JP2019107642A - Manufacturing method of absorbent - Google Patents

Abstract

To provide a manufacturing method of an oral pharmaceutical absorbent good in yield while maintaining absorption performance of a toxic substance of active charcoal, capable of economically manufacturing a pharmaceutical absorbent with suppressing environmental load.SOLUTION: In manufacturing spherical active charcoal having average pore diameter of 1.5 to 3.0 nm, BET specific surface of 700 to 3000 m/g, average particle diameter of 100 to 1100 μm, surface oxide amount of 0.05 meq/g or more and filling density of 0.4 to 0.8 g/mL, and ignition residue at a measurement according to JIS K 1474-1 (2014) of less than 10%, a flame retardant which vaporizes at less than 1000°C, especially one or a plurality of ammonium chloride, ammonium sulfate, ammonium bromide, tetrabromobisphenol A or guanidine hydrochloride is loaded to purified cellulose or regenerated cellulose which is a raw material, carbonized under nitrogen atmosphere at 300 to 700°C, and steam activate at 750 to 1000°C.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing an absorbent for oral administration comprising an activated carbon using cellulose as a raw material, and in particular, an adsorption for oral administration comprising an activated carbon derived from cellulose excellent in adsorption performance of toxic substances in a simple process. The present invention relates to a manufacturing method capable of obtaining an agent.

  Patients with kidney disease or liver disease accumulate toxic substances in the blood and as a result cause encephalopathy such as uremia and loss of consciousness. The number of these patients tends to increase year by year. Hemodialysis-type artificial kidneys and the like that remove toxic substances outside the body are used for treatment of patients. However, such artificial kidneys require specialist technicians for safety and management, and it is also considered that the physical, mental and economic burden of the patient is required for taking blood out of the body. And not necessarily satisfactory.

  As an alternative to artificial organs, adsorbents for oral administration have been developed which are orally ingested and adsorb toxic substances in the body and discharged out of the body (see Patent Document 1, Patent Document 2, etc.). Then, an anti-nephrotic syndrome agent is reported in which petroleum hydrocarbon (pitch) or the like is used as a raw material material, and the particle size is adjusted to be relatively uniform and carbonized and activated (for example, see Patent Document 3) . In addition, an adsorbent for oral administration has been reported in which the particle size of activated carbon itself is relatively uniformed and distribution of pore volume etc. in the activated carbon is attempted to be adjusted (see Patent Document 4). Thus, along with making the particle size relatively uniform, the medicinal activated carbon improves the poor fluidity in the intestine, and at the same time improves the adsorption performance of the activated carbon by adjusting the pores. planned. Therefore, it is taken by many patients with mild chronic renal failure.

  Medicinal activated carbon requires rapid and efficient adsorption to uremic agents and their precursors. However, it is difficult to reduce the particle size while maintaining the spherical shape with existing medicinal activated carbon. In addition, the adjustment of the pores in the conventional medicinal activated carbon is not good and the adsorption performance is not always sufficient, so the daily dose must be increased. In particular, because chronic renal failure patients have limited fluid intake, swallowing with a small amount of fluid has been a great pain for patients.

  Then, the applicant has developed a method for manufacturing an adsorbent for oral administration pharmaceuticals which has low economical and environmental burden and excellent selective adsorption properties (see Patent Document 5 and Patent Document 6), and cellulose which is a natural product-derived component It came to obtain the medicine adsorbent for oral administration of the spherical activated carbon which uses as a raw material.

  An adsorbent for oral administration comprising an activated carbon produced by the method for producing an adsorbent for oral administration derived from cellulose described above is excellent in the adsorption capacity and selective adsorption of toxins to be removed although the dose is small. It was very promising as an application of pharmaceutical adsorbents.

Patent No. 3835698 JP, 2008-303193, A Unexamined-Japanese-Patent No. 6-135841 JP 2002-308785 A Patent No. 5984352 Patent No. 5985027

  The present invention can produce an adsorbent for medical use which is economical and has reduced environmental impact, and has a high yield while maintaining the adsorption performance and selective adsorption of toxic substances of activated carbon even in a simple process. The present invention provides a method of producing a pharmaceutical adsorbent for oral administration.

  That is, in the first invention, the BET specific surface area is 700 to 3000 m 2 / g, the average particle diameter is 100 to 1100 μm, the surface oxide amount is 0.05 meq / g or more, and the packing density is 0.4 to 0.8 g / mL. In the production of a spherical activated carbon, a raw material for purified cellulose or regenerated cellulose is impregnated with a flame retardant that vaporizes at less than 1000 ° C., carbonized at 300 to 700 ° C. under nitrogen atmosphere, and steam activation at 750 to 1000 ° C. The present invention relates to a method for producing an adsorbent for oral administration, which is characterized by

  The second invention relates to the method for producing an adsorbent for oral administration according to the first invention, which is any one or more of ammonium chloride, ammonium sulfate, ammonium bromide, tetrabromobisphenol A and guanidine hydrochloride.

  The third invention relates to the method for producing an adsorbent for oral administration as described in the first or second invention, which is production of spherical activated carbon having an average pore diameter of 1.5 to 3.0 nm.

  A fourth invention is for oral administration according to any of the first to third inventions, which is a production of spherical activated carbon having an ignition residue of less than 10% as measured according to JIS K 1474-1 (2014). The present invention relates to a method for producing a pharmaceutical adsorbent.

  A fifth invention relates to the method for producing an adsorbent according to any one of the first to fourth inventions, wherein the spherical activated carbon is an adsorbent for medicine for oral administration.

  A sixth invention provides the method for producing an adsorbent for oral administration according to the fifth invention, wherein the spherical activated carbon is a therapeutic agent or a preventive agent for renal disease for oral administration or liver disease for oral administration. Concerned.

  According to the method for producing an adsorbent for oral administration according to the first invention, the BET specific surface area is 700 to 3000 m 2 / g, the average particle diameter is 100 to 1100 μm, the surface oxide amount is 0.05 meq / g or more, and the packing density In the production of spherical activated carbon of 0.4 to 0.8 g / mL, a raw material of purified cellulose or regenerated cellulose is impregnated with a flame retardant that vaporizes at less than 1000 ° C. and carbonized at 300 to 700 ° C. under nitrogen atmosphere Since steam activation is performed at 750 to 1000 ° C., it is possible to manufacture an economical adsorbent for medical use with reduced environmental load, and even with a simple process, while maintaining the adsorption performance of toxic substances of activated carbon. Even the ignition residue can be lowered and the yield is good.

  According to the method for producing an adsorbent for a pharmaceutical preparation for oral administration according to the second invention, in the first invention, the flame retardant is any one or one of ammonium chloride, ammonium sulfate, ammonium bromide, tetrabromobisphenol A or guanidine hydrochloride. The multiple adsorbents make it possible to manufacture pharmaceutical adsorbents that are economical and have reduced environmental impact, and have low ignition residue while maintaining the adsorption performance of toxic substances on activated carbon even with simple processes. It can be done and the yield is good.

  According to the method for producing an adsorbent for oral administration pharmaceuticals according to the third invention, in the first or second invention, since it is the production of spherical activated carbon having an average pore diameter of 1.5 to 3.0 nm, activated carbon Adsorption performance of the

  According to the method for producing an adsorbent for oral administration pharmaceutical according to the fourth invention, in the first to third inventions, the ignition residue is less than 10% in the measurement according to JIS K 1474-1 (2014). Therefore, the yield is good and economical.

  According to the method for producing an adsorbent for oral administration relating to the fifth invention, in the first to fourth inventions, since the spherical activated carbon is an adsorbent for pharmaceutical for oral administration, it is promising as a therapeutic agent or prophylactic agent It is possible to provide a pharmaceutical adsorbent for oral administration.

  According to the manufacturing method of the adsorbent for oral administration relating to the sixth invention, in the fifth invention, the spherical activated carbon is a therapeutic agent or prophylactic agent for renal disease for oral administration or liver disease for oral administration. For this reason, it is highly effective in adsorbing the causative agent for kidney disease or liver disease, and can provide a medicinal adsorbent for oral administration promising as a therapeutic agent or a preventive agent.

