WO2010086985A1 - Adsorbant pour administration orale - Google Patents

Adsorbant pour administration orale Download PDF

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Publication number
WO2010086985A1
WO2010086985A1 PCT/JP2009/051482 JP2009051482W WO2010086985A1 WO 2010086985 A1 WO2010086985 A1 WO 2010086985A1 JP 2009051482 W JP2009051482 W JP 2009051482W WO 2010086985 A1 WO2010086985 A1 WO 2010086985A1
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Prior art keywords
activated carbon
spherical activated
adsorbent
total
group amount
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PCT/JP2009/051482
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English (en)
Japanese (ja)
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泰宏 松本
敬 冨安
美名 向所
昇一 大西
有洋 川本
正志 柚木
純也 菊石
徹 先山
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旭有機材工業株式会社
富田製薬株式会社
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Priority to JP2010548302A priority Critical patent/JP5424177B2/ja
Priority to PCT/JP2009/051482 priority patent/WO2010086985A1/fr
Publication of WO2010086985A1 publication Critical patent/WO2010086985A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • the present invention relates to an adsorbent for oral administration.
  • kidney function decreases, uremic substances produced by metabolism cannot be excreted sufficiently from urine. For this reason, toxic substances accumulate in the body and can cause uremic symptoms such as impaired consciousness. Therefore, removal of toxic substances is extremely important for patients with renal disease.
  • Hemodialysis is the most popular treatment method for removing toxic substances from the body.
  • this treatment not only requires special equipment, but also causes physical and mental pain to the patient due to the long time required for the treatment.
  • adsorbents that adsorb toxic substances in the gastrointestinal tract by oral administration and discharge them outside the body have been developed as treatment methods with less burden on patients.
  • This adsorbent is made of spherical activated carbon having specific physical properties, and several patent applications have been made and are commercially available.
  • Japanese Patent Application Laid-Open No. 2002-308785 discloses a diameter of 0.1 to 1 mm, a specific surface area of 700 m 2 / g or more, a total acidic group amount of 0.30 to 1.20 meq / g, and a total basic group amount of 0.20.
  • a medical adsorbent having physical properties of ⁇ 0.70 meq / g is disclosed.
  • Patent No. 3585043 uses a spherical phenol resin as a raw material, has an average particle diameter of 350 ⁇ m or less, a specific surface area of 800 to 2000 m 2 / g, a total 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 pore size of the pore is 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.
  • adsorbents described in any of the patent documents have high adsorptivity for toxic substances such as DL- ⁇ -aminoisobutyric acid.
  • these adsorbents are relatively unsatisfactory in terms of selective adsorptivity of toxic substances because they have relatively high adsorptivity for substances necessary for living bodies such as ⁇ -amylase.
  • the present invention selects a toxic substance that has a high adsorptivity for toxic substances such as DL- ⁇ -aminoisobutyric acid, indole, indoxyl sulfate, and a low adsorbability for substances necessary for living bodies such as ⁇ -amylase and lipase.
  • An object of the present invention is to provide an adsorbent for oral administration having excellent adsorptivity.
  • the adsorbent for oral administration according to the present invention has a higher selective adsorptivity than existing medical adsorbents and also has a high adsorptivity to toxic substances even after adsorption of an enzyme such as ⁇ -amylase.
  • a large number of 1 to 20 protrusions per 1 ⁇ m 2 are formed on the surface, the total pore volume is 0.4 to 0.8 mL / g, and the pore volume ratio with a diameter of 1 nm or less is 37 to 55. %,
  • the total acidic group amount is 0.24 to 0.56 meq / g, and the ratio (a / b) of the total acidic group amount (a) to the total basic group amount (b) is 0.60 to 2.00.
  • An adsorbent for oral administration comprising spherical activated carbon is provided.
  • FIG. 1 is a SEM photograph showing the surface state of the spherical activated carbon of Example 1.
