KR102158133B1 - Tablets containing spherical sorbent for oral administration - Google Patents

Abstract

It is an object of the present invention to provide a tablet containing a spherical sorbent for oral administration having sufficient strength. The above object is a tablet comprising a spherical sorbent for oral administration and a binding additive of the present invention, wherein the spherical sorbent for oral administration is coated with the binding additive, and through the coated binding additive, respectively Spherical adsorbent for oral administration is bound, and the hardness of the tablet is 105 N or more, which can be solved by a tablet.

Description

Tablets containing spherical sorbent for oral administration

The present invention relates to a tablet containing a spherical adsorbent for oral administration (球狀吸着炭). According to the present invention, it is possible to provide a tablet having excellent hardness.

The spherical adsorbent for oral administration can be taken orally, and by adsorbing harmful substances in the digestive tract, it is possible to treat a dysfunction of the kidney or liver (Patent Document 1). In order for this spherical sorbent for oral administration to exhibit the pharmacological effect of adsorption of harmful substances, it is important to maintain the spherical shape of the spherical sorbent for oral administration and to maintain its pore structure. These spherical adsorbents for oral administration are, for example, brand names ``Cremezine (registered trademark) capsule 200 mg'' and ``Cremezine (registered trademark) fine grain distribution 2 g'' (hereinafter, ``KREMEZIN )”).

The daily dose of cremezin for patients with kidney disease is 6 g, and since it is taken in three divided doses, the dose per dose is 2 g. The volume of 2 g of Cremegin's fine-grained agent is about 4 cm ³ , and the volume to be taken is never small. Therefore, when taking 4 cm ³ fine particles, since the spherical activated carbon does not dissolve in water, there were also patients who felt disgust with the feeling of chewing sand in the oral cavity.

On the other hand, in the case of cremegin capsules, the feeling of chewing the sand in the mouth does not occur. However, since a dead volume other than the spherical activated carbon occurs in the capsule, the volume of the capsule increases to about 1.5 times (about 6 cm ³ ) compared to the volume of the fine granule. Specifically, there were patients who complained of a large dose of about 0.613 cm ³ volume of capsules must be taken at a time of 10 capsules.

In addition, there are many patients who cannot take the granules or capsules unless they are accompanied by a large amount of water in order to relieve the feeling of chewing the sand of the granules or because the dosage of the capsule formulation is large. Among patients with kidney disease or kidney failure, there are patients with limited water intake, and when these patients take granules or capsules, it is required to take them with as little water as possible. Patients who are inherently in need of help come with great pain.

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

In order to solve the above problems, it is conceivable to use spherical sorbents for oral administration as tablets. However, unlike general drugs, the spherical adsorbent for oral administration was unable to form tablets by compression or the like (Patent Document 2). That is, since the spherical adsorbent for oral administration is very hard, lacks deformability, and has fragile properties, like glass, the spherical adsorbent for oral administration is destroyed when tablet-molding, and the spherical adsorbent cannot be maintained.

The inventors of the present invention have found that tablets containing spherical sorbents for oral administration that can be used for practical use can be manufactured by a combined method using an additive for preparation of particles exhibiting thin film formation ability (Patent Document 3 ). However, the strength of the obtained tablets was not sufficient.

Accordingly, it is an object of the present invention to provide a tablet comprising a spherical sorbent for oral administration having sufficient strength.

The present inventors have studied intensively on tablets containing spherical sorbent carbon for oral administration (e.g., spherical activated carbon) having sufficient strength. Surprisingly, spherical sorbent for oral administration is coated with a specific binding additive. , It was found that the above problems could be solved by tablets having a hardness of 105 N or more, to which each spherical adsorbent for oral administration was bound through the coated binding additive. In addition, the tablets were found to be obtained by coating a spherical sorbent for oral administration with a binding additive, adding a solvent to the coated spherical sorbent for oral administration, and compression molding.

The present invention is based on this knowledge.

