-303193 Japanese Unexamined Patent Publication No. 6-135841 Japanese Patent Application Publication No. 2002-308785 Patent No. 5701971

Therefore, the present invention was proposed in view of the above-mentioned situation, and even when activated carbon as an adsorbent is formed into a tablet shape that is easy to take by using an additive as a binder, the adsorption performance of activated carbon for toxic substances can be improved. To provide a tablet-type adsorbent for oral administration, which can suppress a decrease in the amount of alcohol and reduce the burden on patients to take it.

That is, the first invention is a tablet-type adsorbent for oral administration containing activated carbon as an adsorbent and an additive as a binder, wherein the average particle size of the activated carbon is 20 to 1000 μm, and the filling The density is 0.3 to 0.5 g/ml, and the additive contains at least one of sodium carboxymethylcellulose or hydroxyethylcellulose, and is added in an amount of 1.0% by weight or less based on 100% by weight of the tablet-type adsorbent. The present invention relates to a tablet-type adsorbent for oral administration, which is characterized by:

A second invention relates to the tablet-type adsorbent for oral administration according to the first invention, wherein the tablet-type adsorbent has a hardness of 10N or more.

A third invention is, in the first _{or second} invention, a volume ratio ( The present invention relates to a tablet-type adsorbent for oral administration having a V _m ) of 5.0 or less.

A fourth invention relates to the tablet-type adsorbent for oral administration according to any one of the first to third inventions, wherein the activated carbon is a carbonized resin of a phenolic resin.

According to a first aspect of the present invention, there is provided a tablet-type adsorbent for oral administration, which comprises activated carbon as an adsorbent and an additive as a binder, wherein the average particle size of the activated carbon is 20 to 1000 μm, the packing density is 0.3 to 0.5 g/ml, the additive contains at least one of sodium carboxymethyl cellulose or hydroxyethyl cellulose, and the amount is 1. Since the additive is added as a binder, it is possible to suppress the deterioration of the adsorption performance of activated carbon for toxic substances even when the activated carbon as an adsorbent is molded into a tablet shape that is easy to take. , it is possible to reduce the burden of medication on patients.

According to the tablet-type adsorbent for oral administration according to the second invention, in the first invention, since the tablet-type adsorbent has a hardness of 10N or more, breakage and wear of the tablet during transportation and packaging are suppressed. and can maintain the dosage form.

According to the tablet-type adsorbent for oral administration according to the third invention, in the first or second invention, the mesopore volume with respect to the sum of micropore volumes (V _mic ) defined by the following formula (i) of the activated carbon is Since the volume ratio (V _m ) of the sum of (V _met ) is 5.0 or less, it is possible to further suppress the decline in the adsorption performance of activated carbon for toxic substances, and it is possible to reduce the burden of administration on patients. can

According to the tablet-type adsorbent for oral administration according to the fourth invention, in any one of the first to third inventions, since the activated carbon is a resin charcoal of a phenol resin, toxic substances can be absorbed when formed into a tablet shape. The activated carbon can suppress a decrease in the adsorption performance of the activated carbon.

The tablet-shaped adsorbent for oral administration of the present invention is formed into a tablet shape using activated carbon as an adsorbent and an additive including activated carbon as a binder. It is desirable that the hardness of the formed tablet-shaped adsorbent is approximately higher than 10N; if the hardness is lower than 10N, the tablet is likely to be damaged or worn during transportation or packaging, and the dosage form may not be maintained. .

Furthermore, the activated carbon is preferably a carbonized resin of phenol resin. By using phenolic resin as the raw material for activated carbon, it is possible to increase activation and increase the specific surface area, while also increasing the ratio (volume ratio) of the sum of mesopore volumes to the sum of micropore volumes, which improves the adsorption of toxic substances. This is because performance can be easily improved. Examples of the phenol resin include known ones such as novolac type, resol type, and composite phenol resins of both. The phenol resin is preferably used in a range that will result in granular or spherical activated carbon having an average particle diameter of 20 to 1000 μm. If the average particle size of the activated carbon is smaller than 20 μm, the activated carbon may become too dense when made into a tablet, resulting in poor disintegration. When the average particle size of the activated carbon exceeds 1000 μm, the surface area where the activated carbons come into contact with each other and bond due to the additive as a binder increases, so the bonding force becomes weak and the hardness of the tablet may decrease.

In addition to phenolic resins, cellulose can also be used as a raw material for activated carbon. When cellulose is used, it is thought that by using activated carbon with many macropores, it is possible to suppress a decrease in adsorption performance derived from activated carbon when it is made into a tablet shape using additives.

In the present invention, as shown in the examples below, it is preferable that the activated carbon is derived from a phenol resin and has a packing density of 0.3 to 0.5 g/ml, which is determined by the above formula (i). By setting the volume ratio (V _m ) of the sum of mesopore volumes (V _met ) to the sum of micropore volumes (V _mic ) to be 5.0 or less, the activated carbon-derived Decrease in adsorption performance can be suppressed.

The phenolic resin is stored in a firing furnace such as a cylindrical retort electric furnace, and the inside of the furnace is kept under an inert atmosphere such as nitrogen, argon, helium, etc., and heated at 300 to 1000°C, preferably 450 to 700°C, for 1 to 20 hours. It is then carbonized to become a resin carbide (“carbonization process”).

After the carbonization step, the resin carbide is placed in a known heating furnace or the like and activated with steam at 750 to 1000°C, preferably 800 to 1000°C, and further 850 to 950°C ("activation step"). The activation time is 0.5 to 50 hours, depending on the production scale, equipment, etc. Alternatively, gas activation such as carbon dioxide may also be used. The activation time is appropriately adjusted depending on the physical properties of the target activated carbon. The activated carbon after activation is washed with dilute hydrochloric acid. The activated carbon washed with dilute hydrochloric acid is washed with water until the pH reaches 5 to 7, for example, by measuring the pH in accordance with JIS K 1474 (2014).