  The pharmaceutical adsorbent produced by the production method of the present invention is a spherical activated carbon in which pores are developed by making the starting material regenerated cellulose, carbonizing the cellulose material, and activating it. The regenerated cellulose as a raw material is a high purity cellulose prepared from pulp by the conventionally known viscose method or copper ammonia method.

  Or it is the cellulose prepared after melt | dissolving a pulp using ionic liquids, such as NMMO (N- methyl morpholine oxide) and BMIMCL (1-butyl 3- methyl imidazolium chloride). In order to adjust the viscosity of the cellulose solution and to adjust the pore distribution of the cellulose coagulum, it is also possible to add 20 wt% or less of soluble or water-insoluble starch to the raw material cellulose. Furthermore, in order to further increase the strength of activated activated carbon, cellulose fibers or inorganic fibers such as silica can be added as a filler in an amount of 20% by weight or less.

  With regard to the form of regenerated cellulose, it is preferable that it be in the form of particles, taking into consideration its application as a pharmaceutical adsorbent. Particularly in view of the fluidity in the intestinal tract, the preferred shape for pharmaceutical active carbon is spherical. Regenerated cellulose etc. can be obtained by coagulating in water or strong acid. When a viscose solution of a predetermined concentration is dropped into a coagulating solution of water or strong acid, or sprayed and captured into a coagulating bath by a known method, spherical cellulose particles are easily formed. The average particle diameter of the spherical cellulose particles is arbitrarily adjusted by the concentration and viscosity of the viscose solution, the diameter of the liquid discharge nozzle at the time of coagulation, the rotational speed of the coagulation liquid, and the like. The discharge apparatus of the cellulose solution is adjusted so that 100-1100 micrometers of activated carbon may be finally obtained as an average particle diameter. The dried spherical cellulose before carbonization has a particle size of 150 to 2000 μm.

  Cellulose particles are generally considered to be used for cosmetic powders and pharmaceutical excipients. Cellulose particles are required to be flexible and self-disintegrating, so no particular hardness is expected. In addition, fine particles of microcrystalline cellulose are used as a molding accelerator such as spheroidization of a drug, and are formulated with the drug to form the core of the drug. However, in the case of microcrystalline cellulose, even if spherical cellulose particles having a certain particle size and hardness can be prepared, maintenance of hardness in the body can not be expected.

  On the other hand, cellulose is a component derived from natural products, and has the advantage that the burden of raw material procurement and raw material preparation is small. In addition, the time required for activation is shorter compared to activated carbon of phenolic resin. Therefore, the present inventors adjust the particle diameter and hardness by controlling the concentration when dissolving cellulose, adjusting the molecular polymerization degree of viscose, or blending / impregnating the non-combustible processing component to increase the hardness. It clarified that it could be adjusted in a wide range. By carbonizing and activating the cellulose spheres obtained thereon, it is possible to obtain a pharmaceutical adsorbent for spherical activated carbon having a desired hardness while using a cellulose raw material which has been difficult in the prior art.

  The spherical activated carbon that is the main component of the pharmaceutical adsorbent will be described from the method for producing it. The spherical cellulose composed of the above-mentioned regenerated cellulose is accommodated in a baking furnace such as a cylindrical retort electric furnace, and the inside of the furnace is carbonized at 300 to 700 ° C. in a nitrogen atmosphere to form spherical carbonized cellulose.

  Alternatively, the spherical cellulose comprising the regenerated cellulose is impregnated in a flame retardant which vaporizes at less than 1000 ° C., for example, a solution of ammonium chloride or ammonium sulfate, a tetrabromobisphenol A solution in which the solvent is methanol, or a mixture thereof. Ru. Thereafter, the spherical cellulose is accommodated in a baking furnace such as a cylindrical retort electric furnace, and the inside of the furnace is carbonized at 300 to 700 ° C. in a nitrogen atmosphere to form spherical carbonized cellulose. The above-mentioned impregnation into the solution is performed for the purpose of making the spherical cellulose flame retardant.

  The spherical carbonized cellulose obtained by any of the above processes is steam activated at 750 to 1000 ° C., preferably 800 to 1000 ° C., further 850 to 950 ° C. The activation time is 0.5 to 50 hours depending on the production scale, equipment and the like.

  According to the above-mentioned manufacturing method, the ash content after combustion is very small, and the yield is improved. By impregnating the raw material cellulose with a flame retardant vaporized at less than 1000 ° C., the flame retardant is thermally decomposed, so it does not remain as a high-temperature residue, so acid cleaning and heat treatment become unnecessary, and process saving becomes possible. . That is, by using a flame retardant that vaporizes at less than 1000 ° C., it is considered that the component of the added flame retardant does not remain as a solid, and the ash content decreases.

  For example, if the flame retardant that vaporizes at less than 1000 ° C. is, for example, ammonium chloride, finally hydrogen chloride and ammonia; if it is ammonium sulfate, sulfur oxides and ammonia; if it is ammonium bromide, then hydrogen bromide and ammonia; If it is tetrabromobisphenol A, it can be pyrolyzed into hydrogen bromide, bromine gas and bromophenols which are decomposed and formed by the debromination reaction, and by volatilizing, the ignition residue after combustion can be made very low. it is conceivable that. Further, it is considered that guanidine hydrochloride, when decomposed into hydrogen chloride and carbon dioxide gas and ammonia, and volatilized in the same manner as the above flame retardant, makes it possible to extremely reduce the ignition residue after combustion. That is, it is possible to obtain spherical activated carbon of high purity while saving steps. It is also possible to use a mixture of two or more of these flame retardants.

  For example, the Minister of Health, Labor and Welfare listens to the opinion of the Pharmaceutical Affairs and Food Sanitation Council to ensure the appropriateness of the properties and quality of medicines in accordance with Article 41 of the Act on Ensuring Quality, Efficacy and Safety of Medicines, Medical Devices, etc. The spherical activated carbon obtained by the manufacturing method can easily meet the standard that the ignition residue of medicinal charcoal in the Japanese Pharmacopoeia, which is a standard written standard of pharmaceuticals, is less than 4.0%. . For this reason, according to the said manufacturing method, highly pure spherical activated carbon can be obtained, although it is a simple process by omitting the acid cleaning and heat treatment process conventionally required. In addition, since the furnace used at the time of carbonization is not corroded, it can be used for a long time, which is economical.

  In any of the production methods, spherical activated carbon is sieved by a sieve or the like, and the particle diameter as spherical activated carbon is adjusted and fractionated. Thus, spherical activated carbon, which is a pharmaceutical adsorbent produced by the production method of the present invention, is obtained. The sieving separates activated carbon having a slow adsorption rate and a particle diameter which can not sufficiently exert its adsorptive power.

  Spherical activated carbon obtained from the above-mentioned production method is adsorbed with a causative agent of liver dysfunction or renal dysfunction listed in the examples to be described later, and the adsorption of enzymes necessary for the living body is suppressed as much as possible, ie selective It is required to improve adsorption performance and to exhibit sufficient adsorption performance with a relatively small dose. In order to find the harmonious range of the properties to be possessed, the pharmaceutical adsorbent comprises [1] average pore diameter, [2] BET specific surface area, [3] average particle size, [4] surface oxide content, [5] loading Specified by the indicator of density. Then, as is clear from the tendency of the embodiment described later, the preferable range value of each index is derived. In addition, the measuring methods, such as physical properties of the said activated carbon described below, various conditions, etc. are explained in full detail in the Example.

  First, [1] the average pore diameter is defined to be 1.5 to 3.0 nm. When the average pore diameter is less than 1.5 nm, the adsorption performance of toxic substances is unfavorably reduced. On the contrary, when the average pore diameter exceeds 3.0 nm, it is not preferable because many pores that adsorb macromolecules such as enzymes and polysaccharides necessary for the living body exist. Therefore, the average pore diameter is preferably in the above range, and more preferably 1.6 to 2.0 nm.