Therefore, the present invention

[1] spherical adsorbent for oral administration, and alginate propylene glycol ester, gati gum, carboxyvinyl polymer, carmellose sodium, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind Gum, tara gum, corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol acrylic acid Comprising at least one binding additive selected from the group consisting of methyl methacrylate copolymer, phosphate crosslinked starch, locust bean gum, hanmae flour, fully-gelatinized starch, oxidized starch and partially-gelatinized starch As a tablet, the spherical sorbent for oral administration is coated with the binding additive, each spherical sorbent for oral administration is bound through the coated binding additive, and the hardness of the tablet is 105 N or more. , refine,

[2] The tablet according to [1], wherein the spherical sorbent carbon for oral administration is a spherical activated carbon,

[3] The tablet according to [2], wherein the spherical activated carbon has an average particle diameter of 0.02 to 1 mm,

[4] Additives for binding of five prisms with one side of 1 mm from the top to the bottom, located at the center of the tablet when viewed from the top and at the ends of a straight line stretched in all directions from the center When the volume ratio of is analyzed by X-ray CT microscope from the top to the bottom, the ratio of the maximum and minimum volume ratio of the binding additive per 1 mm ³ in 5 footnotes is 100 or less, among [1] to [3] The tablet according to any one,

[5] In each of the divided bodies obtained by dividing the length in the flat direction of the tablet into three equal parts, it is composed of 2 mm on one side located at the center of the length in the flat direction and at the center of the tablet viewed from the top. The tablet according to any one of [1] to [3], wherein, when the volume ratio of the cube is analyzed by an X-ray CT microscope, the relative standard deviation of the volume ratio of the cube of the three divided bodies is 5% or less, and

[6] When the tablet is viewed from the top, the volume ratio of the additives for binding of five footnotes, one side 1 mm from the top to the bottom, located at the center of the tablet and at the end of a straight line stretched from the center in all directions from the top. When analyzed with an X-ray CT microscope over a period of time, the ratio of the maximum and minimum value of the volume ratio of the binding additive per 1 mm ³ in 5 footnotes is 100 or less, and the length in the flat direction of the tablet is divided into 3 equal parts. In the divided body, when the volume ratio of a cube consisting of 2 mm on one side located at the center of the length in the flat direction and located at the center of the tablet viewed from the upper surface was analyzed by an X-ray CT microscope, the The tablet according to any one of [1] to [3], wherein the relative standard deviation of the volume fraction of the cube is 5% or less, and

[7] (1) Alginic acid propylene glycol ester, gati gum, carboxyvinyl polymer, camelose sodium, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind gum, tara gum, corn starch, tragacanth, Sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, phosphate crosslinked starch, locust bean gum, hanmae powder, For binding spherical sorbents for oral administration by spraying or dropping a solution containing at least one binding additive selected from the group consisting of fully-gelatinized starch, oxidized starch and partially-gelatinized starch on spherical sorbents for oral administration Preparation of tablets comprising a step of coating with an additive, (2) adding a solvent to the coated spherical adsorbent for oral administration, and compression molding to obtain a molded body, and (3) drying the obtained molded body Way

It is about.

According to the tablet containing the spherical adsorbed carbon (for example, spherical activated carbon) for oral administration of the present invention, a tablet having excellent hardness can be provided. According to the tablet of the present invention, it is possible to reduce the volume compared to a capsule, and thus a tablet having improved dosage can be provided. In other words, in the case of capsules, it is necessary to take 10 capsules of about 0.613 cm ³ volume at a time, and there were also patients complaining that the dose was too high. The volume can be reduced to 65% (about 4 cm ³ ) of cases, so the dosage is improved. Further, according to the tablet of the present invention, it is possible to provide a tablet having improved dosage defects such as a feeling of chewing sand compared to a fine granule. According to the tablet of the present invention, it is possible to provide a tablet capable of sufficiently exhibiting the function of an adsorbent for oral administration without destroying the pore structure by maintaining the spherical shape of the spherical adsorbent for oral administration.

