KR20180118784A - Tablets containing spherical adsorbent carbons for oral administration and a method for producing the same - Google Patents

Abstract

It is an object of the present invention to provide a tablet having a high yield of spherical adsorbent carbon for oral administration, high uniformity of spherical adsorbent char for oral administration and an additive for spherical adsorption, and a method for producing the same. The above object is achieved by a tablet characterized in that the ratio of the maximum value and the minimum value of the volume fraction of additive per one tablet in each of five predetermined footsteps is 100 or less; Wherein the relative standard deviation of the cubic volume of the predetermined three divided bodies is 5% or less; Or the ratio of the maximum value and the minimum value of the additive volume ratio per one ply in each of the predetermined five footprints is not more than 100 and the relative standard deviation of the volume ratio of the cubes of the predetermined three divided bodies is not more than 5% Can be solved.

Description

Tablets containing spherical adsorbent carbons for oral administration and a method for producing the same

The present invention relates to a tablet containing a spherical adsorption charcoal for oral administration and a method for producing the tablet. INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a method for producing tablets having an excellent yield.

The adsorbent for oral administration can be taken orally, and by adsorbing harmful substances in the digestive tract, dysfunction of kidney or liver can be treated (Patent Document 1). In order for this orally administered spherical adsorbent to exert a pharmacological effect of adsorption of harmful substances, it is important to maintain the spherical shape of the spherical adsorbent for oral administration and to maintain the pore structure. This spherical adsorbent for oral administration can be produced, for example, by the following methods: a product name of "CREMEGIN (registered trademark) capsule 200 mg" and "CREMEGIN (registered trademark) fine particle distribution 2 g" (hereinafter referred to as "KREMEZIN ) &Quot;).

The daily dose of Kramethine for patients with kidney disease is 6 g, which is divided into three doses, so the dose per dose is 2 g. The volume of the second g of the granules of cramecine is about 4 cm ³ , and the volume to be taken is never small. Therefore, when 4 cm ³ of fine granules were used, there was a case that the spherical activated carbon did not dissolve in the water, so that the feeling of chewing sand in the oral cavity remained and the user felt disgust.

On the other hand, in the case of the capsule of the crèmezine, the feeling of chewing the sand in the mouth does not occur. However, since a dead volume other than spherical activated carbon is generated in the capsule, the volume of the capsule increases to about 1.5 times (about 6 cm ³ ) as compared with the volume of the fine particles. Specifically, there were some patients complaining that the dose of the capsules of about 0.613 cm ³ was required to be taken 10 capsules at a time.

In addition, there are many patients who can not take the fine granules or capsules together with a large amount of water because of solving the feeling that the sand of the fine granules is chewed or because of the large dose of the capsules. Patients with kidney disease or renal failure have limited water intake and when they take tablets or capsules they are required to take it with as little water as possible, Patients who are in need of help come with great pain.

Patent Document 1: Japanese Patent Laid-open Publication No. 62-11611 Patent Document 2: JP-A-2006-8602 Patent Document 3: International Publication No. 2012/121202

In order to solve the above problems, it is conceivable to purify the spherical adsorbed carbon for oral administration. However, unlike ordinary drugs, spherical adsorbed carbon for oral administration can not be compression-molded by compression or the like (Patent Document 2). Namely, since the spherical adsorbed carbon for oral administration is very hard and has insufficient deformability and weak properties like glass, when spherical adsorbed carbon for oral administration is crushed, the spherical adsorbed carbon for oral administration can not be maintained and spherical shape can not be maintained.

The present inventors have found that a tablet containing a spherical adsorbed carbon for oral administration which can be put to practical use by a kneading method using an additive for particle preparation exhibiting a thin film forming ability has been found (see Patent Document 3 ). However, when tablets were produced using the coupled method, the yield of spherical activated carbon was low. In addition, the tablets obtained by the combined method had low uniformity of the spherical adsorbent for oral administration and the coating additive. In addition, tablets obtained by the coupled method may have a lowered adsorption amount of DL- [beta] -aminoisobutyric acid as compared with granules or capsules.

Accordingly, an object of the present invention is to provide a tablet having a high yield of the spherical adsorbent carbon for oral administration, high uniformity of the spherical adsorbent char for oral administration, and a coating additive, and a method for producing the same.

The inventors of the present invention have conducted intensive studies on tablets having high uniformity of spherical adsorbent carbon for oral administration and spherical adsorbent charcoal and coating additive for oral administration and their preparation and as a result surprisingly found that a solution containing a coating additive Is sprayed or dripped onto a spherical adsorption charcoal for oral administration, and the tablets are produced by the compression molding method, whereby the yield of the spherical adsorbent carbon for oral administration is remarkably improved, and the uniformity of the spherical adsorbent charcoal and the coating additive for oral administration is remarkably improved To obtain an improved tablet.

The present invention is based on this insight.

Therefore,

[1] A tablet comprising an additive and a spherical adsorbent carbon for oral administration, characterized in that the tablet has a center portion when viewed from the top surface and a center portion located at an end portion of a straight line drawn in four directions from the center, When the volume ratio of the additive in the five pillars having one side of 1 mm is analyzed by the X-ray CT microscope from the upper surface to the lower surface, the ratio of the maximum value and the minimum value of the additive volume ratio per 1 5 in each of the five footprints is 100 Or less,

[2] A tablet containing an additive and an adsorbent for oral administration, characterized in that, in each of the divided bodies obtained by dividing the flat length of the tablet into three equal parts, the tablet is located at the center of the length in the flat direction, , The relative standard deviation of the volume ratio of the cubes of the three divided bodies is 5% or less when the volume ratio of the cube composed of one side of 2 mm located at the center of the tablet in the above- refine,

[3] A tablet containing an additive and an adsorbent for oral administration, characterized in that the tablet has a central portion when viewed from the top surface and a center portion located at an end of a straight line drawn in four directions from the center, The ratio of the maximum value and the minimum value of the additive volume ratio per one ply in each of the five footprints is 100 or less when the volume ratio of the additive of the five pads is analyzed by an X-ray CT microscope from the upper surface to the lower surface, The volume ratio of a cubic body having a length of 2 mm on one side located at the center of the tablet in the center of the length of the flat direction and in the center of the tablet viewed from the upper side is analyzed by an X-ray CT microscope , The relative standard deviation of the volume ratio of the cubes of the three divided bodies is 5% or less.

[4] The pharmaceutical composition according to any one of [1] to [4], wherein the additive is selected from the group consisting of sodium alginate, propylene glycol alginate, carmellose, camellose calcium, ghatti gum, carrageenan, carboxyvinyl polymer, carmellose sodium, xanthan gum, guar gum, A starch, a starch, a starch, a starch, a starch, a quince seed gum, glucomannan, copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, dextrin, corn starch, tragacanth, sodium hyaluronate, hydroxyethylcellulose, , Hydroxypropylcellulose, hypromellose, pullulan, povidone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol, acrylic acid-methyl methacrylate copolymer, macrogol 6000, ethyl cellulose, methyl cellulose, phosphoric acid Starch, starch, locust starch, locust bean gum, agar, cherry plum, whole alpha starch, crystalline cellulose, camellose sodium, Starch, low-substituted hydroxypropyl cellulose, purified as described in any one of the alpha portion of the screen [1] to [3] Results wear additive is selected from starch, the group consisting of sugars and sugar alcohols,

[5] The tablet according to any one of [1] to [4], wherein the spherical adsorbent carbon for oral administration is spherical activated carbon,

[6] The tablet according to [5], wherein the spherical activated carbon has an average particle diameter of 0.02 to 1 mm, and

[7] A pharmaceutical composition comprising (1) at least one compound selected from the group consisting of (1) sodium alginate, propylene glycol ester of alginic acid, camelose, camelose calcium, gadji gum, carrageenan, carboxyvinyl polymer, camelose sodium, xanthan gum, guar gum, Gelatin, tamarind gum, tara gum, dextrin, corn starch, tragacanth, sodium hyaluronate, hydroxyethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hiropromellose, pullulan, povidone , Polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol, acrylic acid-methyl methacrylate copolymer, macrogol 6000, ethyl cellulose, methyl cellulose, crosslinked starch phosphate, locust bean gum, agar, one minute, Sodium carboxymethylcellulose, oxidized starch, low-substituted hydroxypropylcellulose, partially-alpha-starch, sugar (2) a step of spraying or dropping a solution containing a coating additive selected from the group consisting of sugar alcohols and sugar alcohols onto a spherical adsorption carbon for oral administration to coat the spherical adsorption carbon for oral administration with a coating additive, A compression molding process in which a solvent is added to a spherical adsorbent carbon for oral administration and a compact is obtained by compression molding, and (3) a step of drying the obtained compact,

.

