JP2022038117A - Tablet-type adsorbent for oral administration - Google Patents

Abstract

To provide a tablet-type adsorbent for oral administration that can reduce a decline in performance of adsorbing toxic substances in activated carbon to reduce the burden on a patient to take a drug, even when the activated carbon as an adsorbent is formed into an easy-to-dose tablet form by using an additive as a binding agent.SOLUTION: Provided is a tablet-type adsorbent for oral administration. The adsorbent comprises activated carbon as an adsorbent and an additive as a binding agent. The activated carbon has an average particle size of 20 to 1000 μm and a packing density of 0.3 to 0.5/ml. The additive comprises at least one of sodium carboxymethyl cellulose or hydroxyethyl cellulose, and is added in an amount of 1.0% by weight or less based on 100% by weight of the tablet-type adsorbent.SELECTED DRAWING: None

Description

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

Patients with renal or liver disease accumulate toxic substances in their blood, resulting in encephalopathy such as uremia and impaired consciousness. The number of these patients tends to increase year by year. Hemodialysis-type artificial kidneys that remove toxic substances from the body are used to treat patients. However, such an artificial kidney requires a specialized technician for handling from the viewpoint of safety management, and it is regarded as a problem that it requires a physical, mental, and financial burden on the patient when removing blood from the body. It is not always satisfactory.

As an alternative method to artificial organs, an adsorbent for oral administration, which is taken orally, adsorbs a toxic substance in the body, and is discharged to the outside of the body, has been developed (see Patent Document 1, Patent Document 2, etc.). An anti-nephrotic syndrome agent using petroleum-based hydrocarbon (pitch) or the like as a raw material, adjusted so that the particle size is relatively uniform, and carbonized and activated has been reported (see, for example, Patent Document 3). .. Further, an adsorbent for oral administration has been reported in which the particle size of the activated carbon itself is made relatively uniform and the distribution of the pore volume and the like in the activated carbon is adjusted (see Patent Document 4). As described above, the medicated activated carbon improves the poor fluidity in the intestine by making the particle size relatively uniform, and at the same time, improves the adsorption performance of the activated carbon by adjusting the pores. planned. Therefore, it is taken by many patients with mild chronic renal failure.

Medicinal activated carbon is required to rapidly and efficiently adsorb the causative substance of uremia and its precursor. However, with existing medicated activated carbon, it is difficult to reduce the particle size while keeping the shape spherical. In addition, the adjustment of pores in the conventional medicated activated carbon is not good, and the adsorption performance is not always sufficient, so the daily dose must be increased. In particular, since the intake of water is restricted in patients with chronic renal failure, swallowing with a small amount of water has been a great pain for the patients.

Then, a tablet-type orally-administered composition in which medicated activated carbon is used as a tablet and is easy to take has been proposed (see, for example, Patent Document 5). Since the dose of medicated activated carbon is large, the volume of administration is large, and since activated carbon does not dissolve in water, if it is a fine-grained type, discomfort in the oral cavity remains and it cannot be said that it is easy to take. In addition, if the capsule type is used, a dead volume is formed, so that the volume to be taken becomes larger and it is difficult to swallow.

Although the above-mentioned tablet-type composition for oral administration is intended to reduce the burden of administration by patients, the binder tends to block the pores on the surface of the activated carbon and the adsorption performance is deteriorated, so that the adsorption performance is deteriorated. Dosage may need to be increased. Therefore, as a result, the burden of taking the drug may not change much, or conversely, the burden may increase.

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

Therefore, the present invention has been proposed in view of the above-mentioned situation, and even when the 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 the toxic substance of the activated carbon Provided is a tablet-type adsorbent for oral administration, which can suppress the decrease in the amount of the adsorbent and can reduce the burden on the patient.

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 activated carbon has an average particle size of 20 to 1000 μm and is filled. The density is 0.3 to 0.5 g / ml, the additive contains at least one of sodium carboxymethyl cellulose or hydroxyethyl cellulose, and 1.0% by weight or less is added to 100% by weight of the tablet-type adsorbent. The present invention relates to a tablet-type adsorbent for oral administration, which is characterized by being.

The second invention relates to the tablet-type adsorbent for oral administration in which the hardness of the tablet-type adsorbent is 10 N or more in the first invention.

The third invention is the volume ratio of the sum of the mesopore volumes (V _met ) to the sum of the micropore volumes (V _mic ) specified in the following formula (i) of the activated carbon in the first or second invention. The present invention relates to a tablet-type adsorbent for oral administration having a V _m ) of 5.0 or less.

The fourth invention relates to a tablet-type adsorbent for oral administration in which the activated carbon is a resin carbide of a phenol resin in any one of the first to third inventions.

