TW201440817A - Adsorbent for oral administration, and agent for treating renal or liver disease - Google Patents

Abstract

The object of the present invention is to provide an adsorbent for oral administration capable of adsorbing tryptophan or indoxyl sulfate in large quantities in the presence of a bile acid. The object can be solved by an adsorbent for oral administration, characterized by comprising: a spherical activated carbon, wherein a bulk density is 0.4 to 0.6 g/mL, and a volume of pores having a pore diameter of 1.5 to 2.0 nm satisfies the following formula (1): y > 6*10<SP>-8</SP>x2-9*10<SP>-5</SP>x+0.0241 (1) wherein y is the volume of pores having a pore diameter of 1.5 to 2.0 nm (mL/g), and x is a specific surface area determined by BET method (m<SP>2</SP>/g).

Description

Oral administration of adsorbent and renal disease therapeutic agent and liver disease therapeutic agent

The present invention relates to an orally-administered adsorbent containing spherical activated carbon containing spherical activated carbon having different degrees of progress (enactivation). Further, the present invention relates to a renal disease treatment or prevention agent and a liver disease treatment or prevention agent comprising the above-mentioned orally administered adsorbent as an active ingredient. The sorbent for oral administration of the present invention has high adsorption capacity for phenolic sulphuric acid which is a toxic toxic substance (Toxin) in the presence of a high concentration of bile acid and tryptophan as a precursor thereof. More toxic substances can be adsorbed during the in vivo retention period from ingestion to extracorporeal discharge.

Patients with defects in renal function or liver function, etc., accumulate or produce harmful toxic substances in the blood and the body due to such organ dysfunction, and thus cause encephalopathy such as uremia or disturbance of consciousness. Since the number of such patients shows a tendency to increase year by year, it has become an important issue to develop an organ substitute device or a therapeutic drug having a function of removing toxic substances to the outside of the body in place of the defective organs. Nowadays, as an artificial kidney, the removal of toxic substances by hemodialysis is most popular. However, such a hemodialysis type artificial kidney system uses a special device, and therefore requires a professional technician in terms of safety management, and has disadvantages such as high physical, mental, and economic burden of the patient due to external removal of blood. Not necessarily satisfactory.

As a method for solving these disadvantages, development and utilization can be used orally and can treat kidneys Oral adsorbent for dysfunction of the liver or liver (Patent Document 1). The oral adsorbent comprises a porous spherical carbonaceous material (ie, spherical activated carbon) having a specific functional group, which can be used as a safety or stability to a living body, and is toxic even in the presence of bile acids in the intestine. The substances (i.e., β-aminoisobutyric acid, γ-amino-n-butyric acid, dimethylamine, and octopamine) are also excellent in adsorption, and have a beneficial effect of less adsorption of enteric beneficial components such as digestive enzymes. It is widely used clinically in patients with liver and kidney dysfunction, such as an orally administered drug with less side effects such as adsorption and constipation. In addition, the adsorbent described in the above-mentioned Patent Document 1 is produced by preparing spherical activated carbon using a pitch such as petroleum pitch as a carbon source, followed by oxidation treatment and reduction treatment.

On the other hand, in the case of a patient with chronic renal failure, it is known that the concentration of the indophenol sulfate in the serum is increased to about 60 times that of the normal one, and it is also known that the oral adsorbent is described by the above-mentioned Patent Document 1. The concentration of the phenolic sulphuric acid in the serum is lowered to delay the progression of renal failure (Non-Patent Documents 1 and 2).

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Publication No. Sho 62-11611

[Patent Document 2] Japanese Patent Laid-Open Publication No. 2006-131461

[Patent Document 3] Japanese Patent Laid-Open Publication No. 2008-303193

[Non-patent literature]

[Non-Patent Document 1] Nissin, Vol. XXXII, No. 6 (1990), pp. 65-71

[Non-Patent Document 2] Clinical Dialysis, Vol. 14, No. 4 (1998), pp. 433-438

Among the oral adsorbents containing spheroidal activated carbon, the adsorption of toxic substances is an extremely important characteristic, and it is particularly important as a phenolic sulphuric acid which is a toxic substance in patients with chronic renal failure in the intestinal environment. The tryptophan acid of the precursor is as large and rapid as possible Adsorption, removal. That is, a large amount of various substances exist in the human intestine, and in particular, a large amount of bile acid (15 mM) exists. Therefore, it is preferable that the spherical activated carbon excellent in the adsorption ability of the toxic substance in the small intestine in which a large amount of bile acid exists.

An object of the present invention is to provide an orally-administered adsorbent which can adsorb a large amount of tryptophan or indophenol sulfuric acid in the presence of bile acids.

The present inventors have diligently developed an oral adsorbent capable of adsorbing and removing a large amount of harmful substances in the presence of a high concentration of bile acid, and as a result, it has been found that a surface having a small bulk density and a large specific surface area has no modified spherical activity. Carbon or surface-modified spherical activated carbon can be obtained as an orally adsorbent which exhibits excellent adsorption capacity in the presence of bile acid. However, the spherical activated carbon having a small bulk density has a disadvantage that the manufacturing cost becomes high due to a low carbonization yield. Further, since the volume per unit weight of the adsorbent increases, it is disadvantageous for a patient who is administered with an adsorbent by oral administration. Therefore, it is expected to increase the adsorption capacity in consideration of the manufacturing cost and the ease of taking the patient.

The present inventors further studied and found that a spherical activated carbon (hereinafter sometimes referred to as "activating activity distribution spherical activated carbon") containing spherical activated carbon having different activation degrees (having a distribution of activity) is used. Oral administration of an adsorbent for oral administration which exhibits superior adsorption ability in the presence of bile acid by the use of an adsorbent. The orally-administered adsorbent according to the present invention is a spherical activated carbon containing a previously known uniform bulk density having the same average bulk density, that is, a spherical activated carbon having an activity without distribution (hereinafter sometimes referred to as "activating The oral administration of the non-distributed spherical activated carbon is excellent in the adsorption and removal ability of the harmful substances in the coexistence of bile acids.

That is, when the average bulk density is the same, the orally administered adsorbent of the present invention has an excellent adsorption capacity of the toxic substance as compared with the prior oral administration adsorbent, so that the volume per unit weight can be increased without increasing the volume. Adsorption of a large amount of harmful substances in the small intestine can reduce the volume taken by the patient.

The present invention is based on the above-mentioned insights.

That is, the present invention relates to [1] an orally administered adsorbent characterized by comprising spherical activated carbon having an average bulk density of 0.4 to 0.6 g/mL and utilizing a nitrogen adsorption method. The pore volume of the pore diameter of 1.5 to 2.0 nm obtained by the SF method satisfies the formula (1) y > 6 × 10 ^-8 x ² -9 × 10 ^-5 x + 0.0241 (1) [wherein, y represents The pore volume (mL/g) of a pore diameter of 1.5 to 2.0 nm obtained by the SF method using a nitrogen adsorption method, x represents a BET specific surface area (m ² /g)]; [2] an oral administration The adsorbent is characterized in that it comprises spherical activated carbon having an average bulk density of 0.4 to 0.6 g/mL and a spherical activated carbon having a bulk density exceeding an average bulk density of 5 weights. The spheroidal activated carbon having a bulk density of less than or equal to the average bulk density is 5% by weight or more, and the sorbent for oral administration as described in [1] or [2], wherein the spherical shape is obtained. The activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a surface-unmodified spherical activated carbon having a total acidic group of less than 0.30 meq; [4] as described in [3] Oral administration of an adsorbent, wherein The modified spheroidal activated carbon has a total acidic group of 0.30 meq/g to 1.20 meq/g and a total basic base of 0.20 meq/g to 0.9 meq/g; [5] a therapeutic or prophylactic agent for kidney diseases, which comprises The sorbent for oral administration according to any one of [1] to [4] as an active ingredient; or [6] a therapeutic or prophylactic agent for liver diseases, which comprises any one of [1] to [4] The oral administration of the adsorbent is described as an active ingredient.

Further, the present specification discloses [8] a method for preventing or treating a kidney disease or a liver disease, which is administered to a subject to be treated for kidney disease or liver disease in an effective amount as described in any one of [1] to [4]. Oral administration of an adsorbent; [9] a spherical activated carbon for use in the treatment (method) of kidney disease or liver disease, and an average bulk density of 0.4 to 0.6 g/mL, which is adsorbed by nitrogen The pore volume of the pore diameter of 1.5 to 2.0 nm obtained by the SF method of the method satisfies the formula (1) y > 6 × 10 ^-8 x ² -9 × 10 ^-5 x + 0.0241 (1)

[wherein, y represents a pore volume (mL/g) of a pore diameter of 1.5 to 2.0 nm obtained by an SF method using a nitrogen adsorption method, and x represents a BET specific surface area (m ² /g)]; [10] a spheroidal activated carbon for use in the treatment (method) of kidney disease or liver disease, and having an average bulk density of 0.4 to 0.6 g/mL, and a ball having a bulk density exceeding an average bulk density The spheroidal activated carbon described in [9] or [10], wherein the spheroidal activated carbon is 5% or more, and the spheroidal activated carbon is not more than 5% by weight. The spherical activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a surface-unmodified spherical activated carbon having a total acidic group of less than 0.30 meq; [12] as described in [11] The surface modified spherical activated carbon, wherein the surface modified spherical activated carbon has a total acidic group of 0.30 meq/g to 1.20 meq/g and a total basic base of 0.20 meq/g to 0.9 meq/g; a use of spheroidal activated carbon for the manufacture of a medicament for the prevention or treatment of kidney disease or liver disease, and the average bulk density of the spherical activated carbon is 0.4 to 0.6 g/mL, by utilizing a nitrogen adsorption method The method obtains the SF pore diameter of the pore volume of 1.5 ~ 2.0nm satisfies the formula (1) y> 6 × 10 -8 x 2 -9 × 10 -5 x + 0.0241 (1)

[wherein, y represents a pore volume (mL/g) of a pore diameter of 1.5 to 2.0 nm obtained by an SF method using a nitrogen adsorption method, and x represents a BET specific surface area (m ² /g)]; [14 a use of a spherical activated carbon for the manufacture of a medicament for the prevention or treatment of kidney disease or liver disease, and the average bulk density of the spherical activated carbon is 0.4 to 0.6 g/mL, and It is obtained by mixing 5% or more of spherical activated carbon having a bulk density of an average bulk density and 5% by weight or more of spherical activated carbon having a bulk density of less bulk density; [15] as [13] or [14] The use of the surface-modified spherical activated carbon described above, wherein the spherical activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a surface having a total acidic group of less than 0.30 meq is not changed. [16] The use of the surface-modified spherical activated carbon according to [15], wherein the surface-modified spherical activated carbon has a total acidic group of 0.30 meq/g to 1.20 meq/g and 0.20 a total basic group of meq/g~0.9meq/g; [17] a use of spheroidal activated carbon for the prevention or treatment of kidney disease or liver disease, and the spheroidal activated carbon The average bulk density is 0.4 to 0.6 g/mL, and the pore volume of the pore diameter of 1.5 to 2.0 nm obtained by the SF method using the nitrogen adsorption method satisfies the formula (1) y>6×10 ^-8 x ² -9 ×10 ^-5 x+0.0241(1)

[wherein, y represents a pore volume (mL/g) of a pore diameter of 1.5 to 2.0 nm obtained by an SF method using a nitrogen adsorption method, and x represents a BET specific surface area (m ² /g)]; [18] a use of spheroidal activated carbon for the prevention or treatment of kidney disease or liver disease, and the average bulk density of the spherical activated carbon is 0.4 to 0.6 g/mL, and by exceeding the average bulk density The spheroidal activated carbon having a bulk density of 5% by weight or more and the spheroidal activated carbon having a bulk density less than the average bulk density are obtained by mixing 5% by weight or more; [19] the surface modification as described in [17] or [18] The use of the spheroidal activated carbon, wherein the spherical activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a surface-unmodified spherical active having a total acidic group of less than 0.30 meq [20] The use of the surface-modified spherical activated carbon according to [19], wherein the surface-modified spherical activated carbon has a total acidic group of 0.30 meq/g to 1.20 meq/g and 0.20 meq/g~ A total basic base of 0.9 meq/g.

The orally administered sorbent of the present invention has a high adsorption capacity for toxic substances in the presence of bile acids, so that toxic toxic substances can be adsorbed extremely rapidly in the intestinal tract. Therefore, it is effective as a therapeutic or preventive agent for kidney diseases or a therapeutic or preventive agent for liver diseases. Further, the amount of the drug can be reduced by the oral administration of the adsorbent.