According to the method for producing tablets comprising the spherical adsorbent carbon for oral administration (for example, spherical activated carbon) of the present invention, the yield of the spherical adsorbent carbon for oral administration to be used can be improved. Further, the tablets containing the spherical adsorbent carbon for oral administration obtained by the production method of the present invention can prevent the localization of the spherical adsorption charcoal and the coating additive for oral administration, Uniformity is improved. Thus, the hardness of the obtained tablets was improved. And, these tablets can exhibit excellent adsorbability of DL- [beta] -aminoisobutyric acid. That is, according to the method for producing tablets of the present invention, it is possible to improve the yield of the spherical adsorbed carbon for oral administration and improve the hardness in the method for producing tablets as compared with the combined method described in Patent Document 3, It is also expected to improve the adsorbability of DL- [beta] -aminoisobutyric acid.

According to the tablet of the present invention, it is possible to reduce the volume as compared with the capsules, and to provide tablets with improved dosability. In other words, in the case of capsules, some patients complain that the dosage of the capsule is about 0.613 cm ³ by 10 capsules at a time, and that the dose is large. In contrast, in the tablets of the present invention, The volume can be reduced to 65% (about 4 cm ³ ) of the case, and the dosage is improved. Further, according to the tablet of the present invention, it is possible to provide a tablet that is improved in drawbacks such as a feeling of chewing of sand as compared with a fine granule. According to the tablet of the present invention, it is possible to provide a tablet that retains the spherical shape of the spherical adsorbed carbon for oral administration and can sufficiently exhibit the function of the adsorbent for oral administration without breaking the pore structure.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram schematically showing the positions of three cubes for analyzing the volume fraction of tablets in the tablet of the present invention on the upper surface (A) and the side surface (B).
Fig. 2 is an analysis view (analysis image) of an X-ray CT microscope (nano3DX) showing the locality of the tablet (A) obtained by the production method of the present invention and the additive in the tablet (B) obtained by the conventional association method.
Fig. 3 is a diagram schematically showing the positions of five footprints for analyzing the volume ratio of additives in the tablet of the present invention on the upper face (A) and the side face (B).
4 is a graph showing changes in the volume ratio of the additive in the tablets of the present invention when analyzed by an X-ray CT microscope from the upper surface to the lower surface.
5 is a photograph showing the adhesion (A) and the adhesion (B) to the molding die (molding die) with respect to the agitating granulator of the spherical activated carbon by the federation method.
6 is a graph and a photograph showing that the division of the additive and the spherical activated carbon is carried out based on the information of the brightness of 256 steps when the volume ratio of the additive is calculated by the analysis software ImageJ.

[1] Tablets containing spherical adsorbed carbon for oral administration

Tablets comprising the spherical adsorbent carbon for oral administration of the present invention include a hair dyeing additive. The binding additive is preferably selected from the group consisting of sodium alginate, alginic acid propylene glycol ester, camelose, camelose calcium, ghatti gum, carrageenan, carboxyvinyl polymer, camelose sodium, xanthan gum, guar gum, But are not limited to, beeswax, bean sprout, gelatin, gelatin, tamarind gum, tara gum, dextrin, corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropylcellulose, , Povidone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol, acrylic acid methyl methacrylate copolymer, macrogol 6000, ethyl cellulose, methyl cellulose, phosphoric acid starch, locust bean gum, agar, one minute, , Crystalline cellulose camosodium sodium, oxidized starch, low-substituted hydroxypropyl cellulose Lawrence's, is selected from the group consisting of partial alpha-starch, sugars and sugar alcohols. The above-mentioned spherical adsorbent for oral administration is preferably spherical activated carbon.

«Spherical adsorbent for oral administration»

The spherical adsorbent carbon for oral administration is not particularly limited as long as it is a spherical adsorbent carbon for oral administration that can be used for medical use, but spherical activated carbon for oral administration, that is, spherical activated carbon which can be used for medical use is preferable . In the present specification, as an example of a spherical adsorbent for oral administration, spherical activated carbon may be used as an example.

For example, the average particle diameter of the spherical activated carbon contained in the tablet of the present invention is not particularly limited, but is preferably 0.02 to 1 mm, more preferably 0.03 to 0.90 mm, and even more preferably 0.05 to 0.80 mm . The spherical activated carbon preferably has a particle size (diameter) in the range of 0.01 to 2 mm, more preferably 0.02 to 1.5 mm, and still more preferably 0.03 to 1 mm.

Means a BET specific surface area of 100 m ² / g or more, but the BET specific surface area of the spherical activated carbon used in the present invention is preferably 500 m ² / g or more, more preferably 700 m ² / g or more More preferably not less than 1300 m ² / g, and particularly preferably not less than 1650 m ² / g.

In order to maintain the pore structure of the spherical adsorbed carbon (for example, spherical activated carbon) for oral administration contained in the tablet and to exhibit the pharmacological effect of adsorption of harmful substances, the spherical adsorbed carbon for oral administration . That is, the adsorptivity of the toxic substance, for example, the selective adsorption rate, is influenced by the diameter, average particle diameter, specific surface area, pore volume in a specific pore diameter range, and the like, Diameter, or mean particle size of the particles, and it is desirable that the pore structure that affects the specific surface area or the pore volume is maintained. In addition, by maintaining the sphericity, side effects such as constipation can be prevented.

«Additives»

The additives used in the tablets of the present invention include a coating additive. By including the coating additive, tablets having high uniformity and excellent strength can be obtained.

The tablet of the present invention is characterized in that it contains the above-mentioned coating additive as an additive, but it may also contain an additive other than the coating additive (hereinafter sometimes referred to as "other additive"). That is, the tablet of the present invention may contain, as an additive, a coating additive and other additives, and may also include only a coating additive. In other words, the additives used in the present invention may be composed of a coating additive and other additives, or may be composed of a coating additive.

(Content of additive)

The weight ratio of the spherical adsorbent carbon (for example, spherical activated carbon) for oral administration to the additive is not particularly limited as long as the effects of the present invention can be obtained. For example, the additive is preferably 1 to 35% by weight, Preferably 1.5 to 35% by weight, and more preferably 2 to 35% by weight. When the weight ratio of the spherical adsorbent carbon for oral administration to the additive is within the above range, tablets with high uniformity can be obtained. When the amount of the additive is too small, it may become difficult to form tablets. If the amount of the additive is too large, the volume of the tablet becomes large, and the dosage of the tablet sometimes increases.

≪ Uniformity of volume ratio of tablets >

The tablets of the present invention have uniform volume ratios in the tablets. That is, since the tablets of the present invention contain spherical adsorbed carbon for oral administration (for example, spherical activated carbon) as an active ingredient when compared with tablets containing a general compound as an active ingredient, Voids exist between the spherical adsorbent pebbles for oral administration. It is conceivable that the hardness of the tablets, the degree of friability, and the like are lowered when the dense portions of the voids and the voided portions are present. In other words, if there is a variation in the volume ratio between the spherical adsorbed carbon for oral administration and the additive in the tablet, the hardness or the degree of shrinkage of the tablet may be reduced. That is, since the volume ratio of tablets is uniform, it is possible to improve the hardness and the degree of shrinkage of the tablets.

The uniformity of the volume ratio of the tablets of the present invention can be specified, for example, by the following method. That is, in each of the divided bodies obtained by dividing the length of the tablet in the flattening direction into three equal parts, the volume ratio of the cubes having one side of 2 mm located at the center of the length in the flat direction and located at the center of the tablet, It can be judged that the uniformity of the tablet is high when the relative standard deviation of the volume ratio of the cubes of the three divided bodies is 5% or less when analyzed by an X-ray CT microscope.