  • 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. 5 is a SEM photograph showing the surface state of the spherical activated carbon of Comparative Example 1.
  • FIG. 6 is an SEM photograph showing the surface state of the spherical activated carbon of Comparative Example 2.
  • FIG. 7 is a SEM photograph showing the surface state of the spherical activated carbon of Comparative Example 3.
  • FIG. 8 is a SEM photograph showing the surface state of the spherical activated carbon of Comparative Example 4.
  • FIG. 9 is a graph showing the indole adsorption rate when the spherical activated carbon of Example 4 and Comparative Example 4 is not adsorbed with ⁇ -amylase.
  • FIG. 10 is a graph showing the indole adsorption rate after the ⁇ -amylase adsorption of the spherical activated carbon of Example 4 and Comparative Example 4.
  • the adsorbent for oral administration has a large number of protrusions of 1 to 20 per 1 ⁇ m 2 on the surface, a total pore volume of 0.4 to 0.8 mL / g, and a pore having a diameter of 1 nm or less
  • the volume ratio is 37 to 55%
  • the total acidic group amount is 0.24 to 0.56 meq / g
  • the ratio (a / b) of the total acidic group amount (a) to the total basic group amount (b) is 0.60.
  • 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.
  • 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 0.2 to 1.8 ⁇ m.
  • 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.
  • the diameter is a diameter.
  • the number of protrusions present per 1 ⁇ m 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.
  • the number of protrusions per 1 ⁇ m 2 is calculated in each SEM photograph.
  • An average value of the number of protrusions per 1 ⁇ m 2 is obtained from the calculated number of protrusions per 1 ⁇ m 2 and the number of SEM photographs.
  • the number of protrusions in which the missing protrusion is half or more of the normal size is measured. Exclude from measurement.
  • the number of protrusions is obtained as an average value as described above, the number of protrusions per 1 ⁇ m 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 ⁇ m.
  • a spherical activated carbon with a large number of protrusions formed on the surface can increase the surface area compared to a spherical activated carbon with a smooth surface, and furthermore, a large number of pores can be distributed and opened on the surface and protrusions. It can adsorb toxic substances well.
  • the increase in pores is because even if substances necessary for the living body (for example, enzymes with a large molecular diameter) adhere to the surface, the substances necessary for the living body remain partially attached due to the protrusions, and the pores are made of enzymes. Reduce the rate of obstruction. As a result, it is possible to maintain the diffusion of the substance to be adsorbed into the pores, and to stably adsorb the toxic substance by the large number of pores even if clogged pores are generated.
  • the increase in the number of pores reduces the external surface area (mesopore and non-pore area) of the spherical activated carbon, which reduces the contact area with substances necessary for living organisms (for example, enzymes with large molecular diameters)
  • the adsorptivity of these substances can be reduced.
  • Spherical activated carbon with a large number of protrusions formed on the surface can prevent adhesion to the inner surface of the digestive tract after oral administration. Since the spherical activated carbon with a smooth surface has a large contact area with the inner surface of the digestive tract, the spherical activated carbon tends to remain in the digestive tract. As a result, side effects such as decreased digestive motility, abdominal bloating, loss of appetite, constipation, nausea and vomiting are increased. Since the spherical activated carbon according to the embodiment has a large number of protrusions on the surface, the contact area with the inner surface of the digestive tract is drastically reduced, and it can be naturally excreted outside the body without remaining in the digestive tract. .
  • Spherical activated carbon with a total pore volume of 0.4 to 0.8 mL / g and a pore volume ratio of 37 nm to 55% with a diameter of 1 nm or less has excellent adsorptivity to toxic substances such as indole and indoxyl sulfate.
  • the adsorptivity of substances necessary for living bodies such as ⁇ -amylase and lipase can be suppressed. That is, it exhibits excellent selective adsorption properties for toxic substances of indole and indoxyl sulfate.