After washing with dilute hydrochloric acid, the activated carbon adsorbent is heated in a mixed gas of oxygen and nitrogen and washed with water to remove impurities such as ash, if necessary. Residual hydrochloric acid and the like are removed by heat treatment. The amount of surface oxides on the activated carbon adsorbent is adjusted through each treatment. After acid washing, the activated carbonized resin is heated to increase the amount of surface oxides on the activated carbon adsorbent. The oxygen concentration during this treatment is 0.1 to 21% by volume. Further, the heating temperature is 150 to 1000°C, preferably 400 to 800°C, and is for 15 minutes to 2 hours.

After the activation treatment or after the heat treatment following the activation treatment, the resin carbide (activated carbon adsorbent) is sorted by sieving into granular or spherical activated carbon having an average particle diameter of 20 to 1000 μm, more preferably 150 to 350 μm. It is better. Adjustment and fractionation of particle size can stabilize the adsorption rate and adsorption capacity of the activated carbon adsorbent. Although the particle size range is not particularly limited, if it is within the above range, a sufficient surface area of the activated carbon adsorbent can be ensured. Furthermore, when the particle diameters are made uniform, the adsorption performance within the gastrointestinal tract can be stabilized. Furthermore, by maintaining the hardness of the particles, further powdering in the gastrointestinal tract after oral administration (after ingestion) is suppressed. Therefore, the shape of the activated carbon of the adsorbent for oral administration is preferably spherical. However, since variations in sphericity due to manufacturing are also allowed, granular materials are also included.

Since phenol resin has an aromatic ring structure in its molecule, the carbonization yield increases. Furthermore, activation produces activated carbon with a large surface area. The activated carbon after activation has a smaller pore diameter and a higher packing density than conventional activated carbons such as wood, coconut shell, and petroleum pitch. Therefore, the use of ionic organic compounds with relatively small molecular weights (with molecular weights in the range of tens to hundreds) containing nitrogen, such as indoxyl sulfate, aminoisobutyric acid, and tryptophan, which are the causative agents of uremia and their precursors, is important. Suitable for adsorption. In addition, phenolic resin has a lower ash content such as nitrogen, phosphorus, sodium, and magnesium than conventional activated carbon raw materials such as wood, and has a high carbon ratio per unit mass. Therefore, activated carbon with few impurities can be obtained.

The above-mentioned activated carbon is required to adsorb as quickly as possible the causative agents of liver dysfunction and renal dysfunction listed in the examples below, and to exhibit sufficient adsorption performance with a relatively small dose. In order to find a harmonious range of properties, activated carbon is defined by indicators such as mercury pore volume and BET specific surface area. As is clear from the trends in the examples described later, among the various indicators, if the value of the BET specific surface area is above a certain level and the volume ratio of the sum of the mesopore volumes to the sum of the micropore volumes is below a certain level, the tablet It was found that when molded, the deterioration in adsorption performance was suppressed.

The packing density is defined as 0.3-0.5 g/ml. In the present invention, the additive used as a binder for forming the activated carbon into a tablet-type adsorbent is in a very small amount of 1.0% by weight or less based on 100% by weight of the tablet-type adsorbent. This is because in order to obtain a tablet-type adsorbent with excellent selective adsorption properties using a small amount of additives, it is convenient for the activated carbon to have a low packing density. However, if the packing density is less than 0.3 g/ml, the dose increases and it becomes difficult to swallow during oral administration. If the packing density exceeds 0.5 g/ml, there is a risk that the desired selective adsorption property will be unbalanced, or that the adsorption performance of the activated carbon will be greatly reduced by the additive.

Further, the volume ratio (V _m ) of the sum of the mesopore volumes to the sum of the micropore volumes is defined to be 5.0 or less, as described above. When the volume ratio is smaller than 5.0, it can be said that the activated carbon has mesopores developed to a certain extent. If mesopores are developed, even if the additive, which is a relatively large molecule, blocks some of the mesopores when it is made into a tablet using an additive, toxic substances can be removed from other mesopores. This is because it is thought that since it becomes possible to introduce the toxic substance into the pores, deterioration in the adsorption performance of toxic substances can be suppressed. When the packing density is 0.3 to 0.5 g/ml and the volume ratio (V _m ) of the sum of mesopore volumes to the sum of micropore volumes is 5.0 or less, the adsorption performance of toxic substances decreases. is further suppressed. Furthermore, the BET specific surface area is preferably 1200 m ² /g or more. If it is 1200 m ² /g or more, the adsorption performance for toxic substances will be high, so it is suitable as an adsorbent for oral administration.

Furthermore, as mentioned above, activated carbon is also defined by the pore size of its pores. In the case of an adsorbent such as activated carbon, pores such as micropores, mesopores, and macropores are present. The adsorption targets and performance of activated carbon change depending on which range of pores is developed more. The activated carbon desired in the present invention is expected to adsorb nitrogen-containing low molecular weight ionic organic compounds such as indoxyl sulfate, aminoisobutyric acid, and tryptophan, which are representative of uremia-causing substances and their precursors. The activated carbon of the tablet-type adsorbent for oral administration of the present invention adsorbs the molecules to be adsorbed more effectively than conventional activated carbon adsorbents.

By relatively increasing the proportion of macropores and mesopores, the adsorbent can easily penetrate into the activated carbon. Further, even if an additive having a relatively large molecule is adsorbed to the mesopores, the toxic substances are unlikely to be inhibited from reaching the micropores. Then, the adsorption target is captured by the micropores connected to the macropores and mesopores, and the adsorption progresses rapidly. Normally, it is thought that the time from ingestion to excretion for food to be broken down by digestion and flowing through the small intestine is approximately 6 to 10 hours. In other words, it is necessary for the tablet-type adsorbent (activated carbon) for oral administration to adsorb the nitrogen-containing low molecule that is the target adsorption target while flowing through the small intestine. Therefore, in consideration of efficient adsorption within the intestinal tract, short-time adsorption is desirable. For these reasons, it is meaningful to develop more pores on the macropore side of activated carbon.