[2] The BET specific surface area is defined to be 700 to 3000 m ² / g. If the BET specific surface area is less than 700 m ² / g, the adsorption performance of toxic substances is unfavorably reduced. When the BET specific surface area exceeds 3000 m ² / g, the strength of the spherical activated carbon itself tends to deteriorate because the pore volume increases in addition to the deterioration of the packing density. Therefore, BET specific surface area, the ranges be suitable, preferably 900~2400m ² / g, more preferably 1000 to 2000 ² / g.

  [3] The average particle size is defined as 100 to 1100 μm. When the average particle size is less than 100 μm, adsorption of useful substances such as digestive enzymes is likely to occur, which is not preferable from the aspect of selective adsorption. In addition, although it can theoretically be assumed for an average particle diameter of less than 100 μm, for example, 20 μm, it is actually difficult to manufacture. When the average particle size exceeds 1100 μm, the adsorption rate is lowered because the particles become too large and the surface area relatively decreases. Therefore, the average particle diameter is preferably in the range described above, preferably 100 to 1000 μm, more preferably 150 to 700 μm. The "average particle diameter" in this specification means the particle diameter at 50% of the integrated value in the particle size distribution determined by the laser diffraction / scattering method using the laser light scattering type particle size distribution measuring apparatus of the later example. Do.

  [4] The amount of surface oxide is specified to be 0.05 meq / g or more. The increase in the amount of surface oxides on the spherical activated carbon surface is to increase the number of ionic functional groups on the activated carbon surface. For this reason, in order to improve the adsorption performance of the ionic organic compound, it is considered that the surface oxide amount is preferably 0.05 meq / g or more, and further preferably 0.10 meq / g or more. In the case where the surface oxide content is less than 0.05 meq / g, it is not preferable because the adsorption characteristics are inferior.

  [5] The packing density is specified to be 0.4 to 0.8 g / mL. If the filling density is less than 0.4 g / mL, the dose increases and it becomes difficult to swallow when administered orally. If the packing density exceeds 0.8 g / mL, the balance of the desired selective adsorptivity is inadequate, which is inappropriate. From the above, the packing density is preferably in the range described above, preferably 0.5 to 0.7 g / mL.

  Spherical activated carbon having the above-mentioned physical properties is a drug intended for oral administration, and serves as a therapeutic or preventive agent for kidney disease or liver disease. As described above, the causative agent of a disease or chronic condition is adsorbed and held in pores developed on the surface of spherical activated carbon, and discharged from the body, thereby preventing the deterioration of the condition and leading to the improvement of the pathological condition. Furthermore, when there is a possibility of metabolic abnormality or congenitally or acquiredly, the internal concentration of the causative agent of a disease or a chronic condition can be lowered by internally administering spherical activated carbon. Therefore, taking it as a preventive to prevent the aggravation of symptoms is also considered.

  Examples of renal diseases include chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephritis syndrome, acute progressive nephritis syndrome, chronic nephritis syndrome, nephrotic syndrome, nephrosclerosis, interstitial nephritis And ureteritis, lipoidonephrosis, diabetic nephropathy, renovascular hypertension, hypertension syndrome, secondary renal disease associated with the above-mentioned primary disease, and mild renal failure before dialysis. Liver diseases include, for example, fulminant hepatitis, chronic hepatitis, viral hepatitis, alcoholic hepatitis, liver fibrosis, liver cirrhosis, liver cancer, autoimmune hepatitis, drug allergic liver disorder, primary biliary cirrhosis, tremor ), Encephalopathy, metabolic disorders, functional disorders can be mentioned.

  The dose when using spherical activated carbon as an adsorbent for oral medicine can not be uniformly defined because it is affected by age, sex, physical size or medical condition. However, in general, in the case where human beings are targeted, doses of 1 to 20 g and 2 to 4 times per day may be assumed in terms of weight of spherical activated carbon. The orally active pharmaceutical adsorbent for spherical activated carbon is administered in the form of a powder, granules, tablets, dragees, capsules, suspensions, sticks, sachets, emulsions, etc.

[Measurement item and measurement method]
The present inventors, regarding the spherical activated carbon of each example and comparative example described later, average particle diameter (μm), BET specific surface area (m ² / g), mercury pore volume (mL / g), N ₂ pore volume Physical properties of (mL / g), average pore diameter (nm), packing density (g / mL), and surface oxide amount (meq / g) were measured. At the same time, the adsorption performance of creatinine, indole, indole acetic acid, indoxyl sulfate and aminoisobutyric acid as toxic substances (toxic causative substances) was evaluated, and the adsorption performance of trypsin as a useful substance was evaluated. At the same time, iodine adsorption capacity (mg / g) was also measured to evaluate the general adsorption performance of activated carbon.

  The average particle diameter (μm) is measured using a laser light scattering type particle size distribution analyzer (SALD3000S) manufactured by Shimadzu Corporation, and the particle diameter at 50% of the integrated value in the particle size distribution determined by laser diffraction / scattering method And

The BET specific surface area (m ² / g) was determined by the BET method by measuring the nitrogen adsorption isotherm at 77 K using BELSORP mini (Bell Japan).

The pore volume (mL / g) was the following two methods.
The N ₂ pore volume V _mi was obtained from the nitrogen adsorption amount in terms of liquid nitrogen at a relative pressure of 0.990, using Gurvitsch's law, using BELSORP mini manufactured by Nippon Bell Co., Ltd. The method targeted the range of pore diameter 0.6 to 100 nm.
The mercury pore volume V _me is a mercury having a pore diameter of 7.5 to 15,000 nm, using an autopore 9500 manufactured by Shimadzu Corporation, with a contact angle of 130 ° and a surface tension of 484 dynes / cm (484 mN / m). The pore volume was determined by the indentation method.

The average pore diameter Dp (nm) was obtained by the following equation (i), assuming that the pore shape is cylindrical. In the formula, V _mi is the aforementioned N ₂ pore volume, and Sa is the BET specific surface area.

  The packing density (g / mL) was measured in accordance with JIS K 1474-1 (2014).

  The amount of surface oxides (meq / g) was determined by applying the method of Boehm, shaking the spherical activated carbon in a 0.05 N aqueous solution of sodium hydroxide and filtering it, and the filtrate was subjected to neutralization titration with 0.05 N hydrochloric acid. The amount of sodium hydroxide was used.

  The iodine adsorption power (mg / g) was measured in accordance with JIS K 1474-1 (2014).

Creatinine, indole, indole acetic acid, indoxyl sulfuric acid and aminoisobutyric acid as toxic substances, and trypsin as useful substances as an example of the adsorptive substance were used to evaluate the adsorption performance of the spherical activated carbon of each trial example. First, each adsorptive substance was dissolved in pH 7.4 phosphate buffer to prepare a standard solution in which the concentration of the adsorptive substance was 0.1 g / L.
To 50 mL of a standard creatinine solution, 2.5 g of each of the spherical activated carbons of Examples and Comparative Examples were added, respectively, and contact shaking was carried out at a temperature of 37 ° C. for 3 hours.
To 50 mL of a standard solution of indole, 0.01 g of each of the spherical activated carbons of Examples and Comparative Examples was added, respectively, and contact shaking was performed at a temperature of 37 ° C. for 3 hours.
To 50 mL of a standard solution of indole acetic acid, 0.01 g of each of the spherical activated carbons of Examples and Comparative Examples was added, respectively, and contact shaking was performed at a temperature of 37 ° C. for 3 hours.
0.01 g of each of the spherical activated carbons of Examples and Comparative Examples was added to 50 mL of a standard solution of indoxyl sulfuric acid, and contact shaking was performed at a temperature of 37 ° C. for 3 hours.
0.01 g of each of the spherical activated carbons of Examples and Comparative Examples was added to 50 mL of a standard solution of aminoisobutyric acid, and contact shaking was carried out at a temperature of 37 ° C. for 3 hours.
0.125 g of each of the spherical activated carbons of Examples and Comparative Examples was added to 50 mL of a standard solution of trypsin, and contact shaking was performed at a temperature of 21 ° C. for 3 hours.