  • the pore volume ratio having a diameter of 1 nm or less means the ratio of the pore volume having a diameter of 1 nm or less to the total pore volume.
  • Spherical activated carbon having a pore volume ratio of 1 nm or less in diameter within the above range and a total pore volume of less than 0.4 mL / g may have poor indoxyl sulfate adsorptivity.
  • Spherical activated carbon having a pore volume ratio of 1 nm or less in diameter within the above range and a total pore volume exceeding 0.8 mL / g may increase the adsorptivity of substances necessary for living bodies such as ⁇ -amylase and lipase. There is.
  • spherical activated carbon having a total pore volume within the above range and a pore volume ratio of 1 nm or less in diameter of less than 37% may reduce the adsorptivity to toxic substances such as indole and indoxyl sulfate.
  • Spherical activated carbon with a total pore volume within the above range and a pore volume fraction with a diameter of 1 nm or less exceeding 55% increases the adsorptivity of toxic substances, but is necessary for living organisms such as ⁇ -amylase and lipase. There is a possibility that the adsorptive property of the toxic substance also increases and the selective adsorptive property of the toxic substance decreases.
  • Spherical activated carbon having a total acidic group amount of 0.24 to 0.56 meq / g and a ratio (a / b) of the total acidic group amount (a) to the total basic group amount (b) of 0.60 to 2.00 Exhibits excellent adsorptivity to toxic substances, particularly DL- ⁇ -aminoisobutyric acid.
  • Spherical activated carbon in which the total acidic group amount and the ratio a / b are out of the above ranges may have a poor adsorptivity for DL- ⁇ -aminoisobutyric acid.
  • a more preferable total acidic group amount is 0.31 to 0.47 meq / g, and a / b is more preferably 0.85 to 1.60.
  • the spherical activated carbon preferably further has the following physical properties.
  • the specific surface area determined by the multipoint BET method is 1050 to 1800 m 2 / g.
  • Spherical activated carbon having such a specific surface area can further improve the adsorptivity of toxic substances.
  • the spherical activated carbon having such an external surface area can further suppress the adsorptivity of a substance necessary for a living body.
  • a more preferred external surface area is 50 to 90 m 2 / g.
  • the average particle size is 100 ⁇ m or more.
  • the upper limit of the average particle diameter is preferably 800 ⁇ m.
  • the particle strength is 1000 g / mm 2 or more.
  • Spherical activated carbon having a particle strength of 1000 g / mm 2 or more can prevent pulverization 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 .
  • 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.
  • aldehyde for example, formaldehyde such as paraformaldehyde or formalin, acetaldehyde, or benzene having a formyl group can be used.
  • 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.
  • the obtained cured spherical phenol is baked at, for example, 600 to 900 ° C. by a baking apparatus such as a rotary kiln. Subsequently, while adding water, the temperature is raised to, for example, 700 to 900 ° C., and steam activation is performed to obtain spherical activated carbon. Subsequently, the spherical activated carbon is oxidized in an oxidizing atmosphere at 400 to 550 ° C., for example, and then fired in an inert gas atmosphere such as nitrogen gas at 700 to 900 ° C. to produce the desired spherical activated carbon. To do.
  • 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.
  • the jelly agent containing the spherical activated carbon or the spherical activated carbon Tablets having a rapidly disintegrating function are preferred.
  • a suspension containing the spherical activated carbon which is easy to process and ensures the uniformity of components, is preferable.
  • a flavoring 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.
  • 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.
  • 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 adsorbent for oral administration according to the embodiment described above has a large number of 1 to 20 protrusions per 1 ⁇ m 2 on the surface, a total pore volume of 0.4 to 0.8 mL / g, and a diameter of 1 nm or less.