As shown in Fig. 1, the tablets have a flat shape except for a pore-forming agent. Fig. 1 (A) shows flat tablets viewed from the top, and Fig. 1 (B) shows flat tablets viewed from the side. When the tablets are seen on the upper surface, the tablets often have a circular shape, an ellipse shape, a square shape, or a rectangular shape as shown in Fig. 1 (A), but the tablets usually have a symmetrical shape, It is possible to specify the " cube of the center of the tablet viewed from the upper surface " as shown by a square dashed line. When the flat tablets are viewed from the side, as shown in Fig. 1 (B), the length in the direction of the flattening can be made into a divided body divided into three equal parts. In each of the divided bodies, Quot ;, " a cube located at the center of the length of the direction " Therefore, it is possible to specify "three cubes each located at the center of the length in the flat direction and located at the center of the tablets seen from the upper surface and having 2 mm on one side". When the tablet is a spherical pellet, it is possible to specify the "center of the length in the flattening direction" and the "center of the tablet from the top surface" with the flat direction in an arbitrary direction.

The above three cubes can be analyzed by an X-ray CT microscope, and the volume ratio of each cubic can be calculated. Then, the relative standard deviation of the volume ratios of the obtained three cubes is calculated, and when the relative standard deviation is 5% or less, it is determined that the uniformity of the tablet is high.

In addition, when the length of the tablets in the direction of the flattening is less than 6 mm, three cubes each having one side of 2 mm may partially overlap. However, even when three cubes overlap each other, it is possible to calculate the relative standard deviation of the cubic volume of the three divided bodies, and when the relative standard deviation thereof is 5% or less, it can be judged that the uniformity of the purification is high have.

The relative standard deviation of the volume ratio is preferably 4.7% or less, and more preferably 4.5% or less. The smaller the relative standard deviation is, the better the uniformity is and the hardness or the degree of shrinkage of the tablet can be improved. Therefore, the lower limit of the relative standard deviation of the volume ratio is most preferably 0% or more, and practically 0.1% or more, 0.3% or more, or 0.4% or more. The relative standard deviation of the volume ratio may be, for example, from 0.1 to 5%, from 0.3 to 4.7%, or from 0.4 to 4.5%.

«Local uniformity of additives»

The tablets of the present invention are uniform in the distribution of the additives in the tablets, that is, the tablets of the present invention are excellent in the uniformity of the volume ratio of the additives as compared with the tablets containing the conventional spherical activated carbon. For example, as shown in Fig. 2 (B), the tablets containing the spherical activated carbon obtained by the conventional associative method have tabular grains in which the additive is localized in a portion close to the surface of the tablet top (the additive is represented by white) The uniformity of the additive is low. When the additive is localized, it is conceivable that the hardness or the degree of abrasion of the tablet decreases. In other words, if there is a variation in the volume ratio of the additive in the tablet, it can be considered that the hardness or the degree of shrinkage of the tablet decreases. That is, since the volume ratio of the additive is uniform, the hardness and the degree of shrinkage of the tablet can be improved.

The uniformity of the volume ratio of the additive of the present invention can be specified, for example, by the following method. The volume ratio of the additive of the five pillars, one side of which is 1 mm on the lower surface in the upper surface, which is located at the center portion when the tablet is viewed from the upper surface and the end portion of the straight line drawn from the center to the four sides, It can be judged that the uniformity of the distribution of the additive is high when the ratio of the maximum value and the minimum value of the additive volume ratio per one ply in the five footnotes is 100 or less. That is, in the tablets of the present invention, the ratio of the maximum value and the minimum value of the additive volume ratio in the five footnotes is 100 or less. On the other hand, in the conventional tablets, the ratio of the maximum value and the minimum value of the additive volume ratio exceeds 100 in five footnotes, and thus the hardness or the degree of shrinkage of the tablets is lowered.

As shown in Fig. 3, the tablets have a flat shape except a true spherical pellet. Fig. 3 (A) shows flat tablets viewed from the top, and Fig. 3 (B) shows flat tablets viewed from the side. When the tablets are seen on the upper surface, the tablets often have a circular shape, an ellipse, a quadrangle, or a rectangular shape as shown in Fig. 3 (A) It is possible to specify the " footstep at the center portion when viewed from the top surface " as shown by the square dashed line of C in Fig. It is also possible to specify "a footstep located at an end of a straight line drawn in four directions from the center" indicated by square broken lines of N, E, S, and W in FIG. 3 (A). When the flat tablets are viewed from the side, as shown by the broken line in Fig. 3 (B), the tablets are located from the upper surface to the lower surface in the flat direction of the tablets. Therefore, it is possible to specify "a footstep at the center when viewed from the top" and a "footstep at the end of the straight drawn from the center of the tablet in four directions".

The above five footprints can be analyzed by X-ray CT microscopy from the upper surface to the lower surface, and the volumetric rate of the additive in each footing can be calculated. Then, at an arbitrary position of the footstep, it is possible to calculate the volume fraction of the additive per volume and obtain the maximum value and the minimum value of the volume fraction of the additive per volume.

In the present invention, it can be judged that the uniformity of the distribution of the additive is high when the ratio of the maximum value and the minimum value of the volume ratio of additive per unit volume is 100 or less. However, the ratio of the maximum value to the minimum value is preferably 99 or less, Preferably 98 or less, and even more preferably 96 or less. As the ratio between the maximum value and the minimum value is smaller, the uniformity of the additive is improved and the hardness or the degree of shrinkage of the tablet can be improved. Therefore, the lower limit of the ratio between the maximum value and the minimum value is most preferably 1 or more, practically 2 or more, 4 or more, or 6 or more. The range of the ratio between the maximum value and the minimum value may be, for example, from 1 to 100, from 2 to 99, from 4 to 98, or from 6 to 96. [

Depending on the shape of the tablet, the height of the footprints at the positions of N, E, S, and W may be lowered in comparison with the footnote at the position of C, but in this case, It is possible to calculate " the ratio of the maximum value and the minimum value of the additive volume ratio " by finding the additive volume ratio from the upper surface to the lower surface.

(X-ray CT microscope)

The X-ray CT microscope for analyzing the volume ratio of the tablet and the volume ratio of the additive in the present invention can be applied to a case where the inside of a sample such as a material or a tablet is divided into a 2D (high dimensional) ). ≪ / RTI > Materials, or tablets can be analyzed with high resolution. For example, as described in this embodiment, it is also possible to analyze the volume ratio of the spherical activated carbon and the tablets made of the additive, or to analyze the volume ratio of only the additive.

As an X-ray CT microscope, commercially available "nano3DX (high resolution 3D X-ray microscope: Rigaku Corporation") and "three-dimensional measuring X-ray CT apparatus TDM series: Yamato Scientific Co. The apparatus has a high resolution of 1 μm or less and can calculate the volume percentage of the tablet or the volume fraction of the additive by using software provided with the apparatus or image processing software ImageJ or the like.

(Wearing additive)

The coating additive used in the tablet of the present invention may be selected from the group consisting of sodium alginate, propylene glycol alginate, camelose, camelose calcium, ghatti gum, carrageenan, carboxyvinyl polymer, camelose sodium, xanthan gum, guar gum, , Corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropylcellulose, hiropromellose, hydroxypropylcellulose, hydroxypropylcellulose, , Pullulan, povidone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol, acrylic acid-methyl methacrylate copolymer, macrogol 6000, ethyl cellulose, methyl cellulose, phosphoric acid starch, locust bean gum, agar, Alpha-starch, crystalline cellulose, sodium camellose, oxidized starch, low-substituted hydroxyap Peel cellulose, part include alpha starch, sugars, sugar alcohols, or a combination thereof. The tablets of the present invention in which the binding additive is coated on the spherical adsorbent for oral administration and the binding additive binds spherical adsorbent carbon for oral administration has a hardness of 105 N or more.

(Other additives)

Hereinafter, additives usable as additives (other additives) other than the coating additive will be described.

In general, additives used in pharmaceuticals are described in " Drug Additives Dictionary 2016 ", and examples thereof include excipients, lubricants, disintegrants, surfactants and binders. The functions of excipients, lubricants, disintegrants, and binders are not necessarily unified, and for example, crystalline cellulose classified as an excipient can function as a disintegrant in most cases, and also improves formability in direct tabletting It also has a function as a binder. Therefore, the functions of each of the excipient, lubricant, disintegrant, and binder may be redundant. Examples of excipients, lubricants, disintegrating agents, and binders are mentioned below, but as additives other than these additives, additives may be used.