Further, the spherical activated carbon used for the oral administration of the adsorbent of the present invention can adsorb nonylphenol sulfuric acid or tryptophan as its precursor at a higher level in the presence of a high concentration of bile acid, or the like. Increasing the volume per unit weight and adsorbing a large amount of harmful substances in the small intestine tube can reduce the volume taken by the patient.

Fig. 1 is a graph showing the results of a tryptophan adsorption test of spherical activated carbon obtained in Examples 1 to 11 and Comparative Examples 1 to 5 in the presence of bile acid.

Fig. 2 is a graph showing the results of the indophenol sulfuric acid adsorption test of the spherical activated carbon obtained in Examples 1 to 11 and Comparative Examples 1 to 5 in the presence of bile acid.

3 is a graph showing the relationship between the BET specific surface area of the spherical activated carbon obtained in Examples 1 to 11 and Comparative Examples 1 to 5 and the pore volume of the pore diameter of 1.5 to 2.0 nm obtained by the SF method. .

The adsorbent for oral administration according to the present invention is characterized in that the average bulk density is 0.4 to 0.6 g/mL, and the pore volume of the pore diameter of 1.5 to 2.0 nm obtained by the SF method using the nitrogen adsorption method satisfies Formula (1) y>6×10 ^-8 x ² -9×10 ^-5 x+0.0241(1)

[wherein, y represents a pore volume (mL/g) of a pore diameter of 1.5 to 2.0 nm obtained by an SF method using a nitrogen adsorption method, and x represents a BET specific surface area (m ² /g)] Activated carbon.

(Adsorption amount of tryptophan or indophenol sulfuric acid)

The spherical activated carbon used as the adsorbent for oral administration of the present invention has an activity distribution as described above. For example, as the physical property relating to the progress of the activation, a bulk density or a BET specific surface area can be cited. As shown in the following examples, spherical activated carbon having an activity distribution can be obtained by mixing spherical activated carbon having different bulk densities (Examples 1 to 11). The spheroidal activated carbon having the activity distribution has a tryptophan and phenol sulfate in the presence of bile acid, compared with the spheroidal activated carbon (Comparative Examples 2 to 4) which does not have the same bulk density. Excellent adsorption capacity. That is, the spherical activated carbon having the activity distribution has an excellent adsorption amount of tryptophan acid and indophenol sulfuric acid in the presence of bile acid as compared with the spherical activated carbon having no activity distribution (Figs. 1 and 2).

The unmodified spheroidal activated carbon produced in Comparative Examples 1 to 5 without the activity distribution showed the adsorption amount of tryptophan or indophenol sulfate as the bulk density became smaller as shown in Figs. 1 and 2 increase. The adsorption amount of the unmodified spheroidal activated carbon obtained in Comparative Examples 1 to 5 in the presence of bile acid to tryptophan in a solution containing 100 mg/L of tryptophan was obtained from the formula (2) y = -23375x. ⁴ +44075x ³ -27926x ² +6155.3x-120.8(2) (where y represents the amount of tryptophan adsorption and x represents bulk density)

Said. Further, the adsorption amount of the non-modified spherical activated carbon obtained in Comparative Examples 1 to 5 in the presence of bile acid to the indophenol sulfuric acid in the solution containing 100 mg/L of indophenol sulfuric acid was obtained from the formula (3). y'=-4416.7x ⁴ +8950x ³ -6020.8x ² +1401x-25.8(3) (wherein, y' represents the amount of adsorption of indophenol sulfuric acid, and x represents bulk density).

Further, the surface-modified spherical activated carbon produced in Comparative Examples 6 to 8 which does not have the activity distribution is also those satisfying the above formulas (2) and (3).

On the other hand, the spherical activated carbon used as the adsorbent for oral administration of the present invention has an activity distribution. Therefore, the adsorption amount of the tryptophan acid in the solution containing 100 mg/L of tryptophan in the presence of bile acid in the coexistence of the surface unmodified spherical activated carbon obtained in Examples 1 to 11 satisfies the formula (4) y>- 23375x ⁴ +44075x ³ -27926x ² +6155.3x-120.8(4) (wherein y represents the amount of tryptophan adsorption, and x represents bulk density).

On the other hand, the upper limit of the amount of adsorption of the spheroidal activated carbon tryptophan used in the orally administered adsorbent of the present invention is not particularly limited, and it is preferred to satisfy the formula (5).

Y≦-640x ² +150x+210.2(5) (where y represents the amount of tryptophan adsorption and x represents bulk density)

Further, the adsorption amount of the non-modified spherical activated carbon obtained in Examples 1 to 11 in the coexistence of bile acid to the indophenol sulfuric acid in the solution containing 100 mg/L of indophenol sulfuric acid satisfies the formula (6) y. '>-4416.7x ⁴ +8950x ³ -6020.8x ² +1401x-25.8(6) (wherein, y' represents the amount of adsorption of indophenol sulfuric acid, and x represents bulk density).

On the other hand, the upper limit of the adsorption amount of the spherical activated carbon phenol sulfate used for the orally administered adsorbent of the present invention is not particularly limited, and it is preferably those satisfying the formula (7).

Y≦-235x ² +131.5x+34.8(7) (where y represents the adsorption amount of indophenol sulfuric acid, and x represents the bulk density)

The surface-unmodified spherical activated carbon obtained in Examples 1 to 11 is a surface-modified ball having an activity-producing distribution manufactured in Examples 12 to 14 which satisfies the above formula (4) and/or (6). The activated carbon is also those satisfying the above formula (4) and/or (6).

The bile acid which is present when the amount of tryptophan adsorbed and the amount of nonylphenol sulfate adsorbed is not particularly limited, and sodium cholate can be used. The concentration of the bile acid is also not particularly limited, and 6458 mg can be dissolved in 1000 mL of purified water.

Furthermore, bile acids other than sodium cholate (such as sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate) can be used to determine tryptophan adsorption at concentrations other than 0.645 w/v%. The amount and the amount of phenolic sulfuric acid adsorbed. Further, according to the measured value, instead of the tryptophan acid adsorption amount and the indophenol sulfuric acid adsorption amount of the above formulas (1) and (2), it is understood that the spherical activated carbon satisfying the equation can be obtained. It is also included in the scope of the invention.

(The relationship between the pore volume of the pore diameter of 1.5 to 2.0 nm and the BET specific surface area)

The spherical activated carbon used as the adsorbent for oral administration of the present invention has an activity distribution as described above. The spherical activated carbon used for the oral administration of the adsorbent of the present invention has a pore volume of 1.5 to 2.0 nm in pore diameter determined by the SF method using a nitrogen adsorption method, and satisfies the formula (1) y > 6 ×. 10 ^-8 x ² -9×10 ^-5 x+0.0241(1)

[wherein, y represents a pore volume (mL/g) of a pore diameter of 1.5 to 2.0 nm obtained by an SF method using a nitrogen adsorption method, and x represents a BET specific surface area (m ² /g)].

The pore volume of the pore diameter of 1.5 to 2.0 nm obtained by the SF method is classified into the pore volume of the micropore. The spherical activated carbon used as the orally administered adsorbent of the present invention forms micropores by activation. The carbon material selectively decomposes and depletes the unstructured portion of the carbon material as the activation progresses, and forms fine pores (micropores) by opening the closed micropores in the carbon structure (between the carbon crystals). . That is, as the activation progresses, the closed cells become open cells, which become micropores. Such a microporous system is formed only by the progress of activation, and is an indicator indicating the degree of progress of activation.

Further, since the BET specific surface area also reflects the physical property value of the micropores, it is a physical property related to the progress of the activation.

Therefore, the relationship between the pore volume of the pore diameter of 1.5 to 2.0 nm and the BET specific surface area indicates a preferable index of the progress of the activation.

The surface-unmodified spherical activated carbon system produced in Comparative Examples 1 to 5 which does not have an activity distribution is shown in Fig. 3. As the BET specific surface area becomes larger, the pore volume of the pore diameter of 1.5 to 2.0 nm is accumulated. Increase in land. The pore volume of the surface unmodified spherical activated carbon obtained in Comparative Examples 1 to 5 having a pore diameter of 1.5 to 2.0 nm is represented by the formula (8) y = 6 × 10 ^-8 x ² -9 × 10 ^-5 x+0.0241(8)

[wherein, y represents a pore volume (mL/g) of a pore diameter of 1.5 to 2.0 nm obtained by an SF method using a nitrogen adsorption method, and x represents a BET specific surface area (m ² /g)]

Said.

Further, the surface-modified spherical activated carbon which was produced in Comparative Examples 6 to 8 and which did not have the activity distribution was also in the above formula (8).

Further, since the formula (8) is an index indicating the degree of progress of the activation, as long as the activation distribution is not obtained, the relationship is not deviated, and whether or not the spherical activated carbon has an index of the activity distribution is obtained.

On the other hand, the spherical activated carbon used as the adsorbent for oral administration of the present invention has an activity distribution. The pore volume of the surface unmodified spherical activated carbon obtained in Examples 1 to 11 with respect to the pore diameter of the BET specific surface area of 1.5 to 2.0 nm satisfies the formula (1) y > 6 × 10 ^-8 x ² - 9×10 ^-5 x+0.0241(1)

[wherein, y represents a pore volume (mL/g) of a pore diameter of 1.5 to 2.0 nm obtained by an SF method using a nitrogen adsorption method, and x represents a BET specific surface area (m ² /g)]. The relationship between the pore volume of the pore diameter of 1.5 to 2.0 nm indicating the progress of the activation and the BET specific surface area is a quadratic function, and thus the spherical activated carbon having the activity distribution of the present invention does not satisfy the formula ( 8) and satisfy the formula (1).

That is, the surface-unmodified spheroidal activated carbon having a distribution with respect to the activation activity of the orally administered adsorbent of the present invention is compared with the surface-unmodified spheroidal activated carbon having no distribution for the degree of activation. The pore volume of the pores having a diameter of 1.5 to 2.0 nm which is determined by the SF method in the BET specific surface area is higher (Fig. 3). Further, the surface-modified spherical activated carbon having the activation distribution produced in Examples 12 to 14 was also in the above formula (1).

In other words, the term "spheroidal activated carbon has a distribution for the degree of activation" means that the spherical activated carbon satisfies the condition of the formula (1), and more specifically, the spherical activated carbon having the same BET specific surface area, by SF. The pore volume of the pore diameter of 1.5 to 2.0 nm obtained by the method is high. The spherical activated carbon having an activity distribution can be obtained by mixing spherical activated carbon having no activity distribution.

The spherical activated carbon used in the present invention has a pore volume of from 1.5 to 2.0 nm in a pore volume of y>6×10 ^-8 x ² -9×10 ⁻⁵ x+0.0241 (wherein y represents a pore diameter of 1.5). a pore volume of ~2.0 nm (mL/g), x represents a BET specific surface area (m ² /g), and more preferably y>6×10 ^-8 x ² -9×10 ⁻⁵ x+0.0308 (wherein , y represents the pore volume (mL/g) of the pore diameter of 1.5 to 2.0 nm, and x represents the BET specific surface area (m ² /g)), and most preferably y>6×10 ^-8 x ² -9×10 ^{− 5} x+0.0361 (wherein, y represents a pore volume (mL/g) having a pore diameter of 1.5 to 2.0 nm, and x represents a BET specific surface area (m ² /g)).

The upper limit of the pore volume of the pore diameter of 1.5 to 2.0 nm with respect to the BET specific surface area is not particularly limited, and is y<8×10 ^-22 x ² +0.0001x-0.1057 (wherein y represents a pore diameter of 1.5~). A pore volume of 2.0 nm (mL/g), and x represents a BET specific surface area (m ² /g)).

The pore volume of the pore diameter of 1.5 to 2.0 nm can be measured by a nitrogen adsorption method, and can be carried out by the Saito-Foley method (hereinafter referred to as "SF method"), the Horverth-Kawazoe method, and the Density Functional Theory method. In the present invention, the pore volume obtained by the SF method in which the pore shape is assumed to be cylindrical is analyzed.

