WO2010001485A1 - Adsorbent for oral administration - Google Patents

Abstract

An adsorbent for oral administration comprising a spherical active carbon of 0.2 to 0.5 cc/g total pore volume and 30 to 45% volume ratio of 1 nm or less diameter pores, provided on its surface with a multiplicity of projections. The adsorbent for oral administration has high capability of adsorbing harmful toxic substances, such as indole, while being low in the adsorptivity of in vivo needed substances, such as tryptophan and lysine, namely, excelling in the selective adsorption of harmful toxic substances.

Description

Adsorbent for oral administration

The present invention relates to an adsorbent for oral administration.

Patients with impaired kidney function cannot excrete toxic toxic substances such as nitrogenous substances in the blood and other waste products from the urine. For this reason, toxic substances can accumulate in the body and cause uremia symptoms such as impaired consciousness. Therefore, removal of toxic substances is extremely important in suppressing the progression of renal diseases.

Hemodialysis is the most popular treatment method for removing toxic substances from the body. However, this treatment requires not only a special device but also a long time for the treatment, which causes physical and mental pain to the patient.

On the other hand, adsorbents that adsorb harmful toxic substances in the intestine by oral administration have been developed for the purpose of suppressing the progression of renal diseases. This adsorbent is made of spherical activated carbon having specific physical properties, and several patent applications have been made and are commercially available.

For example, Japanese Patent No. 3585043 uses a spherical phenol resin as a raw material, and has an average particle diameter of 350 μm or less, a specific surface area of 800 to 2000 m ² / g, a pore volume of 0.2 to 1.0 mL / g, and a diameter of 1.0 nm or less. A medical adsorbent having physical properties such that the pores are 55% or more of the total pore volume and the pore volume of 20 to 1000 nm in diameter is 0.04 mL / g or less is disclosed.

Japanese Patent Application Laid-Open No. 2006-15334 has physical properties of an average particle diameter of 100 to 800 μm, a specific surface area of 800 to 3000 m ² / g, and a pore volume of 0.02 to 10 μm in diameter of 0.10 to 0.60 mL / g. Medical adsorbents are disclosed.

The adsorbents described in any of the patent documents have high adsorptivity for harmful toxic substances such as indole. However, these adsorbents are relatively unsatisfactory in terms of the selective adsorptivity of harmful toxic substances because they have a relatively high adsorptivity for necessary substances such as tryptophan and lysine.

The present invention relates to an adsorbent for oral administration that has a high adsorptivity to harmful toxic substances such as indole and a low adsorptivity to necessary substances such as tryptophan and lysine, and has an excellent selective adsorptivity for harmful toxic substances. The purpose is to provide.

According to the present invention, a spherical activated carbon having a large number of protrusions on the surface, a total pore volume of 0.2 to 0.5 cc / g, and a volume ratio of pores having a diameter of 1 nm or less of 30 to 45% is obtained. An adsorbent for oral administration is provided.

1 is a SEM photograph showing the surface state of the spherical activated carbon of Example 1. FIG. FIG. 2 is a SEM photograph showing the surface state of the spherical activated carbon of Example 2. FIG. 3 is a SEM photograph showing the surface state of the spherical activated carbon of Example 3. 4 is a SEM photograph showing the surface state of the spherical activated carbon of Example 4. FIG. FIG. 5 is a SEM photograph showing the surface state of the spherical activated carbon of Example 5. FIG. 6 is a SEM photograph showing the surface state of the spherical activated carbon of Comparative Example 1. FIG. 7 is an SEM photograph showing the surface state of the spherical activated carbon of Comparative Example 2. FIG. 8 is a SEM photograph showing the surface state of the spherical activated carbon of Comparative Example 3.

Hereinafter, the adsorbent for oral administration according to the embodiment of the present invention will be described in detail.

The adsorbent for oral administration according to the embodiment has a large number of protrusions formed on the surface, the total pore volume is 0.2 to 0.5 cc / g, and the volume ratio of pores having a diameter of 1 nm or less is 30 to 45. % Spherical activated carbon.