1 is a diagram schematically showing the positions of three cubes for analyzing the volume ratio of the tablet in the tablet of the present invention from the top (A) and the side (B).
Fig. 2 is an analysis image of an X-ray CT microscope (nano3DX) showing the localization of additives in the tablet (A) obtained by the production method of the present invention and the tablet (B) obtained by the conventional combination method. .
3 is a diagram schematically showing the positions of five footnotes for analyzing the volume ratio of an additive in the tablet of the present invention from the top (A) and the side (B).
Fig. 4 is a graph showing changes when the volume ratio of the additive in the tablet of the present invention is analyzed by an X-ray CT microscope from an upper surface to a lower surface.
Fig. 5 is a photograph showing the residual (A) and adhesion (B) of the spherical activated carbon to the agitating granulator by the coalescence method.
6 is a graph and a photograph showing that when the volume ratio of the additive is calculated by the analysis software ImageJ, the division between the additive and the spherical activated carbon is performed based on information of 256 levels of brightness.

[1] Tablets containing spherical adsorbent for oral administration

The tablet containing the spherical sorbent for oral administration of the present invention includes a spherical sorbent for oral administration, and propylene glycol alginate, gati gum, carboxyvinyl polymer, sodium carmellose, xanthan gum, guar gum, glucomannan, copolyvidone, Gelatin, tamarind gum, tara gum, corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol acrylic acid methacrylic Acid methyl copolymer, phosphate crosslinked starch, locust bean gum, single meal, fully-gelatinized starch, oxidized starch, and at least one binding additive selected from the group consisting of partially-gelatinized starch. The spherical sorbent for oral administration is coated with the binding additive, each spherical sorbent for oral administration is bound through the coated binding additive, and the hardness of the tablet is 105 N or more.

≪Spherical adsorption bomb for oral administration≫

The spherical sorbent for oral administration is not particularly limited as long as it is a spherical sorbent for oral administration that can be used for medical purposes, but is preferably a spherical activated carbon for oral administration, that is, a spherical activated carbon that can be used orally for medical purposes. In addition, in this specification, as an example of the spherical adsorption carbon for oral administration, it may demonstrate using spherical activated carbon.

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. . Further, the range of the particle diameter (diameter) of the spherical activated carbon is preferably 0.01 to 2 mm, more preferably 0.02 to 1.5 mm, and even more preferably 0.03 to 1 mm.

"Spherical activated carbon" means that the BET specific surface area is 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. It is preferable, 1300 m ² /g or more is even more preferable, and 1650 m ² /g or more is particularly preferable.

The shape of the spherical sorbent for oral administration (for example, spherical activated carbon) contained in the tablet maintains its pore structure and maintains the spherical shape of the spherical sorbent for oral administration in order to exhibit the pharmacological effect of adsorption of harmful substances. It is desirable to do. That is, the adsorption capacity of toxic substances, e.g., the selective adsorption rate, is affected by the diameter, average particle diameter, specific surface area, and pore volume in a specific pore diameter range, so that the spherical adsorbent for oral administration is not damaged. , It is preferable that the spherical shape which affects the diameter, or the average particle diameter is maintained, and the pore structure which affects the specific surface area or the pore volume is maintained. In addition, by maintaining the spherical shape, side effects such as constipation can be prevented.

≪Additive for binding≫

The binding additives used in the tablets of the present invention are propylene glycol alginate, gati gum, carboxyvinyl polymer, sodium camelose, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind gum, tara gum, corn starch , Tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, phosphate crosslinked starch, locust bean Gum, single meal, fully-gelatinized starch, oxidized starch, partially-gelatinized starch, or combinations thereof. The tablet of the present invention in which the binding additive is coated on a spherical sorbent for oral administration and the binding additive binds each spherical sorbent for oral administration has a hardness of 105 N or more.