(the surface is not modified with spherical activated carbon)

The surface-unmodified spherical activated carbon is a porous body obtained by performing an activation treatment after heat-treating a carbon precursor, and is a spherical activity which is subjected to surface modification treatment by oxidation treatment and reduction treatment after the activation treatment. Carbon, or spheroidal activated carbon obtained by heat treatment in a non-oxidizing environment after the above-described activation treatment. From the viewpoint of the constitution of the functional group, the surface unmodified spherical activated carbon means a spherical activated carbon having a total acid group of less than 0.30 meq/g. The total acid group is preferably 0.25 meq/g or less, more preferably 0.20 meq/g. under.

(surface modified spherical activated carbon)

The surface-modified spherical activated carbon is subjected to a heat treatment after heat treatment of the carbon precursor, and then subjected to surface modification treatment by oxidation treatment or surface modification treatment by oxidation treatment and reduction treatment. The plastids show a modest interaction with acids and bases. From the viewpoint of the constitution of the functional group, the surface-modified spherical activated carbon refers to a spherical activated carbon having an acid point of 0.30 meq/g or more. In particular, the surface modified spheroidal activated carbon with a total acid group of 0.30 to 1.20 meq/g and a total basic group of 0.20 to 0.9 meq/g is adsorbed by a water-soluble toxin such as DL-β-aminoisobutyric acid. The performance is higher, so it is better. In particular, the total acidic group is preferably from 0.30 to 1.00 meq/g, and the total basic group is preferably from 0.30 to 0.70 meq/g.

(average bulk density)

The average bulk density of the spherical activated carbon used in the present invention is 0.40 g/mL to 0.60 g/mL, more preferably 0.42 g/mL to 0.58 g/mL, and most preferably 0.45 g/mL to 0.55 g/mL. If the bulk density exceeds 0.60 g/mL, the adsorption amount of indophenol sulfuric acid and tryptophan is reduced, which is not preferable. Moreover, even if the average bulk density is less than 0.40 g/mL, the adsorption capacity of indophenol sulfuric acid and tryptophan is excellent, but as the bulk density becomes smaller, the strength of the spherical activated carbon becomes weaker and pulverizes, so the ball cannot be held. shape. Further, the yield of the spherical activated carbon is deteriorated, and the economy in the production of activated carbon is lowered, so that it is preferably 0.40 g/mL or more.

In the present specification, the term "average bulk density" means "the bulk density of spherical activated carbon containing spherical activated carbon having different activation degrees". For example, the bulk density of the spherical activated carbon in the case where two or more kinds of spherical activated carbons having different bulk densities prepared by the conventional method are mixed can be used as the average bulk density. However, this measurement method does not differ from the usual method for measuring bulk density.

Specifically, the bulk density ρ _{B is} obtained by dividing the dry weight W (g) of the spherical activated carbon when the spherical activated carbon is filled in the container by the volume V (mL) of the filled spherical activated carbon. The value can be obtained according to the following calculation formula.

The bulk density of spherical activated carbon is a preferred indicator of the degree of activation. That is, the smaller the bulk density, the faster the progress of the activation. In the production step of the spherical activated carbon, the following steam activation is performed by forming relatively small pores in the initial stage of activation, and as the activation progresses, the pore diameter is enlarged, and as a result, the bulk density is lowered.

"Manufacture of activated carbon with activity distribution"

The method for producing the spherical activated carbon used in the oral administration of the adsorbent of the present invention is not limited as long as it has an activity distribution, and can be produced, for example, by a method of mixing spherical activated carbon having different activation degrees.

(by mixing manufacturing methods)

The spherical activated carbon used in the present invention can be produced by mixing two or more kinds of spheroidal activated carbons having no distribution of activity, that is, non-distributed spherical activated carbon, prepared by the prior method. Therefore, the spherical activated carbon can be produced by mixing 5% by weight or more of the spherical activated carbon having a bulk density exceeding the average bulk density, and 5% by weight or more of the spherical activated carbon having a bulk density less than the average bulk density.

The activation reaction refers to a reaction in which the pore structure of the carbon material is expanded to impart pores, and the progress of the activation can be based on the type or amount of the raw material, the type, composition, concentration, or activation temperature, activation time, etc. of the reaction gas. And control. If the activation is performed in a uniform manner such as the activation temperature, the activation time, or the concentration of the activating gas, the activation distribution does not occur. The distributed spherical activated carbon used in the present invention can be produced, for example, by mixing two or more kinds of non-distributed spherical activated carbon having different degrees of activation.

In the present specification, the term "spheroidal activated carbon having a bulk density exceeding the average bulk density" means an average of two or more non-distributed spherical activated carbons having different bulk densities and having an average larger than the distribution of spherical activated carbon. Bulk density of spheroidal activated carbon.

The difference between the bulk density of the spherical activated carbon exceeding the average bulk density and the average bulk density of the spherical activated carbon activated carbon of the present invention is not limited, and the lower limit is 0.0025 g/mL or more, preferably 0.005 g/mL or more. It is preferably 0.01 g/mL or more, more preferably 0.02 g/mL, and still more preferably 0.05 g/mL. The upper limit is not limited and is 0.3 g/mL, preferably 0.2 g/mL.

In the present specification, the term "spheroidal activated carbon having a bulk density which does not reach an average bulk density" means a mixture of two or more types of non-distributed spherical activated carbon having different bulk densities and having a smaller spherical shape. The average bulk density of activated carbon is the bulk density of spheroidal activated carbon. The difference between the bulk density of the spherical activated carbon that does not reach the average bulk density and the average bulk density of the spherical activated carbon activated carbon of the present invention is not limited, and the lower limit is 0.0025 g/mL or more, preferably 0.005 g/mL or more. More preferably, it is 0.01 g/mL or more, more preferably 0.02 g/mL, and still more preferably 0.05 g/mL. The upper limit is not limited and is 0.3 g/mL, preferably 0.2 g/mL.

The distributed spherical activated carbon contains 5% or more of spherical activated carbon having a bulk density exceeding an average bulk density, preferably 10% by weight or more, more preferably 15% by weight or more, and most preferably 20% by weight or more. . Further, the spherical activated carbon having a bulk density which does not reach the average bulk density is preferably 5% by weight or more, more preferably 10% by weight or more, still more preferably 15% by weight or more, and most preferably 20% by weight or more.

The ratio of the amount of the spherical activated carbon exceeding the average bulk density to the bulk density of the spherical activated carbon which is less than the average bulk density is not particularly limited, and may be appropriately determined, for example, in the range of 1:99 to 99:1. Preferably, it is 20:80 to 80:20, more preferably 40:60 to 60:40, further preferably 45:55 to 55:45, and most preferably 50:50. This mixing ratio is also suitable for the case where three or more kinds of bulky spherical activated carbon are mixed.

Further, in addition to the bulky activated carbon having a bulk density exceeding the average bulk density and the spheroidal activated carbon having a bulk density less than the bulk density, the above-described distribution spherical life used in the present invention The carbon may also comprise a loosely distributed spherical activated carbon of the same bulk density as the average bulk. For example, a distribution spherical activity having an average bulk density of 0.5 g/mL can be prepared using a non-distributed spherical activated carbon having a bulk density of 0.5 g/mL. In this case, the amount of the non-distributed spherical activated carbon to be added having the same bulk density is 90% by weight or less, preferably 80% by weight or less, more preferably 70% by weight based on the distribution of the spherical activated carbon obtained. Below %, it is preferably 60% by weight or less.

The spherical activated carbon used for the mixing is not limited, and the above-mentioned surface-unmodified spherical activated carbon and surface-modified spherical activated carbon can be used. In particular, the effect of the present invention can be obtained by using spherical activated carbon having a small bulk density as "spherical activated carbon having a bulk density which does not reach an average bulk density".

For example, the bulk density of the surface-unmodified spherical activated carbon used as the "spherical activated carbon having a bulk density of loose bulk density" is not particularly limited, and is preferably 0.30 to 0.50 g/mL, more preferably 0.30. 0.46 g/mL.

Further, the specific surface area of the surface-unmodified spherical activated carbon is not particularly limited, and the specific surface area determined by the BET method is preferably 1600 m ² /g or more, more preferably 2,000 m ² /g or more.

Further, the pore volume of 20 to 10000 nm of the surface-unmodified spherical activated carbon is not particularly limited, but is preferably 0.21 mL/g or less.

Further, the surface unmodified spherical activated carbon system is represented by the formula (1) Vm = (V _2.0 - V _1.1 ) / (V _1.1 - V _0.64 ) (1)

[In the formula, V _2.0 , V _1.1 and V _0.64 are micropores obtained by the pore volume diameter of 2.0 nm or less, 1.1 nm or less and 0.64 nm or less cumulative pore volume calculated by the SF method, respectively, based on the nitrogen adsorption amount]. The volume ratio (Vm) is preferably 0.80 or more of spherical activated carbon, more preferably 1.0 or more of spherical activated carbon.

Further, the average particle diameter of the surface-unmodified spherical activated carbon is not particularly limited, but is preferably 50 to 200 μm.

For example, the bulk density of the surface-modified spherical activated carbon used as the "spheroidal activated carbon having a bulk density of loose bulk density" is not particularly limited, and is preferably 0.30 to 0.50 g/mL, more preferably It is 0.30~0.46g/mL.

Further, the surface modified spherical activated carbon the specific surface area of the mass is also not particularly limited, and is determined by the BET method, the specific surface area is preferably 1600m ² / g or more, more preferably 1900m ² / g or more.

Further, the pore volume of 20 to 10000 nm of the surface-unmodified spherical activated carbon is not particularly limited, but is preferably 0.21 mL/g or less.

Further, the surface unmodified spherical activated carbon system is represented by the formula (1) Vm = (V _2.0 - V _1.1 ) / (V _1.1 - V _0.64 ) (1)

[In the formula, V _2.0 , V _1.1 and V _0.64 are micropores obtained by the pore volume diameter of 2.0 nm or less, 1.1 nm or less and 0.64 nm or less cumulative pore volume calculated by the SF method, respectively, based on the nitrogen adsorption amount]. The volume ratio (Vm) is preferably 0.8 or more of spherical activated carbon, more preferably 1.0 or more of spherical activated carbon.

Further, the average particle diameter of the surface-unmodified spherical activated carbon is not particularly limited, but is preferably 50 to 200 μm.

(specific surface area)

The specific surface area of the spherical activated carbon can be determined by the BET method or the Langmuir method. The specific surface area of the spherical activated carbon used as the adsorbent for oral administration of the present invention is 700 m ² /g or more, more preferably 700 Å / g or more, as determined by the BET method. 1200m ² / g or more, and particularly preferably 1600m ² / g or more, most preferably 1900m ² / g or more. The spheroidal activated carbon having an SSA of less than 700 m ² /g is inferior in the adsorption property of the toxic substance in the presence of bile acid, and thus is not preferable. The upper limit of the SSA is not particularly limited, and from the viewpoint of bulk density and strength, the SSA is preferably 3,000 m ² /g or less.

(fine pore volume)

The volume of the pores of the spherical activated carbon having a pore diameter of 20 to 10000 nm used for the orally administered adsorbent of the present invention is preferably 0.21 mL/g or less, more preferably 0.20 mL/g or less, and further preferably 0.19mL/g or less. When the pore volume of the pores having a diameter of 20 to 10000 nm exceeds 0.21 mL/g, the amount of adsorption of useful substances such as digestive enzymes increases. Therefore, it is not good. The lower limit is not particularly limited, but is preferably 0.02 mL/g or more.

The spherical activated carbon having a pore diameter of 7.5 to 15000 nm used for the orally administered adsorbent of the present invention has a pore volume of 0.01 mL/g or more, preferably 0.05 mL/g or more, more preferably 0.08 mL/ The amount of g or more is more preferably 0.1 mL/g or more, and most preferably 0.2 mL/g or more. The pores having a pore diameter of 7.5 to 15000 nm have a large volume, and the adsorption rate of the toxic substance is excellent. Further, the upper limit of the pore volume of the pore diameter of 7.5 to 15000 nm is not particularly limited, but is preferably 1.0 mL/g or less. When the pore volume of the pore diameter of 7.5 to 15000 nm exceeds 1.0 mL/g, the amount of adsorption of a useful substance such as digestive enzyme increases, which is not preferable.

(micropore volume ratio)

For example, in the IUPAC system, pores of 2 nm or less are defined as micropores, 2 to 50 nm are defined as mesopores, and 50 nm or more is defined as macropores. The spherical activated carbon used as the orally administered adsorbent of the present invention mainly forms relatively small pores by gas activation. Further, by forming the micropores, the spherical activated carbon is reduced in density and the specific surface area is increased, whereby the adsorption performance of the toxic substance in the presence of bile acid is increased.