The excipient is an additive mainly used for increasing (diluent) or diluting (diluting agent), and specifically includes starch, calcium hydrogen phosphate, synthetic aluminum silicate, or magnesium trisilicate.

In addition, the binder is an additive which is used for imparting a bonding force with the main agent or an extender and is used for molding, and is used for maintaining the formulations, preventing breakage during the packaging process or transportation, and increasing the mechanical strength . Specific examples thereof include crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, powdered cellulose, hypromellose, methylcellulose, hydroxypropylcellulose, starch, fully alpha-starch, partially alpha-starch, dextrin, Gum, sodium alginate, tragacanth, refined gelatin, polyvinyl alcohol, and povidone.

Disintegrants are also additives that are used to disintegrate and disperse the formulation into particulates when wetted in the digestive tract when the tablet is taken. Specific examples thereof include camelose, camelose calcium, low-substituted hydroxypropylcellulose, hiropromellose, powdered cellulose, starch, sodium carboxymethylstarch or hydroxypropyl starch.

The lubricant is an additive having a function of improving various properties such as fluidity, filling property, adhesiveness and moldability of a powder in tableting, and is used for improving the quality of tablets and the production efficiency. Specific examples include sucrose fatty acid esters, talc, magnesium stearate, and stearic acid.

Surfactants include alkyl allyl polyether alcohols, higher alcohol sulfates, N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate, sodium N-cocoyl-N-methylaminoethylsulfonate, cholesterol, Type monostearic acid glycerin, sucrose fatty acid ester, squalane, stearyl alcohol, stearic acid polyoxyl 40, cetanol, cetomacrogol 1000, diethyl sebacate, sorbitan fatty acid ester, sorbitan sesquioleic acid ester, dodecylbenzene Polyoxyethylene oleylamine, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl alcohol, , Polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate Polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) Polyoxypropylene (40) glycol, polyoxyethylene (124) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) , Sodium polyoxyethylene (2 EO) lauryl ether sulfate (70%), polyoxyl 35 castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, monooleic acid sorbitan monostearate Glycerin, sorbitan monostearate, sorbitan monolaurate, N-coconut fatty acid acyl L-arginine ethyl DL-pyrrolidone carboxylate, lauryl dimethylamine oxide, lauryl pyrrolidone, sodium lauryl sulfate , Sodium lauroylmercurate, sodium phosphate polyoxyethylene lauryl ether or phosphoric acid polyoxyethylene oleyl ether (8 MOL), and the like.

(Content of coating additive)

The weight ratio between the spherical adsorbent carbon (for example, spherical activated carbon) for oral administration and the coating additive is not particularly limited as long as the effect of the present invention can be obtained, but the content of the coating additive in the tablets of the present invention is preferably Is at least 1% by weight, more preferably at least 1.5% by weight, and even more preferably at least 2% by weight. When the amount of the coating additive is too small, the hardness of the obtained tablet may be lowered. The upper limit of the binder additive is not limited, but the binder additive is preferably 35% by weight or less, more preferably 30% by weight or less, and even more preferably 25% by weight or less. Too much of the waxing additive may lead to larger volume of tablets, resulting in increased dosage of tablets. The content of the coating additive in the tablets of the present invention ranges preferably from 1 to 35% by weight (or from 1 to 30% by weight or from 1 to 25% by weight, (Or 1.5 to 25% by weight or 1.5 to 20% by weight), and more preferably 2 to 25% by weight (or 2 to 20% by weight) By weight or 2 to 17% by weight).

The tablets of the present invention may contain other additives as additives, but the weight ratio of the coating additive to the other additives is not particularly limited as long as the effect of the present invention can be obtained, The amount of other additives is preferably 10,000 parts by weight or less, more preferably 1,000 parts by weight or less, still more preferably 100 parts by weight or less, and most preferably 50 parts by weight or less. If the amount of other additives is too large, the hardness of the resultant tablet may be lowered. The lower limit of the weight ratio is not particularly limited, and the content of other additives may be, for example, 0.1 parts by weight or more, 1 part by weight or more, and 10 parts by weight or more based on 100 parts by weight of the coating additive .

[2] Method for producing tablets

The method for producing a tablet of the present invention comprises the steps of: (1) preparing a tablet by mixing the following ingredients: (1) sodium alginate, propylene glycol ester alginate, camelose, But are not limited to, glutaraldehyde, glucosamine, glucosamine, glucosamine, glucopyranose, glucosamine, glucosamine, glucosamine, glucosamine, Polyvinyl alcohol, acrylic acid-methyl methacrylate copolymer, macrogol 6000, ethyl cellulose, methyl cellulose, phosphoric acid starch, locust bean gum, agar, one minute, Fully alpha starch, crystalline cellulose, sodium camellose, oxidized starch, low-substituted hydroxypropylcellulose A solution containing a coating additive selected from the group consisting of starch, partially-modified starch, saccharides and sugar alcohols is sprayed or dripped onto a spherical adsorbed carbon (for example, spherical activated carbon) for oral administration to obtain spherical adsorption (2) a compression molding step of obtaining a shaped body by adding a solvent to the coated spherical adsorbed carbon for oral administration, which is then subjected to compression molding, and (3) a step of drying the obtained shaped body do.

As the " coating additive " used in the method for producing tablets of the present invention, the coating additive described in item [1] Tablets containing the spherical adsorbed carbon for oral administration may be used.

«Coating process (1)»

The coating step (1) may be carried out in the same manner as in the coating step (1), except that the coating step (1) is carried out in the same manner as in the coating step (1) Gelatin, tamarind gum, tara gum, dextrin, corn starch, tragacanth, sodium hyaluronate, hydroxyethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hiropromellose, pullulan, povidone , Polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol, acrylic acid-methyl methacrylate copolymer, macrogol 6000, ethyl cellulose, methyl cellulose, crosslinked starch phosphate, locust bean gum, agar, one minute, Sodium carboxymethylcellulose, oxidized starch, low-substituted hydroxypropylcellulose, partial alpha- A solution containing a coating additive selected from the group consisting of starch, saccharides and sugar alcohols is sprayed onto a spherical adsorbed carbon for oral administration (for example, spherical activated carbon) so that the spherical adsorbed carbon for oral administration is coated with a coating additive do. As a coating method, a spraying method is used. Examples of the spraying method include a top spraying method, a tangential spraying method, a bottom spraying method, and a side spraying method.

For example, in the case of the top spray method, the spraying solution is prepared by dissolving the coating additive and other additives in a solvent. Then, for example, the spherical adsorbed carbon for oral administration is put into an electric flow coating apparatus or a fluidized bed granulating apparatus, and the spray liquid is sprayed from above.

The solvent used in the spray liquid is not particularly limited and any organic solvent which can be used as a pharmaceutical additive can be used. Examples of the solvent include water, acetic acid, acetone, anisole, 1-butanol, 2-butanol, propyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl ethyl ketone, methyl ethyl ketone, , 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl Teal is a ketone, in a methylcyclohexane, N- methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1, 2-trichloroethyl, and the like ten or xylene. The surfactant is not particularly limited, and examples thereof include alkyl allyl polyether alcohols, higher alcohol sulfur oxides, N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylic acid salts, N-cocoyl- Sucrose fatty acid esters, squalane, stearyl alcohol, stearic acid polyoxyl 40, cetanol, cetomacrogol 1000, diethyl sebacate, sorbitan fatty acid esters, sorbitan fatty acid esters, sorbitan fatty acid esters, Sodium dodecylbenzenesulfonate, sorbitan trioleate, ammonium nonylphenoxy polyoxyethylene ethane sulfonate ester, polyoxyethylene octylphenyl ether, polyoxyethylene oleylamine, polyoxyethylene hydrogenated castor oil 20 , Polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, Polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol , Polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (124) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene Polyoxyethylene (4) cetyl ether, polyoxyethylene (2 EO) lauryl ether sodium sulfate (70%), polyoxyl 35 castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, mono Oleic acid sorbitan, monostearic acid glycerin, monostearic acid sorbitan, monolauric acid sorbitan, N-coconut fatty acid acyl L-arginine ethyl DL-pyrrolidonecarboxylic acid salt, lauryldimethylamine oxide liquid, Lauryl pyrrolidone, sodium lauryl sulfate, lauric acid diethanolamide, lauroyl sarcosine sodium, lauromacrogol, sodium phosphate polyoxyethylene lauryl ether or phosphoric acid polyoxyethylene oleyl ether (8 MOL) And the like.