  • Pore volume ratio of 37 to 55%, total acidic group amount is 0.24 to 0.56 meq / g, and the ratio (a / b) of total acidic group amount (a) to total basic group amount (b) is Since it contains spherical activated carbon of 0.60 to 2.00, it has high adsorptivity for toxic substances such as DL- ⁇ -aminoisobutyric acid, indole, indoxyl sulfate, and is necessary for living bodies such as ⁇ -amylase and lipase. Excellent adsorptive adsorptivity with low substance adsorptivity.
  • the spherical activated carbon according to the embodiment is negatively charged at pH 6.8 in the intestinal environment, a repulsive action works with an enzyme such as ⁇ -amylase that is also negatively charged at the same pH. It is possible to suppress the attachment of substances (eg, ⁇ -amylase) that are neutral to alkaline and are necessary for the living body.
  • substances eg, ⁇ -amylase
  • a large number of 1-20 protrusions per 1 ⁇ m 2 are formed on the surface, a large number of pores can be formed on the surface portion and the protrusions. Therefore, a substance necessary for a living body (for example, ⁇ -amylase) Even if it adheres, it becomes possible to adsorb toxic substances efficiently and stably as described in the projection effect of (1) above.
  • 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 compared to the spherical activated carbon having a smooth surface, and adhesion to the intestinal inner wall can be suppressed. As a result, it is possible to prevent side effects such as constipation associated with adhesion to the intestinal inner wall.
  • 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 having a purity of 92% by mass, 750 parts by mass of water, 5 parts by mass of dodecylbenzenesulfonic acid and gum arabic (Senegal species) After charging 0.2 parts by mass, 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 30 minutes. Subsequent to the firing, the mixture was heated to 800 ° C. while adding water, steam-activated for 6 hours, and then cooled to room temperature to obtain spherical activated carbon. After charging 20 parts by mass of the obtained spherical activated carbon in a rotary kiln, the mixture was heated to 475 ° C. and oxidized for 3 hours and 15 minutes while flowing air. Subsequent to the oxidation, while flowing nitrogen instead of air, the mixture was heated to 800 ° C. and baked for 5 minutes, 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 in a rotary kiln, and then heated to 650 ° C. and baked for 30 minutes. Subsequent to firing, the mixture was heated to 800 ° C. while adding water, steam activated for 7.5 hours, and then cooled to room temperature to obtain spherical activated carbon. After charging 20 parts by mass of the obtained spherical activated carbon in a rotary kiln, the mixture was heated to 475 ° C. and oxidized for 3 hours and 15 minutes while flowing air. Subsequent to the oxidation, while flowing nitrogen instead of air, the mixture was heated to 800 ° C. and baked for 5 minutes, 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 in a rotary kiln, and then heated to 650 ° C. and baked for 30 minutes. Subsequent to firing, the mixture was heated to 800 ° C. while adding water, steam activated for 7.5 hours, and then cooled to room temperature to obtain spherical activated carbon. After charging 20 parts by mass of the obtained spherical activated carbon in a rotary kiln, the mixture was heated to 475 ° C. while flowing air and oxidized for 5 hours and 15 minutes. Subsequent to the oxidation, while flowing nitrogen instead of air, the mixture was heated to 800 ° C. and baked for 5 minutes, 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 in a rotary kiln, and then heated to 650 ° C. and baked for 30 minutes. Subsequent to the firing, the mixture was heated to 800 ° C. while adding water, steam-activated for 14 hours, and then cooled to room temperature to obtain spherical activated carbon. After charging 20 parts by mass of the obtained spherical activated carbon in a rotary kiln, the mixture was heated to 475 ° C. while flowing air and oxidized for 5 hours and 15 minutes. Subsequent to the oxidation, while flowing nitrogen instead of air, the mixture was heated to 800 ° C. and baked for 5 minutes, 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 in a rotary kiln, and then heated to 650 ° C. and baked for 30 minutes. Following the firing, the mixture was heated to 800 ° C. while adding water, steam activated for 5 hours, and then cooled to room temperature to produce spherical activated carbon.