According to the first invention, the tablet-type adsorbent for oral administration is a tablet-type adsorbent for oral administration containing activated charcoal as an adsorbent and an additive as a binder, and the average particle size of the activated charcoal is large. 1. Since it is added in an amount of 0% by weight or less, it is possible to suppress a decrease in the adsorption performance of toxic substances of the activated charcoal even when the activated charcoal as an adsorbent is formed into a tablet shape that is easy to take by the additive as a binder. , It is possible to reduce the burden of taking the patient.

According to the tablet-type adsorbent for oral administration according to the second invention, in the first invention, since the hardness of the tablet-type adsorbent is 10 N or more, damage and wear of the tablet during transportation and packaging are suppressed. And the dosage form can be maintained.

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 the micropore volumes (V _mic ) specified in the following formula (i) of the activated carbon. Since the volume ratio (V _m ) of the sum of (V _met ) is 5.0 or less, it is possible to further suppress the deterioration of the adsorption performance of the toxic substance of activated carbon, and it is possible to reduce the burden of administration by the patient. can

According to the tablet-type adsorbent for oral administration according to the fourth invention, since the activated carbon is a resin carbide of a phenol resin in any of the first to third inventions, it is a toxic substance when molded into a tablet type. It is possible to use activated carbon that can suppress the deterioration of the adsorption performance of the above.

The tablet-type adsorbent for oral administration of the present invention is formed into a tablet shape by using activated carbon as an adsorbent and an additive using activated carbon as a binder. The hardness of the molded tablet-type adsorbent is preferably higher than about 10N, and 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. ..

In addition, the activated carbon should be a resin carbide of a phenol resin. By using phenolic resin as the raw material for activated carbon, it is possible to increase the ratio (volume ratio) of the sum of the mesopore volumes to the sum of the micropore volumes while increasing the activation and increasing the specific surface area, and adsorbing toxic substances. This is because it is easy to improve the performance. Examples of the phenol resin include known ones such as novolak type and resol type, as well as a composite phenol resin of both. The phenolic resin is preferably in a range of granular or spherical activated carbon having an average particle diameter in the range 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 tablets, and the disintegration property may deteriorate. 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 are bonded to each other becomes large due to the additive as a binder, so that the bonding force may be weakened and the hardness of the tablet may be lowered.

In addition to phenolic resin, cellulose can be used as a raw material for activated carbon. When cellulose is used, it is considered that by using activated carbon with many macropores, it is possible to suppress the deterioration of the adsorption performance derived from activated carbon when it is made into a tablet type by using an additive.

In the present invention, as shown in Examples described later, 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, and 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 5.0 or less, it is derived from activated carbon when it is made into a tablet type using additives. It is possible to suppress the deterioration of adsorption performance.

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

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

After washing with dilute hydrochloric acid, if necessary, the activated carbon adsorbent is heat-treated and washed with water in a mixed gas of oxygen and nitrogen to remove impurities such as ash. The residual hydrochloric acid and the like are removed by the heat treatment. Then, the amount of surface oxide of the activated carbon adsorbent is adjusted by going through each treatment. After pickling, the amount of surface oxide of the activated carbon adsorbent increases through heat treatment of the activated resin carbide. The oxygen concentration during the treatment is 0.1 to 21% by volume. The heating temperature is 150 to 1000 ° C, preferably 400 to 800 ° C, and is 15 minutes to 2 hours.

The resin carbide (activated carbon adsorbent) after the activation treatment or after the heat treatment following the activation treatment is sorted into granular or spherical activated carbon having an average particle diameter of 20 to 1000 μm, more preferably 150 to 350 μm by sieving. Is good. By adjusting and separating the particle size, the adsorption rate of the activated carbon adsorbent can be stabilized and the adsorption capacity can be stabilized. The range of the particle size is not particularly limited, but if it is within the above range, the surface area of the activated carbon adsorbent can be secured. In addition, if the particle sizes are the same, the adsorption performance in the digestive tract can be stabilized. Moreover, the hardness of the particles is maintained, and further powdering in the digestive tract after oral administration (after administration) is suppressed. Therefore, the shape of the activated carbon of the adsorbent for oral administration is preferably spherical. However, since variations in sphericity due to manufacturing are allowed, granules are also included.

Since the phenol resin has an aromatic ring structure in the molecule, the carbonization yield is increased. 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, palm husks, and petroleum pitches. Therefore, nitrogen-containing nitrogen-containing ionic organic compounds having a relatively small molecular weight (molecular weight in the range of tens to hundreds) such as indoxyl sulfate, aminoisobutyric acid, and tryptophan represented by the causative substance of uremia and its precursors. Suitable for adsorption. In addition, phenolic resin has a lower ash content such as nitrogen, phosphorus, sodium, and magnesium as compared with the wood of the conventional activated carbon raw material, and the ratio of carbon per unit mass is high. Therefore, activated carbon with few impurities can be obtained.