The pore volume of the micropores of 2 nm or less can be measured by a nitrogen adsorption method, and can be analyzed by the Saito-Foley method (hereinafter referred to as "SF method"), the Horverth-Kawazoe method, and the Density Functional Theory method. In the present invention, the pore volume obtained by the SF method in which the pore shape is assumed to be cylindrical is analyzed.

Specifically, the pore volume of the spherical activated carbon used as the adsorbent for oral administration of the present invention is desirably from Vm = (V _2.0 - V _1.1 ) / (V _1.1 - V _0.64 ) [wherein V _2.0 is a cumulative pore volume of a pore diameter of 2.0 nm or less calculated by the SF method according to the amount of nitrogen adsorption, and V _1.1 is a cumulative pore diameter of 1.1 nm or less calculated by the SF method according to the amount of nitrogen adsorption. The pore volume, V _0.64 , is based on the amount of nitrogen adsorbed and the pore volume ratio Vm obtained by the cumulative pore volume of pore diameter 0.64 nm or less calculated by the SF method. If the micropore volume is relatively low, relatively large bile acid molecules cause pore occlusion and inhibit adsorption of uremic substances or precursors smaller than the molecular size, which is not preferable. As the micropore volume ratio increases, relatively large bile acid molecules do not cause pore occlusion, and adsorption of a uremic substance smaller than a molecular size or a precursor thereof is excellent, and thus is preferable.

(diameter)

The diameter of the spherical activated carbon used as the adsorbent for oral administration of the present invention is not particularly limited, but is preferably 0.01 to 1 mm, more preferably 0.02 to 0.8 mm. If the diameter of the spherical activated carbon is less than 0.01 mm, the surface area of the spherical activated carbon increases, which tends to cause adsorption of a beneficial substance such as digestive enzyme, which is not preferable. Moreover, when the diameter exceeds 1 mm, the diffusion distance of the toxic substance into the interior of the spherical activated carbon increases, and the adsorption speed decreases, which is not preferable.

(The average particle size)

In the present specification, the average particle diameter refers to a particle diameter (Dv50) at a particle size cumulative ratio of 50% in a volume-based cumulative line graph.

The range of the average particle diameter of the spherical activated carbon used as the adsorbent for oral administration of the present invention is not particularly limited, and is 0.01 to 1 mm. When the average particle diameter of the spherical activated carbon is less than 0.01 mm, the surface area of the spherical activated carbon increases, which tends to cause adsorption of a beneficial substance such as digestive enzyme, which is not preferable. Further, when the average particle diameter exceeds 1 mm, the diffusion distance of the toxic substance into the inside of the spherical activated carbon increases, and the adsorption rate decreases, which is not preferable. The reason for this is that the average particle diameter is preferably 0.02 to 0.8 mm, and in particular, the spherical activated carbon having an average particle diameter of 50 to 200 μm is excellent in initial adsorption ability, and can be adsorbed extremely rapidly in the residence time of the upper small intestine tube. Toxic toxic substances in the living body. A more preferable range of the average particle diameter is 50 to 170 μm, and a preferred range is 50 to 150 μm.

(Particle size distribution)

The spherical activated carbon used as the orally administered adsorbent of the present invention preferably has a narrow particle size distribution. For example, the ratio of the weight average particle diameter D ₁ (=ΣnD/Σn) averaged by the number reference to the weight average particle diameter D ₄ (=Σ(nD ⁴ )/Σ(nD ³ )) of the weight reference distribution (D) _{In the case of 4} /D ₁ ), the spherical activated carbon used as the adsorbent for oral administration of the present invention has a ratio (D ₄ /D ₁ ) of preferably 3 or less, more preferably 2 or less. More preferably, it is 1.5 or less. Here, the closer the ratio (D ₄ /D ₁ ) is to 1, the narrower the particle size distribution. Further, in the above calculation formula, D is a representative particle diameter of the particle diameter region, and n is a number.

(total acid base and total basic base)

The total acidic group and the total basic group of the spherical activated carbon used as the orally administered adsorbent of the present invention are not particularly limited. In particular, in the case of a mixture of unmodified spherical activated carbon and surface-modified spherical activated carbon, the amount of total acidic groups and total basic groups is not limited. However, in the case where the spherical activated carbon is a surface-modified spheroidal activated carbon, the total acidic group is preferably less than 0.30 meq/g. Further, in the case where the spherical activated carbon is a surface-modified spherical activated carbon, it is preferably 0.30 meq/g or more, the total acidic group is 0.30 to 1.20 meq/g, and the total basic group is preferably 0.20 to 0.9. Meq/g.

As is known to the inventors, in the spherical activated carbon used as the adsorbent for oral administration, spherical activated carbon having an activity distribution is completely unknown.

For example, the activated carbon specifically prepared in Examples 1 to 7 of Patent Document 2 does not describe the activation activity distribution at all, and according to the description of the manufacture of the examples, the activation activity distribution is not apparent. For example, in the first embodiment, the water vapor atmosphere was set to a temperature of 8 ° C in 1 minute, and the temperature was raised to 850 ° C. The temperature was maintained at 850 ° C for 9 hours to carry out steam activation, but the activation activity distribution was not obtained. Further, it is not described at all that activated carbon having an activity distribution is excellent in adsorption ability to toxic substances in the presence of a large amount of bile acids.

Further, in Patent Document 3, the activation activity distribution is not described at all, and according to the description of the manufacture of the examples, the activation activity distribution is not apparent. For example, in Example 1, 50 kg of a carbonaceous material was added to a rotary kiln, and an activation treatment was performed for 13 hours at 950 ° C in a 100% steam atmosphere, and no spheroidal activated carbon having a different activation degree was mixed. Therefore, it does not have an activity distribution. Further, the activated carbon having the activity distribution is not loaded at all, and the adsorption ability to the toxic substance is excellent in the coexistence of a large amount of bile acids.

The reason why the orally administered adsorbent of the present invention has an excellent effect as described above Although it is not clear now, it can be speculated as follows. However, the present invention is not limited to the following assumptions.

There is a high concentration of bile acid in the living body. The bile acid is one of the surfactants used to aid in the absorption of water-insoluble lipids. Therefore, in order to micronize lipids, bile acids require a concentration above the critical cell concentration, and are present in the human small intestine at a concentration of 15 mM when satiety. Typical examples of bile acids include sodium cholate, sodium deoxycholate, sodium tauroate, sodium glycocholate, and the like, and molecules having a molecular weight of 400 to 600. Further, if the bile acid molecules are aggregated and microcytosed, the size of the microcells becomes several nm, and becomes a tryptophan sulfate which is a toxic substance (Toxin) which is a toxic substance in the body or a tryptophan phase which is a precursor thereof. Than, it exists in a larger size.

In the presence of such a high concentration of bile acid, larger size bile acid molecules or bile acid microcells do not cause adsorption inhibition such as pore occlusion, in order to adsorb phenolic sulfuric acid which is a toxic toxic substance of a smaller size or As a precursor of tryptophan, it is effective for oral administration of adsorbents having a low bulk density, a large specific surface area, and a relatively high pore volume of 1.5 to 2.0 nm, and the adsorption capacity is bulk. The lower the specific surface area, and the higher the pore volume of the pore diameter of 1.5 to 2.0 nm, the more the index is increased.

It is considered that the spheroidal activated carbon of the present invention has an activity distribution in a specific bulk density range and a specific surface area range which are exponentially adsorbed, thereby having no spheroidal activated carbon having an activity distribution at the same average bulk density. In contrast, it does not increase the volume of administration, and has an excellent effect of adsorbing toxic substances in the presence of bile acids.

(carbon source)

The spherical activated carbon used as the orally administered adsorbent of the present invention may use any carbonaceous material as a carbon source. As the carbonaceous material that can be used, for example, synthetic resin or pitch can be used. As the synthetic resin, a thermofusible resin or a thermally infusible resin can be used. Here, the hot-melt resin is a resin which is melted and decomposed as the temperature rises without performing a non-melting treatment, and is a resin which cannot obtain activated carbon. However, if Activated carbon can be produced by first performing a non-melting treatment and then performing an activation treatment. On the other hand, the thermal non-melting resin is a resin which can be carbonized to obtain activated carbon without performing a deactivation treatment without performing a non-melting treatment. In addition, the non-melting treatment means that the oxidation treatment is performed at 150 to 400 ° C in an atmosphere containing oxygen, for example.

A typical example of the hot-melt resin is a thermoplastic resin, and examples thereof include a crosslinked ethylene-based resin. On the other hand, a representative example of the heat non-melting resin is a thermosetting resin, and examples thereof include a phenol resin or a furan resin. As the known thermoplastic resin or thermosetting resin, any thermoplastic resin or thermosetting resin capable of forming a spherical body can be used. In the case of obtaining a spherical activated carbon from a self-crosslinking vinyl resin, it is necessary to carry out the above-described non-melting treatment, and in contrast, an ion exchange resin produced by imparting a functional group to a crosslinked ethylene resin is obtained. In the case of spherical activated carbon, it is not necessary to carry out the above non-melting treatment. It is considered that the crosslinked ethylene-based resin is modified from a heat-meltable resin to a thermally infusible resin by a functional group imparting treatment or a functional group to be introduced. That is, the crosslinked ethylene-based resin is contained in the hot-melt resin of the present specification, and the ion-exchange resin is included in the thermal non-melting resin of the present specification.

The carbon source of the spherical activated carbon used in the present invention is not particularly limited, and a synthetic resin is preferably used in terms of ease of handling. Examples of the synthetic resin include a thermosetting resin (for example, a phenol resin and a furan resin) as a heat infusible resin, an ion exchange resin, and a thermoplastic resin (for example, a crosslinked ethylene resin) as a heat-meltable resin. Here, the thermosetting resin is liable to form a hollow in the spherical activated carbon, and has a risk of being stuck into the intestine when the strength is weak and pulverized. Further, since the ion exchange resin contains sulfur or the like, care must be taken when it is used for oral administration. Therefore, as the carbon source of the spherical activated carbon, a thermoplastic resin (for example, a crosslinked vinyl resin) is more preferably used.

(hot melt resin)

When a hot melt resin (for example, a crosslinked vinyl resin) is used as the carbon source, substantially the same operation as the previous production method using the asphalt can be used. For example, the spherical body containing the hot-melt resin is softened by heat treatment and deformed into a non-spherical shape or a spherical body. Therefore, before the activation treatment, oxidation is performed at 150 to 400 ° C using an oxidizing agent as a non-melting treatment. Treatment, whereby softening can be suppressed. As the oxidizing agent, O ₂ or a mixed gas obtained by diluting them with air or nitrogen or the like can be used.

The crosslinked ethylene-based resin as the hot-melt resin is softened and melted by heat treatment in a non-oxidizing gas atmosphere, and the carbonization yield is less than 10%, but it is treated as a non-melting treatment in an oxygen-containing environment. The oxidation treatment is carried out at 150 ° C to 400 ° C, and the spherical carbonaceous material can be obtained at a higher carbonization yield of 30% or more without softening and melting, and the spherical activity can be obtained by activating the treatment. carbon.

Further, when the spherical body of the hot-melt resin after the non-melting treatment is subjected to heat treatment, when a large amount of pyrolysis gas or the like is generated, appropriate pre-calcination can be performed before the activation operation to remove the thermal decomposition in advance. product.

Then, the active treatment is carried out at a temperature of 700 to 1000 ° C in a gas stream reactive with carbon (for example, steam or carbonic acid gas) to obtain spherical activated carbon. In the present specification, the term "activated carbon" refers to a porous body obtained by subjecting a carbon precursor such as a spherical hot-melt resin to heat treatment and then performing an activation treatment. The term "spherical activated carbon" means a spherical shape. And the specific surface area is 100 m ² /g or more. The average particle diameter of the spherical body of the hot-melt resin used as the starting material is not particularly limited, but is preferably about 0.02 to 1.5 mm, more preferably 50 μm to 800 μm, still more preferably 70 μm to 500 μm.

As the above-mentioned crosslinked ethylene-based resin used as a starting material, for example, a spherical polymer obtained by emulsion polymerization, bulk polymerization or solution polymerization can be used, or a spherical polymer obtained by suspension polymerization is preferably used. In order to uniformly melt the spherical crosslinked ethylene-based resin having a diameter of 50 μm or more, it is necessary to form pores in advance for the crosslinked vinyl resin. The pore formation of the resin can be achieved by adding a pore former during polymerization. The surface area of the crosslinked vinyl resin which is necessary for the crosslinked ethylene resin to be uniformly melted is preferably 10 m ² /g or more, and more preferably 50 m ² /g or more.