In addition to these indicators, the average pore diameter may also be mentioned. Therefore, the average pore diameter is preferably in the range of 1.5 to 2.5 nm. By adjusting the average pore diameter of the activated carbon adsorbent within this range, the adsorption of relatively low-molecular ionic organic compounds with a molecular weight of several tens to several hundreds becomes even better. At the same time, activated carbon can suppress the adsorption of macromolecular compounds necessary for living organisms, such as enzymes and polysaccharides, which have a molecular weight of several thousand to tens of thousands. If the average pore diameter of the activated carbon exceeds 2.5 nm, it is not preferable because there are many pores that adsorb polymers such as enzymes and polysaccharides. Furthermore, if the average pore diameter of the activated carbon is less than 1.5 nm, the pore volume itself decreases, which may reduce the adsorption power.

The above-mentioned activated carbon is used as a drug for oral administration, and serves as a therapeutic or preventive agent for kidney disease or liver disease. The causative substances of diseases and chronic symptoms are adsorbed and retained within the pores developed on the surface of activated carbon, and are excreted from the body, thereby suppressing the worsening of symptoms and leading to improvement of the disease state. Furthermore, in cases where there is a congenital or acquired metabolic abnormality or a risk of such abnormality, by orally ingesting activated charcoal in advance, the concentration of the causative agent of the disease or chronic symptoms in the body can be lowered. Therefore, taking it as a preventive measure to prevent worsening of symptoms may be considered.

Kidney diseases include, for example, 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, and interstitial nephritis. , tubulopathy, lipoid nephrosis, diabetic nephropathy, renovascular hypertension, hypertensive syndrome, or secondary renal disease associated with the above-mentioned primary disease, as well as mild renal failure before dialysis. Examples of liver diseases include fulminant hepatitis, chronic hepatitis, viral hepatitis, alcoholic hepatitis, liver fibrosis, cirrhosis, liver cancer, autoimmune hepatitis, drug-allergic liver damage, primary biliary cirrhosis, and tremor. ), encephalopathy, metabolic abnormalities, and functional abnormalities.

When using activated carbon as an adsorbent for oral administration, it is difficult to set a uniform dosage because it is influenced by age, sex, physique, medical condition, etc. However, in general, when targeting humans, it is assumed that the weight of activated charcoal is 1 to 20 g per day, and the dosage is 2 to 4 times. In terms of volume, it is necessary to take 2 to 6 cm ³ at a time, which is very painful for the patient. Therefore, we decided to make it in tablet form to make it easier to take and to reduce the burden on patients.

Due to its nature, activated carbon cannot be compressed into tablets using conventional manufacturing methods, so it is molded into tablets using the binding force of a binder via a solvent such as water. When molding into a tablet using an additive as a binder, the additive covers the pores on the surface of the activated carbon, which tends to clog the pores and reduce the adsorption performance of the activated carbon. If the adsorption performance of activated carbon decreases due to the formation into a tablet shape, there is a risk that the dose will increase, which increases the burden on patients to take the drug. In other words, when forming a tablet, it is necessary to suppress the deterioration of the adsorption performance of activated carbon.

Therefore, as described above, the amount of the additive as a binder added is 1.0% by weight, and the activated carbon is formed into a tablet shape using a very small amount of the additive. In order to enable molding even with a small amount of additives, the packing density of the activated carbon is set to 0.3 to 0.5 g/ml, making it possible to mold the activated carbon into a tablet shape and suppressing the deterioration of the adsorption performance of the activated carbon. can do. Further, by controlling the volume ratio (V _m ) of the sum of the mesopore volumes to the sum of the micropore volumes of the activated carbon to be below a certain level, the deterioration of the adsorption performance of the activated carbon when formed into a tablet shape is suppressed.

The additive as a binder is at least one type of sodium carboxymethyl cellulose or hydroxyethyl cellulose, and these additives make it possible to form activated carbon into a tablet shape even if the amount added is small. Compared to fine-grain adsorbents, it is possible to suppress increases in the dose or volume to be taken. One of the above additives may be used, or both may be mixed, or other additives may be mixed. Moreover, a disintegrant can also be used in combination for the purpose of compensating for the disintegrability of the tablet.

[Preparation of activated carbon]
The following activated carbons 1 to 5 were used in the production of a prototype tablet-type adsorbent for oral administration. Activated carbons 1 to 5 derived from phenolic resin corresponding to the prototype examples were prepared by carbonizing and activating the raw material phenolic resin.

<Activated carbon 1>
In a 1 liter separable flask, 160.0 parts by weight of 90% phenol, 111.8 parts by weight of 37% formaldehyde, 0.7 parts by weight of oxalic acid as an acidic catalyst, 2.5 parts by weight of gum arabic as an emulsifier, and water. 168.8 parts by weight was added and heated to 95° C. or higher to appropriately polymerize. Next, 147.0 parts by weight of 90% phenol, 143.1 parts by weight of formaldehyde, 19.3 parts by weight of hexamethylenetetramine and 8.3 parts by weight of triethylenetetramine as basic catalysts, and 41.4 parts by weight of water were added in the same manner. The mixture was placed in a separable flask and heated for 1 hour while maintaining the temperature at 60°C to proceed with the reaction. Thereafter, the mixture was heated to 95° C. or higher and refluxed for 4 hours to obtain a phenol resin. 100 g of the phenol resin was placed in a cylindrical retort electric furnace and nitrogen was sealed in it, and then the temperature was raised at 100°C/1 hour until it reached 900°C. Thereafter, steam was injected into the furnace and the temperature was maintained at 900° C. for 2 hours for activation, thereby obtaining activated carbon 1.

<Activated carbon 2>
In a 1-liter separable flask, 98.0 parts by weight of 90% phenol, 53.2 parts by weight of 37% formaldehyde, 0.4 parts by weight of oxalic acid as an acid catalyst, 1.6 parts by weight of gum arabic as an emulsifier, and water. 147.9 parts by weight was added and heated to 95° C. or higher to appropriately polymerize. Next, 189.0 parts by weight of 90% phenol, 220.3 parts by weight of 37% formaldehyde, 18.1 parts by weight of hexamethylenetetramine and 7.7 parts by weight of triethylenetetramine as basic catalysts, and 38.7 parts by weight of water. was put into the same separable flask and heated for 1 hour while maintaining the temperature at 60°C to proceed with the reaction. Thereafter, the mixture was heated to 95° C. or higher and refluxed for 4 hours to obtain a phenol resin. Activated carbon 2 was obtained in the same manner as activated carbon 1 except that the phenol resin was used.