  • Comparative Example 2 300 parts by mass of the cured spherical phenol resin obtained by the same method as in Example 1 was charged in a rotary kiln, and then heated to 650 ° C. and baked for 30 minutes. Following the firing, the mixture was heated to 800 ° C. while adding water, steam activated for 7.5 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 in a rotary kiln, and then heated to 650 ° C. and baked for 30 minutes. Following the firing, the mixture was heated to 900 ° C. while adding water, and after steam activation for 6 hours, the mixture was cooled to room temperature to obtain spherical activated carbon. After charging 20 parts by mass of the obtained spherical activated carbon in a rotary kiln, the mixture was heated to 475 ° C. while flowing air and oxidized for 3 hours and 15 minutes. Then, it cooled to room temperature and manufactured spherical activated carbon.
  • FIGS. 1 to 7 show representative SEM photographs of spherical activated carbons of Examples 1 to 4 and Comparative Examples 1 to 3, respectively.
  • the spherical activated carbons of Examples 1 to 4 and Comparative Examples 1 to 3 have a shape having a curve in at least a part of the outer edge (for example, a circle, an ellipse, a flat ellipse in which a part of the outer edge is a straight line, etc.). It was confirmed that a large number of protrusions had been formed on the surface.
  • the number of protrusions projected on SEM photographs taken at three locations of the spherical activated carbon in each example is measured.
  • the number of protrusions projected on each SEM photograph per 1 ⁇ m 2 is calculated.
  • the average number of protrusions per 1 ⁇ m 2 on the surface of the spherical activated carbon was determined by adding the number of protrusions per 1 ⁇ m 2 calculated from the three SEM photographs and dividing this added number by 3. The results are shown in Table 1 below.
  • 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 ⁇ m 2 in Table 1 below is a value obtained by rounding off the first decimal place.
  • FIG. 8 shows the total pore volume, total acidic group amount, total basic group amount, total acidic group amount (a) and total basic group amount (b) ratio (a / b), ratio shown in Table 1 below. It is a SEM photograph of the spherical activated carbon of the comparative example 4 (commercial item) which has a surface area, an external surface area, an average particle diameter, and particle strength. From these SEM photographs, it was confirmed that the surface of the spherical activated carbon of Comparative Example 4 was substantially smooth.
  • the spherical activated carbon was pretreated at 300 ° C. under reduced pressure for 3 hours, and then a nitrogen adsorption isotherm at 77 K was measured by a nitrogen gas adsorption method using NOVA4000e manufactured by Yuasa Ionics.
  • the total pore volume was calculated based on the nitrogen adsorption amount when the relative pressure (P / P 0 ) of the nitrogen adsorption isotherm was sufficiently close to 1 (0.992 to 0.999).
  • the specific surface area was determined by the multipoint BET method at a relative pressure (P / P 0 ) of 0.02 to 0.2.
  • the pore volume ratio with a diameter of 1 nm or less was calculated as the ratio of the pore volume with a pore diameter of 1 nm or less to the total pore volume by obtaining the pore distribution by the MP method.
  • the external surface area was determined by the slope of a straight line at a portion where the thickness (t) of the adsorption film after the bending point is large in the t plot obtained from the nitrogen adsorption isotherm.
  • Total acidic group amount In 50 mL of 0.05 mol / L NaOH solution, 1 g of spherical activated carbon sample pulverized to 200 mesh or less was added, shaken for 48 hours, the sample was filtered, and the total consumption of NaOH was determined by neutralization titration. The amount of acidic group (meq / g) was determined.
  • the total acidic group amount is a
  • the basic group amount is b
  • the ratio (a / b) is shown in Table 1 below.
  • ⁇ Particle strength> Each spherical activated carbon was sieved to a particle size of 355 ⁇ m or more and less than 425 ⁇ m. One particle was weighted, the load when the particle was crushed was measured for 20 particles, and the particle strength was calculated by the following equation.