The above-mentioned activated carbon is required to adsorb the causative substances of hepatic dysfunction and renal dysfunction listed in the examples below as quickly as possible, and to exhibit sufficient adsorption performance with a relatively small dose. Activated carbon is defined by an index such as a mercury pore volume value or a BET specific surface area in order to find a harmonized range of properties to be provided. Then, as is clear from the tendency of the examples described later, among the indexes, when the value of the BET specific surface area is equal to or more than a certain value and the volume ratio of the sum of the mesopore volumes to the sum of the micropore volumes is not more than a certain value, the tablet. It was found that the deterioration of adsorption performance was suppressed when the mold was used.

The packing density is specified as 0.3 to 0.5 g / ml. In the present invention, the additive as a binder for molding activated carbon into a tablet-type adsorbent is 1.0% by weight or less with respect to 100% by weight of the tablet-type adsorbent, which is a very small amount. This is because it is convenient for the activated carbon to have a low packing density in order to obtain a tablet-type adsorbent having excellent selective adsorptivity with a small amount of additives. However, if the filling 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, the desired balance of selective adsorption may be lost, or the adsorption performance of activated carbon may be significantly deteriorated 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 as 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 some extent. If the mesopores are well developed, when the additive is used to form a tablet, even if the additive, which is a relatively large molecule, blocks some mesopores, toxic substances can be microscopically removed from the other mesopores. This is because it is possible to introduce the substance into the pores, and it is considered that the deterioration of the adsorption performance of the toxic substance 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 the mesopore volumes to the sum of the micropore volumes is 5.0 or less, the adsorption performance of toxic substances deteriorates. Is further suppressed. Furthermore, the BET specific surface area is preferably 1200 m ² / g or more. When it is 1200 m ² / g or more, the adsorption performance of toxic substances is high, so that it is suitable as an adsorbent for oral administration.

Also, as mentioned above, activated carbon is also defined by the pore size of the pores. In the case of an adsorbent such as activated carbon, any of micropores, mesopores, and macropores is present. Among them, the adsorption target and performance of activated carbon change depending on which range of pores are developed more. The activated carbon desired in the present invention assumes the adsorption of nitrogen-containing low molecular weight ionic organic compounds such as indoxyl sulfate, aminoisobutyric acid, and tryptophan represented by the causative substance of uremia and its precursor. The activated carbon of the tablet-type adsorbent for oral administration of the present invention is to adsorb the molecule to be adsorbed more effectively than the conventional activated carbon adsorbent.

Since the proportions on the macropore and mesopore sides are relatively increased, the adsorption target can easily penetrate into the activated carbon. Further, even if the additive, which is a relatively large molecule, is adsorbed on the mesopores, the arrival of the toxic substance to the micropores is not easily hindered. Then, the adsorption target is captured by the micropores connected to the macropores and the mesopores, and the adsorption proceeds rapidly. Usually, it is considered that the time from feeding to excretion that food is decomposed by digestion and flows in the small intestine is about 6 to 10 hours. That is, it is necessary for the tablet-type adsorbent for oral administration (activated carbon) to adsorb small molecules containing nitrogen, which is the target adsorption target, while flowing in the small intestine. Therefore, considering efficient adsorption in the intestinal tract, it can be said that short-time adsorption is desirable. From these facts, it is meaningful to develop many pores on the macropore side of activated carbon.

In addition to these indicators, the average pore diameter can 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 the range, the adsorption of relatively low molecular weight ionic organic compounds having a molecular weight of several tens to several hundreds becomes even better. At the same time, activated carbon can suppress the adsorption of high molecular weight compounds necessary for living organisms such as enzymes and polysaccharides having a molecular weight of several thousand to tens of thousands. When the average pore diameter of activated carbon exceeds 2.5 nm, it is not preferable because many pores adsorbing polymers such as enzymes and polysaccharides are present. Further, if the average pore diameter of the activated carbon is less than 1.5 nm, the pore volume itself may decrease and the adsorptive power may decrease.

The above-mentioned activated carbon is used as a drug for oral administration, and is a therapeutic or prophylactic agent for renal disease or liver disease. By adsorbing and retaining the causative substances of diseases and chronic symptoms in the pores developed on the surface of activated carbon and discharging them to the outside of the body, the deterioration of symptoms is suppressed and the pathological condition is improved. Furthermore, if there is a congenital or acquired metabolic disorder or a possibility of such abnormality, the concentration of the causative substance of the disease or chronic symptom in the body can be lowered by taking activated carbon in advance. Therefore, it may be taken as a preventive measure to prevent worsening of symptoms.