<Activated carbon 3>
In a 1 liter separable flask, 163.0 parts by weight of 90% phenol, 88.6 parts by weight of 37% formaldehyde, 0.7 parts by weight of oxalic acid as an acidic catalyst, 2.2 parts by weight of gum arabic as an emulsifier, and water. 152.6 parts by weight was added and heated to 95° C. or higher to appropriately polymerize. Next, 126.6 parts by weight of 90% phenol, 177.1 parts by weight of 37% formaldehyde, 18.2 parts by weight of hexamethylenetetramine and 7.8 parts by weight of triethylenetetramine as basic catalysts, and 44.0 parts by weight of water. was put into the same separable flask and heated for 1 hour while maintaining the temperature at 60°C to proceed with the reaction. Thereafter, the mixture was heated to 95° C. or higher and refluxed for 4 hours to obtain a phenol resin. Activated carbon 3 was obtained in the same manner as activated carbon 1 except that the phenol resin was used.

<Activated carbon 4>
After putting 500 g of phenol resin (manufactured by Lignite Co., Ltd., "LPS-1046") into a cylindrical retort electric furnace and sealing it with nitrogen, the temperature was raised at 100°C for 1 hour, and the temperature was maintained at 600°C for 1 hour. The phenolic resin inside was carbonized. Thereafter, the carbide was heated to 900° C., steam was injected into the furnace, and the temperature was maintained at 900° C. for 5 hours for activation to obtain activated carbon A. Further, 80 g of the activated carbon A was put into a cylindrical retort electric furnace and nitrogen was sealed therein, and then the temperature was raised at a rate of 100°C/1 hour until it reached 900°C. Thereafter, steam was injected into the furnace and maintained at 900° C. for 0.5 hours for further activation, and activated carbon 4 was obtained.

<Activated carbon 5>
Using the activated carbon A created in the process of preparing activated carbon 4, 80 g of the activated carbon A was placed in a cylindrical retort electric furnace, nitrogen was sealed in it, and the temperature was raised at 100°C/1 hour until it reached 900°C. . Thereafter, steam was injected into the furnace and maintained at 900° C. for 1 hour for further activation, to obtain activated carbon 5.

[Activated carbon measurement]
[BET specific surface area]
The specific surface area (m ² /g) was determined by measuring the nitrogen adsorption isotherm at 77K using an automatic specific surface area/pore distribution measuring device (manufactured by Microtrac Bell Co., Ltd., "BELSORP-mini II"), and using the BET method. (BET specific surface area).

[Filling density]
The packing density (g/ml) was measured according to JIS K 1474 (2014).

[Average particle size]
The average particle diameter (μm) is measured using a laser light scattering particle size distribution analyzer (Shimadzu Corporation, "SALD3000S"), and is calculated at 50% of the integrated value of the particle size distribution determined by the laser diffraction/scattering method. Particle size.

[Micropore volume]
In this specification, micropores are pores with a pore diameter of less than 3 nm, and the sum of micropore volumes (V _mic ) (ml/g) is defined as the pore volume value of pores with a pore diameter of less than 3 nm. It was calculated as the sum of (ml/g). The nitrogen adsorption isotherm at 77K was measured using an automatic specific surface area/pore distribution measuring device ("BELSORP-mini II", manufactured by Microtrac Bell Co., Ltd.). From the obtained adsorption isotherm, calculations were made using the attached analysis software using the Saito-Foley three-color method, targeting a range of pore diameters of less than 3 nm. The various parameters used in the calculation are as follows.
Diameter of adsorbate molecule: 0.3000nm
Adsorbent atom diameter: 0.3400nm
Number of molecules per unit surface area of adsorbate in adsorption state: 8.5200E+18 molecules/m ²
Number of atoms per unit surface area of adsorbent: 1.3100E+19 molecules/m ²
Magnetic susceptibility of adsorbate molecules: 3.2500E-29cm ³
Magnetic susceptibility of adsorbent molecules: 1.3000E- ^29cm3
Polarizability of adsorbate molecules: 1.6300E- ^24cm3
Polarizability of adsorbent molecules: 2.5000E- ^24cm3

[Mesopore volume]
In this specification, mesopores are pores with a pore diameter of 3 to 50 nm, and the sum of mesopore volumes (V _met ) (ml/g) is determined using "Autopore 9500" (manufactured by Shimadzu Corporation). The contact angle was set to 130°, the surface tension was set to 484 dynes/cm (4.84 mN/m), and the pore volume value by mercury intrusion method with a pore diameter of 3 to 50 nm was calculated as the sum of the mesopore volumes (ml/g). I asked for it as.

[Volume ratio]
The volume ratio (V _m ) is the value obtained by dividing the sum of micropore volumes (V _mic ) (ml/g) by the sum of mesopore volumes (V _met ) (ml/g), and is calculated by the above formula (i). Calculated from.

[Macropore volume]
In this specification, macropores are pores with a pore diameter of 50 to 15,000 nm, and the sum of macropore volumes (ml/g) is determined by using "Autopore 9500" (manufactured by Shimadzu Corporation) and contact angle The pore volume value was determined as the sum of the macropore volumes (ml/g) by mercury porosimetry with a pore diameter of 50 to 15,000 nm at a temperature of 130° and a surface tension of 484 dynes/cm (4.84 mN/m).

The physical properties of activated carbons 1 to 5 are shown in Table 1. From the top of Table 1, BET specific surface area (m ² /g), packing density (g/ml), average particle diameter (μm), sum of micropore volumes (V _mic ) (ml/g), mesopore volume (V _met ) (ml/g), the volume ratio (V _m ), and the sum of macropore volumes (ml/g).

[Additives used]
The inventor used the following additives to obtain tablet-type adsorbents for oral administration of each trial production example.
・Carboxymethylcellulose sodium (CMC-Na): (manufactured by Daicel Corporation)
・Hydroxyethyl cellulose (HEC): (manufactured by Sumitomo Seika Co., Ltd.)
・Pullulan (PUL): (manufactured by Hayashibara Co., Ltd.)
・Hydroxypropylcellulose (HPC): (manufactured by Nippon Soda Co., Ltd.)