  • the particle intensity measuring device Grano (Okada Seiko Co., Ltd.) was used for the measuring device.
  • Particle strength G 4P / ⁇ D 2
  • P is a load (g) when the particles are crushed
  • D is a particle diameter (mm).
  • ⁇ Average particle size> The particle size distribution of the spherical activated carbon was measured by a light scattering method using a particle size distribution measuring device (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 defined as the average particle diameter.
  • the residual amount of DL- ⁇ -aminoisobutyric acid in the blank solution and the sample solution was determined, and the DL- ⁇ -aminoisobutyric acid adsorption amount (mg / G).
  • the sample solution was tested by an absorbance measurement method using a pH 7.4 phosphate buffer as a control, and the absorbance at a wavelength of 265 nm was measured.
  • the blank solution was diluted 2-fold with a pH 7.4 phosphate buffer, and the absorbance was measured in the same manner as the sample solution.
  • the calibration curve was prepared by adding 0%, 5%, 10%, 25%, 50% of the indole stock solution to pH 7.4 phosphate buffer, and measuring the absorbance of these solutions at a wavelength of 265 nm. It was created by plotting the relationship between the indole stock solution concentration and the absorbance.
  • the indole remaining amount of the blank solution and the sample solution was determined, and the indole adsorption amount (mg / g) was determined from the difference between the indole remaining amount of the blank solution and the sample solution.
  • the test was performed by an absorbance measurement method, and the absorbance at a wavelength of 282 nm was measured.
  • the calibration curve was prepared by adding 0%, 25%, 50%, 75%, and 100% ⁇ -amylase stock solution to pH 7.4 phosphate buffer, and measuring the absorbance of these solutions at a wavelength of 282 nm, respectively. The measurement was made by plotting the relationship between the ⁇ -amylase stock solution concentration and the absorbance.
  • the remaining amount of ⁇ -amylase in the blank solution and the sample solution was determined, and the amount of ⁇ -amylase adsorbed (mg / g) was determined from the difference in the remaining amount of ⁇ -amylase between the blank solution and the sample solution.
  • ⁇ Lipase adsorption test> A test was conducted according to the ⁇ -amylase adsorption test except that the lipase stock solution was 100 ppm and the temperature at the time of shaking was 21 ° C., and the lipase adsorption amount (mg / g) of each spherical activated carbon was determined.
  • the spherical activated carbons of Examples 1 to 4 are smooth with no protrusions on the surface, and the total pore volume and the pore volume ratio with a diameter of 1 nm or less are the upper limit values of the present invention.
  • the adsorptivity of DL- ⁇ -aminoisobutyric acid and indole is equivalent or better than the commercially available spherical activated carbon of Comparative Example 4
  • the adsorptivity of indoxyl sulfate is the same or slightly inferior, while the adsorptivity of ⁇ -amylase and lipase, which are necessary for living bodies, is extremely low, about half, and DL- ⁇ -aminoisobutyric acid, indole and indoxyl It can be seen that the selective adsorption property of sulfuric acid is excellent.
  • the spherical activated carbon of Comparative Example 1 has a large number of protrusions formed on the surface
  • the total acidic group amount and a / b are lower limit values of 0.24 meq / g and less than 0.60 (0.14 meq) of the present invention, respectively.
  • / G, 0.33 the pore volume fraction with a diameter of 1 nm or less is less than 37% (34.5%) of the lower limit of the present invention, and therefore the adsorptivity of DL- ⁇ -aminoisobutyric acid and indoxyl sulfate is It turns out that it becomes extremely low compared with the spherical activated carbon of Examples 1-4.
  • the spherical activated carbon of Comparative Example 2 has a large number of protrusions formed on the surface
  • the total acidic group amount and a / b are lower limit values of 0.24 meq / g and less than 0.60 (0.18 meq) of the present invention, respectively. / G, 0.49)
  • the total pore volume is less than the lower limit of 0.4 mL / g (0.39 mL / g) of the present invention
  • the adsorptivity of DL- ⁇ -aminoisobutyric acid and indoxyl sulfate It turns out that it becomes extremely low compared with the spherical activated carbon of Examples 1-4.