For example, when a crosslinked vinyl resin is prepared by suspension polymerization, a spherical crosslinked vinyl resin can be prepared by including a vinyl monomer, a crosslinking agent, a pore former, and a polymerization initiator. The organic phase is added to an aqueous dispersion medium containing a dispersion stabilizer, and a large amount of organic droplets suspended in the aqueous phase are formed by stirring and mixing, and then heated to polymerize the monomers in the organic droplets.

As the vinyl monomer, any vinyl monomer which can be formed into a spherical shape can be used, and for example, an aromatic vinyl monomer such as styrene, a vinyl hydrogen or a phenyl hydrogen substituted styrene derivative, or A compound or the like in which a heterocyclic or polycyclic compound is bonded to a vinyl group instead of a phenyl group. Specific examples of the aromatic vinyl monomer include α- or β-methylstyrene, α- or β-ethylstyrene, methoxystyrene, phenylstyrene or chlorostyrene. Iso, or o-, m- or p-methylstyrene, ethyl styrene, methoxy styrene, methyl decyl styrene, hydroxy styrene, chlorostyrene, cyanostyrene, nitrostyrene, amine Styrene, carboxystyrene or sulfoxystyrene, sodium styrene sulfonate, etc., or vinyl pyridine, vinyl thiophene, vinyl pyrrolidone, vinyl naphthalene, vinyl fluorene or vinyl Benzene, etc. Further, an aliphatic vinyl monomer may be used, and specific examples thereof include vinyl esters such as ethylene, propylene, isobutylene, diisobutylene, vinyl chloride, acrylate, methacrylate, and vinyl acetate; and vinyl groups; a ketene such as ketone or vinyl ethyl ketone; a vinyl aldehyde such as acrolein or methacrolein; or a vinyl ether such as vinyl methyl ether or vinyl ether; acrylonitrile, ethacrylonitrile, and diphenyl propylene. A vinyl nitrile such as a nitrile or a chloroacrylonitrile.

Further, as the crosslinking agent, any crosslinking agent which can be used for crosslinking of the above vinyl monomer can be used, and for example, divinylbenzene, divinylpyridine, divinyltoluene or divinylnaphthalene can be used. Polyethylene or poly(diallyl phthalate), ethylene glycol diacrylate, ethylene glycol dimethanol, divinyl xylene, divinyl ethylbenzene, divinyl fluorene, ethylene glycol or glycerol Aromatic ethers, polyethylene or polyarylene ethers of pentaerythritol, ethylene glycol Or a polyethylene or polyarylether of a dithio derivative, or a polyethylene or polyarylene ether of resorcinol, diketene, diethylene sulfide, allyl acrylate, butadiene maleate Propyl ester, diallyl fumarate, diallyl succinate, diallyl carbonate, diallyl malonate, diallyl oxalate, diallyl adipate , diallyl azelamate, triallyl triaminecarboxylate, triallyl aconitic acid, triallyl citrate, triallyl phosphate, N,N'-methylenebis propylene amide, 1,2-bis(α-methylmethylenesulfonamide) ethylene, trivinylbenzene, trivinylnaphthalene, polyvinylhydrazine or trivinylcyclohexane. Examples of particularly preferred crosslinkers include polyethylene aromatic hydrocarbons (e.g., divinylbenzene), ethylene glycol trimethacrylate (e.g., ethylene glycol dimethacrylate), or polyvinyl hydrocarbons (e.g., Trivinylcyclohexane). The best is divinylbenzene in terms of its excellent thermal decomposition property.

As a suitable porogen, an alkanol having 4 to 10 carbon atoms (for example, n-butanol, second butanol, 2-ethylhexanol, decyl alcohol or 4-methyl-2-pentanol) may be mentioned. An alkyl ester having at least 7 carbon atoms (eg, n-hexyl acetate, 2-ethylhexyl acetate, methyl oleate, dibutyl sebacate, dibutyl adipate or dibutyl carbonate), carbon atom 4 to 10 alkyl ketones (such as dibutyl ketone or methyl isobutyl ketone), or alkyl carboxylic acids (such as heptanoic acid), aromatic hydrocarbons (such as toluene, xylene or benzene), higher saturated aliphatic Hydrocarbons (such as hexane, heptane or isooctane) or cyclic aliphatic hydrocarbons (such as cyclohexane).

The polymerization initiator is not particularly limited, and those generally used in the field can be used, and an oil-soluble polymerization initiator which is soluble in a polymerizable monomer is preferable. Examples of the polymerization initiator include a dialkyl peroxide, a dinonyl peroxide, a peroxyester, a peroxydicarbonate, or an azo compound. More specifically, for example, a dialkyl peroxide such as methyl ethyl peroxide, dibutyl butyl peroxide or dicumyl peroxide; isobutyl peroxide, benzamidine peroxide, 2 , 4-dichlorobenzamide peroxide, 3,5,5-trimethylhexyl peroxide, and other di-n-butyl peroxide; peroxidic pivalic acid tert-butyl ester, peroxypivalic acid Trihexyl ester, tert-butyl peroxy neodecanoate, trihexyl peroxy neodecanoate, 1-cyclohexyl-1-methylethyl peroxy neodecanoate, peroxy neodecanoic acid 1,1, 3,3-tetramethylbutyl ester, peroxy neodecanoate Peroxy esters such as propyl phenyl ester, (α,α-bis-neoprene peroxidation) diisopropylbenzene; bis(4-t-butylcyclohexyl) peroxydicarbonate, di-n-propyl- Oxydicarbonate, diisopropyl peroxydicarbonate, di(2-ethylethylperoxy)dicarbonate, dimethoxybutyl peroxydicarbonate, di(3-methyl-3- Peroxydicarbonate such as methoxybutyl peroxy)dicarbonate; 2,2'-azobisisobutyronitrile, 2,2'-azobis(4-methoxy-2,4-di An azo compound such as methylvaleronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile) or 1,1'-azobis(1-cyclohexanecarbonitrile).

(hot non-melting resin)

When a thermally non-melting resin (for example, a thermosetting resin or an ion exchange resin) is used as a carbon source in the preparation of the spherical activated carbon used as the adsorbent for oral administration of the present invention, the use of the asphalt may be utilized. The previous manufacturing method was essentially the same operation. For example, spheroids containing a thermally infusible resin may be first subjected to a living treatment in a gas stream reactive with carbon (for example, steam or carbonic acid gas) at a temperature of 700 to 1000 ° C to obtain spherical activated carbon. Further, in the same manner as in the case of the above-mentioned hot-melt resin, when the spherical body of the thermally infusible resin is subjected to heat treatment, when a large amount of pyrolysis gas or the like is generated, it can be appropriately performed before the activation operation. Precalcination to remove the thermal decomposition products in advance. The average particle diameter of the spherical body of the thermally infusible resin used as the starting material is not particularly limited, but is preferably about 0.02 to 1.5 mm, more preferably 50 μm to 800 μm, still more preferably 70 μm to 500 μm.

The above-mentioned hot non-melting resin used as a starting material is a material which can shape a spherical body, and it is important that it does not melt or soften in a heat treatment of 500 ° C or less and does not cause shape deformation.

As the above thermally infusible resin used as a starting material, it is preferred that the carbonization yield obtained by the heat treatment is high. If the carbonization yield is low, the strength as the spherical activated carbon becomes weak. Further, since unnecessary pores are formed, the bulk density of the spherical activated carbon is lowered, and the specific surface area per unit volume is lowered, so that the administration volume is increased and the oral administration becomes difficult. Therefore, the higher the carbonization yield of the hot non-melting resin, the better, and the yield obtained by the heat treatment at 800 ° C in a non-oxidizing gas atmosphere is preferably 30% by weight. More preferably, it is 35 weight% or more.

Specific examples of the thermosetting resin used as a starting material include a phenol resin, for example, a novolac type phenol resin, a resol type phenol resin, a novolac type alkylphenol resin, or a resol type. In addition to the alkylphenol-based resin, a furan resin, a urea resin, a melamine resin, an epoxy resin or the like can also be used. As the thermosetting resin, a copolymer of divinylbenzene and styrene, acrylonitrile, acrylic acid or methacrylic acid can be further used.

Further, as the hot non-melting resin, an ion exchange resin can be used. The ion exchange resin usually comprises a copolymer of divinylbenzene and styrene, acrylonitrile, acrylic acid or methacrylic acid (that is, a crosslinked vinyl resin as a hot melt resin), and basically has an ion exchange group bonded to have a stereo The structure on the copolymer matrix of the network skeleton. The ion exchange resin is roughly classified into a strongly acidic ion exchange resin having a sulfonic acid group, a weakly acidic ion exchange resin having a carboxylic acid group or a sulfonic acid group, and a strong basic ion exchange having a quaternary ammonium salt according to the kind of the ion exchange group. a resin, a weakly basic ion exchange resin having a primary or tertiary amine, and a so-called mixed ion exchange resin having two acidic and basic ion exchange groups as other special resins. In the present invention, these can be used. All ion exchange resins were used as raw materials.

Using a non-melting resin (especially an ion exchange resin) as a carbon source, performing a revitalizing treatment in a gas stream reactive with carbon (for example, steam or carbonic acid gas) at a temperature of 700 to 1000 ° C, thereby obtaining a surface Unmodified spheroidal activated carbon. Further, the surface-modified spherical activated carbon is subjected to oxidation only, oxidation, or reduction treatment to obtain surface-modified spherical activated carbon.

(Control of the physical properties of synthetic resins)

When the spheroidal activated carbon of the present invention is prepared by using the above-mentioned hot-melt resin or hot-melt resin, the physical properties of the spherical activated carbon (for example, average particle diameter, pore volume, particle size distribution or Specific surface area, etc.). For example, the average particle size and particle size distribution of the resin depend on the size of the droplets in the aqueous phase, and the size of the droplets may be based on the suspension. The amount, the speed of the agitation, the shape of the agitating wing or the monomer ratio in the aqueous phase (the ratio of the amount of water to the amount of monomer) is controlled. For example, if the amount of the suspending agent is increased, the droplets can be reduced, and if the stirring speed is increased, the droplets can be reduced, and further, if the amount of the monomer in the water phase is reduced, not only the droplets can be controlled. In view of the fact that it is easy to eliminate the heat of polymerization, if the monomer ratio is too small, the amount of the monomer per batch is reduced, so that the amount of the synthetic resin obtained is reduced, and the productivity is improved. In terms of opinion, it is not good.

Further, when the pore diameter and the specific surface area are controlled to be 10 nm or more, the pore diameter and the specific surface area can be mainly controlled according to the amount and type of the pores, and when the diameter of the pores to be controlled is 10 nm or less, It can be controlled according to the activation conditions of water vapor. Further, the fine structure of the surface-modified spherical activated carbon may be controlled depending on the type of the resin, the type and amount of the crosslinking agent, the non-melting conditions, the firing conditions, and/or the activation temperature.

As the activation reaction, the activation treatment is carried out in a gas stream reactive with carbon (for example, steam or carbonic acid gas) at a temperature of 700 to 1000 ° C, whereby surface unmodified spherical activated carbon is obtained. Further, by subjecting the surface-unmodified spherical activated carbon to oxidation only, oxidation or reduction treatment, surface-modified spherical activated carbon which can be used as the adsorbent for oral administration of the present invention can be obtained. The bulk density can be controlled according to the activation conditions, for example, by increasing the activation time, increasing the activation temperature, and increasing the concentration of the gas stream reactive with carbon, the bulk density can be reduced.

(asphalt)

In the case where asphalt is used as a carbon source in the preparation of the spherical activated carbon used as the adsorbent for oral administration of the present invention, it can be produced, for example, by the following method.

A two-ring or three-ring aromatic compound having a boiling point of 200 ° C or more or a mixture thereof is added as an additive to an asphalt such as petroleum pitch or stone carbon pitch, and the mixture is heated and mixed, and then molded to obtain an asphalt molded body. The size of the asphalt molded body can be controlled according to the nozzle diameter at the time of extrusion molding or the pulverization conditions of the asphalt molded body. The smaller the volume of the asphalt molded body, the more it can be made. Small spherical asphalt, spherical activated carbon having a smaller particle size can be obtained.