<Prototype example 1>
0.3018 g of activated carbon 1, 0.0019 g of sodium carboxymethylcellulose (CMC-Na) (0.6%) as an additive, and 0.3177 g of water were mixed to make a mixture, and the mixture was made into a mixture of 13 mm in diameter and 6 mm in depth. It was filled into a mold (molding mold) and molded. After the mold was left in a dryer, it was heated and dried at an internal temperature of 100° C. for 1 hour or more, and then taken out from the mold to prepare a tablet-shaped adsorbent for oral administration as Prototype Example 1.

<Prototype example 2>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 1 was 0.3003g, sodium carboxymethyl cellulose (CMC-Na) (0.9%) 0.0028g, and water 0.3827g. The tablet-type adsorbent for oral administration of Example 2 was prepared.

<Prototype example 3>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 1 was 0.2987g, sodium carboxymethylcellulose (CMC-Na) (1.5%) 0.0045g, and water 0.3532g. The tablets for oral administration of Example 3 were prepared.

<Prototype example 4>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 1 was 0.2976g, sodium carboxymethyl cellulose (CMC-Na) (2.0%) 0.0060g, and water 0.3694g. The tablets for oral administration of Example 4 were prepared.

<Prototype example 5>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 2 was 0.3436g, sodium carboxymethyl cellulose (CMC-Na) (0.6%) 0.0021g, and water 0.3293g. The tablets for oral administration of Example 5 were prepared.

<Prototype example 6>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 2 was 0.3446g, sodium carboxymethylcellulose (CMC-Na) (0.9%) 0.0032g, and water 0.3617g. The tablets for oral administration of Example 6 were prepared.

<Prototype example 7>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 2 was 0.3408g, sodium carboxymethylcellulose (CMC-Na) (1.5%) 0.051g, and water 0.3438g. The tablets for oral administration of Example 7 were prepared.

<Prototype example 8>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 2 was 0.3405g, sodium carboxymethyl cellulose (CMC-Na) (2.0%) 0.0069g, and water 0.3310g. The tablets for oral administration of Example 8 were prepared.

<Prototype example 9>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 3 was 0.3759g, sodium carboxymethyl cellulose (CMC-Na) (0.6%) 0.0023g, and water 0.3317g. The tablets for oral administration of Example 9 were prepared.

<Prototype example 10>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 3 was 0.3566g, sodium carboxymethylcellulose (CMC-Na) (0.9%) 0.0034g, and water 0.3566g. The tablets for oral administration of Example 10 were prepared.

<Prototype example 11>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 3 was 0.3713g, sodium carboxymethylcellulose (CMC-Na) (1.5%) 0.0057g, and water 0.3432g. The tablets for oral administration of Example 11 were prepared.

<Prototype example 12>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 3 was 0.3712g, sodium carboxymethylcellulose (CMC-Na) (2.0%) 0.0076g, and water 0.3941g. The tablets for oral administration of Example 12 were prepared.

<Prototype example 13>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 4 was 0.5686g, sodium carboxymethylcellulose (CMC-Na) (0.6%) 0.0034g, and water 0.3953g. The tablets for oral administration of Example 13 were prepared.

<Prototype example 14>
Prototype production was conducted in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 4 was 0.5717g, sodium carboxymethyl cellulose (CMC-Na) (0.9%) 0.0052g, and water 0.3518g. The tablets for oral administration of Example 14 were prepared.

<Prototype example 15>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 4 was 0.5629g, sodium carboxymethylcellulose (CMC-Na) (1.5%) 0.0086g, and water 0.4135g. The tablets for oral administration of Example 15 were prepared.

<Prototype example 16>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 4 was 0.5600g, sodium carboxymethyl cellulose (CMC-Na) (2.0%) 0.0115g, and water 0.4316g. The tablets for oral administration of Example 16 were prepared.

<Prototype example 17>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 5 was 0.5213g, sodium carboxymethylcellulose (CMC-Na) (0.6%) 0.0031g, and water 0.3546g. The tablets for oral administration of Example 17 were prepared.

<Prototype example 18>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 5 was 0.5255g, sodium carboxymethylcellulose (CMC-Na) (0.9%) 0.0047g, and water 0.4021g. The tablets for oral administration of Example 18 were prepared.

<Prototype example 19>
Prototype production was conducted in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 5 was 0.5156g, sodium carboxymethylcellulose (CMC-Na) (1.5%) 0.0079g, and water 0.4666g. The tablets for oral administration of Example 19 were prepared.

<Prototype example 20>
Prototype production was carried out in the same manner as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 5 was 0.5132g, sodium carboxymethyl cellulose (CMC-Na) (2.0%) 0.0105g, and water 0.4269g. The tablets for oral administration of Example 20 were prepared.

<Prototype example 21>
The tablet adsorbent for oral administration of Prototype Example 1 was the same as the tablet-type adsorbent for oral administration of Prototype Example 1, except that activated carbon 1 was 0.3019 g, hydroxyethyl cellulose (HEC) (0.6%) 0.0018 g, and water 0.2708 g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 22>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that the activated carbon 1 was 0.3009 g, 0.0027 g of hydroxyethyl cellulose (HEC) (0.9%), and 0.2862 g of water. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 23>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 1 was 0.2982 g, hydroxyethyl cellulose (HEC) (1.5%) 0.0045 g, and water was 0.2777 g. It was made into a tablet for oral administration.

<Prototype example 24>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 1 was 0.2970 g, hydroxyethyl cellulose (HEC) (2.0%) 0.0060 g, and water was 0.3180 g. It was made into a tablet for oral administration.

<Prototype example 25>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 2 was 0.3438 g, hydroxyethyl cellulose (HEC) (0.6%) 0.0021 g, and water was 0.3295 g. It was made into a tablet for oral administration.

<Prototype example 26>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 2 was 0.3425 g, hydroxyethyl cellulose (HEC) (0.9%) 0.0032 g, and water was 0.2979 g. It was made into a tablet for oral administration.

<Prototype example 27>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 2 was 0.3415 g, hydroxyethyl cellulose (HEC) (1.5%) 0.0052 g, and water was 0.2941 g. It was made into a tablet for oral administration.