The tablet of the present invention is characterized by containing the above-described binding additive as an additive, but may also contain additives other than the binding additive (hereinafter sometimes referred to as "other additives"). That is, the tablet of the present invention may contain, as an additive, a binder additive and other additives, or may contain only a binder additive. In other words, the additive used in the present invention may be composed of an additive for binding and other additives, or may be composed of an additive for binding.

(Other additives)

Hereinafter, additives that can be used as additives (other additives) other than the binder additive will be described.

In general, additives used in pharmaceuticals are described in the "Drug Additive Dictionary 2016", and examples thereof include excipients, lubricants, disintegrants, surfactants, and binders. The functions of excipients, lubricants, disintegrants, and binders are not necessarily single, for example, crystalline cellulose classified as an excipient also functions as a disintegrant in most cases, and in direct tableting, it is possible to improve moldability. It also has a function as a binder. Therefore, the functions of each of the excipient, lubricant, disintegrant, and binder may overlap. Examples of excipients, lubricants, disintegrants, and binders are given below, but additives not classified into these additives may be used as other additives.

The excipient is an additive mainly used for increasing (extending agent) or dilution (diluent), and specifically, starch, calcium hydrogen phosphate, synthetic aluminum silicate, or magnesium trisilicate may be mentioned.

In addition, binders are additives used to impart binding force to the main drug or extender and to form, maintain the formulation, prevent damage during packaging or transport, and are used to increase mechanical strength. . Specifically, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium camelose, powdered cellulose, hypromellose, methyl cellulose, hydroxypropyl cellulose, starch, fully gelatinized starch, partially gelated starch, dextrin, arabic Gum, sodium alginate, tragacanth, purified gelatin, polyvinyl alcohol, or povidone.

In addition, the disintegrant is an additive used to disintegrate and disperse the formulation into fine particles by being wetted in the digestive tract when a tablet is taken. Specifically, a low-substituted hydroxypropyl cellulose, hypromellose, powdered cellulose, starch, sodium carboxymethyl starch, or hydroxypropyl starch can be cited specifically.

The lubricant is an additive having a function of improving various properties such as powder flowability, filling property, adhesion, and moldability in tableting, and is used to improve the quality and manufacturing efficiency of tablets. Specifically, sucrose fatty acid ester, talc, magnesium stearate, stearic acid, and the like are exemplified.

Surfactants are alkylallyl polyether alcohol, higher alcohol sulfur oxide, N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate, N-cocoyl-N-methyl aminoethyl sulfonic acid sodium, cholesterol, self-emulsification Glycerin monostearate, sucrose fatty acid ester, squalane, stearyl alcohol, polyoxyl stearate 40, cetanol, cetomacrogol 1000, diethyl sebacic acid, sorbitan fatty acid ester, sorbitan sesquioleic acid ester, Sodium dodecylbenzenesulfonate, sorbitan trioleate, nonylphenoxy polyoxyethylene ethane sulfate ammonium solution, polyoxyethylene octylphenyl ether, polyoxyethylene oleylamine, polyoxyethylene cured castor oil 20, polyoxyethylene cured Castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbite 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) cetyl ether, polyoxyethylene (2 EO) lauryl ether sodium sulfate (70%), polyoxyl 35 castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, N-palm oil fatty acid acyl L-arginine ethyl DL -Pyrrolidone carboxylate, lauryl dimethylamine oxide solution, lauryl pyrrolidone, sodium lauryl sulfate, lauric diethanolamide, lauroyl sarcosine sodium, lauromacrogol, sodium phosphate polyoxyethylene Uryl ether or phosphoric acid polyoxyethylene oleyl ether (8 MOL).