  • the spherical activated carbon of Comparative Example 3 has a large number of protrusions formed on the surface, the total acidic group amount and a / b exceed the upper limit values of 0.56 meq / g and 2.00 of the present invention (0. 65 meq / g, 2.60), and the total pore volume exceeds the upper limit of 0.8 mL / g of the present invention (0.87 mL / g), so that the adsorptivity of DL- ⁇ -aminoisobutyric acid is in Examples 1 to 4.
  • the adsorptivity of ⁇ -amylase and lipase which are substances necessary for living bodies, is about twice that of the spherical activated carbon of Examples 1 to 4. It turns out that it becomes extremely high.
  • Example 4 the indole adsorption rate of the spherical activated carbons of Example 4 and Comparative Example 4 when ⁇ -amylase was not adsorbed and after ⁇ -amylase adsorption was tested by the following method.
  • the test was performed by an absorbance measurement method, and the absorbance at a wavelength of 265 nm was measured.
  • the calibration curve was prepared by adding 0%, 5%, 10%, 25%, 50% of the indole stock solution to pH 7.4 phosphate buffer, and measuring the absorbance of these solutions at a wavelength of 265 nm. It was created by plotting the relationship between the indole stock solution concentration and the absorbance.
  • FIG. 9 shows the indole adsorption rate (relation between adsorption time and indole adsorption amount) when ⁇ -amylase is not adsorbed.
  • the circled points plot the relationship between the adsorption time and the indole adsorption amount of Example 4 and the square points of Comparative Example 4.
  • the collected spherical activated carbon was air-dried in a room for 1 hour, then accurately weighed 0.020 g, and placed in an Erlenmeyer flask with a stopper.
  • An indole stock solution with a concentration of 100 ppm adjusted with a pH 7.4 phosphate buffer was accurately collected with a 50 mL whole pipette and placed in an Erlenmeyer flask.
  • the sample was shaken at a shaking rate of 150 times / minute in a 37 ° C. water bath. After 15 minutes from the start, 30 minutes and 60 minutes later, 3 mL of the supernatant was accurately collected and filtered through a membrane filter having a pore size of 0.45 ⁇ m as a sample solution.
  • the sample solution after 180 minutes was similarly prepared in another flask, and the supernatant was collected after 180 minutes.
  • the test was performed by an absorbance measurement method, and the absorbance at a wavelength of 265 nm was measured.
  • the calibration curve was prepared by adding 0%, 5%, 10%, 25%, 50% of the indole stock solution to pH 7.4 phosphate buffer, and measuring the absorbance of these solutions at a wavelength of 265 nm. It was created by plotting the relationship between the indole stock solution concentration and the absorbance.
  • FIG. 10 shows the indole adsorption rate (relation between adsorption time and indole adsorption amount) after ⁇ -amylase adsorption.
  • the circle points plot the relationship between the adsorption time and the indole adsorption amount of Example 4 and the square points of Comparative Example 4.
  • the spherical activated carbons of Example 4 and Comparative Example 4 have no difference in the indole adsorption rate when ⁇ -amylase is not adsorbed.
  • the indole adsorption rate after ⁇ -amylase adsorption is significantly higher in the spherical activated carbon of Example 4 than in the spherical activated carbon of Comparative Example 4, as is apparent from FIG.
  • the reason why the spherical activated carbon of Example 4 shows a high indole adsorption rate after ⁇ -amylase adsorption is that a large number of protrusions are formed on the surface of the spherical activated carbon.
  • the adsorptivity of toxic substances such as DL- ⁇ -aminoisobutyric acid, indole and indoxyl sulfate is high, and the adsorptivity of substances necessary for living bodies such as ⁇ -amylase and lipase is low. It is possible to provide an adsorbent for oral administration that is excellent in selective adsorption of a substance and is useful as a therapeutic agent for a patient with decreased kidney function.