<Prototype example 28>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 2 was 0.3398 g, hydroxyethyl cellulose (HEC) (2.0%) 0.0070 g, and water was 0.3163 g. It was made into a tablet for oral administration.

<Prototype example 29>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 3 was 0.3763 g, hydroxyethyl cellulose (HEC) (0.6%) 0.0024 g, and water was 0.2992 g. It was made into a tablet for oral administration.

<Prototype example 30>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 3 was 0.3739 g, hydroxyethyl cellulose (HEC) (0.9%) 0.0034 g, and water was 0.2702 g. It was made into a tablet for oral administration.

<Prototype example 31>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 3 was 0.3703 g, hydroxyethyl cellulose (HEC) (1.5%) 0.0058 g, and water was 0.3268 g. It was made into a tablet for oral administration.

<Prototype example 32>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 3 was 0.3698 g, hydroxyethyl cellulose (HEC) (2.0%) 0.0076 g, and water was 0.3202 g. It was made into a tablet for oral administration.

<Prototype example 33>
The tablet adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 3, except that activated carbon 4 was 0.5683 g, hydroxyethyl cellulose (HEC) (0.6%) 0.0034 g, and water was 0.03090 g. It was made into a tablet for oral administration.

<Prototype example 34>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 4 was 0.5718 g, hydroxyethyl cellulose (HEC) (0.9%) 0.0052 g, and water was 0.3218 g. It was made into a tablet for oral administration.

<Prototype example 35>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 4 was 0.5629 g, hydroxyethyl cellulose (HEC) (1.5%) 0.0087 g, and water was 0.3733 g. It was made into a tablet for oral administration.

<Prototype example 36>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 4 was 0.5615 g, hydroxyethyl cellulose (HEC) (2.0%) 0.0115 g, and water was 0.4142 g. It was made into a tablet for oral administration.

<Prototype example 37>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 5 was 0.5212 g, hydroxyethyl cellulose (HEC) (0.6%) (0.0032 g), and water was 0.4607 g. It was made into a tablet for oral administration.

<Prototype example 38>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 5 was 0.5267 g, hydroxyethyl cellulose (HEC) (0.9%) 0.0048 g, and water was 0.3348 g. It was made into a tablet for oral administration.

<Prototype example 39>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 5 was 0.5154 g, hydroxyethyl cellulose (HEC) (1.5%) 0.0078 g, and water was 0.4147 g. It was made into a tablet for oral administration.

<Prototype example 40>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 5 was 0.5128 g, hydroxyethyl cellulose (HEC) (2.0%) 0.0105 g, and water was 0.4258 g. It was made into a tablet for oral administration.

<Prototype example 41>
The tablet-type adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 1 was 0.3002 g, pullulan (PUL) (0.6%) 0.0019 g, and water was 0.3341 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 42>
The tablet-type adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 1 was 0.2999 g, pullulan (PUL) (0.9%) 0.0027 g, and water was 0.3251 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 43>
The tablet-type adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 2 was 0.3441 g, pullulan (PUL) (0.6%) 0.0021 g, and water was 0.3694 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 44>
The tablet-type adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 2 was 0.3420 g, pullulan (PUL) (0.9%) 0.0032 g, and water was 0.3657 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 45>
The tablet-type adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 3 was 0.3764 g, pullulan (PUL) (0.6%) 0.0024 g, and water was 0.3500 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 46>
The tablet-type adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 3 was 0.3748 g, pullulan (PUL) (0.9%) 0.0034 g, and water was 0.3770 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 47>
The tablet-type adsorbent for oral administration of Prototype Example 1 was the same as that of Prototype Example 1, except that activated carbon 4 was 0.5687 g, pullulan (PUL) (0.6%) 0.0034 g, and water was 0.3993 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 48>
The tablet-type adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 4 was 0.5730 g, pullulan (PUL) (0.9%) 0.0052 g, and water was 0.4362 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 49>
The tablet-type adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 5 was 0.5219g, pullulan (PUL) (0.6%) 0.0032g, and water was 0.3991g. It was made into a tablet-type adsorbent for administration.

<Prototype example 50>
The tablet adsorbent for oral administration in Prototype Example 1 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 5 was 0.5224 g, pullulan (PUL) (0.9%) 0.0048 g, and water was 0.4042 g. It was made into a tablet-type adsorbent for administration.

<Prototype example 51>
Prototype Example 51 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 1 was 0.3018g, hydroxypropyl cellulose (HPC) (0.6%) 0.0018g, and water 0.2880g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 52>
Prototype Example 52 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 1 was 0.3008g, hydroxypropylcellulose (HPC) (0.9%) 0.0027g, and water 0.2811g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 53>
Prototype Example 53 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 2 was 0.3443g, hydroxypropyl cellulose (HPC) (0.6%) 0.0021g, and water 0.3282g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 54>
Prototype Example 54 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 2 was 0.3440 g, hydroxypropyl cellulose (HPC) (0.9%) 0.0031 g, and water 0.3055 g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 55>
Prototype Example 55 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 3 was 0.3744g, hydroxypropyl cellulose (HPC) (0.6%) 0.0023g, and water 0.3561g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 56>
Prototype Example 56 was the same as the tablet-type adsorbent for oral administration of Prototype Example 1, except that activated carbon 3 was 0.3754 g, hydroxypropyl cellulose (HPC) (0.9%) 0.0035 g, and water 0.2491 g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 57>
Prototype Example 57 was the same as the tablet-type adsorbent for oral administration of Prototype Example 1, except that activated carbon 4 was 0.5687g, hydroxypropyl cellulose (HPC) (0.6%) 0.0035g, and water 0.3141g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 58>
Prototype Example 58 was the same as the tablet-type adsorbent for oral administration of Prototype Example 1, except that activated carbon 4 was 0.5732g, hydroxypropyl cellulose (HPC) (0.9%) 0.0052g, and water 0.2952g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 59>
Prototype Example 59 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1, except that activated carbon 5 was 0.5217g, hydroxypropylcellulose (HPC) (0.6%) 0.0032g, and water 0.4189g. It was made into a tablet-type adsorbent for oral administration.