Examples of renal diseases include chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephritic syndrome, acute advanced nephritic syndrome, chronic nephritis syndrome, nephrotic syndrome, nephrotic syndrome, and interstitial nephritis. , Pyelonephritis, lipoid nephrotic syndrome, diabetic nephritis, renovascular hypertension, hypertension syndrome, or secondary renal disease associated with the primary disease, as well as mild renal failure before dialysis. Liver diseases include, for example, fulminant hepatitis, chronic hepatitis, viral hepatitis, alcoholic hepatitis, liver fibrosis, liver cirrhosis, liver cancer, autoimmune hepatitis, drug allergic hepatitis, primary biliary cirrhosis, and tremor. ), Encephalopathy, metabolic disorders, and dysfunction.

The dose of activated carbon when used as an adsorbent for oral administration is affected by age, gender, physique, medical condition, etc., so it is difficult to specify it uniformly. However, in general, when targeting humans, it is assumed that 1 to 20 g of activated carbon is taken per day, 2 to 4 times per day. 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 easier to take and reduce the burden on the patient by making it a tablet type.

Since activated carbon cannot be tableted by the conventional manufacturing method due to its nature, it is molded into a tablet shape by the binding force of a binder via a solvent such as water. When molded into a tablet shape using an additive as a binder, the additive covers the pores on the surface of the activated carbon, which tends to block the pores and reduce the adsorption performance of the activated carbon. If the adsorption performance of activated carbon deteriorates due to molding into a tablet mold, the dose may rather increase, and the burden on the patient to take the activated carbon increases. That is, it is necessary to suppress the deterioration of the adsorption performance of activated carbon when molding the tablet mold.

Therefore, as described above, the amount of the additive added as a binder is set to 1.0% by weight, and the activated carbon is formed into a tablet shape with a very small amount of the additive. The filling density of activated carbon is set to 0.3 to 0.5 g / ml so that it can be molded even with a small amount of additives, so that activated carbon can be molded into a tablet shape and the deterioration of the adsorption performance of activated carbon is suppressed. can do. Further, by setting 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 constant or less, the deterioration of the adsorption performance of the activated carbon when molded into a tablet shape is suppressed.

The additive as a binder is at least one of carboxymethyl cellulose sodium and hydroxyethyl cellulose, and according to these additives, activated carbon can be formed into a tablet shape even with a small amount of addition. Compared with the fine-grained type adsorbent, it is possible to suppress an increase in dose or volume. As the additive, one of the above may be used, both may be mixed, or another additive may be mixed. In addition, a disintegrant may be used in combination for the purpose of compensating for the disintegration property of the tablet.

[Preparation of activated carbon]
The following activated carbons 1 to 5 were used in the preparation of the tablet-type adsorbent for oral administration of the prototype example. Activated carbons 1 to 5 derived from phenol resin corresponding to the prototype example were prepared by carbonizing and activating the raw material phenol 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 Arabica rubber as an emulsifier, and water. 168.8 parts by weight was added and heated to 95 ° C. or higher for appropriate polymerization. Next, 147.0 parts by weight of 90% phenol, 143.1 parts by weight of formaldehyde, 19.3 parts by weight of hexamethylenetetramine as a basic catalyst, 8.3 parts by weight of triethylenetetramine, and 41.4 parts by weight of water were added. It was placed in a separable flask and heated for 1 hour while maintaining 60 ° C. to proceed with the reaction. Then, it was heated to 95 ° C. or higher and refluxed for 4 hours to obtain a phenol resin. After putting 100 g of the phenol resin into a cylindrical retort electric furnace and filling it with nitrogen, the temperature was raised at 100 ° C./1 hour and heated to 900 ° C. Then, steam was injected into the furnace and maintained at 900 ° C. for 2 hours for activation to obtain 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 arabic rubber as an emulsifier, and water. 147.9 parts by weight was added and heated to 95 ° C. or higher for appropriate polymerization. Next, 80% by weight of 90% phenol, 220.3 parts by weight of 37% formaldehyde, 18.1 parts by weight of hexamethylenetetramine as a basic catalyst, 7.7 parts by weight of triethylenetetramine, and 38.7 parts by weight of water. Was placed in the same separable flask and heated for 1 hour while maintaining 60 ° C. to proceed with the reaction. Then, it was heated to 95 ° C. or higher and refluxed for 4 hours to obtain a phenol resin. The same procedure as for activated carbon 1 was carried out except that the phenol resin was used, and activated carbon 2 was obtained.

<Activated carbon 3>
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 arabic rubber as an emulsifier, and water in 1 liter separable flask. 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 as a basic catalyst, 7.8 parts by weight of triethylenetetramine, and 44.0 parts by weight of water. Was placed in the same separable flask and heated for 1 hour while maintaining 60 ° C. to proceed with the reaction. Then, it was heated to 95 ° C. or higher and refluxed for 4 hours to obtain a phenol resin. The same procedure as for activated carbon 1 was carried out except that the phenol resin was used, and activated carbon 3 was obtained.