A large number of protrusions formed on the surface of the spherical activated carbon have a shape having a curve on at least a part of the outer edge on the surface (for example, SEM photograph) on which the spherical activated carbon is projected. Here, “a shape having a curve on at least a part of the outer edge” means a shape in which all the outer edges are curved, and a shape in which the outer edge is a straight line and a curve connected from one end of the straight line to the other end. Examples of the shape in which the outer edges are all curved include a circle, an ellipse, a flat ellipse, and a shape that is bound to a part of the outer edge of the ellipse. Examples of the shape composed of a straight line and a curve connecting from one end of the straight line to the other end include a shape in which a part of the outer edge of the circle forms a straight line, a shape in which a part of the outer edge of the ellipse forms a straight line, and the like. . The protrusions of these shapes may be formed individually on the surface of the spherical activated carbon or may be formed together.

The projection having such a shape preferably has a diameter of 0.1 to 1.2 μm. Here, the “projection diameter” is the maximum length of the length that crosses the center from two points on the outer edge by observing a protrusion having a curved shape on at least a part of the outer edge on the surface on which the spherical activated carbon is projected. Means. For example, in the case of a circular protrusion, the diameter is a diameter.

It is desirable that a large number of protrusions be formed on the surface of the spherical activated carbon at 1 to 20, more preferably 1 to 15, most preferably 1 to 10 per 1 μm ² . Here, the number of protrusions present per 1 μm ^{2 on the} spherical activated carbon surface can be calculated by the following method. That is, SEM photographs at a predetermined magnification are taken at a plurality of locations on the surface of the spherical activated carbon. The number of protrusions projected on each SEM photograph is measured. By dividing the measured number of protrusions by the area of the SEM photograph obtained from the magnification at the time of photographing, the number of protrusions per 1 μm ² is calculated in each SEM photograph. An average value of the number of protrusions per 1 μm ² is obtained from the calculated number of protrusions per 1 μm ^{2 and} the number of SEM photographs. In addition, when a protrusion existing in the field of view of the SEM photograph is missing at the edge of the field of view, the number of protrusions in which the missing protrusion is half or more of the normal size is measured. Exclude from measurement. Further, since the number of protrusions is obtained as an average value as described above, the number of protrusions per 1 μm ² may not have an integer but may have a decimal point.

The height of the protrusion formed on the surface of the spherical activated carbon is not particularly limited, but is preferably 0.04 to 0.2 μm.

Adsorbability of harmful toxic substances by spherical activated carbon can be improved by defining the total pore volume to 0.2 to 0.5 cc / g.

In spherical activated carbon, the volume ratio of pores having a diameter of 1 nm or less means the ratio of the pores to the total pore volume. Spherical activated carbon with a volume ratio of pores with a diameter of 1 nm or less of 30-45% improves the adsorptivity of harmful toxic substances and selectively adsorbs harmful toxic substances in order to suppress the adsorptivity of necessary substances in the body. Can be improved. If the volume ratio of pores having a diameter of 1 nm or less is less than 30%, the adsorptivity of harmful toxic substances may be reduced. On the other hand, if the volume ratio of pores having a diameter of 1 nm or less exceeds 45%, the adsorptivity of harmful toxic substances increases, but the adsorptivity of necessary substances in living bodies also increases, and the selective adsorptivity of harmful toxic substances. May decrease. A more preferable volume ratio of pores having a diameter of 1 nm or less is 34 to 41%.

The spherical activated carbon preferably further has the following physical properties.

(1) The specific surface area determined by the BET method is 600 m ² / g to 1000 m ² / g. The adsorptivity of harmful toxic substances by the spherical activated carbon can be further improved by defining the specific surface area within the above range.

(2) The average particle size is 250 μm or more. The upper limit of the average particle diameter is preferably 800 μm.