  Thereafter, the filtrate obtained by filtration is measured for TOC concentration (mg / L) in each filtrate using a total organic carbon meter (TOC 5000A, manufactured by Shimadzu Corporation), and the mass of the substance to be adsorbed in each filtrate Was calculated. The adsorption rate (%) of each adsorbed substance was determined from the formula (ii).

[Production of Spherical Activated Carbon of Examples and Comparative Examples]
Example 1
2 kg of dissolved pulp LNDP (made by Nippon Paper Chemicals Co., Ltd.) containing 90% by weight of α-cellulose per unit weight and a sodium hydroxide solution (concentration 18.5%) are soaked at 55 ° C. for 15 minutes and then pressed to make excess Sodium hydroxide was removed to produce an alkali cellulose (AC) having a cellulose concentration of 33.5% by weight. Alkali cellulose is aged at 40 ° C. for 7 hours, and 5 kg of the alkali cellulose is reacted with 436 mL of carbon disulfide having a purity of 97% or more for 70 minutes to obtain cellulose xanthate having a viscosity of 0.055 Pa · s (55 cP) at 40 ° C. I got

  After completion of the reaction, about 13 L of dilute sodium hydroxide solution was added to cellulose xanthate and stirred for 100 minutes to obtain viscose. Furthermore, through the steps of defoaming, ripening and filtration, viscose with a cellulose concentration of 9.0% was prepared. The prepared viscose is diluted with distilled water to a viscose concentration of 70%, and the diluted viscose is supplied to a rotating body with an outer diameter of 85 mm through an inlet tube and dropped by spraying, so that dilute sulfuric acid installed below The droplets were captured in a bath to obtain cellulose (so-called regenerated cellulose) spheres. Here, the dropping method is preferably a drop method or a centrifugal method. At this time, the cellulose spheres were immersed in a dilute sulfuric acid bath for 30 minutes or more. The cellulose spheres were washed with a large excess of water to remove dilute sulfuric acid, and then immersed in dilute aqueous sodium hydroxide solution for 1 hour or more. After washing again with a large excess of water to remove the sodium hydroxide content in the spheres, it was dried at 80 ° C. to obtain spherical cellulose.

  To 500 g of spherical cellulose obtained by the above preparation, 1000 mL of an aqueous solution of ammonium chloride (concentration 5%) was added, and allowed to stand for 2 hours. Thereafter, the water was drained and dried overnight at 80 ° C. with a drier. 400 g of spherical cellulose that had undergone ammonium chloride treatment was placed in a cylindrical retort electric furnace, sealed with nitrogen, and then heated to 900 ° C. to carbonize. Thereafter, steam was added to the carbide and activated by maintaining at that temperature for 2.5 hours to obtain spherical activated carbon of Example 1 (substantial yield was 18.7%).

Example 2
A spherical activated carbon of Example 2 was obtained according to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 was changed to an ammonium sulfate solution (concentration 5%, 1000 mL) (substantial yield is 12.7% Met).

Example 3
According to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 is a mixed solution of ammonium chloride aqueous solution (concentration 2.5%, 500 mL) and ammonium sulfate solution (concentration 2.5%, 500 mL) Spherical activated carbon of Example 3 was obtained (substantial yield was 16.1%).

Example 4
Spherical activated carbon of Example 4 was obtained according to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 was changed to an ammonium bromide solution (concentration 5%, 1000 mL) (substantial yield is 18) 1%).

Example 5
Example 5 Spherical activated carbon was obtained according to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 was changed to tetrabromobisphenol A solution (concentration 5%, 1000 mL) using methanol as the solvent. The real yield was 16.5%).

Example 6
The spherical activated carbon of Example 6 was obtained according to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 was changed to guanidine hydrochloride solution (concentration 5%, 1000 mL) (substantial yield is 14.4. 1%).

Comparative Example 1
To 500 g of the spherical cellulose obtained by the above preparation, 1000 mL of an aqueous ammonium phosphate solution (concentration 5%) was added and allowed to stand for 2 hours. Thereafter, the water was drained and dried overnight at 80 ° C. with a drier. After putting 400 g of spherical cellulose which had undergone ammonium phosphate treatment into a cylindrical retort electric furnace and sealing nitrogen, it was heated to 900 ° C. to carbonize. Thereafter, steam was added to the carbide, and the carbide was maintained at that temperature for 2.5 hours for activation to obtain spherical activated carbon of Comparative Example 1 (substantial yield was 13.1%).

Comparative Example 2
A spherical activated carbon according to Comparative Example 2 was obtained according to Comparative Example 1 except that the aqueous ammonium phosphate solution in Comparative Example 1 was changed to an aqueous solution of sodium polyborate (concentration 5%, 1000 mL) (substantial yield is 10.5%). ).

Comparative Example 3
A spherical activated carbon according to Comparative Example 3 was obtained according to Comparative Example 1 except that the aqueous solution of ammonium phosphate in Comparative Example 1 was changed to an aqueous solution of sodium polyphosphate (concentration 5%, 1000 mL) (substantial yield is 8.0%). ).

  The ignition residue (%) is shown in Table 1 for the spherical activated carbon of each Example and Comparative Example.

Then, each physical-property value of spherical activated carbon was described in Table 2 and 3 about each Example and comparative example. From the top of the table, real yield (%), average particle size (μm), BET specific surface area (m ² / g), mercury pore volume (mL / g), N ₂ pore volume (mL / g) , Average pore diameter (nm), packing density (g / mL), surface oxide amount (meq / g), iodine adsorption power (mg / g), creatinine, indole, indole acetic acid, indoxyl sulfuric acid, aminoisobutyric acid and trypsin Adsorption rate (%) of Here, a substantial yield means the yield of the activated carbon which deducted the ignition residue among the activated carbon yields after baking a raw material.

[Results and discussion]
As understood from Table 1, the spherical activated carbon of each example is any one of ammonium chloride, ammonium sulfate, ammonium bromide, tetrabromobisphenol A or guanidine hydrochloride which is a flame retardant which vaporizes at a temperature of less than 1000 ° C. as a flame retardant. Alternatively, since the flame retardant is thermally decomposed and vaporized at the time of production because a plurality is attached and produced, the ignition residue is lowered. Therefore, the ash content (loss) is small and the yield is high. In addition, since the ignition residue after steam activation is very low, the acid cleaning and heat treatment steps can be omitted while the ignition residue specification in the aforementioned Japanese Pharmacopoeia can be easily satisfied. Thus, an efficient and economically superior pharmaceutical adsorbent can be produced.

  As understood from Tables 2 and 3, the spherical activated carbons obtained in each Example were obtained by carbonizing and steam activation by adding ammonium phosphate, sodium polyborate or sodium polyphosphate as a flame retardant (comparative example) The physical properties were almost the same as or higher than in 1) to 3). The packing density of the spherical activated carbons of the examples is also equal to or higher than that of the comparative examples, suggesting the possibility of a very compact dosage form of the pharmaceutical adsorbent according to the embodiment. Further, the spherical activated carbon of each example is extremely excellent in the adsorption performance because the adsorption rate of toxic substances such as creatinine is higher than the result of the adsorption measurement. And, since the adsorption performance of trypsin, which is a useful substance, is suppressed, it is also extremely excellent in selective adsorption. Therefore, it can be said that it is desirable as a medical adsorbent that absorbs toxic substances efficiently.

  INDUSTRIAL APPLICABILITY The production method of the present invention can produce activated carbon excellent in adsorption performance with a high yield by a simple process, is economical, and can suppress environmental impact. In addition, the spherical activated carbon produced by the production method of the present invention reaches the digestive organs by oral administration, and the use of a pharmaceutical adsorbent that efficiently absorbs and excretes toxic substances is very promising.