<Activated carbon 4>
500 g of phenolic resin (“LPS-1046” manufactured by Lignite Co., Ltd.) was put into a cylindrical retort electric furnace to enclose nitrogen, then the temperature was raised at 100 ° C./1 hour, and the temperature was maintained at 600 ° C. for 1 hour. The phenolic resin inside was carbonized. Then, the carbide was heated to 900 ° C., steam was injected into the furnace, and the carbide 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 to enclose nitrogen, and then the temperature was raised at 100 ° C./1 hour and heated to 900 ° C. Then, steam was injected into the furnace and maintained at 900 ° C. for 0.5 hours for further activation to obtain activated carbon 4.

<Activated carbon 5>
Using the activated carbon A prepared in the preparation process of the activated carbon 4, 80 g of the activated carbon A was put into a cylindrical retort electric furnace, filled with nitrogen, heated at 100 ° C./1 hour, and heated to 900 ° C. .. Then, steam was injected into the furnace and maintained at 900 ° C. for 1 hour for further activation to obtain activated carbon 5.

[Measurement of activated carbon]
[BET specific surface area]
The specific surface area (m ² / g) is determined by measuring the nitrogen adsorption isotherm at 77K using an automatic specific surface area / pore distribution measuring device (“BELSORP-miniII” manufactured by Microtrac Bell Co., Ltd.) 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 size (μm) is measured using a laser light scattering type particle size distribution measuring device (“SALD3000S” manufactured by Shimadzu Corporation), and is at an integrated value of 50% in the particle size distribution obtained by the laser diffraction / scattering method. The particle size was used.

[Micro pore volume]
In the present specification, the micropores are pores having a pore diameter of less than 3 nm, and the sum of the micropore volumes (V _mic ) (ml / g) is a pore volume value of 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-miniII” manufactured by Microtrac Bell Co., Ltd.). From the obtained adsorption isotherm, it was calculated using the attached analysis software for the range of pore diameter less than 3 nm by the three colors of Saito-Folley. The various parameters used in the calculation are as follows.
Diameter of adsorbent molecule: 0.3000 nm
Adsorbent atom diameter: 0.3400 nm
Number of molecules per unit surface area of adsorbent in the adsorbed state: 8.5200E + 18 molecules / m ²
Atomic number per unit surface area of adsorbent: 1.3100E + 19 molecules / m ²
Magnetic susceptibility of adsorbent molecules: 3.2500E-29cm ³
Magnetic susceptibility of adsorbent molecule: 1.3000E-29cm ³
Polarizability of adsorbent molecules: 1.6300E-24cm ³
Polarizability of adsorbent molecule: 2.5000E-24cm ³

[Meso hole volume]
In the present specification, the mesopores are pores having a pore diameter of 3 to 50 nm, and the sum of the mesopore volumes (V _met ) (ml / g) is "Autopore 9500" (manufactured by Shimadzu Corporation). The contact angle is set to 130 °, the surface tension is set to 484 dynes / cm (4.84 mN / m), and the pore volume value by the mercury intrusion method with a pore diameter of 3 to 50 nm is the sum of the mesopore volumes (ml / g). Asked as.

[Volume ratio]
The volume ratio (V _m ) is a 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 the above-mentioned equation (i). Calculated from.

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

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

[Additives used]
The inventor used the following additives in order to obtain a tablet-type adsorbent for oral administration of each prototype.
-Sodium Carboxymethyl Cellulose (CMC-Na): (manufactured by Daicel Corporation)
-Hydroxyethyl cellulose (HEC): (manufactured by Sumitomo Seika Chemical Co., Ltd.)
・ Pullulan: (manufactured by Hayashibara Co., Ltd.)
-Hydroxypropyl cellulose (HPC): (manufactured by Nippon Soda Corporation)

<Prototype example 1>
Activated carbon 1 was mixed with 0.3018 g, 0.0019 g of the additive sodium carboxymethyl cellulose (CMC-Na) (0.6%) and 0.3177 g of water to form a kneaded product, having a diameter of 13 mm and a depth of 6 mm. It was molded by filling it in a mold (molding mold). After the mold was allowed to stand in the dryer, it was heated and dried at an in-machine temperature of 100 ° C. for 1 hour or more, and then taken out from the mold to be used as a tablet-type adsorbent for oral administration of Prototype Example 1.

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

<Prototype example 3>
The same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that activated carbon 1 was 0.2987 g, sodium carboxymethyl cellulose (CMC-Na) (1.5%) was 0.0045 g, and water was 0.3532 g. The tablet for oral administration of Example 3 was used.