(3) The particle strength is 10,000 g / mm ² or more. Spherical activated carbon having a particle strength of 10,000 g / mm ² or more can prevent fine particles in the intestine during oral administration and prevent adhesion to the intestinal wall. The upper limit of the particle strength is preferably 18000 g / mm ² .

The method for measuring various physical properties of such a spherical activated carbon will be described in detail in later examples.

Next, an example of a method for producing spherical activated carbon contained in the orally administered adsorbent according to the embodiment will be described.

First, a cured spherical phenol resin is produced by a condensation reaction of phenols and aldehydes in the presence of an emulsion stabilizer.

Phenols include, for example, phenol, cresol, xylenol; phenols having 1 to 4 alkyl groups having 1 to 10 carbon atoms as substituents, such as ethylphenol, propylphenol, and butylphenol; phenylphenol, resorcinol, catechol, and pyrogallol. Can be used.

As the aldehydes, for example, formaldehyde, acetaldehyde, or benzenes having a formyl group can be used.

As the emulsion stabilizer, for example, gum arabic (Senegal species) can be used.

The raw materials and the emulsion stabilizer can be used alone or in combination of two or more.

Next, the obtained cured spherical phenol is baked by a baking apparatus such as a rotary kiln. Subsequently, water is added, and the activated carbon is heated to about 1000 ° C. to activate water vapor to produce spherical activated carbon.

The adsorbent for oral administration according to the embodiment is composed of spherical activated carbon having the above physical properties alone or a mixture of many kinds of spherical activated carbon having the above physical properties.

Examples of the dosage form of the adsorbent for oral administration according to the embodiment include powders, fine granules, granules, tablets, capsules, suspensions, and jelly agents. In consideration of application to patients with swallowing function of elderly people, application to patients with water restriction such as dialysis patients, good sensation of taking, the jelly agent containing the spherical activated carbon or the spherical activated carbon Tablets having a rapidly disintegrating function are preferred. In order to obtain only a good feeling of dosing, a suspension containing the spherical activated carbon, which is easy to process and ensures the uniformity of components, is preferable.

As the jelly agent, for example, a flavoring agent, a coloring agent, a flavoring agent, a preservative, a gelling agent, an emulsifier, and a pH adjuster are blended in the spherical activated carbon. In the tablet having a quick disintegrating function, a disintegrating agent, a lubricant, a binder, an excipient, a fluidizing agent, a coloring agent, a flavoring agent, a sweetening agent and a stabilizing agent are blended in the spherical activated carbon. As for the suspending agent, a coloring agent, a flavoring agent, an antiseptic, a gelling agent, an emulsifier, a pH adjusting agent, a buffering agent, a suspending agent, a dispersing agent, an antifoaming agent and a thickening agent are blended in the spherical activated carbon. The

The adsorbent for oral administration according to the embodiment described above has a large number of protrusions formed on the surface, a total pore volume of 0.2 to 0.5 cc / g, and a volume ratio of pores having a diameter of 1 nm or less. Because it contains spherical activated carbon that is 30-45%, it has a high adsorptivity to harmful toxic substances such as indole due to the interaction of many protrusions and the volume ratio of pores. Excellent selective adsorption with low adsorption of necessary substances.

In particular, on the surface projected with spherical activated carbon, by making the diameter of the protrusion having a curved shape on at least a part of the outer edge be 0.1 to 1.2 μm, further excellent selective adsorption of harmful toxic substances can be achieved. The adsorbent for oral administration can be obtained. Further, by forming 1 to 20 protrusions having the shape and diameter on the surface of the spherical activated carbon per 1 μm ^2, it is possible to obtain an adsorbent for oral administration having even more excellent selective adsorption of harmful toxic substances. .

Also, since the spherical activated carbon has a large number of protrusions formed on the surface, the contact area with the intestinal inner wall can be reduced as compared with the spherical activated carbon having a smooth surface, so that adhesion to the intestinal inner wall can be suppressed. As a result, it becomes possible to prevent constipation associated with adhesion to the intestinal inner wall.