  The present invention relates to a method for producing an absorbent for oral administration comprising an activated carbon using cellulose as a raw material, and in particular, an adsorption for oral administration comprising an activated carbon derived from cellulose excellent in adsorption performance of toxic substances in a simple process. The present invention relates to a manufacturing method capable of obtaining an agent.

  Patients with kidney disease or liver disease accumulate toxic substances in the blood and as a result cause encephalopathy such as uremia and loss of consciousness. The number of these patients tends to increase year by year. Hemodialysis-type artificial kidneys and the like that remove toxic substances outside the body are used for treatment of patients. However, such artificial kidneys require specialist technicians for safety and management, and it is also considered that the physical, mental and economic burden of the patient is required for taking blood out of the body. And not necessarily satisfactory.

  As an alternative to artificial organs, adsorbents for oral administration have been developed which are orally ingested and adsorb toxic substances in the body and discharged out of the body (see Patent Document 1, Patent Document 2, etc.). Then, an anti-nephrotic syndrome agent is reported in which petroleum hydrocarbon (pitch) or the like is used as a raw material material, and the particle size is adjusted to be relatively uniform and carbonized and activated (for example, see Patent Document 3) . In addition, an adsorbent for oral administration has been reported in which the particle size of activated carbon itself is relatively uniformed and distribution of pore volume etc. in the activated carbon is attempted to be adjusted (see Patent Document 4). Thus, along with making the particle size relatively uniform, the medicinal activated carbon improves the poor fluidity in the intestine, and at the same time improves the adsorption performance of the activated carbon by adjusting the pores. planned. Therefore, it is taken by many patients with mild chronic renal failure.

  Medicinal activated carbon requires rapid and efficient adsorption to uremic agents and their precursors. However, it is difficult to reduce the particle size while maintaining the spherical shape with existing medicinal activated carbon. In addition, the adjustment of the pores in the conventional medicinal activated carbon is not good and the adsorption performance is not always sufficient, so the daily dose must be increased. In particular, because chronic renal failure patients have limited fluid intake, swallowing with a small amount of fluid has been a great pain for patients.

  Then, the applicant has developed a method for manufacturing an adsorbent for oral administration pharmaceuticals which has low economical and environmental burden and excellent selective adsorption properties (see Patent Document 5 and Patent Document 6), and cellulose which is a natural product-derived component It came to obtain the medicine adsorbent for oral administration of the spherical activated carbon which uses as a raw material.

  An adsorbent for oral administration comprising an activated carbon produced by the method for producing an adsorbent for oral administration derived from cellulose described above is excellent in the adsorption capacity and selective adsorption of toxins to be removed although the dose is small. It was very promising as an application of pharmaceutical adsorbents.

Patent No. 3835698 JP, 2008-303193, A Unexamined-Japanese-Patent No. 6-135841 JP 2002-308785 A Patent No. 5984352 Patent No. 5985027

  The present invention can produce an adsorbent for medical use which is economical and has reduced environmental impact, and has a high yield while maintaining the adsorption performance and selective adsorption of toxic substances of activated carbon even in a simple process. The present invention provides a method of producing a pharmaceutical adsorbent for oral administration.

That is, in the first invention, the BET specific surface area is 700 to 3000 m ² / g, the average particle diameter is 100 to 1100 μm, the surface oxide amount is 0.05 meq / g or more , and the packing density is 0.4 to 0.8 g / mL And a flame retardant which is vaporized at less than 1000 ° C. is attached to purified cellulose or regenerated cellulose which is a raw material in the production of spherical activated carbon having an average pore diameter of 1.5 to 3.0 nm , under a nitrogen atmosphere at 300 to 700 ° C. in carbonized, it has rows of steam activation at 750 to 1000 ° C., that ignition residue in the measurement conforming to JIS K 1474-1 without performing acid cleaning (2014) to obtain a spherical activated carbon to less than 10% The present invention relates to a method for producing an adsorbent for oral administration, which is characterized by the present invention.

  The second invention relates to the method for producing an adsorbent for oral administration according to the first invention, which is any one or more of ammonium chloride, ammonium sulfate, ammonium bromide, tetrabromobisphenol A and guanidine hydrochloride.

A third invention relates to the method for producing an adsorbent according to the first or second invention, wherein the spherical activated carbon is an adsorbent for medicine for oral administration.

A fourth invention relates to the method for producing an adsorbent for oral administration described in the third invention, wherein the spherical activated carbon is a therapeutic agent or a preventive agent for renal disease for oral administration or liver disease for oral administration. Concerned.

According to the method for producing an adsorbent for oral administration according to the first invention, the BET specific surface area is 700 to 3000 m ² / g, the average particle diameter is 100 to 1100 μm, the surface oxide amount is 0.05 meq / g or more , A flame retardant which is vaporized at less than 1000 ° C. to purified cellulose or regenerated cellulose which is a raw material in the production of spherical activated carbon having a density of 0.4 to 0.8 g / mL and an average pore diameter of 1.5 to 3.0 nm was impregnated, carbonized under 300 to 700 ° C. nitrogen atmosphere, it has rows of steam activation at 750 to 1000 ° C., the residue on ignition in the measurement conforming to JIS K 1474-1 without performing acid cleaning (2014) In order to obtain spherical activated carbon of less than 10%, it is possible to manufacture an adsorbent for medical use that is economical and has reduced environmental impact, and the adsorption performance of the toxic substance of activated carbon can be maintained even with a simple process. While lifting also can reduce the ignition residue, yield a goodness rather economical adsorption performance of activated carbon is increased.

  According to the method for producing an adsorbent for a pharmaceutical preparation for oral administration according to the second invention, in the first invention, the flame retardant is any one or one of ammonium chloride, ammonium sulfate, ammonium bromide, tetrabromobisphenol A or guanidine hydrochloride. The multiple adsorbents make it possible to manufacture pharmaceutical adsorbents that are economical and have reduced environmental impact, and have low ignition residue while maintaining the adsorption performance of toxic substances on activated carbon even with simple processes. It can be done and the yield is good.

According to the method for producing an adsorbent for oral administration relating to the third invention, in the first or second invention, since the spherical activated carbon is an adsorbent for oral administration, it is promising as a therapeutic agent or a preventive agent It is possible to provide a pharmaceutical adsorbent for oral administration.

According to the method for producing an adsorbent for oral administration relating to the fourth invention, in the third invention, the spherical activated carbon is a therapeutic agent or preventive agent for renal disease for oral administration or liver disease for oral administration. For this reason, it is highly effective in adsorbing the causative agent for kidney disease or liver disease, and can provide a medicinal adsorbent for oral administration promising as a therapeutic agent or a preventive agent.

  The pharmaceutical adsorbent produced by the production method of the present invention is a spherical activated carbon in which pores are developed by making the starting material regenerated cellulose, carbonizing the cellulose material, and activating it. The regenerated cellulose as a raw material is a high purity cellulose prepared from pulp by the conventionally known viscose method or copper ammonia method.

  Or it is the cellulose prepared after melt | dissolving a pulp using ionic liquids, such as NMMO (N- methyl morpholine oxide) and BMIMCL (1-butyl 3- methyl imidazolium chloride). In order to adjust the viscosity of the cellulose solution and to adjust the pore distribution of the cellulose coagulum, it is also possible to add 20 wt% or less of soluble or water-insoluble starch to the raw material cellulose. Furthermore, in order to further increase the strength of activated activated carbon, cellulose fibers or inorganic fibers such as silica can be added as a filler in an amount of 20% by weight or less.