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

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

<Prototype example 6>
Activated carbon 2 was 0.3446 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that carboxymethyl cellulose sodium (CMC-Na) (0.9%) 0.0032 g and water 0.3617 g were used. The tablet for oral administration of Example 6 was used.

<Prototype example 7>
Activated carbon 2 was 0.3408 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that 0.051 g of sodium carboxymethyl cellulose (CMC-Na) (1.5%) and 0.3438 g of water were used. The tablet for oral administration of Example 7 was used.

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

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

<Prototype example 10>
Activated carbon 3 was 0.3566 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that carboxymethyl cellulose sodium (CMC-Na) (0.9%) 0.0034 g and water 0.3566 g were used. The tablet for oral administration of Example 10 was used.

<Prototype example 11>
Activated carbon 3 was 0.3713 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that 0.0057 g of sodium carboxymethyl cellulose (CMC-Na) (1.5%) and 0.3432 g of water were used for trial production. The tablet for oral administration of Example 11 was used.

<Prototype example 12>
Activated carbon 3 was 0.3712 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that 0.0076 g of sodium carboxymethyl cellulose (CMC-Na) (2.0%) and 0.3941 g of water were used for trial production. The tablet for oral administration of Example 12 was used.

<Prototype example 13>
Activated carbon 4 was 0.5686 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that carboxymethyl cellulose sodium (CMC-Na) (0.6%) 0.0034 g and water 0.3953 g were used. The tablet for oral administration of Example 13 was used.

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

<Prototype example 15>
Activated carbon 4 was 0.5629 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that carboxymethyl cellulose sodium (CMC-Na) (1.5%) was 0.0086 g and water was 0.4135 g. The tablet for oral administration of Example 15 was used.

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

<Prototype example 17>
Activated carbon 5 was 0.5213 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that carboxymethyl cellulose sodium (CMC-Na) (0.6%) was 0.0031 g and water was 0.3546 g. The tablet for oral administration of Example 17 was used.

<Prototype example 18>
Activated carbon 5 was 0.5255 g, and the same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that 0.0047 g of sodium carboxymethyl cellulose (CMC-Na) (0.9%) and 0.4021 g of water were used for trial production. The tablet for oral administration of Example 18 was used.

<Prototype example 19>
The same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that the amount of activated carbon 5 was 0.5156 g, and the amount was 0.0079 g of sodium carboxymethyl cellulose (CMC-Na) (1.5%) and 0.4666 g of water. The tablet for oral administration of Example 19 was used.

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

<Prototype example 21>
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, and Trial Example 21 was used. It was a tablet-type adsorbent for oral administration.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

<Prototype example 41>
The same as the tablet-type adsorbent for oral administration of 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, and the oral dose of Prototype Example 41 was taken. It was used as a tablet-type adsorbent for administration.

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

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

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

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

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

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

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

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

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

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

<Prototype example 52>
The same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that activated carbon 1 was 0.3008 g, hydroxypropyl cellulose (HPC) (0.9%) 0.0027 g and water 0.2811 g, and Prototype Example 52. Was used as a tablet-type adsorbent for oral administration.

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

<Prototype example 54>
The same as the tablet-type adsorbent for oral administration of 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, and Prototype Example 54 Was used as a tablet-type adsorbent for oral administration.

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

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

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

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

<Prototype example 59>
The same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that the amount of activated carbon 5 was 0.5217 g, hydroxypropyl cellulose (HPC) (0.6%) 0.0032 g and water 0.4189 g, was the same as that of Prototype Example 59. Was used as a tablet-type adsorbent for oral administration.

<Prototype example 60>
The same as the tablet-type adsorbent for oral administration of Prototype Example 1 except that the amount of activated carbon 5 was 0.5248 g, hydroxypropyl cellulose (HPC) (0.9%) 0.0047 g and water 0.3689 g, and Prototype Example 60 was used. Was used as a tablet-type adsorbent for oral administration.

[Measurement of tablet-type adsorbent for oral administration]
[Formability]
As for moldability, "○" indicates that each prototype could be molded into a tablet mold, and "×" indicates that the product could not be molded into a tablet mold or had defects such as defects or cracks during the process of removal from the mold. And said.

〔hardness〕
For the hardness (N), a digital hardness tester (manufactured by AS ONE Co., Ltd., “KHT-40N”) was used, and the breaking strength at the time when the tablet-type adsorbent for oral administration was broken was measured as the hardness.

The physical characteristics of each prototype are shown in Tables 2 to 16. The composition of the activated carbon used, the type of the additive, the concentration (%) of the additive, and the solid-liquid ratio (ml / g) are shown together with the possibility of tablet molding and the hardness (N). The solid-liquid ratio is a value obtained by dividing the volume of water obtained by 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, and 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.