Next, the pitch molded body is dispersed in hot water of 50 to 120 ° C under stirring, granulated, and then finely spheroidized, and then cooled to obtain a spherical pitch molded body. The average particle diameter of the spherical asphalt molded body is not particularly limited, but is preferably about 0.02 to 1.5 mm, more preferably 60 to 350 μm, still more preferably 60 to 300 μm. Further, the additive is extracted from the spherical asphalt molded body by using a solvent having low solubility to the pitch and having high solubility to the additive, and the obtained porous pitch is oxidized by using an oxidizing agent to form an infusible porous pitch. The obtained porous pitch which is infusible to heat is further treated in a carbon-reactive gas stream such as steam or carbonic acid gas at a temperature of 800 to 1000 ° C to obtain spherical activated carbon.

In particular, in order to produce spherical activated carbon of microspheres having an average particle diameter of about 50 to 200 μm, it is preferable to control the temperature at the time of spinning naphthalene and pitch, increase the amount of polyvinyl alcohol, or in a short time. Perform a cooling step, etc.

The purpose of the above aromatic additive is to extract and remove the above-mentioned additive from the formed asphalt molded body to make the molded body porous, and to facilitate the structure control and firing of the carbonaceous material oxidized by the subsequent step. The above-mentioned additive is, for example, one or a mixture of two or more kinds of aromatic compounds such as naphthalene, methylnaphthalene, phenylnaphthalene, benzylnaphthalene, methylhydrazine, phenanthrene or biphenyl. The amount of addition to the pitch is preferably in the range of 10 to 50 parts by weight based on 100 parts by weight of the pitch.

Heating is carried out in order to achieve uniform mixing and is carried out in a molten state. The molding may be carried out in a molten state, or may be carried out by cooling the mixture and then pulverizing, but the particle size distribution may be controlled in a narrower range, preferably in a molten state. The mixed pitch is extruded into a filament shape, followed by cutting or pulverizing it at equal intervals. The particle size can be controlled according to the diameter of the nozzle when the mixed asphalt is extruded, and a smaller mixture molded body can be produced by using a finer nozzle.

Used as a solvent for extracting and removing additives from a mixture of bitumen and additives The agent is preferably an aliphatic hydrocarbon such as butane, pentane, hexane or heptane, a mixture of aliphatic hydrocarbons such as naphtha or kerosene, or an aliphatic alcohol such as methanol, ethanol, propanol or butanol. Wait.

By extracting the additive from the mixture of the pitch and the additive by using such a solvent, the shape of the formed body can be maintained and the additive can be directly removed from the formed body. At this time, a peeling hole of an additive is formed in the molded body, and it is presumed that an asphalt molded body having uniform porosity is obtained.

Then, the pitch-formed body exhibiting porosity obtained in the above-described manner is made into a porous material which is not melted by heat by a non-melting treatment, that is, an oxidizing treatment using an oxidizing agent and preferably at a temperature of from 150 ° C to 400 ° C. Melt asphalt shaped body. As the oxidizing agent, O ₂ or a mixed gas obtained by diluting them with air or nitrogen or the like can be used.

When the asphalt is used as a carbon source in the preparation of the spherical activated carbon used as the adsorbent for oral administration of the present invention, the amount of the aromatic additive can be controlled, and the precipitation conditions in the asphalt can be controlled to control the fineness. Hole volume.

As the pitch used as the starting material, it is preferred that the carbonization yield obtained by the heat treatment is high. If the carbonization yield is low, the strength as the spherical activated carbon becomes weak. Further, since unnecessary pores are formed, the bulk density of the spherical activated carbon is lowered, and the specific surface area per unit volume is lowered, so that the administration volume is increased and the oral administration becomes difficult. Therefore, the higher the carbonization yield of the pitch, the better, and the yield obtained by the heat treatment at 800 ° C in a non-oxidizing gas atmosphere is preferably 50% by weight or more, more preferably 60% by weight or more.

(surface modification)

The surface of the obtained unmodified spheroidal activated carbon having the desired pores is subjected to oxidation treatment, oxidation treatment and reduction treatment by using a hot melt resin, a hot non-melting resin or pitch as a carbon source. The surface-modified spherical activated carbon used in the present invention is obtained. The oxidation treatment can be carried out at an oxygen content of 0.1 to 50% by volume, preferably 1 to 30% by volume, and more preferably 3 to 20% by volume. The amount is in the range of 300 to 800 ° C, preferably 320 to 600 ° C. The reduction treatment can be carried out at a temperature of 800 to 1200 ° C, preferably 800 to 1000 ° C, in a non-oxidizing gas atmosphere. In a specific oxygen-containing environment, pure oxygen, nitrogen oxide or air or the like can be used as the oxygen source. Further, the environment which is inert to carbon means nitrogen, argon or helium, or the like, or a mixture thereof. In the present specification, the surface-modified spherical activated carbon refers to a porous body obtained by subjecting the spherical activated carbon to only the oxidation treatment, the oxidation treatment, and the reduction treatment. In particular, by performing the oxidation treatment and the reduction treatment, the adsorption characteristics of the toxic substances in the upper small intestine tube are enhanced by applying the acid point and the alkaline point to the surface of the spherical activated carbon with a better balance. For example, by subjecting the spherical activated carbon to oxidation treatment and reduction treatment, the specificity for adsorbable toxic substances can be enhanced.

The physical properties, the average particle diameter, the bulk density, the specific surface area, the pore volume, and the particle size distribution of the spherical activated carbon used as the orally administered adsorbent of the present invention are measured by the following methods.

(1) Average particle size (Dv50)

A particle size cumulative line graph of a volume basis was prepared using a laser diffraction type particle size distribution measuring apparatus [Shimadzu Corporation: SALAD-3000S], and a particle diameter of 50% of the particle size cumulative rate was defined as an average particle diameter (Dv50).

(2) bulk density

The measurement was carried out in accordance with the packing density measurement method of JIS K 1474-5.7.2.

(3) Specific surface area (calculation method of specific surface area by BET method)

The gas adsorption amount of the spherical activated carbon sample can be measured using a specific surface area measuring device (for example, "ASAP2010" or "ASAP2020" manufactured by MICROMERITICS Co., Ltd.) by a gas adsorption method, and the specific surface area can be calculated according to the following formula. Specifically, the spherical activated carbon as a sample was filled in a sample tube, and dried under reduced pressure at 350 ° C, and then the weight of the sample after drying was measured. Next, the sample tube was cooled to -196 ° C, nitrogen was introduced into the sample tube to adsorb nitrogen on the spherical activated carbon sample, and the nitrogen partial pressure and the adsorption amount were measured. Relationship (adsorption isotherm).

The BET plot was performed by setting the relative pressure of nitrogen to p and setting the adsorption amount at this time to v (cm ³ /g STP). That is, p/(v(1-p)) is selected on the vertical axis, p is selected on the horizontal axis, and p is plotted in the range of 0.05 to 0.20, and the specific surface area S (unit = m ² /g) is based on From the following equation, the slope b (unit = g/cm ³ ) and the slice c (unit = g/cm ³ ) were obtained.

Here, MA is 0.162 nm ^{2 in terms} of the cross-sectional area of nitrogen molecules.

(4) Specific surface area (calculation method of specific surface area using Langmuir's formula)

The gas adsorption amount of the spherical activated carbon sample can be measured using a specific surface area measuring device (for example, "ASAP2010" or "ASAP2020" manufactured by MICROMERITICS Co., Ltd.) by a gas adsorption method, and the specific surface area can be calculated according to the Langmuir formula. Specifically, the spherical activated carbon as a sample was filled in a sample tube, and dried under reduced pressure at 350 ° C, and then the weight of the sample after drying was measured. Next, the sample tube was cooled to -196 ° C, nitrogen was introduced into the sample tube to adsorb nitrogen on the spherical activated carbon sample, and the relationship between the nitrogen partial pressure and the adsorption amount (adsorption isotherm) was measured.

The Langmuir plot was performed by setting the relative pressure of nitrogen to p and setting the amount of adsorption at this time to v (cm ³ /g STP). That is, p/v is selected on the vertical axis, p is selected on the horizontal axis, and p is plotted in the range of 0.05 to 0.20. If the slope is set to b (g/cm ³ ), the specific surface area S ( The unit = m ² /g) was obtained from the following formula.

Here, MA is 0.162 nm ^{2 in terms} of the cross-sectional area of nitrogen molecules.

(5) Fine pore distribution (calculation of Saito-Foley)

The relationship between the nitrogen partial pressure and the adsorption amount of the spherical activated carbon sample at a liquid nitrogen temperature (-196 ° C) using a specific surface area measuring device (ASAP2010 or ASAP2020: manufactured by Micromeritics Co., Ltd.) using a gas adsorption method (adsorption isotherm) ). From the obtained adsorption isotherm, the analytical software attached to the above specific surface area measuring device (ASAP2010 or ASAP2020) is used and calculated according to Saito-Foley [Saito, A. and Foley, HC, AlChE Journal 37(3), 429 (1991)] Calculate the pore distribution. The shape of the pores is analyzed according to the geometry of the slit, which is the original calculation method of Horverth-Kawazoe [Horvath, G. and Kawazoe, K., J. Chem. Eng. Japan 16 (6), 470 (1983)], but The structure of carbon is a structure in which the three-dimensionality is scattered in the hardly graphitizable carbon, so the cylinder geometry is selected here [Saito, A. and Foley, HC, AlChE Journal 37(3), 429 (1991)] Calculated by calculation.

The various parameters used for the calculation are shown below.

Interaction Parameter: 1.56×10 ^-43 ergs‧cm ⁴

Diameter of Adsorptive Molecule: 0.3000nm

Diameter of Sample Molecule: 0.3400nm

Density Conversion Factor: 0.001547 (cm ³ liquid / cm ³ STP)

(6) Using the pore volume of the mercury intrusion method

The pore volume can be measured using a mercury pore meter (for example, "AUTOPORE 9200" manufactured by MICROMERITICS). The spherical activated carbon as a sample was placed in a sample container, and degassed under a pressure of 2.67 Pa or less for 30 minutes. Next, mercury was introduced into the sample container, and the pressure was gradually pressurized to press the mercury into the pores of the spherical activated carbon sample (maximum pressure = 414 MPa). According to the relationship between the pressure at this time and the amount of mercury intrusion The pore volume distribution of the spherical activated carbon sample was measured using the following calculation formulas.

Specifically, the volume of mercury injected into the spherical activated carbon sample from the pressure (0.06 MPa) corresponding to the pore diameter of 21 μm to the highest pressure (414 MPa: pore diameter of 3 nm) was measured. For the calculation of the pore diameter, when the mercury is pressed into the cylindrical pores of the diameter (D) by the pressure (P), if the surface tension of the mercury is set to "γ", the mercury and the pores are formed. When the contact angle of the wall is "θ", the following formula is obtained in terms of the balance between the surface tension and the pressure acting on the cross section of the pores: -πDγcos θ = π(D/2) ² ‧P.

therefore

It becomes D=(-4γcosθ)/P.

In the present specification, the surface tension of mercury is set to 484 dyne/cm, the contact angle of mercury to carbon is set to 130 degrees, the pressure P is set to MPa, and the pore diameter D is represented by μm, according to the following formula: D=1.24 /P

The relationship between the pressure P and the pore diameter D is obtained. For example, the pore volume in the range of pore diameters of 20 to 10,000 nm corresponds to the volume of mercury pressed from the mercury intrusion pressure of 0.124 MPa to 62 MPa. The pore volume in the range of the pore diameter of 7.5 to 15000 nm corresponds to the volume of mercury pressed from the mercury intrusion pressure of 0.083 MPa to 165 MPa. The pore volume in the range of pore diameters of 3 to 20 nm corresponds to the volume of mercury pressed from the mercury intrusion pressure of 413 MPa to 62 MPa.

Further, since the spherical activated carbon used as the adsorbent for oral administration of the present invention has a very small particle diameter, the voids between the sample particles filled in the sample container are also small. Therefore, in the measurement operation of the pore volume by the mercury intrusion method, there is a stage in which mercury is pressed into the inter-particle gap, and the press-in stage indicates the action of the pores having a pore diameter of 8000 to 15000 nm. For example, it can be confirmed by observation with an electron microscope that the spherical activated carbon used as the adsorbent for oral administration of the present invention does not have a pore diameter. Fine pores of 8000~15000nm. Therefore, in the present specification, the amount of mercury added to the inter-particle gap is also included in the "pore volume of the pore diameter of 20 to 15000 nm" or the "pore volume of the pore diameter of 7.5 to 15000 nm".