  With regard to the form of regenerated cellulose, it is preferable that it be in the form of particles, taking into consideration its application as a pharmaceutical adsorbent. Particularly in view of the fluidity in the intestinal tract, the preferred shape for pharmaceutical active carbon is spherical. Regenerated cellulose etc. can be obtained by coagulating in water or strong acid. When a viscose solution of a predetermined concentration is dropped into a coagulating solution of water or strong acid, or sprayed and captured into a coagulating bath by a known method, spherical cellulose particles are easily formed. The average particle diameter of the spherical cellulose particles is arbitrarily adjusted by the concentration and viscosity of the viscose solution, the diameter of the liquid discharge nozzle at the time of coagulation, the rotational speed of the coagulation liquid, and the like. The discharge apparatus of the cellulose solution is adjusted so that 100-1100 micrometers of activated carbon may be finally obtained as an average particle diameter. The dried spherical cellulose before carbonization has a particle size of 150 to 2000 μm.

  Cellulose particles are generally considered to be used for cosmetic powders and pharmaceutical excipients. Cellulose particles are required to be flexible and self-disintegrating, so no particular hardness is expected. In addition, fine particles of microcrystalline cellulose are used as a molding accelerator such as spheroidization of a drug, and are formulated with the drug to form the core of the drug. However, in the case of microcrystalline cellulose, even if spherical cellulose particles having a certain particle size and hardness can be prepared, maintenance of hardness in the body can not be expected.

  On the other hand, cellulose is a component derived from natural products, and has the advantage that the burden of raw material procurement and raw material preparation is small. In addition, the time required for activation is shorter compared to activated carbon of phenolic resin. Therefore, the present inventors adjust the particle diameter and hardness by controlling the concentration when dissolving cellulose, adjusting the molecular polymerization degree of viscose, or blending / impregnating the non-combustible processing component to increase the hardness. It clarified that it could be adjusted in a wide range. By carbonizing and activating the cellulose spheres obtained thereon, it is possible to obtain a pharmaceutical adsorbent for spherical activated carbon having a desired hardness while using a cellulose raw material which has been difficult in the prior art.

  The spherical activated carbon that is the main component of the pharmaceutical adsorbent will be described from the method for producing it. The spherical cellulose composed of the above-mentioned regenerated cellulose is accommodated in a baking furnace such as a cylindrical retort electric furnace, and the inside of the furnace is carbonized at 300 to 700 ° C. in a nitrogen atmosphere to form spherical carbonized cellulose.

  Alternatively, the spherical cellulose comprising the regenerated cellulose is impregnated in a flame retardant which vaporizes at less than 1000 ° C., for example, a solution of ammonium chloride or ammonium sulfate, a tetrabromobisphenol A solution in which the solvent is methanol, or a mixture thereof. Ru. Thereafter, the spherical cellulose is accommodated in a baking furnace such as a cylindrical retort electric furnace, and the inside of the furnace is carbonized at 300 to 700 ° C. in a nitrogen atmosphere to form spherical carbonized cellulose. The above-mentioned impregnation into the solution is performed for the purpose of making the spherical cellulose flame retardant.

  The spherical carbonized cellulose obtained by any of the above processes is steam activated at 750 to 1000 ° C., preferably 800 to 1000 ° C., further 850 to 950 ° C. The activation time is 0.5 to 50 hours depending on the production scale, equipment and the like.

  According to the above-mentioned manufacturing method, the ash content after combustion is very small, and the yield is improved. By impregnating the raw material cellulose with a flame retardant vaporized at less than 1000 ° C., the flame retardant is thermally decomposed, so it does not remain as a high-temperature residue, so acid cleaning and heat treatment become unnecessary, and process saving becomes possible. . That is, by using a flame retardant that vaporizes at less than 1000 ° C., it is considered that the component of the added flame retardant does not remain as a solid, and the ash content decreases.

  For example, if the flame retardant that vaporizes at less than 1000 ° C. is, for example, ammonium chloride, finally hydrogen chloride and ammonia; if it is ammonium sulfate, sulfur oxides and ammonia; if it is ammonium bromide, then hydrogen bromide and ammonia; If it is tetrabromobisphenol A, it can be pyrolyzed into hydrogen bromide, bromine gas and bromophenols which are decomposed and formed by the debromination reaction, and by volatilizing, the ignition residue after combustion can be made very low. it is conceivable that. Further, it is considered that guanidine hydrochloride, when decomposed into hydrogen chloride and carbon dioxide gas and ammonia, and volatilized in the same manner as the above flame retardant, makes it possible to extremely reduce the ignition residue after combustion. That is, it is possible to obtain spherical activated carbon of high purity while saving steps. It is also possible to use a mixture of two or more of these flame retardants.

  For example, the Minister of Health, Labor and Welfare listens to the opinion of the Pharmaceutical Affairs and Food Sanitation Council to ensure the appropriateness of the properties and quality of medicines in accordance with Article 41 of the Act on Ensuring Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices etc. The spherical activated carbon obtained by the manufacturing method can easily meet the standard that the ignition residue of medicinal charcoal in the Japanese Pharmacopoeia, which is a standard written standard of pharmaceuticals, is less than 4.0%. . For this reason, according to the said manufacturing method, highly pure spherical activated carbon can be obtained, although it is a simple process by omitting the acid cleaning and heat treatment process conventionally required. In addition, since the furnace used at the time of carbonization is not corroded, it can be used for a long time, which is economical.

  In any of the production methods, spherical activated carbon is sieved by a sieve or the like, and the particle diameter as spherical activated carbon is adjusted and fractionated. Thus, spherical activated carbon, which is a pharmaceutical adsorbent produced by the production method of the present invention, is obtained. The sieving separates activated carbon having a slow adsorption rate and a particle diameter which can not sufficiently exert its adsorptive power.

  Spherical activated carbon obtained from the above-mentioned production method is adsorbed with a causative agent of liver dysfunction or renal dysfunction listed in the examples to be described later, and the adsorption of enzymes necessary for the living body is suppressed as much as possible, ie selective It is required to improve adsorption performance and to exhibit sufficient adsorption performance with a relatively small dose. In order to find the harmonious range of the properties to be possessed, the pharmaceutical adsorbent comprises [1] average pore diameter, [2] BET specific surface area, [3] average particle size, [4] surface oxide content, [5] loading Specified by the indicator of density. Then, as is clear from the tendency of the embodiment described later, the preferable range value of each index is derived. In addition, the measuring methods, such as physical properties of the said activated carbon described below, various conditions, etc. are explained in full detail in the Example.

  First, [1] the average pore diameter is defined to be 1.5 to 3.0 nm. When the average pore diameter is less than 1.5 nm, the adsorption performance of toxic substances is unfavorably reduced. On the contrary, when the average pore diameter exceeds 3.0 nm, it is not preferable because many pores that adsorb macromolecules such as enzymes and polysaccharides necessary for the living body exist. Therefore, the average pore diameter is preferably in the above range, and more preferably 1.6 to 2.0 nm.

[2] The BET specific surface area is defined to be 700 to 3000 m ² / g. If the BET specific surface area is less than 700 m ² / g, the adsorption performance of toxic substances is unfavorably reduced. When the BET specific surface area exceeds 3000 m ² / g, the strength of the spherical activated carbon itself tends to deteriorate because the pore volume increases in addition to the deterioration of the packing density. Therefore, BET specific surface area, the ranges be suitable, preferably 900~2400m ² / g, more preferably 1000 to 2000 ² / g.

  [3] The average particle size is defined as 100 to 1100 μm. When the average particle size is less than 100 μm, adsorption of useful substances such as digestive enzymes is likely to occur, which is not preferable from the aspect of selective adsorption. In addition, although it can theoretically be assumed for an average particle diameter of less than 100 μm, for example, 20 μm, it is actually difficult to manufacture. When the average particle size exceeds 1100 μm, the adsorption rate is lowered because the particles become too large and the surface area relatively decreases. Therefore, the average particle diameter is preferably in the range described above, preferably 100 to 1000 μm, more preferably 150 to 700 μm. The "average particle diameter" in this specification means the particle diameter at 50% of the integrated value in the particle size distribution determined by the laser diffraction / scattering method using the laser light scattering type particle size distribution measuring apparatus of the later example. Do.