<Prototype example 60>
Prototype Example 60 was the same as the tablet-type adsorbent for oral administration in Prototype Example 1 except that activated carbon 5 was 0.5248g, hydroxypropylcellulose (HPC) (0.9%) 0.0047g, and water 0.3689g. It was made into a tablet-type adsorbent for oral administration.

[Measurement of tablet-type adsorbent for oral administration]
[Moldability]
For moldability, each prototype was rated "○" if it could be molded into a tablet shape, and "x" if it could not be molded into a tablet shape or had defects such as chips or cracks during the process of taking it out of the mold. And so.

〔hardness〕
The hardness (N) was measured using a digital hardness meter (manufactured by As One Corporation, "KHT-40N"), and the breaking strength at the time when the tablet-type adsorbent for oral administration was broken was measured as hardness.

The physical properties of each prototype are shown in Tables 2 to 16. In addition to the feasibility of tablet molding and the hardness (N), the composition includes the type of activated carbon used, the type of additive, the concentration (%) of the additive, and the solid-liquid ratio (ml/g). Note that the solid-liquid ratio is the value obtained by dividing the volume of water used in the trial production by the total weight of activated carbon and additives. Tables 2 to 6 show the results of prototype examples 1 to 20 using sodium carboxymethyl cellulose (CMC-Na) as an additive, Tables 7 to 11 show the results of prototype examples 21 to 40 using hydroxyethyl cellulose (HEC), The results of Prototype Examples 41 to 50 using PUL) are shown in Tables 12 to 14, and the results of Prototype Examples 51 to 60 using hydroxypropyl cellulose (HPC) are shown in Tables 14 to 16.

[Adsorption performance evaluation]
The inventor conducted an adsorption test to measure the adsorption rate of nitrogen-containing compounds that can cause uremia and the like. Therefore, we selected four types of toxic substances from nitrogen-containing low-molecular compounds: "indole,""indole acetic acid,""indoxylsulfate," and "tryptophan," and used activated carbons 1 to 5 and each prototype for oral administration. The adsorption rate (%) of the four types of molecules was measured for the tablet-shaped adsorbent.

Regarding the adsorption rates of the four types of substances, standard solutions with a concentration of 0.1 g/l were prepared by dissolving each of the above substances in a phosphate buffer solution of pH 7.4.
To 50 ml of a standard solution of indole, 0.01 g of each of granular activated carbons 1 to 5, which had been heat-dried in advance at 120° C. for 15 minutes or more in a static dryer, was added, followed by contact shaking at a temperature of 37° C. for 3 hours.
To 50 ml of a standard solution of indole acetic acid was added 0.01 g each of granular activated carbons 1 to 5, which had been heat-dried in advance at 120° C. for 15 minutes or more in a static dryer, and subjected to contact shaking at a temperature of 37° C. for 3 hours.
To 50 ml of a standard solution of indoxyl sulfuric acid, 0.01 g each of granular activated carbon 1 to 5, which had been heat-dried in advance at 120° C. for 15 minutes or more in a static dryer, was added, followed by contact shaking at a temperature of 37° C. for 3 hours.
To 50 ml of a standard solution of tryptophan, 0.01 g of each of activated carbons 1 to 5, which had been heat-dried in advance at 120° C. for 15 minutes or more in a static dryer, was added, followed by contact shaking at a temperature of 37° C. for 3 hours.

Thereafter, the absorbance at 279 nm of the filtrate obtained by filtration was measured by spectrophotometry using a spectrophotometer (Shimadzu Corporation, "UVmini-1240"). The adsorption rate (%) of each adsorbed substance was determined from equation (ii).

Table 17 shows the adsorption rate of each substance in activated carbons 1 to 5.

Then, the degree of decrease in adsorption performance was calculated as the adsorption ratio by dividing the adsorption rate of the tablet-type adsorbent for oral administration by the adsorption rate of each activated carbon used. Tables 18 to 22 show the results of prototype examples 1 to 20 using sodium carboxymethyl cellulose (CMC-Na) as an additive, Tables 23 to 27 show the results of prototype examples 21 to 40 using hydroxyethyl cellulose (HEC), The results of Prototype Examples 41 to 50 using PUL) are shown in Tables 28 to 30, and the results of Prototype Examples 51 to 60 using hydroxypropyl cellulose (HPC) are shown in Tables 30 to 32.

Regarding the adsorption rate of each prototype tablet-type adsorbent for oral administration, the tablet-type adsorbent for oral administration was appropriately crushed using a spatula, and then heated and dried at 120°C for 15 minutes or more in a stationary dryer. . Thereafter, 0.01 g of the crushed tablet-type adsorbent for oral administration, which is the actual total amount of activated carbon excluding additives, was added to 50 ml of standard solutions of the four substances, and the mixture was subjected to contact shaking at a temperature of 37° C. for 3 hours. . Thereafter, the absorbance at 279 nm of the filtrate obtained by filtration was measured by spectrophotometry using a spectrophotometer (Shimadzu Corporation, "UVmini-1240"). The adsorption rate (%) of each adsorbed substance was determined from the above equation (ii).

[Results/Discussion]
As shown in Tables 2 to 16, pullulan and hydroxypropylcellulose were used when the amount of binder added was 0.6% by weight based on 100% by weight of the tablet-type adsorbent. In trial production examples 41, 43, 45, 51, 53, 55, 57, and 59, it was not possible to form the tablet into a tablet shape. It is thought that the binding force of the binder was not sufficiently exerted because the concentration of the additive was low. Prototypes 1 to 40 using sodium carboxymethyl cellulose or hydroxyethyl cellulose as the binder were all able to be formed into tablets well. Sodium methylcellulose or hydroxyethylcellulose has been shown to be suitable.

In addition, although there was a tendency for the hardness of the tablet-type adsorbent to increase as the concentration of the binder was increased, we used carboxymethyl cellulose sodium or hydroxyethyl cellulose as the binder, and the amount added was 1.0% by weight. In the prototype examples 2, 6, 10, 14, 18, 22, 26, 30, 34, and 38, which have a low hardness of 0.9% by weight, the hardness is higher than 10N, and the tablet type adsorption is easy to handle. It was shown that it is more suitable as an agent. In addition, even in prototype examples 1, 5, 13, 17, 25, 29, and 37, in which the amount of the binder added was 0.6 parts by weight, the hardness was 10 N or more, and in prototype examples 9 and 21, the hardness was approximately was 10N, and it was understood that sufficient moldability was ensured even with a small amount added.