Hereinafter, embodiments of the present invention will be described in detail.

Example 1
In a reaction vessel equipped with a thermometer, a stirrer and a reflux condenser, 500 parts by mass of phenol, 260 parts by mass of solid paraformaldehyde containing 8% by mass of water, 750 parts by mass of water, 5 parts by mass of dodecylbenzenesulfonic acid, and After charging 0.2 parts by mass of gum arabic (Senegal seed), the contents were heated and reacted with stirring. After the reaction, the inside of the reaction vessel was cooled to room temperature and washed after filtration to obtain a cured spherical phenol resin. 300 parts by mass of the obtained cured spherical phenol resin was charged into a rotary kiln, and then heated to 650 ° C. and baked for 1 hour. Subsequent to firing, the mixture was heated to 1000 ° C. while adding water, subjected to steam activation for 0.5 hours, and then cooled to room temperature to produce spherical activated carbon.

(Example 2)
300 parts by mass of the cured spherical phenol resin obtained by the same method as in Example 1 was charged into a rotary kiln, and then heated to 900 ° C. and baked for 1 hour. Subsequent to firing, the mixture was heated to 1000 ° C. while adding water, subjected to steam activation for 0.5 hours, and then cooled to room temperature to produce spherical activated carbon.

(Example 3)
300 parts by mass of the cured spherical phenol resin obtained by the same method as in Example 1 was charged into a rotary kiln, and then heated to 900 ° C. and baked for 1 hour. Subsequent to the firing, the mixture was cooled to 800 ° C., subjected to steam activation for 3 hours while adding water, and then cooled to room temperature to produce spherical activated carbon.

Example 4
300 parts by mass of the cured spherical phenol resin obtained by the same method as in Example 1 was charged into a rotary kiln, and then heated to 900 ° C. and baked for 1 hour. Following the firing, the mixture was cooled to 800 ° C., and steam activation was carried out for 4 hours while adding water. After heating again to 1000 degreeC and baking for 0.5 hour, it cooled to room temperature and manufactured spherical activated carbon.

(Example 5)
300 parts by mass of the cured spherical phenol resin obtained by the same method as in Example 1 was charged into a rotary kiln, and then heated to 900 ° C. and baked for 1 hour. Following the firing, the mixture was cooled to 800 ° C., and steam activation was performed for 5 hours while adding water, and then cooled to room temperature to produce spherical activated carbon.

(Comparative Example 1)
300 parts by mass of the cured spherical phenol resin obtained by the same method as in Example 1 was charged into a rotary kiln, and then heated to 900 ° C. and baked for 1 hour. Subsequent to firing, the mixture was cooled to 800 ° C., subjected to steam activation for 2 hours while adding water, and then cooled to room temperature to produce spherical activated carbon.

For the obtained spherical activated carbons of Examples 1 to 5 and Comparative Example 1, the surface state (protrusion shape), pore volume, specific surface area, average particle diameter and particle hardness were measured by the following methods. These results are shown in Table 1 below.

1. Surface condition (protrusion shape)
SEM photographs (magnification: 25000 times) were taken at three locations on the surface of the spherical activated carbon. The SEM photograph corresponds to a surface on which spherical activated carbon is projected. 1 to 6 show representative SEM photographs of the spherical activated carbons of Examples 1 to 5 and Comparative Example 1, respectively. From these SEM photographs, the spherical activated carbons of Examples 1 to 5 and Comparative Example 1 have many shapes having a curve at least at a part of the outer edge (for example, a circle, an ellipse, a flat ellipse whose part of the outer edge is a straight line, etc.). It was confirmed that no protrusions were formed on the surface.

From these SEM photographs, observe the protrusion with a curved shape on at least a part of the outer edge formed on the surface of the spherical activated carbon, and measure the maximum length of the length across the center from two points on the outer edge as the diameter of the protrusion did. Table 1 below shows the minimum diameter and the maximum diameter among the many protrusions formed on the spherical activated carbon surfaces of Examples 1 to 5 and Comparative Example 1.