(7) Particle size distribution

The laser diffraction type particle size distribution measuring apparatus [Shimadzu Corporation: SALAD-3000S] is used to measure the particle size distribution of the number basis, and the representative particle diameter D of the measured particle size region and the number of the measured particle diameter regions are determined. The value of n, according to the following formula

The length average particle diameter D ₁ and the weight average particle diameter D ₄ were calculated.

(8) Total acidity

1 g of a spherical activated carbon sample material was added to 50 mL of a 0.05 N (N) NaOH solution, and an 8-word oscillator ("TRIPLE SHAKER NR-80" manufactured by Tietech Co., Ltd.) was used to oscillate according to 8 characters, and the amplitude was 3 cm. After shaking at 37 ° C for 48 hours at 76 cycles/min, the surface-modified spherical activated carbon sample was filtered off and the consumption of NaOH was determined by neutralization titration.

(9) Total basicity

1 g of a spherical activated carbon sample was added to 50 mL of 0.05 equivalent (N) HCl solution, and an 8-word oscillator ("TRIPLE SHAKER NR-" manufactured by Tietech Co., Ltd. was used. 80"), after oscillating at 37 ° C for 24 hours according to 8-word oscillation, amplitude 3 cm, 76 cycles/min, the surface-modified spherical activated carbon sample was filtered off and the consumption of HCl was determined by neutralization titration. the amount.

The adsorbent for oral administration of the present invention contains the spherical activated carbon as an active ingredient, but may also contain only spherical activated carbon, or may contain pharmaceutically acceptable substances in addition to spherical activated carbon. Additives. The additive may, for example, be an excipient, a disintegrator, a surfactant, a binder, a lubricant, a sour, a foaming agent, a sweetener, a perfume, a coloring agent, a stabilizer, or a flavoring agent.

The administration form in the case where the adsorbent for oral administration is a spherical activated carbon includes, for example, a powder, a granule, a capsule, or a divided package. In addition, examples of the administration form in the case where the adsorbent for oral administration is a spherical activated carbon and an additive include a powder, a granule, a tablet, a sugar-coated tablet, a capsule, a suspension, an adhesive, and a sub-package. Package or emulsion.

[2] Oral administration of an adsorbent for the treatment or prevention of kidney disease or liver disease

The spherical activated carbon used as the orally administered adsorbent of the present invention is excellent in the adsorptivity of the toxic substance of the liver disease augmentation factor or the kidney disease, and thus can be used as a therapeutic or preventive oral administration for kidney disease. The adsorbent is orally administered by an adsorbent or as a therapeutic or prophylactic agent for liver diseases.

Examples of kidney diseases include chronic renal failure, acute renal failure, chronic renal nephritis, acute renal nephritis, chronic nephritis, acute renal inflammation, acute progressive renal inflammation, chronic renal inflammation, renal syndrome, and nephrosclerosis. Interstitial nephritis, renal tubular disease, fatty kidney disease, diabetic nephropathy, renal vascular hypertension or hypertension syndrome or secondary kidney disease accompanied by the above-mentioned original disease, and then mild renal failure before dialysis, It can be used to improve the condition of mild renal failure before dialysis or to improve the condition during dialysis (refer to "Clinical Nephrology" Asakura Bookstore, Honda Nishi, Koji Kenji, Sui Chuanqing, 1990 Edition and "Neonology" Medical College尾前前雄, 藤见惺 Edited, 1981 edition).

Further, examples of the liver disease include blasting hepatitis, chronic hepatitis, viral hepatitis, alcoholic hepatitis, hepatic fibrosis, cirrhosis, liver cancer, autoimmune hepatitis, allergic liver disease, and primary disease. Biliary cirrhosis, tremors, encephalopathy, metabolic abnormalities or dysfunction. In addition to this, it can also be used for the treatment of diseases caused by harmful substances existing in the body, that is, psychosis.

Therefore, the adsorbent for oral administration of the present invention contains the above-mentioned spherical activated carbon as an active ingredient when it is used as a therapeutic agent for kidney diseases. When the orally administered sorbent of the present invention is used as a therapeutic agent for a kidney disease or a therapeutic agent for a liver disease, the dose is different depending on the human or other animal to be administered, and is also affected by age and individual. Because of the influence of the difference or the condition, the dosage outside the following range may be appropriate. However, the oral administration amount in the case of humans is usually divided into 3 to 4 times and taken 1 to 20 g per day. Further, it can be appropriately increased or decreased depending on the symptoms. The dosage form can be a powder, granule, lozenge, dragee, capsule, suspension, adhesive, sub-package or emulsion. In the case of administration as a capsule, an enteric capsule may be used as needed in addition to the usual gelatin. In the case of use as a tablet, it is necessary to dissolve the ingot into the original microparticles in the body. Further, it may be used in the form of a complexing agent prepared by mixing an electrolyte such as an aluminum gel or a Kayexalate as another drug.

The spherical activated carbon having an activity distribution can be used as a therapeutic or prophylactic agent for kidney diseases or a therapeutic or preventive agent for liver diseases according to a form of a mixture of a previously known spheroidal activated carbon having no distribution of activity. Alternatively, a spherical activated carbon having an activity distribution may be used as a therapeutic or prophylactic agent for kidney disease or a therapeutic or preventive agent for liver diseases in combination with a previously known spherical activated carbon having no distribution for activating activity.

[3] Treatment of kidney disease or liver disease

The spheroidal activated carbon used for the oral administration of the adsorbent of the present invention can be used for the prevention or treatment of kidney disease or liver disease. Therefore, the treatment of the kidney disease or liver disease of the present invention The method is characterized in that an orally administered sorbent comprising the above spherical activated carbon is administered in an effective amount to a subject to be treated for kidney disease or liver disease.

The administration route, the administration amount, the administration interval, and the like of the spherical activated carbon can be appropriately determined depending on the type of the disease, the age of the patient, the sex, the body weight, the degree of the symptoms, the administration method, and the like.

[4] Spherical activated carbon for treatment of kidney disease or liver disease

The spheroidal activated carbon used for the oral administration of the adsorbent of the present invention can be used in a method of preventing or treating a kidney disease or a liver disease. Therefore, the spheroidal activated carbon of the present invention is used in a method of preventing or treating a kidney disease or a liver disease.

The amount of the above-mentioned spherical activated carbon to be used for prevention or treatment can be appropriately determined depending on the type of the disease, the age of the patient, the sex, the body weight, the degree of the symptoms, the administration method, and the like.

[5] Use of a therapeutic medicine for spheroidal activated carbon for kidney disease or liver disease

The spherical activated carbon used for the oral administration of the adsorbent of the present invention can be used for the manufacture of a medicament for the prevention or treatment of kidney disease or liver disease. Therefore, the use of the present invention is for the manufacture of a medicament for the prevention or treatment of kidney disease or liver disease of spherical activated carbon.

The content of the spherical activated carbon in the medicine for prevention or treatment can be appropriately determined depending on the type of the disease, the age of the patient, the sex, the body weight, the degree of the symptoms, the administration method, and the like.

[6] Use of spherical activated carbon for the treatment of kidney disease or liver disease

The spheroidal activated carbon used in the oral administration of the adsorbent of the present invention can be used for the treatment of kidney disease or liver disease. Therefore, the use of the present invention is for the prevention or treatment of spherical activated carbon for kidney disease or liver disease.

The use or the like in the prevention or treatment of the above-mentioned spherical activated carbon can be appropriately determined depending on the type of the disease, the age of the patient, the sex, the body weight, the degree of the symptoms, the administration method, and the like.

[Examples]

Hereinafter, the present invention will be specifically described by way of examples, but the scope of the invention is not limited thereto.

Comparative Example 1

4800 g of deionized water, 7.2 g of methylcellulose, and 1.0 g of sodium nitrite were placed in a 10 L polymerization tank, and 481 g of styrene and 57% of divinylbenzene (57% divinylbenzene) were appropriately added thereto. 43% of ethylvinylbenzene) 1119g, 2,2'-azobis(2,4-dimethylvaleronitrile) 9.3g, and 560g of hexane as pores were immediately replaced with nitrogen in the system. The two phase system was stirred at 140 rpm and heated directly to 55 ° C for 20 hours. The obtained resin was filtered, dried under reduced pressure, and hexane was removed from the resin by distillation, and then dried under reduced pressure at 90 ° C for 12 hours to obtain a spherical porous synthetic resin having an average particle diameter of 246 μm. The porous synthetic resin has a specific surface area of about 240 m ² /g.

The obtained spherical porous synthetic resin was added to a reaction apparatus equipped with a porous plate, and was not melted by a vertical tubular furnace. The non-melting condition was such that dry air was passed from the lower portion of the reaction tube to the upper portion, and the temperature was raised to 190 ° C, and then the temperature was raised from 190 ° C to 290 ° C at 10 ° C / h to obtain a spherical porous oxidized resin. The spherical porous oxidized resin was calcined in a nitrogen atmosphere at 850 ° C, and then batch-activated by using a flow layer of a trough reactor at 850 ° C in a nitrogen atmosphere containing water vapor. Spherical activated carbon was obtained until the bulk density became 0.70 g/mL. The properties of the obtained spherical activated carbon are shown in Tables 3 and 4.

Comparative Example 2

In the above Comparative Example 1, the operation of the above Comparative Example 1 was repeated except that the activation treatment was carried out until the bulk density of 0.70 g/mL and the activation treatment was carried out until the bulk density was 0.60 g/mL, thereby obtaining spherical activated carbon.

Comparative Example 3

In the above Comparative Example 1, the activation treatment was performed instead of the activation treatment to a bulk density of 0.70 g/mL. The operation of the above Comparative Example 1 was repeated until the bulk density was 0.50 g/mL, thereby obtaining spherical activated carbon.

Comparative Example 4

In the above Comparative Example 1, the operation of the above Comparative Example 1 was repeated except that the activation treatment was carried out until the bulk density of 0.70 g/mL and the activation treatment was carried out until the bulk density was 0.40 g/mL, thereby obtaining spherical activated carbon.

Comparative Example 5

In the above Comparative Example 1, the operation of the above Comparative Example 1 was repeated except that the activation treatment was carried out until the bulk density of 0.70 g/mL and the activation treatment was carried out until the bulk density was 0.30 g/mL, thereby obtaining spherical activated carbon.

Comparative Example 6

4800 g of deionized water, 7.2 g of methylcellulose, and 1.0 g of sodium nitrite were placed in a 10 L polymerization tank, and 481 g of styrene and 57% of divinylbenzene (57% divinylbenzene) were appropriately added thereto. 43% of ethylvinylbenzene) 1119g, 2,2'-azobis(2,4-dimethylvaleronitrile) 9.3g, and 560g of hexane as pores were immediately replaced with nitrogen in the system. The two phase system was stirred at 140 rpm and heated directly to 55 ° C for 20 hours. The obtained resin was filtered, dried under reduced pressure, and hexane was removed from the resin by distillation, and then dried under reduced pressure at 90 ° C for 12 hours to obtain a spherical porous synthetic resin having an average particle diameter of 246 μm. The porous synthetic resin has a specific surface area of about 240 m ² /g.

The obtained spherical porous synthetic resin was added to a reaction apparatus equipped with a porous plate, and was not melted by a vertical tubular furnace. The non-melting condition was such that dry air was passed from the lower portion of the reaction tube to the upper portion, and the temperature was raised to 190 ° C, and then the temperature was raised from 190 ° C to 290 ° C at 10 ° C / h to obtain a spherical porous oxidized resin. The spherical porous oxidized resin was calcined in a nitrogen atmosphere at 850 ° C, and then batch-activated by using a flow layer of a trough reactor at 850 ° C in a nitrogen atmosphere containing water vapor until loose Spherical activated carbon was obtained at a density of 0.63 g/mL.

Further, the obtained spherical activated carbon was oxidized in the air bed at 470 ° C for 3 hours, and then the surface modified ball was obtained by a reducing treatment using a fluidized bed under a nitrogen atmosphere at 900 ° C for 17 minutes. Activated carbon. The bulk density of the surface-modified spherical activated carbon obtained was 0.60 g/mL.

Comparative Example 7

In the above Comparative Example 6, the operation of the above Comparative Example 6 was repeated except that the activation treatment was carried out until the bulk density of 0.63 g/mL and the activation treatment was carried out until the bulk density was 0.48 g/mL, whereby the surface-modified spherical activity was obtained. carbon. The bulk density of the surface-modified spherical activated carbon obtained was 0.50 g/mL.