The amount of the coating additive to the amount of the solvent is not particularly limited as long as the coating additive is substantially uniformly coated on the spherical adsorbed carbon for oral administration (for example, spherical activated carbon), but the coating additive is preferably added to the solvent Is preferably 0.01 to 100 w / v%, more preferably 0.1 to 50 w / v%, still more preferably 1 to 15 w / v%.

&Quot; Compression molding process (2) "

In the compression molding step (2), a solvent is added to the coated spherical adsorbed carbon for adsorption (for example, spherical activated carbon), and compression molding is performed. For example, tablets having a strength of 105 N or more can be obtained by adding a solvent to the spherical adsorbent carbon for coating orally administrated, followed by compression molding and drying.

Examples of the solvent include an organic solvent, water, and a mixture thereof. The volume ratio of the organic solvent and water in the organic solvent and water mixture is not particularly limited but is preferably 5:95 to 95: 5, more preferably 15:85 to 85:15, still more preferably 30: 70 to 70: 30. With this range, the water can be infiltrated into the coating additive covering the spherical adsorbed carbon for oral administration.

(Organic solvent)

The organic solvent that can be used in the above production method is not particularly limited as long as the effect of the present invention can be obtained. Examples of the organic solvent include acetic acid, acetone, anisole, 1-butanol, 2-butanol, n-butyl acetate, Methyl ethyl ketone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl ethyl ketone, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, formic acid ethyl formate, Propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methyl Cyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1, 2-trichloroethene or xylene.

&Quot; Drying step (3) "

In the method for producing a tablet of the present invention, the obtained molded article is dried. The drying method is not limited as long as the solvent of the molded body is evaporated. Examples of the drying method include freeze drying, vacuum drying, blow drying, natural drying, and heat drying.

For example, in the case of heat drying, the heating temperature is not particularly limited, but is preferably, for example, from 50 to 200 ° C, more preferably from 80 to 180 ° C. The heating time is not particularly limited, but is preferably 10 minutes to 3 hours, more preferably 30 minutes to 2 hours.

However, when the heating temperature is high, the heating time can be shortened, and a person skilled in the art can appropriately determine the heating temperature and the heating time.

The water content of the tablets obtained by the drying step (3) is not particularly limited, but is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight.

Example

Hereinafter, the present invention will be described in detail by way of examples, but they should not be construed as limiting the scope of the present invention.

≪ Preparation Example 1: Production of porous spherical carbonaceous material &

A porous spherical carbonaceous substance was obtained in the same manner as described in Example 1 of Japanese Patent No. 3522708 (Japanese Patent Application Laid-Open No. 2002-308785). Specific operations are as follows.

68 kg of petroleum pitch (softening point = 210 ° C; quinoline insoluble matter = 1% by weight or less; H / C atomic ratio = 0.63) and 32 kg of naphthalene were charged into a 300 L internal pressure vessel equipped with a stirring blade, Deg.] C, cooled to 80 to 90 [deg.] C and extruded to obtain a cord-like molded body. Subsequently, the string-shaped molded body was crushed so that the ratio of the diameter to the length became about 1 to 2.

0.23% by weight of polyvinyl alcohol (degree of saponification = 88%) was dissolved in the aqueous solution of polyvinyl alcohol, and the resultant solution was heated to 93 DEG C and the resultant solution was spheronized by stirring and dispersion. And the mixture was cooled at 20 DEG C for 3 hours to solidify the pitch and precipitate naphthalene crystals to obtain a spherical pitch body slurry.

Most of the water was removed by filtration, and naphthalene in the pitch-formed body was extracted and removed with n-hexane of about 6 times the weight of the spherical pitch formed body. The porous spherical pitch thus obtained was heated to 235 DEG C while passing heated air through a fluidized bed (fluidized bed), maintained at 235 DEG C for 1 hour and oxidized to obtain a porous spherical oxidation pitch that was not compatible with heat .

Subsequently, the porous spherical oxidation pitch was subjected to activation treatment at 900 DEG C for 170 minutes in a nitrogen gas atmosphere containing water vapor of 50 vol% by using a fluidized bed to obtain a porous spherical activated carbon, Oxidation treatment was carried out at 470 ° C for 3 hours and 15 minutes under a mixed gas atmosphere of 18.5 vol% nitrogen and oxygen, and then reduction treatment was carried out at 900 ° C for 17 minutes in a flowing nitrogen gas atmosphere to obtain a porous spherical carbonaceous material. The porous spherical carbonaceous material thus obtained was used as spherical activated carbon in the following pharmacological test example.

The main characteristics of the obtained carbonaceous material are as follows.

Specific surface area = 1300 m ² / g (BET method);

Pore volume = 0.08 mL / g

(Pore volume in the range of 20 to 15,000 nm in pore diameter obtained by the mercury infiltration method);

Average particle diameter = 350 [mu] m;

Total acidity = 0.67 meq / g;

Total basic group = 0.54 meq / g;

Compressive strength = 31.2 MPa; And

The strain rate (strain rate) when the pressure of 2 MPa is applied is 0.7%.

≪ Preparation Example 2: Production of porous spherical carbonaceous material &

A porous spherical carbonaceous substance (surface-modified spherical activated carbon) was obtained in the same manner as in the method described in Example 1 of Japanese Laid-Open Patent Publication No. 2005-314416. Specific operations are as follows.

220 g of deionized water and 58 g of methylcellulose were placed in a 1 L separable flask and to this were added 105 g of styrene, 57% of purity divinylbenzene (57% of divinylbenzene and 43% of ethyl 1.68 g of 2,2'-azobis (2,4-dimethylvaleronitrile) and 63 g of 1-butanol as a porogen were appropriately added, and then the system was replaced with nitrogen gas This two-phase system was stirred at 200 rpm, heated to 55 캜, and then maintained as it was for 20 hours. The obtained resin was filtered and dried with a rotary evaporator. 1-Butanol was removed from the resin by distillation in a vacuum dryer, and then dried under reduced pressure at 90 DEG C for 12 hours to obtain a spherical A porous synthetic resin was obtained. The specific surface area of the porous synthetic resin was about 90 m ² / g.

100 g of the obtained spherical porous synthetic resin was charged into a reaction tube equipped with a perforated plate and subjected to an infusibilization treatment in a vertical tubular furnace. Dry air was flowed from the lower part of the reaction tube to the upper part at a rate of 3 L / min, the temperature was raised to 260 ° C at 5 ° C / h, and then maintained at 260 ° C for 4 hours to obtain spherical porous oxide resin. The spherical porous oxidized resin was heat-treated at 600 ° C for 1 hour in a nitrogen atmosphere and then subjected to activation treatment at 820 ° C for 10 hours in a nitrogen gas atmosphere containing 64.5 vol% of water vapor using a fluidized bed to obtain spherical activated carbon. The obtained spherical activated carbon was subjected to oxidation treatment at 470 ° C for 3 hours and 15 minutes under a mixed gas atmosphere of nitrogen and oxygen at an oxygen concentration of 18.5 vol% in the fluidized bed, and then subjected to reduction treatment at 900 ° C for 17 minutes in a flowing nitrogen gas atmosphere To obtain surface-modified spherical activated carbon.

The main characteristics of the obtained surface-modified spherical activated carbon are as follows.

Specific surface area = 1763 m ² / g (BET method);

Pore volume = 0.05 mL / g

(Pore volume in the range of 20 to 15,000 nm in pore diameter obtained by mercury porosimetry);

Average particle diameter = 111 mu m (Dv50);

Total acidity = 0.59 meq / g;

Total basic group = 0.61 meq / g;

Bulk density = 0.50 g / cm < ³ >;

Crushing strength = 436.5 MPa; And

Distortion when applying 2 MPa pressure = 0.2%.

In this specification, the example in which tablets were produced using the spherical activated carbon obtained in Production Example 2 is not described, but the tablets of the present invention can be obtained in the same manner as the spherical activated carbon obtained in Production Example 1. [

≪ Example 1 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 1 was sprayed. Thereafter, it was dried to obtain 535.5 g of a coated product. The obtained coated product was added with 1.2 mL of an ethanol / water mixed solution (6: 4) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 15 mm.