Further, the number of protrusions projected on the three SEM photographs was measured. By dividing the measured number of protrusions by the area obtained from the magnification of the SEM photograph, the number of protrusions projected on each SEM photograph per 1 μm ² was calculated. The average number of protrusions per 1 μm ^{2 on the} surface of the spherical activated carbon was determined by adding the number of protrusions per 1 μm ² calculated from the three SEM photographs and dividing this added number by 3. The results are shown in Table 1 below. In addition, when a protrusion existing in the field of view of the SEM photograph is missing at the edge of the field of view, the number of protrusions in which the missing protrusion is half or more of the normal size is measured. Excluded from measurement. The number of protrusions per 1 μm ^{2 in} Table 1 below is a value obtained by rounding off the first decimal place.

7 and 8 are SEMs of spherical activated carbons of Comparative Example 2 (commercial product 1) and Comparative Example 3 (commercial product 2) having the pore volume, specific surface area, average particle diameter and particle hardness shown in Table 1 below, respectively. It is a photograph. From these SEM photographs, it was confirmed that the surfaces of the spherical activated carbons of Comparative Examples 2 and 3 were substantially smooth.

2. Specific surface area and pore volume After pre-treatment of spherical activated carbon under reduced pressure at 300 ° C. for 3 hours, a specific surface area / pore distribution measuring device (manufactured by Yuasa Ionics Co., Ltd .; NOVA4000e) was used for the nitrogen gas adsorption method. Specific surface area and pore volume were measured.

The specific surface area and pore volume were measured by the multipoint BET method at a relative pressure (P / P ₀ ) of 0.02 to 0.2.

The volume ratio of pores having a diameter of 1 nm or less was determined by measuring the pore distribution by the MP method and calculating the ratio of the total pore volume of pores having a diameter of 1 nm or less to the total pore volume.

3. Average particle size of spherical activated carbon The particle size distribution of spherical activated carbon was measured by a light scattering method using a particle size distribution measuring device (manufactured by Nikkiso Co., Ltd .; Microtrac particle size distribution measuring device 9320HRA (x-100)). From this particle size distribution, when the cumulative curve was determined by setting the volume of the entire particle to 100%, the particle size at which the curve reached 50% was determined as the average particle size. That is, the cumulative average diameter (center diameter: Median diameter) was taken as the average particle diameter.

4). Particle strength of spherical activated carbon The spherical activated carbon was sieved to a particle size of 355 μm or more and less than 425 μm. One particle was weighted, the load when the particle was crushed was measured, and the particle strength was calculated from the following equation. As the measuring device, a particle hardness measuring device (Okada Seiko Co., Ltd .: Grano) was used.

Particle strength (G) = 4P / πD ²
Where P is the load (g) when the particles are crushed,
D is the particle diameter (mm),
It is.

Next, the adsorption performance of indole (hazardous toxic substance), tryptophan, and lysine (both necessary substances for living body) by the spherical activated carbon of Examples 1 to 5 and Comparative Examples 1 to 3 was measured according to the following test. The results are shown in Table 2 below.

<Indole adsorption test>
Each spherical activated carbon was pretreated by drying at 105 ° C. for 2 hours, and then accurately weighed 0.01 g and put into a conical flask with a stopper. An indole stock solution having a concentration of 50 ppm prepared with a phosphate buffer solution at pH 7.4 was accurately collected using a 50 mL whole pipette and transferred to the Erlenmeyer flask. Subsequently, the Erlenmeyer flask was placed in a 40 ° C. water bath and shaken for 3 hours. After shaking, the liquid was collected from the Erlenmeyer flask and filtered through a chromatodisc having a pore size of 0.45 μm. The absorbance of light with a wavelength of 265 nm was measured for the filtrate, and the amount of adsorption was calculated. That is, the absorbance at 0% indole stock solution (pH 7.4 phosphate buffer), 25%, 50%, 75% and 100% was measured to prepare a calibration curve showing the relationship between the indole concentration and the absorbance. The actually measured absorbance was collated with this calibration curve to calculate the indole concentration of the filtrate. The indole adsorption amount of each spherical activated carbon was determined by subtracting the initial indole concentration from the calculated indole concentration.