[Evaluation of adsorption performance]
The inventor conducted an adsorption test to measure the adsorption rate of nitrogen-containing compounds that can cause uremia and the like. Therefore, four types of substances, "indole", "indole acetic acid", "indoxyl sulfate" and "tryptophan", were selected from the nitrogen-containing low molecular weight compounds as toxic substances, and activated coals 1 to 5 and each prototype were used for oral administration. For the tablet-type adsorbent, the adsorption rate (%) of the four types of molecules was measured.

Regarding the adsorption rates of the four substances, each of the above substances was dissolved in a phosphate buffer solution having a pH of 7.4 to prepare a standard solution having a concentration of 0.1 g / l.
To 50 ml of the standard solution of indole, 0.01 g of each of granular activated carbons 1 to 5 previously heated and dried at 120 ° C. in a static dryer for 15 minutes or longer was added, and the mixture was contact-shaken at a temperature of 37 ° C. for 3 hours.
To 50 ml of a standard solution of indoleacetic acid, 0.01 g of granular activated carbon 1 to 5 previously heated and dried at 120 ° C. in a static dryer for 15 minutes or longer was added, and the mixture was contact-shaken at a temperature of 37 ° C. for 3 hours.
To 50 ml of a standard solution of indoxyl sulfate, 0.01 g of granular activated carbon 1 to 5 which had been previously heated and dried at 120 ° C. in a static dryer for 15 minutes or longer was added, and the mixture was contact-shaken at a temperature of 37 ° C. for 3 hours.
To 50 ml of a standard solution of tryptophan, 0.01 g of activated carbon 1 to 5 previously heated and dried at 120 ° C. in a static dryer for 15 minutes or longer were added, and the mixture was contact-shaken at a temperature of 37 ° C. for 3 hours.

Then, the filtrate obtained by filtration was measured for absorbance at 279 nm by an absorptiometry using a spectrophotometer (Shimadzu Corporation, “UVmini-1240”). The adsorption rate (%) of each substance to be adsorbed was obtained from the formula (ii).

The adsorption rate of each substance of activated carbons 1 to 5 is shown in Table 17.

Then, the adsorption rate of the tablet-type adsorbent for oral administration was divided by the adsorption rate of each activated carbon used, and the degree of deterioration of the adsorption performance was calculated as the adsorption ratio. The results of Prototype Examples 1 to 20 using sodium carboxymethyl cellulose (CMC-Na) as an additive are shown in Tables 18 to 22, and the results of Prototype Examples 21 to 40 using hydroxyethyl cellulose (HEC) are shown in Tables 23 to 27. 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 the tablet-type adsorbent for oral administration in each prototype, the tablet-type adsorbent for oral administration was appropriately crushed using a spatula and then heated and dried at 120 ° C. in a static dryer for 15 minutes or more. .. Then, 0.01 g of a tablet-type adsorbent for oral administration crushed in a total amount of substantially activated carbon excluding additives was added to 50 ml of a standard solution of the four substances, and the mixture was contact-shaken at a temperature of 37 ° C. for 3 hours. .. Then, the filtrate obtained by filtration was measured for absorbance at 279 nm by an absorptiometry using a spectrophotometer (Shimadzu Corporation, “UVmini-1240”). The adsorption rate (%) of each substance to be adsorbed was obtained from the above equation (ii).

[Results / Discussion]
As shown in Tables 2 to 16, when the addition amount of the binder as an additive is 0.6% by weight with respect to 100% by weight of the tablet-type adsorbent, pullulan and hydroxypropyl cellulose are used. In the prototype examples 41, 43, 45, 51, 53, 55, 57, 59, it was not possible to mold into a tablet shape. It is probable that the binding force of the binder was not sufficiently exerted because the concentration of the additive was low. In Prototype Examples 1 to 40 using sodium carboxymethyl cellulose or hydroxyethyl cellulose as a binder, it was possible to mold them into a tablet shape satisfactorily. Therefore, carboxy was used as a binder having a high binding force at a low concentration. Sodium methylcellulose or hydroxyethylcellulose have been shown to be suitable.

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

In particular, in the trial example using sodium carboxymethyl cellulose as a binder, when added at concentrations of 1.5% by weight and 2.0% by weight, the trial example having an addition amount of 1.5% by weight has a hardness of 1.5% by weight. It was understood that there was no change even if the amount of the binder added was more than a certain amount.