In particular, in a prototype example using sodium carboxymethylcellulose as a binder, when it was added at concentrations of 1.5% and 2.0% by weight, the hardness of the prototype example with an addition amount of 1.5% by weight was higher. It was understood that the amount of binder may be high, and that there is no change even if the amount of binder added is above a certain amount.

Next, as shown in Tables 18 to 22, Prototype Examples 1 to 20 using sodium carboxymethyl cellulose as the binder, and Prototype Examples 1 to 12 using activated carbons 1 to 3, which are activated carbons with low packing density, and When comparing prototype examples 13 to 20 using activated carbon 4 and 5, which are activated carbons with a high packing density, the adsorption rate and adsorption ratio of indole acetic acid and indoxyl sulfuric acid were particularly high in prototype examples 13 to 20, which used activated carbon 4 and 5. The results were significantly inferior. Activated carbon with a high packing density has many carbon parts and few pores, so even if the pores are blocked by additives in a very small amount, it has a large effect on the adsorption rate, so it was formed into a tablet shape based on the adsorption performance of the activated carbon raw material. It is thought that the drop in adsorption performance became greater when the temperature was lowered. For this reason, it is preferable that the activated carbon used in the tablet-type adsorbent has a low packing density, particularly a packing density of 0.3 to 0.5 g/ml.

Furthermore, it was understood that the balance of pores formed in activated carbon also contributes to the adsorption performance of toxic substances and to suppressing the decrease in adsorption performance when formed into a tablet shape. A small volume ratio (V _m ) indicates that micropores and mesopores have developed in a well-balanced manner. Each toxic substance can smoothly reach the micropores from the macropores through the mesopores and be adsorbed. Furthermore, since it is thought that a certain degree of pores are blocked by the binder, it is better to use activated carbon, which has more developed mesopores than normal activated carbon, to reduce adsorption performance when formed into a tablet shape. It is thought that it is possible to suppress the From this, it is preferable to use activated carbon in which the volume ratio (V _m ) of the sum of mesopore volumes to the sum of micropore volumes is 5.0 or less.

In addition, as shown in Prototype Examples 21 to 40 using hydroxyethyl cellulose as a binder shown in Tables 23 to 27, in addition to the packing density and volume ratio, if the specific surface area is 1400 m ² /g or more, indole acetic acid It was found that the deterioration of adsorption performance can be further suppressed.

The types of binders are shown in Tables 18 to 32, and as mentioned above, pullulan and hydroxypropyl cellulose are not very suitable for forming into tablets with small amounts added, and sodium carboxymethyl cellulose or hydroxyethyl cellulose was used. Comparing the prototype example and the prototype example using pullulan or hydroxypropyl cellulose, it was found that the adsorption performance of the activated carbon raw material deteriorated significantly when molded into a tablet shape. For this reason, sodium carboxymethylcellulose or hydroxyethylcellulose is suitable as a binder additive that can form activated carbon into a tablet shape even with a small amount of addition, and can also suppress a decline in the adsorption performance of activated carbon. It was shown that

As shown in Tables 18 to 20 and 23 to 25, when the amount of additive as a binder is 1% by weight or less, the deterioration of the adsorption performance of the activated carbon raw material when molded into a tablet shape can be suppressed. It was shown that It is easily understood that the decrease in adsorption performance due to the pores of activated carbon being blocked by the binder can be suppressed by reducing the amount of binder added. However, considering the physical properties of activated carbon shown in Tables 1 to 32 and the measurement results of the tablet-type adsorbents of each prototype, it is clear that the physical properties of the raw activated carbon and the type of binder do not depend only on the amount of binder added. It was found that this contributes to suppressing the decline in adsorption performance.

[summary]
As shown in the above prototype examples, the tablet-shaped adsorbent is formed into a tablet by using activated carbon with a low packing density as the base carbon and adding a very small amount of sodium carboxymethyl cellulose or hydroxyethyl cellulose as an additive. It was found that the decline in the adsorption performance of charcoal for toxic substances can be suppressed. In addition, by reducing the volume ratio of the sum of mesopore volumes to the sum of micropore volumes, even if additives are adsorbed to macropores or mesopores, it becomes difficult for toxic substances to reach micropores. It was understood that this contributes to suppressing the decline in adsorption performance of tablet-type adsorbents for oral administration. It was shown that by using sodium carboxymethylcellulose or hydroxyethylcellulose as an additive, it has a certain hardness even in a very small amount, and is suitable for a tablet-type adsorbent.

The tablet-type adsorbent for oral administration of the present invention can suppress the decline in the adsorption performance of activated carbon, which is an adsorbent with high adsorption performance for toxic substances, making it easier to take and suppressing increases in dosage and volume. , it is possible to reduce the burden of medication on patients. In addition, since it is easy to take, it is possible to quickly adsorb nitrogen-containing compounds that reach the digestive tract and cause uremia, renal function, liver dysfunction, etc. through oral administration, and is therefore promising as a therapeutic or preventive agent. It is.

Claims (4)

A tablet-type adsorbent for oral administration comprising activated carbon as an adsorbent and an additive as a binder,
The average particle diameter of the activated carbon is 20 to 1000 μm, and the packing density is 0.3 to 0.5 g/ml,
A tablet-type adsorbent for oral administration, characterized in that the additive contains at least one of sodium carboxymethylcellulose or hydroxyethylcellulose, and is added in an amount of 1.0% by weight or less based on 100% by weight of the tablet-type adsorbent. . The tablet-type adsorbent for oral administration according to claim 1, wherein the tablet-type adsorbent has a hardness of 10N or more. The oral cavity according to claim 1 or 2, wherein the volume ratio (V _m ) of the mesopore volume (V _met ) to the micropore volume (V _mic ) defined by the following formula (i) of the activated carbon is 5.0 or less. Tablet type adsorbent for administration.

The tablet-type adsorbent for oral administration according to any one of claims 1 to 3, wherein the activated carbon is a resin charcoal of a phenolic resin.