<Tryptophan adsorption test>
The tryptophan adsorption amount of each spherical activated carbon was determined according to the indole adsorption test except that the tryptophan stock solution was 100 ppm, the temperature at shaking was 37 ° C., and the light wavelength at the time of absorbance measurement was 280 nm.

<Lysine adsorption test>
Each spherical activated carbon was pretreated by drying at 105 ° C. for 2 hours, and then accurately weighed 0.01 g and put into a conical flask with a stopper. A lysine stock solution having a concentration of 100 ppm diluted with a phosphate buffer solution at pH 7.4 was accurately collected using a 50 mL whole pipette, and transferred to the Erlenmeyer flask. Subsequently, the Erlenmeyer flask was placed in a 37 ° C. water bath and shaken for 3 hours. After shaking, the liquid was collected from the Erlenmeyer flask and filtered through a chromatodisc having a pore size of 0.45 μm. The filtrate was subjected to amino acid analysis using an amino acid analyzer (JEOL Ltd .; JLC-500 / V2) and a high resolution column. The amount of lysine adsorbed on each spherical activated carbon was determined by subtracting the initial lysine concentration from the lysine concentration measured in this analysis.

As apparent from Tables 1 and 2, the spherical activated carbons of Examples 1 to 5 are commercially available with no protrusions on the surface and smooth, and the volume ratio of pores having a diameter of 1 nm or less exceeds the upper limit of 45% of the present invention. Although the indole adsorptivity is slightly inferior to the spherical activated carbons of Comparative Examples 2 and 3, which are products, the adsorbability of tryptophan and lysine, which are vital substances, is low, and the indole selective adsorptivity is excellent. I understand that.

In addition, although the spherical activated carbon of Comparative Example 1 has a large number of protrusions on the surface, the volume ratio of pores having a diameter of 1 nm or less is less than 30% (29.6%) of the lower limit of the present invention. It can be seen that the adsorptivity of is extremely lower than the spherical activated carbons of Examples 1 to 5.

As described above, according to the present invention, the adsorptivity of harmful toxic substances such as indole is high, the adsorptivity of necessary substances such as tryptophan and lysine is low, the selective adsorptivity of harmful toxic substances is excellent, and the kidney function Therefore, it is possible to provide an adsorbent for oral administration that is useful as a therapeutic agent for patients with reduced blood pressure.

Claims (8)

Adsorption for oral administration comprising spherical activated carbon with numerous protrusions formed on the surface, total pore volume of 0.2 to 0.5 cc / g, and pore volume ratio of diameter of 1 nm or less of 30 to 45% Agent. The adsorbent for oral administration according to claim 1, wherein the projection has a shape with a curve at least at a part of the outer edge on the surface on which the spherical activated carbon is projected, and has a diameter of 0.1 to 1.2 µm. The adsorbent for oral administration according to claim 2, wherein 1-20 protrusions per 1 μm ² are formed on the spherical activated carbon surface. The adsorbent for oral administration according to claim 2, wherein 1 to 15 protrusions are formed on the spherical activated carbon surface per 1 μm ² . The adsorbent for oral administration according to claim 2, wherein 1 to 10 protrusions are formed on the spherical activated carbon surface per 1 μm ² . The adsorbent for oral administration according to claim 1, wherein the specific surface area of the spherical activated carbon determined by the BET method is 600 m ² / g to 1000 m ² / g. The adsorbent for oral administration according to claim 1, wherein the spherical activated carbon has an average particle size of 250 µm or more. The adsorbent for oral administration according to claim 1, wherein the spherical activated carbon has a particle strength of 10,000 g / mm ² or more.

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