Next, as shown in Prototype Examples 1 to 20 using sodium carboxymethyl cellulose as a binder shown in Tables 18 to 22, with Prototype Examples 1 to 12 using activated carbons 1 to 3 which are activated carbons having a low filling density. Comparing with the trial examples 13 to 20 using activated carbons 4 and 5 which are activated carbons having a high packing density, the adsorption rate and adsorption ratio of indoxyl sulfate and indoxyl sulfate in the prototypes 13 to 20 using activated carbons 4 and 5 in particular. Was significantly inferior. Activated carbon with a high packing density has many charcoal parts and few pores, so even if the amount is very small, the blockage of the pores by the additive has a large effect on the adsorption rate, and it was molded into a tablet shape due to the adsorption performance of the activated carbon raw material. It is considered that the deterioration of the adsorption performance at the time became large. For this reason, it is preferable that the activated carbon used for 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 the pores formed in the activated carbon also contributes to the suppression of the adsorption performance of toxic substances and the deterioration of the adsorption performance when molded into a tablet shape. A small volume ratio (V _m ) indicates that the micropores and mesopores are well-balanced, and the presence of sufficient macropores and the presence of mesopores above a certain level indicates that the adsorption target. Each toxic substance can smoothly reach the micropores from the macropores through the mesopores and be adsorbed. Furthermore, since it is considered that a certain degree of pores are blocked by the binder, it is better to use activated carbon having more mesopores than ordinary activated carbon, which lowers the adsorption performance when molded into a tablet shape. Is considered to be able to be suppressed. For this reason, it is preferable to use activated carbon having a volume ratio (V _m ) of the sum of the mesopore volumes to the sum of the micropore volumes of 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, indoleacetic acid is assumed to have a specific surface area of 1400 m ² / g or more in addition to the packing density and volume ratio. It was found that the deterioration of the adsorption performance of the above can be further suppressed.

The types of binders are shown in Tables 18-32, and as mentioned above, pullulan and hydroxypropyl cellulose are not very suitable for molding into tablet molds with a small amount of addition, and sodium carboxymethyl cellulose or hydroxyethyl cellulose was used. Comparing the trial example and the trial example using pullulan or hydroxypropyl cellulose, the adsorption performance of the activated carbon raw material was significantly reduced due to the adsorption performance when molded into a tablet shape. Therefore, sodium carboxymethyl cellulose or hydroxyethyl cellulose is suitable as an additive as a binder that can form activated carbon into a tablet shape even with a small amount of addition and can suppress deterioration of the adsorption performance of activated carbon. Was shown to be.

As shown in Tables 18 to 20 and 23 to 25, when the blending amount of the additive as a binder is 1% by weight or less, the adsorption performance of the activated carbon raw material can be suppressed from the deterioration of the adsorption performance when molded into a tablet shape. Was shown. It is easily understood that the decrease in adsorption performance due to the blockage of the pores of the activated carbon by the binder is suppressed by reducing the amount of the binder added. However, in view of the physical properties of the activated carbon shown in Tables 1 to 32 and the measurement results of the tablet-type adsorbent of each prototype, not only the amount of the binder added but also the physical properties of the activated carbon as a raw material and the type of the binder. It was found that it contributes to the suppression of deterioration of adsorption performance.

[summary]
As described above, as shown in each prototype, the tablet-type adsorbent molded into a tablet shape by using activated carbon having a low filling density as the main carbon and adding a very small amount of sodium carboxymethyl cellulose or hydroxyethyl cellulose as an additive is the original. It was found that it is possible to suppress the deterioration of the adsorption performance of toxic substances in charcoal. Further, by reducing the volume ratio of the sum of the mesopore volumes to the sum of the micropore volumes, even if the additive is adsorbed on the macropores or the mesopores, the arrival of the toxic substance to the micropores is less likely to be hindered. It was understood that it contributes to the suppression of the deterioration of the adsorption performance of the tablet-type adsorbent for oral administration. By using sodium carboxymethyl cellulose or hydroxyethyl cellulose as an additive, it has a certain hardness even in a very small amount, and it has been shown that it is suitable for a tablet-type adsorbent.

The tablet-type adsorbent for oral administration of the present invention can suppress a decrease in the adsorption performance of activated carbon as an adsorbent having a high adsorption performance for toxic substances, which makes it easier to take and suppresses an increase in dosage and volume. , It is possible to reduce the burden of taking the patient. In addition, since it is easy to take, it can reach the digestive organs by oral administration and can rapidly adsorb nitrogen-containing compounds that cause uremia, renal function, liver dysfunction, etc., and is promising as a therapeutic or preventive agent. Is.

Claims (4)

A tablet-type adsorbent for oral administration containing activated carbon as an adsorbent and an additive as a binder.
The activated carbon has an average particle size of 20 to 1000 μm and a packing density of 0.3 to 0.5 g / ml.
The tablet-type adsorbent for oral administration comprises at least one of carboxymethyl cellulose sodium or hydroxyethyl cellulose, 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 10 N or more. The oral according to claim 1 or 2, wherein the volume ratio (V _m ) of the mesopore volume (V _met ) to the micropore volume (V _mic ) specified in 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 carbide of a phenol resin.