  [4] The amount of surface oxide is specified to be 0.05 meq / g or more. The increase in the amount of surface oxides on the spherical activated carbon surface is to increase the number of ionic functional groups on the activated carbon surface. For this reason, in order to improve the adsorption performance of the ionic organic compound, it is considered that the surface oxide amount is preferably 0.05 meq / g or more, and further preferably 0.10 meq / g or more. In the case where the surface oxide content is less than 0.05 meq / g, it is not preferable because the adsorption characteristics are inferior.

  [5] The packing density is specified to be 0.4 to 0.8 g / mL. If the filling density is less than 0.4 g / mL, the dose increases and it becomes difficult to swallow when administered orally. If the packing density exceeds 0.8 g / mL, the balance of the desired selective adsorptivity is inadequate, which is inappropriate. From the above, the packing density is preferably in the range described above, preferably 0.5 to 0.7 g / mL.

  Spherical activated carbon having the above-mentioned physical properties is a drug intended for oral administration, and serves as a therapeutic or preventive agent for kidney disease or liver disease. As described above, the causative agent of a disease or chronic condition is adsorbed and held in pores developed on the surface of spherical activated carbon, and discharged from the body, thereby preventing the deterioration of the condition and leading to the improvement of the pathological condition. Furthermore, when there is a possibility of metabolic abnormality or congenitally or acquiredly, the internal concentration of the causative agent of a disease or a chronic condition can be lowered by internally administering spherical activated carbon. Therefore, taking it as a preventive to prevent the aggravation of symptoms is also considered.

  Examples of renal diseases include chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephritis syndrome, acute progressive nephritis syndrome, chronic nephritis syndrome, nephrotic syndrome, nephrosclerosis, interstitial nephritis And ureteritis, lipoidonephrosis, diabetic nephropathy, renovascular hypertension, hypertension syndrome, secondary renal disease associated with the above-mentioned primary disease, and mild renal failure before dialysis. Liver diseases include, for example, fulminant hepatitis, chronic hepatitis, viral hepatitis, alcoholic hepatitis, liver fibrosis, liver cirrhosis, liver cancer, autoimmune hepatitis, drug allergic liver disorder, primary biliary cirrhosis, tremor ), Encephalopathy, metabolic disorders, functional disorders can be mentioned.

  The dose when using spherical activated carbon as an adsorbent for oral medicine can not be uniformly defined because it is affected by age, sex, physical size or medical condition. However, in general, in the case where human beings are targeted, doses of 1 to 20 g and 2 to 4 times per day may be assumed in terms of weight of spherical activated carbon. The orally active pharmaceutical adsorbent for spherical activated carbon is administered in the form of a powder, granules, tablets, dragees, capsules, suspensions, sticks, sachets, emulsions, etc.

[Measurement item and measurement method]
The present inventors, regarding the spherical activated carbon of each example and comparative example described later, average particle diameter (μm), BET specific surface area (m ² / g), mercury pore volume (mL / g), N ₂ pore volume Physical properties of (mL / g), average pore diameter (nm), packing density (g / mL), and surface oxide amount (meq / g) were measured. At the same time, the adsorption performance of creatinine, indole, indole acetic acid, indoxyl sulfate and aminoisobutyric acid as toxic substances (toxic causative substances) was evaluated, and the adsorption performance of trypsin as a useful substance was evaluated. At the same time, iodine adsorption capacity (mg / g) was also measured to evaluate the general adsorption performance of activated carbon.

  The average particle diameter (μm) is measured using a laser light scattering type particle size distribution analyzer (SALD3000S) manufactured by Shimadzu Corporation, and the particle diameter at 50% of the integrated value in the particle size distribution determined by laser diffraction / scattering method And

The BET specific surface area (m ² / g) was determined by the BET method by measuring the nitrogen adsorption isotherm at 77 K using BELSORP mini (Bell Japan).

The pore volume (mL / g) was the following two methods.
The N ₂ pore volume V _mi was obtained from the nitrogen adsorption amount in terms of liquid nitrogen at a relative pressure of 0.990, using Gurvitsch's law, using BELSORP mini manufactured by Nippon Bell Co., Ltd. The method targeted the range of pore diameter 0.6 to 100 nm.
The mercury pore volume V _me is a mercury having a pore diameter of 7.5 to 15,000 nm, using an autopore 9500 manufactured by Shimadzu Corporation, with a contact angle of 130 ° and a surface tension of 484 dynes / cm (484 mN / m). The pore volume was determined by the indentation method.

The average pore diameter Dp (nm) was obtained by the following equation (i), assuming that the pore shape is cylindrical. In the formula, V _mi is the aforementioned N ₂ pore volume, and Sa is the BET specific surface area.

  The packing density (g / mL) was measured in accordance with JIS K 1474-1 (2014).

  The amount of surface oxides (meq / g) was determined by applying the method of Boehm, shaking the spherical activated carbon in a 0.05 N aqueous solution of sodium hydroxide and filtering it, and the filtrate was subjected to neutralization titration with 0.05 N hydrochloric acid. The amount of sodium hydroxide was used.

  The iodine adsorption power (mg / g) was measured in accordance with JIS K 1474-1 (2014).

Creatinine, indole, indole acetic acid, indoxyl sulfuric acid and aminoisobutyric acid as toxic substances, and trypsin as useful substances as an example of the adsorptive substance were used to evaluate the adsorption performance of the spherical activated carbon of each trial example. First, each adsorptive substance was dissolved in pH 7.4 phosphate buffer to prepare a standard solution in which the concentration of the adsorptive substance was 0.1 g / L.
To 50 mL of a standard creatinine solution, 2.5 g of each of the spherical activated carbons of Examples and Comparative Examples were added, respectively, and contact shaking was carried out at a temperature of 37 ° C. for 3 hours.
To 50 mL of a standard solution of indole, 0.01 g of each of the spherical activated carbons of Examples and Comparative Examples was added, respectively, and contact shaking was performed at a temperature of 37 ° C. for 3 hours.
To 50 mL of a standard solution of indole acetic acid, 0.01 g of each of the spherical activated carbons of Examples and Comparative Examples was added, respectively, and contact shaking was performed at a temperature of 37 ° C. for 3 hours.
0.01 g of each of the spherical activated carbons of Examples and Comparative Examples was added to 50 mL of a standard solution of indoxyl sulfuric acid, and contact shaking was performed at a temperature of 37 ° C. for 3 hours.
0.01 g of each of the spherical activated carbons of Examples and Comparative Examples was added to 50 mL of a standard solution of aminoisobutyric acid, and contact shaking was carried out at a temperature of 37 ° C. for 3 hours.
0.125 g of each of the spherical activated carbons of Examples and Comparative Examples was added to 50 mL of a standard solution of trypsin, and contact shaking was performed at a temperature of 21 ° C. for 3 hours.

  Thereafter, the filtrate obtained by filtration is measured for TOC concentration (mg / L) in each filtrate using a total organic carbon meter (TOC 5000A, manufactured by Shimadzu Corporation), and the mass of the substance to be adsorbed in each filtrate Was calculated. The adsorption rate (%) of each adsorbed substance was determined from the formula (ii).

[Production of Spherical Activated Carbon of Examples and Comparative Examples]
Example 1
2 kg of dissolved pulp LNDP (made by Nippon Paper Chemicals Co., Ltd.) containing 90% by weight of α-cellulose per unit weight and a sodium hydroxide solution (concentration 18.5%) are soaked at 55 ° C. for 15 minutes and then pressed to make excess Sodium hydroxide was removed to produce an alkali cellulose (AC) having a cellulose concentration of 33.5% by weight. Alkali cellulose is aged at 40 ° C. for 7 hours, and 5 kg of the alkali cellulose is reacted with 436 mL of carbon disulfide having a purity of 97% or more for 70 minutes to obtain cellulose xanthate having a viscosity of 0.055 Pa · s (55 cP) at 40 ° C. I got

  After completion of the reaction, about 13 L of dilute sodium hydroxide solution was added to cellulose xanthate and stirred for 100 minutes to obtain viscose. Furthermore, through the steps of defoaming, ripening and filtration, viscose with a cellulose concentration of 9.0% was prepared. The prepared viscose is diluted with distilled water to a viscose concentration of 70%, and the diluted viscose is supplied to a rotating body with an outer diameter of 85 mm through an inlet tube and dropped by spraying, so that dilute sulfuric acid installed below The droplets were captured in a bath to obtain cellulose (so-called regenerated cellulose) spheres. Here, the dropping method is preferably a drop method or a centrifugal method. At this time, the cellulose spheres were immersed in a dilute sulfuric acid bath for 30 minutes or more. The cellulose spheres were washed with a large excess of water to remove dilute sulfuric acid, and then immersed in dilute aqueous sodium hydroxide solution for 1 hour or more. After washing again with a large excess of water to remove the sodium hydroxide content in the spheres, it was dried at 80 ° C. to obtain spherical cellulose.