Table 2 shows the recovery rates of the coated products. The recovery rate (%) of the coated product is calculated by the amount of the obtained coated product / the theoretical amount of the coated product × 100. The higher the recovery rate, the better the yield of the spherical adsorbed carbon for oral administration.

The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Pullulan 30 g Sodium lauryl sulfate 4.5 g Purified water 500 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 534.5 535.5 100.2

≪ Example 2 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 3 was sprayed. Thereafter, it was dried to obtain 751.78 g of a coated product. The obtained coated product was added with 1.2 mL of an ethanol / water mixed solution (6: 4) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 4 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Pullulan 234.11 g Sodium lauryl sulfate 35.12 g Purified water 2340 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 769.23 751.78 97.7

≪ Example 3 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 5 was sprayed. Thereafter, it was dried to obtain 512.5 g of a coated product. The obtained coated product was filled in a teflon (registered trademark) molding die (diameter 12 mm, depth 10.2 mm, R 16 mm), water was added at a rate of 0.9 mL to 1 g of the covering product, The tablets were lightly compressed with a molding rod attached to a stirrer, and the tablets were cleaned and dried to obtain tablets having a diameter of 12 mm.

Table 6 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Pullulan 30 g Purified water 500 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 530.0 512.5 96.7

≪ Example 4 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 7 was sprayed. Thereafter, it was dried to obtain 500.0 g of a coated product. The resulting coated product was added to an ethanol / water mixture (4: 6) at a rate of 1.9 mL per 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 8 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Sodium alginate 30 g Purified water 1000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 530.0 500.0 94.3

≪ Example 5 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 9 was sprayed. Thereafter, it was dried to obtain 506.8 g of a coated product. The obtained coated product was added to 1.4 g of an ethanol / water mixture (5: 5) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 10 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Alginic acid propylene glycol ester 30 g Purified water 1100 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 530.0 506.8 95.6

[0045]

≪ Example 6 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 11 was sprayed. Thereafter, it was dried to obtain 564.4 g of a covered product. The obtained coated product was added with 1.1 mL of an ethanol / water mixed solution (6: 4) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 12 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Gatti Sword 100 g Purified water 1000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 600.0 564.4 94.1

≪ Example 7 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 13 was sprayed. Thereafter, the product was dried to obtain 530.8 g of a coated product. The obtained coated product was added with 1.2 mL of an ethanol / water mixed solution (2: 8) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 14 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Carboxyvinyl polymer 45 g Purified water 3000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 545.0 530.8 97.4

≪ Embodiment 8 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 15 was sprayed. Thereafter, the product was dried to obtain 497.8 g of a coated product. The obtained coated product was added with 1.1 mL of an ethanol / water mixed solution (5: 5) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 16 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Carmeloose sodium 30 g Purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 530.0 497.8 93.9

[0054]

≪ Example 9 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 17 was sprayed. Thereafter, the product was dried to obtain 518.1 g of a coated product. The obtained coated product was added with 1.0 mL of an ethanol / water mixed solution (4: 6) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 18 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Xanthan gum 45 g Purified water 3000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 545.0 518.1 95.1

≪ Example 10 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 19 was sprayed. Thereafter, the product was dried to obtain 537.3 g of a coated product. The obtained coated product was added with 1.4 mL of an ethanol / water mixed solution (1: 9) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 20 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Guar gum 60 g Purified water 4000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 560.0 537.3 95.9

≪ Example 11 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 21 was sprayed. Thereafter, the product was dried to obtain 525.2 g of a coated product. The obtained coated product was added with 1.3 mL of an ethanol / water mixed solution (1: 9) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 22 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Glucomannan 45 g Purified water 3000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 545.0 525.2 96.4

≪ Example 12 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 23 was sprayed. Thereafter, it was dried to obtain 622.6 g of a coated product. The obtained coated product was added with 0.6 mL of an ethanol / water mixed solution (1: 9) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 24 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Copolyvidone 225 g Purified water 1200 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 725.0 622.6 85.9

≪ Example 13 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 25 was sprayed. Thereafter, the product was dried to obtain 548.3 g of a coated product. The obtained coated product was added with 1.2 mL of an ethanol / water mixed solution (1: 9) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 26 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Tarragon 75 g Purified water 6000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 575.0 548.3 95.4

≪ Example 14 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 27 was sprayed. Thereafter, the product was dried to obtain 524.0 g of a coated product. The obtained coated product was added with 1.1 mL of an ethanol / water mixed solution (1: 9) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 28 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Tragacant 45 g Purified water 3000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 545.0 524.0 96.1

≪ Example 15 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 29 was sprayed. Thereafter, the product was dried to obtain 543.5 g of a coated product. The obtained coated product was added with 1.1 mL of an ethanol / water mixed solution (4: 6) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 30 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Sodium hyaluronate 60 g Purified water 3500 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 560.0 543.5 97.1

≪ Example 16 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 31 was sprayed. Thereafter, the product was dried to obtain 531.9 g of a coated product. The obtained coated product was added with 1.2 mL of an ethanol / water mixture (5: 5) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 32 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Hydroxyethylcellulose 60 g Purified water 2000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 560.0 531.9 95.0

≪ Example 17 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 33 was sprayed. Thereafter, the product was dried to obtain 543.3 g of a coated product. The obtained coated product was added with 1.2 mL of an ethanol / water mixed solution (4: 6) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 34 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Hydroxypropylcellulose 75 g Purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 575.0 543.3 94.5

≪ Example 18 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 35 was sprayed. Thereafter, it was dried to obtain 502.9 g of a covered product. The obtained coated product was added to 1.4 g of an ethanol / water mixed solution (6: 4) with respect to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 36 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Hi Prom Melose 36 g Purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 536.0 502.9 93.8

≪ Example 19 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 37 was sprayed. Thereafter, it was dried to obtain 515.4 g of a covered product. The obtained coated product was added with 1.2 mL of an ethanol / water mixed solution (6: 4) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 38 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Methyl cellulose 75 g Purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 575.0 515.4 89.6

≪ Example 20 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 39 was sprayed. Thereafter, the product was dried to obtain 530.8 g of a coated product. The obtained coated product was added to 1.4 g of an ethanol / water mixed solution (6: 4) with respect to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 40 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Phosphoric acid starch 50 g Heated purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 550.0 530.8 96.5

≪ Example 21 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 41 was sprayed. Thereafter, it was dried to obtain 552.0 g of a coated product. The obtained coated product was added with 1.1 mL of an ethanol / water mixed solution (1: 9) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 42 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Locust bean gum 75 g Purified water 3000 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 575.0 552.0 96.0

≪ Example 22 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 43 was sprayed. Thereafter, it was dried to obtain 490.6 g of a coated product. The obtained coated product was added with 1.1 mL of an ethanol / water mixed solution (6: 4) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 44 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Agar 15 g Heated purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 515.0 490.6 95.3

≪ Example 23 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 45 was sprayed. Thereafter, the product was dried to obtain 545.5 g of a coated product. The obtained coated product was added with 1.1 mL of an ethanol / water mixed solution (6: 4) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 46 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending A minute 70 g Purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 570.0 545.5 95.7

≪ Example 24 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 47 was sprayed. Thereafter, the product was dried to obtain 516.4 g of a coated product. The obtained coated product was added with 1.0 mL of an ethanol / water mixed solution (1: 9) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 48 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Fully alpha starch 35 g Purified water 1100 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 535.0 516.4 96.5

≪ Example 25 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 49 was sprayed. Thereafter, the product was dried to obtain 533.3 g of a coated product. The obtained coated product was added to 1.4 g of an ethanol / water mixed solution (6: 4) with respect to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 50 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Oxidized starch 60 g Heated purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 560.0 533.3 95.2

≪ Example 26 >

500 g of the spherical activated carbon obtained in Production Example 1 was charged into an electric flow coating apparatus (MP-01), and the spray liquid of the prescription shown in Table 51 was sprayed. Thereafter, it was dried to obtain 520.7 g of a coated product. The obtained coated product was added with 0.9 mL of an ethanol / water mixed solution (2: 8) to 1 g of the coated product using a low-pressure molding machine, followed by molding and drying to obtain tablets having a diameter of 12 mm.