Comparative Example 8

In the above Comparative Example 6, the operation of the above Comparative Example 6 was repeated except that the activation treatment was carried out until the bulk density of 0.63 g/mL and the activation treatment was carried out until the bulk density was 0.37 g/mL, whereby the surface-modified spherical activity was obtained. carbon. The bulk density of the surface-modified spherical activated carbon obtained was 0.40 g/mL.

Reference Example 1

A spherical phenol-based resin (trade name "Phenol resin Resitop for industrial use (Marilyn HF-100, manufactured No. 60303); manufactured by Qun Rong Chemical Co., Ltd.) was placed in a quartz vertical reaction tube with a perforated plate. The temperature was raised to 300 ° C over 0.5 hours under a nitrogen gas stream, and after heating to 700 ° C over 2 hours, it was kept for 30 minutes. Thereafter, the activation treatment was further carried out in a nitrogen atmosphere containing water vapor at 850 ° C until the bulk density was 0.40 g/mL to obtain spherical activated carbon.

"Embodiment 1"

The spherical activated carbons of Comparative Examples 1, 3 and 5 described above were mixed at a weight ratio of 5:90:5, whereby spherical activated carbon having an average bulk density of 0.50 g/mL was obtained.

<<Example 2》

The spherical activated carbon of the above Comparative Examples 1, 3 and 5 was used in a weight ratio of 10:80:10. Mixing, thereby obtaining spherical activated carbon having an average bulk density of 0.50 g/mL.

Example 3

The spherical activated carbons of Comparative Examples 1 and 5 described above were mixed at a weight ratio of 50:50 to obtain spherical activated carbon having an average bulk density of 0.50 g/mL.

Example 4

The spherical activated carbons of the above Comparative Examples 2 to 4 were mixed at a weight ratio of 15:70:15 to obtain spherical activated carbon having an average bulk density of 0.50 g/mL.

"Embodiment 5"

The spherical activated carbons of the above Comparative Examples 2 to 4 were mixed at a weight ratio of 30:40:30 to obtain spherical activated carbon having an average bulk density of 0.50 g/mL.

"Embodiment 6"

The spherical activated carbons of Comparative Examples 2 and 4 described above were mixed at a weight ratio of 50:50 to obtain spherical activated carbon having an average bulk density of 0.50 g/mL.

<<Example 7》

The spherical activated carbons of the above Comparative Examples 1 to 5 were mixed at a weight ratio of 20:20:20:20:20 to obtain spherical activated carbon having an average bulk density of 0.50 g/mL.

"Embodiment 8"

The spherical activated carbons of the above Comparative Examples 1 to 3 were mixed at a weight ratio of 15:70:15 to obtain spherical activated carbon having an average bulk density of 0.60 g/mL.

"Embodiment 9"

The spherical activated carbons of Comparative Examples 1 and 5 described above were mixed at a weight ratio of 75:25 to obtain spherical activated carbon having an average bulk density of 0.60 g/mL.

"Embodiment 10"

The spherical activated carbons of the above Comparative Examples 3 to 5 were mixed at a weight ratio of 15:70:15 to obtain spherical activated carbon having an average bulk density of 0.40 g/mL.

"Embodiment 11"

The spherical activated carbons of the above Comparative Examples 1 and 5 were mixed at a weight ratio of 25:75 to obtain spherical activated carbon having an average bulk density of 0.40 g/mL.

"Embodiment 12"

The spherical activated carbon of the above Comparative Examples 6 to 8 was mixed at a weight ratio of 15:70:15, whereby a spherical activated carbon having an average bulk density of 0.50 g/mL was obtained.

"Embodiment 13"

The spherical activated carbon of the above Comparative Examples 6 to 8 was mixed at a weight ratio of 30:40:30, whereby a spherical activated carbon having an average bulk density of 0.50 g/mL was obtained.

<<Example 14》

The spherical activated carbons of the above Comparative Examples 6 and 8 were mixed at a weight ratio of 50:50 to obtain spherical activated carbon having an average bulk density of 0.50 g/mL.

[Evaluation method of oral adsorbent]

The various characteristics shown in the following Tables 1 to 6 were measured by the following methods.

(1) Average particle size

The measurement was carried out by the above-described laser diffraction type particle size distribution measuring apparatus.

(2) pore volume

The micropore pore volume of each of the spherical activated carbons obtained in the above examples and comparative examples was determined by the SF method using the above nitrogen adsorption method, and the pore volume and pore diameter of the pore diameter of 20 to 10000 nm were determined. The pore volume of 7.5 to 150,000 nm and the pore volume of pore diameter of 3 to 20 nm are obtained by the above-described mercury intrusion method.

(3) Specific surface area obtained by BET method and Langmuir method

The measurement was carried out by the above BET method and Langmuir method.

(4) bulk density

The sample was filled in a 50 mL graduated cylinder until it became 50 mL, and after shaking for 50 times, the bulk weight was divided by the volume to calculate the bulk density. The results are shown in Tables 1 to 6. Furthermore, the measured values obtained by the method are obtained by the packing density measurement method of JIS K 1474-5.7.2. The measured values are not subject to any difference within the valid numerical ranges shown in Tables 1 to 6.

(5) Total acid base

1 g of a spherical activated carbon sample was added to 50 mL of a 0.05 N (N) NaOH solution, and an 8-word oscillator ("TRIPLE SHAKER NR-80" manufactured by Tietech Co., Ltd.) was used to oscillate according to 8 characters, amplitude 3 cm, 76. After shaking at 37 ° C for 48 hours at a period of /min, the surface-modified spherical activated carbon sample was filtered off and the consumption of NaOH was determined by neutralization titration.

(6) Total basicity

1 g of a spherical activated carbon sample was added to 50 mL of a 0.05 N (N) HCl solution, and an 8-word oscillator ("TRIPLE SHAKER NR-80" manufactured by Tietech Co., Ltd.) was used and oscillated according to 8 characters, and an amplitude of 3 cm. After shaking at 37 ° C for 24 hours at 76 cycles/min, the surface-modified spherical activated carbon sample was filtered off and the consumption of HCl was determined by neutralization titration.

(7) Adsorption test of potassium phenol sulfate

After the sample was dried, 0.05 g of the dried sample was weighed and placed in a 50 mL screw sample vial. On the other hand, accurately weigh 100 mg of potassium phenol sulfate and 6458 mg of sodium cholate and add a phosphate buffer solution of pH 7.4 to dissolve, and accurately prepare a 1000 mL solution (potassium phenol sulfate solution). 50 mL of the solution was accurately added to the above-mentioned 50 mL screw sample vial, and shaken at 10 rpm and 37 ± 1 ° C for 2 hours using a rotary mixer ("Mixing rotor variable VMR-5R" manufactured by AS ONE Co., Ltd.). The contents of the screw sample vial were suction-filtered using a membrane filter having a pore size of 0.65 μm, and about 20 mL of the initial filtrate was removed, and about 10 mL of the filtrate was diluted with acetonitrile to prepare a filtrate: acetonitrile = 1:1. Sample solution.

For the calibration curve, accurately extract the potassium nonylphenol sulfate solution in a volumetric flask in the amounts of 0 mL, 25 mL, 50 mL, 75 mL, and 100 mL, and prepare a calibration curve solution using a phosphate buffer solution having a pH of 7.4 to a volume of 100 mL. , diluted by acetonitrile Calibration curve stock solution: Acetonitrile = 1:1 calibration curve solution.

The adsorption amount (mg/g) of indophenol sulfate was calculated by measuring the absorbance of the sample solution and the calibration curve solution at a wavelength of 278 nm using HPLC (High Performance Liquid Chromatography). The results are shown in Tables 5 and 6.

(8) Tryptophan acid adsorption test

The various spheroidal activated carbons and surface-modified spherical activated carbons obtained in Examples 1 to 14 and Comparative Examples 1 to 8 were subjected to a tryptophan adsorption test by the following method.

After the sample was dried, 0.01 g of the dried sample was weighed and placed in a 50 mL screw sample vial. On the other hand, 100 mg of tryptophan and 6458 mg of sodium cholate were accurately weighed, and a phosphate buffer solution of pH 7.4 was added to dissolve, and a 1000 mL solution (tryptophan stock solution) was accurately prepared, and 50 mL of the solution was added thereto. The 50 mL screw sample vial was shaken at 10 rpm and 37 ± 1 ° C for 2 hours using a rotary mixer ("Mixing rotor variable VMR-5R" manufactured by AS ONE Co., Ltd.). The contents of the screw bottle that finished the oscillation were suction-filtered by a membrane filter having a pore size of 0.65 μm, about 20 mL of the initial filtrate was removed, and about 10 mL of the filtrate was diluted with acetonitrile to prepare a filtrate: acetonitrile = 1: 1 sample solution.

For the calibration curve, the tryptophan stock solution was accurately dispensed in a volumetric flask in the amounts of 0 mL, 25 mL, 50 mL, 75 mL, and 100 mL, and a calibration curve stock solution having a constant volume of 100 mL of a phosphate buffer solution having a pH of 7.4 was prepared and used. The acetonitrile was diluted to prepare a calibration curve stock solution: acetonitrile = 1:1 calibration curve solution.

The tryptophan adsorption amount (mg/g) was calculated by measuring the absorbance of the sample solution and the calibration curve solution at a wavelength of 278 nm by HPLC (High Performance Liquid Chromatography). The results are shown in Tables 5 and 6.

[Industrial availability]

The orally administered adsorbent of the present invention can be used as an adsorbent for oral administration for the treatment or prevention of kidney diseases, or as a therapeutic or preventive adsorbent for liver diseases.

Examples of kidney diseases include chronic renal failure, acute renal failure, chronic renal nephritis, acute renal nephritis, chronic nephritis, acute renal inflammation, and acute progression. Renal inflammatory syndrome, chronic renal inflammatory syndrome, renal disease, renal sclerosis, interstitial nephritis, renal tubular disease, fatty kidney disease, diabetic nephropathy, renal vascular hypertension or hypertension syndrome or accompanying the recurrence of the above-mentioned original disease Kidney disease, and mild renal failure before dialysis, can also be used for the improvement of mild renal failure before dialysis or the improvement of the disease during dialysis (refer to "Clinical Nephrology" Asakura Bookstore, Honda Nishi, Koji Qian Ji, Sui Chuanqing, 1990 edition and "Neurology" Medical College, Tatsumi Tatsuo, Fujimori, 1981 edition).

Further, examples of the liver disease include blasting hepatitis, chronic hepatitis, viral hepatitis, alcoholic hepatitis, hepatic fibrosis, cirrhosis, liver cancer, autoimmune hepatitis, allergic liver disease, and primary disease. Biliary cirrhosis, tremors, encephalopathy, metabolic abnormalities or dysfunction. In addition to this, it can also be used for the treatment of diseases caused by harmful substances existing in the body, that is, psychosis.

The invention has been described above on the basis of specific aspects, but modifications or improvements are also intended to be included within the scope of the invention.

Claims (6)

An adsorbent for oral administration comprising a spherical activated carbon having an average bulk density of 0.4 to 0.6 g/mL and a pore obtained by an SF method using a nitrogen adsorption method The pore volume of 1.5 to 2.0 nm in diameter satisfies the formula (1) y > 6 × 10 ^-8 x ² -9 × 10 ^-5 x + 0.0241 (1) [wherein y represents the SF method by the nitrogen adsorption method. The pore volume (mL/g) of the pore diameter of 1.5 to 2.0 nm was determined, and x represents a BET specific surface area (m ² /g)]. An orally-administered adsorbent characterized by comprising spherical activated carbon having an average bulk density of 0.4 to 0.6 g/mL and a spherical shape by a bulk density exceeding an average bulk density It is obtained by mixing 5% by weight or more of activated carbon and 5% by weight or more of spherical activated carbon which is less than the bulk density. The orally-administered adsorbent according to claim 1 or 2, wherein the spherical activated carbon is a surface-modified spherical activated carbon having a total acidic group of 0.30 meq or more, or a total acidic group having a total of less than 0.30 meq. The surface is not modified with spherical activated carbon. The sorbent for oral administration according to claim 3, wherein the surface-modified spherical activated carbon has a total acidic group of 0.30 meq/g to 1.20 meq/g and a total alkalinity of 0.20 meq/g to 0.9 meq/g. base. A therapeutic or prophylactic agent for kidney disease comprising the sorbent for oral administration according to claim 1 or 2 as an active ingredient. A therapeutic or prophylactic agent for liver diseases comprising the sorbent for oral administration according to claim 1 or 2 as an active ingredient.