To 500 g of spherical cellulose obtained by the above preparation, 1000 mL of an aqueous solution of ammonium chloride (concentration 5%) was added, and allowed to stand for 2 hours. Thereafter, the water was drained and dried overnight at 80 ° C. with a drier. After encapsulating nitrogen put spherical cellulose 400g passing through the ammonium chloride treatment in a cylindrical retort electric furnace, and heated to 900 ° C.. Spherical cellulose was carbonized in the process of temperature increase . Thereafter, steam was added to the carbide and activated by maintaining at that temperature for 2.5 hours to obtain spherical activated carbon of Example 1 (substantial yield was 18.7%).

Example 2
A spherical activated carbon of Example 2 was obtained according to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 was changed to an ammonium sulfate solution (concentration 5%, 1000 mL) (substantial yield is 12.7% Met).

Example 3
According to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 is a mixed solution of ammonium chloride aqueous solution (concentration 2.5%, 500 mL) and ammonium sulfate solution (concentration 2.5%, 500 mL) Spherical activated carbon of Example 3 was obtained (substantial yield was 16.1%).

Example 4
Spherical activated carbon of Example 4 was obtained according to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 was changed to an ammonium bromide solution (concentration 5%, 1000 mL) (substantial yield is 18) 1%).

Example 5
Example 5 Spherical activated carbon was obtained according to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 was changed to tetrabromobisphenol A solution (concentration 5%, 1000 mL) using methanol as the solvent. The real yield was 16.5%).

Example 6
The spherical activated carbon of Example 6 was obtained according to Example 1 except that the flame retardant (ammonium chloride water) solution in Example 1 was changed to guanidine hydrochloride solution (concentration 5%, 1000 mL) (substantial yield is 14.4. 1%).

Comparative Example 1
To 500 g of the spherical cellulose obtained by the above preparation, 1000 mL of an aqueous ammonium phosphate solution (concentration 5%) was added and allowed to stand for 2 hours. Thereafter, the water was drained and dried overnight at 80 ° C. with a drier. After putting 400 g of spherical cellulose which had undergone ammonium phosphate treatment into a cylindrical retort electric furnace and sealing nitrogen, it was heated to 900.degree . Spherical cellulose was carbonized in the process of temperature increase . Thereafter, steam was added to the carbide, and the carbide was maintained at that temperature for 2.5 hours for activation to obtain spherical activated carbon of Comparative Example 1 (substantial yield was 13.1%).

Comparative Example 2
A spherical activated carbon according to Comparative Example 2 was obtained according to Comparative Example 1 except that the aqueous ammonium phosphate solution in Comparative Example 1 was changed to an aqueous solution of sodium polyborate (concentration 5%, 1000 mL) (substantial yield is 10.5%). ).

Comparative Example 3
A spherical activated carbon according to Comparative Example 3 was obtained according to Comparative Example 1 except that the aqueous solution of ammonium phosphate in Comparative Example 1 was changed to an aqueous solution of sodium polyphosphate (concentration 5%, 1000 mL) (substantial yield is 8.0%). ).

  The ignition residue (%) is shown in Table 1 for the spherical activated carbon of each Example and Comparative Example.

Then, each physical-property value of spherical activated carbon was described in Table 2 and 3 about each Example and comparative example. From the top of the table, real yield (%), average particle size (μm), BET specific surface area (m ² / g), mercury pore volume (mL / g), N ₂ pore volume (mL / g) , Average pore diameter (nm), packing density (g / mL), surface oxide amount (meq / g), iodine adsorption power (mg / g), creatinine, indole, indole acetic acid, indoxyl sulfuric acid, aminoisobutyric acid and trypsin Adsorption rate (%) of Here, a substantial yield means the yield of the activated carbon which deducted the ignition residue among the activated carbon yields after baking a raw material.

[Results and discussion]
As understood from Table 1, the spherical activated carbon of each example is any one of ammonium chloride, ammonium sulfate, ammonium bromide, tetrabromobisphenol A or guanidine hydrochloride which is a flame retardant which vaporizes at a temperature of less than 1000 ° C. as a flame retardant. Alternatively, since the flame retardant is thermally decomposed and vaporized at the time of production because a plurality is attached and produced, the ignition residue is lowered. Therefore, the ash content (loss) is small and the yield is high. In addition, since the ignition residue after steam activation is very low, the acid cleaning and heat treatment steps can be omitted while the ignition residue specification in the aforementioned Japanese Pharmacopoeia can be easily satisfied. Thus, an efficient and economically superior pharmaceutical adsorbent can be produced.

  As understood from Tables 2 and 3, the spherical activated carbons obtained in each Example were obtained by carbonizing and steam activation by adding ammonium phosphate, sodium polyborate or sodium polyphosphate as a flame retardant (comparative example) The physical properties were almost the same as or higher than in 1) to 3). The packing density of the spherical activated carbons of the examples is also equal to or higher than that of the comparative examples, suggesting the possibility of a very compact dosage form of the pharmaceutical adsorbent according to the embodiment. Further, the spherical activated carbon of each example is extremely excellent in the adsorption performance because the adsorption rate of toxic substances such as creatinine is higher than the result of the adsorption measurement. And, since the adsorption performance of trypsin, which is a useful substance, is suppressed, it is also extremely excellent in selective adsorption. Therefore, it can be said that it is desirable as a medical adsorbent that absorbs toxic substances efficiently.

  INDUSTRIAL APPLICABILITY The production method of the present invention can produce activated carbon excellent in adsorption performance with a high yield by a simple process, is economical, and can suppress environmental impact. In addition, the spherical activated carbon produced by the production method of the present invention reaches the digestive organs by oral administration, and the use of a pharmaceutical adsorbent that efficiently absorbs and excretes toxic substances is very promising.

Claims (6)

In the production of spherical activated carbon having a BET specific surface area of 700 to 3000 m ² / g, an average particle diameter of 100 to 1100 μm, a surface oxide content of 0.05 meq / g or more and a packing density of 0.4 to 0.8 g / mL
To the raw material purified cellulose or regenerated cellulose,
Attach a flame retardant that vaporizes at less than 1000 ° C,
It carbonizes at 300-700 degreeC under nitrogen atmosphere, and carries out steam activation at 750-1000 degreeC. The manufacturing method of the adsorbent characterized by the above-mentioned.   The method for producing an adsorbent according to claim 1, wherein the flame retardant is any one or more of ammonium chloride, ammonium sulfate, ammonium bromide, tetrabromobisphenol A and guanidine hydrochloride.   The method for producing an adsorbent according to claim 1 or 2, which is production of spherical activated carbon having an average pore diameter of 1.5 to 3.0 nm.   The method for producing an adsorbent according to any one of claims 1 to 3, which is the production of spherical activated carbon having an ignition residue of less than 10% as measured in accordance with JIS K 1474-1 (2014).   The method for producing an adsorbent according to any one of claims 1 to 4, wherein the spherical activated carbon is an adsorbent for medicine for oral administration.   The method for producing an adsorbent for oral administration according to claim 5, wherein the spherical activated carbon is a therapeutic agent or a preventive for renal disease for oral administration or liver disease for oral administration.