Table 52 shows the recovery rates of the coated products. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

Ingredients Amount of blending Partially Alpha Starch 50 g Purified water 600 mL

Theoretical amount (g) The amount (g) Recovery rate of coated products (%) 550.0 520.7 94.7

≪ Comparative Example 1 >

500 g of the spherical activated carbon obtained in Production Example 1 was placed in a stirring granulator (VG-01), and a solution prepared by dissolving 25 g of pullulan in 600 mL of purified water while stirring was added for 5 minutes and then kneaded for 10 minutes, The Union recovered the water. Table 53 shows the recovery rates of the associates.

≪ Comparative Example 2 >

20 g of the spherical activated carbon obtained in Production Example 1, 1.2 g of pullulan and 0.18 g of sodium lauryl sulfate were uniformly dispersed in a beaker, and further 24 mL of purified water was added. The resulting mixture was fed using a spatula so as to prevent the additive from becoming agglomerated. The prepared alumina (slurry) was charged into a molding die (diameter 12 mm, depth 10.2 mm), rubbed with a spatula, and the upper surface was lightly compressed with a molding rod attached to a stirrer to form a tablet surface. By performing drying for each molding type, tablets were obtained. The obtained tablets were analyzed by an X-ray CT microscope, and as a result, the volume ratios of the tablets shown in Table 54 and the volume ratios of the additives in tablets shown in Table 55 were obtained.

≪ Comparative Example 3 >

20 g of the spherical activated carbon obtained in Preparation Example 1, 9.36 g of pullulan and 1.40 g of sodium lauryl sulfate were uniformly dispersed in a beaker, and further 28 ml of purified water was added. The resulting mixture was fed using a spatula so as to prevent the formation of agglomerates of additives. The prepared alumina (slurry) was charged into a molding die (diameter 12 mm, depth 10.2 mm), rubbed with a spatula, and the upper surface was lightly compressed with a molding rod attached to a stirrer to form a tablet surface. By performing drying for each molding type, tablets were obtained. The obtained tablets were analyzed by an X-ray CT microscope, and the results of the volume ratio of additives in tablets shown in Table 55 were obtained.

Yield (%) of spherical activated carbon Example 1 (1) 100.2 Comparative Example 1 (1) 87.8

5, the yield was 87.8% because the spherical activated carbon remained in the mixer or adhered to the mold. In the production method of the present invention in Example 1, however, the spherical activated carbon The yield was 100.2%.

«Analysis of Volume Rate of Tablets in X-ray CT Microscopes»

The inside of the tablet was analyzed under the following conditions using an X-ray CT microscope nano3DX (manufactured by Rigaku Kabushiki Kaisha) for the purification of the two lots obtained in Example 1 and the purification of the three lots obtained in Comparative Example 2 .

Source: Mo

Voltage: 50 kV

Current: 24 mA

Pixel size: 8.64 μm / voxel

Number of shots: 1200 sheets

Shooting time: about 3 hours

Using the accessory analysis software, the volume ratio of a cubic body having one side of 2 mm at the upper portion, middle portion and lower portion of the triple-divided tablet was obtained. The relative standard deviation (RSD) of the volume ratios of the three cubes of the three-lot tablet obtained in Comparative Example 2 was as high as 5.5%, 7.1%, and 5.3%. On the other hand, the RSDs of the volume ratios of the three cubes of the two-lot tablets obtained in Example 1 were 1.0% and 2.4%, respectively, and the tablets of the present invention had high uniformity (Table 54).

The inside of the tablet was analyzed under the following conditions using an X-ray CT microscope TDM1000H-II (2K) (Yamato Kagaku K.K.) for each one-lot purification obtained in Examples 2 to 26.

Sailor: W

Voltage: 50 kV (Examples 2 to 26)

Current: 0.080 mA (Example 2), 0.085 mA (Examples 3-26)

Pixel size: 17.5 μm / voxel (Example 2), 12.7 μm / voxel (Examples 3 to 26)

Number of shots: 700 ~ 1500 (Set arbitrarily according to tablet thickness)

Shooting time: 20 minutes (Example 2), 10 minutes (Examples 3 to 26)

Using the analysis software ImageJ, the volume ratios of the cubes of 2 mm on one side at the upper, middle, and lower portions of the triple-divided tablets were determined. Based on the information of brightness of 256 steps in the obtained image, spherical activated carbon and additive are separated from each other by voids by the automatic threshold calculation by the Otsu method, and this image is divided into 2 mm thick The ratio of the number of pixels of the spherical activated carbon and the additive was calculated as the volume ratio (see Table 54).

Example 1
(One) Example 1 (2) Example 2 Comparative Example 2
(One) Comparative Example 2
(2) Comparative Example 2
(3) Volume fraction of tablets Top 61.3 61.9 81.9 63.3 64.3 63.2 Central 62.3 59.8 82.3 57.5 56.9 59.6 bottom 62.5 62.7 82.5 63.3 57.0 56.9 Average 62.0 61.5 82.2 61.4 59.4 59.9 RSD (%) 1.0 2.4 0.4 5.5 7.1 5.3 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Volume fraction of tablets Top 58.5 55.0 57.2 64.3 61.7 59.9 Central 56.9 57.0 55.7 65.9 59.2 58.8 bottom 56.4 57.1 59.0 66.3 61.0 61.0 Average 57.3 56.4 57.3 65.5 60.6 59.9 RSD (%) 1.9 2.1 2.9 1.6 2.1 1.8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Volume fraction of tablets Top 64.3 58.4 59.3 67.5 65.3 61.1 Central 63.6 58.6 56.2 69.4 60.2 62.7 bottom 61.5 63.1 61.4 68.9 64.6 61.8 Average 63.1 60.0 58.9 68.6 63.4 61.9 RSD (%) 2.3 4.4 4.5 1.5 4.3 1.3 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Volume fraction of tablets Top 63.7 63.1 63.9 57.6 60.7 60.9 Central 60.1 62.2 63.6 57.5 61.5 61.6 bottom 63.6 65.8 66.0 58.9 61.3 62.1 Average 62.5 63.7 64.5 58.0 61.1 61.5 RSD (%) 3.3 2.9 2.0 1.3 0.7 0.9 Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Volume fraction of tablets Top 61.8 56.5 61.6 59.2 63.1 60.2 Central 60.4 58.0 63.2 58.8 58.6 60.2 bottom 64.8 56.8 64.3 59.7 58.8 62.2 Average 62.3 57.1 63.1 59.3 60.2 60.9 RSD (%) 3.6 1.4 2.2 0.7 4.2 1.9

≪ Analysis of the volume ratio of the additive of the tablet in the X-ray CT microscope >

The tablets obtained in Examples 1 to 26 and the tablets obtained in Comparative Examples 2 and 3 were analyzed using an X-ray CT microscope TDM1000H-II (2K) (Yamato Kagaku K.K.) under the following conditions under the following conditions did.

Sailor: W

Voltage: 40 kV (Example 1, Comparative Example 2), 50 kV (Examples 2 to 26, Comparative Example 3)

Current: 0.095 mA (Example 1, Comparative Example 2), 0.080 mA (Example 2, Comparative Example 3), 0.085 mA (Examples 3-26)

(Example 1), 14.4 μm / voxel (Comparative Example 2), 17.5 μm / voxel (Example 2, Comparative Example 3), 12.7 μm / voxel (Examples 3 to 26)

Number of shots: 700 ~ 1500 (Set arbitrarily according to tablet thickness)

30 minutes (Example 1, Comparative Example 2), 20 minutes (Example 2, Comparative Example 3), 10 minutes (Examples 3 to 26)

The tablets of Example 1, tablets of Examples 3 to 26 and tablets of Comparative Example 2 were each coated with one tablet, while tablets of Example 2 and Comparative Example 3 were tableted with three tablets, , S, and W were calculated by analyzing the softness ImageJ. The lightness distribution of the number of pixels of lightness corresponding to the spherical activated carbon takes a normal distribution based on the information of the brightness of 256 steps in the obtained image and that the lightness is not less than the value obtained by adding 2.5 times the standard deviation to the average value of the lightness And the ratio of the number of pixels to the number of pixels of the additive when the additive area ratio and the number of pixels corresponding to the predetermined thickness were integrated to obtain the additive volume ratio (FIG. 6). Table 55 shows the ratio of the maximum value and the minimum value of the additive volume ratio in each footnote and the maximum value and the minimum value in the five footnotes. 4 shows fluctuations of the additive area ratio and the volume ratio at the position C in the comparative example 2 from the upper surface to the lower surface.