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Abstract

L'invention porte sur un adsorbant pour administration orale comprenant du charbon actif sphérique comportant de nombreuses projections formées sur la surface, c'est-à-dire dans une quantité de 1 à 20 par µm², et un volume total de pores de 0,4 à 0,8 mL/g, et dans lequel la proportion de pores ayant un diamètre de 1 nm ou moins est de 37 à 55 % en volume, la quantité totale de groupe d'acide étant de 0,24 à 0,56 méq/g et le rapport de la quantité totale de groupe d'acide (a) sur la quantité totale de groupe basique (b), (a/b), étant de 0,60 à 2,00. L'adsorbant adsorbe de façon élevée des substances toxiques telles que l'acide DL-β-aminoisobutyrique, l'indole et l'acide indoxylsulfurique et adsorbe de façon faible des substances nécessaires pour le corps vivant, telles que l'α-amylase et la lipase. L'adsorbant est excellent en sélectivité d'adsorption vis-à-vis de telles substances toxiques.
PCT/JP2009/051482 2009-01-29 2009-01-29 Adsorbant pour administration orale WO2010086985A1 (fr)

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WO2013162382A1 (fr) * 2012-04-26 2013-10-31 Niva Procédé de détoxification ou de mesure d'au moins un composé ou d'au moins un fluide dans un corps hôte
WO2014129616A1 (fr) * 2013-02-22 2014-08-28 株式会社クレハ Adsorbant pour administration par voie orale, médicament pour maladie rénale, et médicament pour maladie du foie
US8865617B2 (en) 2010-08-02 2014-10-21 Asahi Organic Chemicals Industry Co., Ltd. Orally administered adsorbent, method of producing the same, and drug produced by using the same
JP2015017086A (ja) * 2013-06-12 2015-01-29 第一三共ヘルスケア株式会社 経口用組成物
WO2016031908A1 (fr) * 2014-08-27 2016-03-03 株式会社クレハ Adsorbant pour administration par voie orale, agent thérapeutique pour maladies rénales et agent thérapeutique pour maladies hépatiques

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WO2004039381A1 (fr) * 2002-11-01 2004-05-13 Kureha Chemical Industry Co., Ltd. Adsorbants pour administration orale, remedes preventifs ou curatifs contre les maladies des reins et remedes preventifs ou curatifs contre les maladies du foie
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JP2007045775A (ja) * 2005-08-11 2007-02-22 Japan Organo Co Ltd 含水活性炭及びその製造方法
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8865617B2 (en) 2010-08-02 2014-10-21 Asahi Organic Chemicals Industry Co., Ltd. Orally administered adsorbent, method of producing the same, and drug produced by using the same
WO2013162382A1 (fr) * 2012-04-26 2013-10-31 Niva Procédé de détoxification ou de mesure d'au moins un composé ou d'au moins un fluide dans un corps hôte
US9408866B2 (en) 2012-04-26 2016-08-09 Niva Method for detoxification or measurement of at least one compound or at least one fluid in a host body
WO2014129616A1 (fr) * 2013-02-22 2014-08-28 株式会社クレハ Adsorbant pour administration par voie orale, médicament pour maladie rénale, et médicament pour maladie du foie
JP2015017086A (ja) * 2013-06-12 2015-01-29 第一三共ヘルスケア株式会社 経口用組成物
WO2016031908A1 (fr) * 2014-08-27 2016-03-03 株式会社クレハ Adsorbant pour administration par voie orale, agent thérapeutique pour maladies rénales et agent thérapeutique pour maladies hépatiques
JPWO2016031908A1 (ja) * 2014-08-27 2017-04-27 株式会社クレハ 経口投与用吸着剤並びに腎疾患治療剤及び肝疾患治療剤

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