As shown in Fig. 4, the volumetric additive ratio of the tablets obtained by the conventional coalescence method largely fluctuated between the lower surface and the lower surface of the tablets.

Example 1 Example 2 (1) Example 2 (2) Example 2 (3) Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Volume ratio of additive (%) C 1.671 0.198 15.4 14.477 2.448 11.6 9.833 1.929 9.7 16.331 3.345 6.1 N 2.364 0.161 18.137 1.564 18.633 2.267 16.759 3.898 E 2.252 0.296 11.721 5.717 9.774 3.323 17.675 9.104 S 0.774 0.154 14.602 3.364 12.673 2.812 20.523 4.596 W 1.791 0.265 16.118 8.258 10.954 5.230 10.653 7.979 Example 3 Example 4 Example 5 Example 6 Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Volume ratio of additive (%) C 9.964 1.136 94.0 5.321 0.503 59.8 2.531 0.093 62.4 6.872 1.045 12.5 N 5.019 0.137 1.423 0.099 2.439 0.171 9.055 1.528 E 6.129 0.125 2.147 0.126 2.213 0.141 12.719 3.450 S 5.918 0.106 2.598 0.300 0.998 0.043 10.259 1.019 W 6.108 0.184 1.365 0.089 2.685 0.1216 11.634 1.449 Example 7 Example 8 Example 9 Example 10 Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Volume ratio of additive (%) C 2.984 0.416 88.7 3.824 0.252 95.6 3.243 0.697 45.7 3.197 0.161 34.0 N 1.445 0.066 0.620 0.050 2.248 0.331 3.468 0.268 E 2.270 0.061 3.138 0.040 2.121 0.071 1.874 0.102 S 1.702 0.034 1.535 0.161 2.576 0.228 1.616 0.118 W 1.752 0.036 2.901 0.071 2.015 0.257 2.248 0.392 Example 11 Example 12 Example 13 Example 14 Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Volume ratio of additive (%) C 2.971 0.431 35.4 7.237 0.850 21.9 3.751 0.303 12.4 3.176 0.584 50.3 N 2.361 0.107 4.868 1.121 3.368 0.355 3.975 0.133 E 0.931 0.084 5.373 0.895 2.802 0.382 2.451 0.160 S 1.640 0.104 5.985 0.330 2.441 0.442 1.982 0.202 W 1.171 0.130 4.645 0.852 2.468 0.515 3.366 0.079 Example 15 Example 16 Example 17 Example 18 Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Volume ratio of additive (%) C 3.535 0.416 15.1 3.375 0.216 44.4 3.931 0.916 7.3 2.136 0.317 70.9 N 1.686 0.574 1.178 0.244 2.566 2.566 2.198 0.031 E 2.673 0.476 1.441 0.112 2.959 0.539 1.893 0.063 S 2.593 0.234 0.987 0.110 3.784 0.777 1.197 0.079 W 2.767 0.315 1.869 0.076 2.554 0.709 1.465 0.056 Example 19 Example 20 Example 21 Example 22 Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Volume ratio of additive (%) C 3.080 0.326 77.1 2.924 0.043 93.9 3.677 0.855 10.7 3.311 0.141 89.0 N 0.934 0.079 3.191 0.038 3.480 0.586 1.208 0.045 E 0.570 0.043 0.599 0.034 2.720 0.404 1.013 0.057 S 1.008 0.088 1.339 0.052 4.327 0.697 0.734 0.101 W 3.314 0.154 1.508 0.127 4.221 0.638 3.383 0.038 Example 23 Example 24 Example 25 Example 26 Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Volume ratio of additive (%) C 4.707 0.277 21.5 2.447 0.140 90.6 3.762 0.975 32.0 2.169 0.134 80.3 N 3.531 0.474 1.631 0.029 5.478 0.797 1.190 0.027 E 3.164 0.472 0.655 0.027 5.354 0.930 1.279 0.052 S 2.695 0.226 1.536 0.052 6.057 1.407 0.947 0.051 W 2.436 0.219 1.218 0.027 4.364 0.189 1.059 0.028 Comparative Example 2 Comparative Example 3 (1) Comparative Example 3 (2) Comparative Example 3 (3) Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Maximum value Minimum value ratio Volume ratio of additive (%) C 11.479 0.011 1775.9 2.444 0.126 102.4 3.377 0.013 915.6 4.195 0.019 524.6 N 19.535 0.820 11.979 0.495 11.903 0.686 7.115 0.050 E 10.708 0.216 8.904 0.413 6.643 0.665 9.968 0.443 S 10.594 0.080 12.903 1.193 6.912 0.030 9.406 0.524 W 16.406 0.029 12.518 0.310 10.570 0.422 8.993 0.905

Claims (7)

An additive, and a spherical adsorbent carbon for oral administration,
The volume ratio of the additive of the five pillars of 1 mm on one side of the lower surface in the upper surface, which is positioned at the central portion when viewed from the upper surface of the tablet and at the end portion of the straight line drawn in four directions from the center, Characterized in that, when interpreted by a microscope, the ratio of the maximum and minimum values of the volume fraction of additive per 1 ply in each of the five footnotes is 100 or less. A tablet containing an adsorbent for oral administration,
The volume ratio of a cubic body having a length of 2 mm on one side located at the center of the tablet viewed from the upper side and a volume ratio of a cubic body located at the center of the tablet in the direction of X Line CT microscope, the relative standard deviation of the volume ratio of the cubes of the three divided bodies is 5% or less. An additive, and a spherical adsorbent carbon for oral administration,
The volume ratio of the additive of the five pillars of 1 mm on one side of the lower surface in the upper surface, which is positioned at the central portion when viewed from the upper surface of the tablet and at the end portion of the straight line drawn in four directions from the center, When analyzed by a microscope, the ratio of the maximum value and the minimum value of the additive volume ratio per one ply in the five footnotes is 100 or less,
The volume ratio of a cubic body having a length of 2 mm on one side located at the center of the tablet viewed from the upper side and a volume ratio of a cubic body located at the center of the tablet in the direction of X Line CT microscope, the relative standard deviation of the volume ratio of the cubes of the three divided bodies is 5% or less. 4. The composition according to any one of claims 1 to 3, wherein the additive is selected from the group consisting of sodium alginate, propylene glycol alginate ester, camelose, camellose calcium, ghatti gum, carrageenan, carboxyvinyl polymer, camelose sodium, Corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, Polyvinyl alcohol, acrylic acid-methyl methacrylate copolymer, macrogol 6000, ethyl cellulose, methyl cellulose, phosphoric acid crosslinked starch, locust bean gum, polyvinyl alcohol, polyvinylpyrrolidone, Agar, one minute, whole alpha starch, crystalline cellulose, sodium camellose, oxidized starch, low substitution degree Hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropylcellulose, partially-alpha-starch, sugars and sugar alcohols. The tablet according to any one of claims 1 to 4, wherein the spherical adsorbent for oral administration is spherical activated carbon. The tablet according to claim 5, wherein the spherical activated carbon has an average particle diameter of 0.02 to 1 mm. (1) A pharmaceutical composition comprising (1) at least one compound selected from the group consisting of sodium alginate, alginic acid propylene glycol ester, camelose, camelose calcium, gadji gum, carrageenan, carboxyvinyl polymer, camelose sodium, xanthan gum, guar gum, Gelatin, tamarind gum, tara gum, dextrin, corn starch, tragacanth, sodium hyaluronate, hydroxyethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hiropromellose, pullulan, povidone, polyethylene oxide , Polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, macrogol 6000, ethylcellulose, methylcellulose, crosslinked starch phosphate, locust bean gum, agar, one minute, fully alpha starch, crystalline cellulose camellose Sodium, oxidized starch, low-substituted hydroxypropylcellulose, partially-alpha-starch, saccharides Per step of spraying or dropping by coating a result wear additives, spherical carbon adsorbent for oral administration of the solution containing a grain wear additives selected from the group consisting of alcohols for oral administration for a spherical adsorbing carbon,
(2) a compression molding step for obtaining a molded article by adding a solvent to the coated spherical adsorbent carbon for adsorption and compression molding, and
(3) a step of drying the obtained molded article
≪ / RTI >

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