(Content of binding additive)

The weight ratio of the spherical adsorbent carbon for oral administration (for example, spherical activated carbon) and the binding additive is not particularly limited as long as the effect of the present invention is obtained, but the content of the binding additive in the tablet of the present invention is preferably Is 1% by weight or more, more preferably 1.5% by weight or more, and even more preferably 2% by weight or more. When the amount of the binding additive is too small, the hardness of the obtained tablet may decrease. The upper limit of the binding additive is not limited, but the binding additive is preferably 35% by weight or less, more preferably 30% by weight or less, and even more preferably 25% by weight or less. If there are too many binding additives, the volume of the tablet becomes large, and the dosage of the tablet may increase. The range of the content of the binding additive in the tablet of the present invention is preferably 1 to 35% by weight (or 1 to 30% by weight, or 1 to 25% by weight), since the hardness of the obtained tablet is likely to be 105 N or more. It may be.), more preferably 1.5 to 30% by weight (or 1.5 to 25% by weight may be 1.5 to 20% by weight.), even more preferably 2 to 25% by weight (or 2 to 2) It may be 20% by weight or 2 to 17% by weight.).

In addition, the tablet of the present invention may contain other additives as additives, but the weight ratio of the binding additive and other additives is not particularly limited as long as the effect of the present invention is obtained, but preferably 100 weights of the binding additive With respect to parts, the other additives are preferably 10000 parts by weight or less, more preferably 1000 parts by weight or less, even 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 tablet obtained may decrease. In addition, the lower limit of the weight ratio is not particularly limited, and the content of the other additives may be, for example, 0.1 parts by weight or more, 1 part by weight or more, or 10 parts by weight or more, based on 100 parts by weight of the binding additive. .

≪Clothing≫

In the tablet of the present invention, spherical sorbent carbon for oral administration (for example, spherical activated carbon) is coated with the above binding additive, and the spherical activated carbon is bound through the coated binding additive.

≪Hardness≫

The hardness of the tablet of the present invention is not particularly limited as long as it is 105 N or more, but is preferably 110 N or more, in some embodiments, 120 N or more, in some embodiments, 140 N or more, and in any embodiment 160 N It is above, and it is 180 N or more in a certain aspect, and 200 N or more in a certain aspect. By having a hardness of 105 N or more, it is possible to maintain the formulation and more effectively prevent breakage during the packaging process and transport. In addition, the upper limit of the hardness is not particularly limited, and for example, it may be 500 N or less, 400 N or less, or 350 N or less. The range of the hardness is not particularly limited, for example, 105 to 500 N, 105 to 400 N, 105 to 350 N, 110 to 500 N, 110 to 400 N, 110 to 350 N, 120 to 500 N, 120 to 400 N, 120~350 N, 140~500 N, 140~400 N, 140~350 N, 160~500 N, 160~400 N, 160~350 N, 180~500 N, 180~400 N, 180~ 350 N, 200-500 N, 200-400 N, 200-350 N, etc. are mentioned.

≪Other problems under the Union Law, the means to solve them, and their effects≫

In the case of using the conventional association method, not only the strength of the obtained tablet was not sufficient, but also the following problems. That is, when tablets were manufactured using the combined method, the yield of spherical activated carbon was low. Further, the tablets obtained by the combined method had low uniformity of the spherical adsorbent for oral administration and the binding additive. In addition, in the tablets obtained by the combined method, the adsorption amount of DL-β-aminoisobutyric acid may decrease compared to granules or capsules.

As a result of intensive research on tablets with high yield of spherical sorbents for oral administration and high uniformity of spherical sorbents for oral administration and binding additives, and a method of manufacturing the same, surprisingly, a solution containing the binding additives By spraying or dropping onto a spherical sorbent for oral administration and preparing tablets by compression molding, the yield of the spherical sorbent for oral administration is drastically improved, and the uniformity of the spherical sorbent for oral administration and the binding additive is also dramatically improved. It was found that improved tablets could be obtained. More specifically, it will be described below in the description of the uniformity of the volume ratio of the tablet or the uniformity of the localization of the additive.

According to the method for producing a tablet containing spherical sorbent carbon for oral administration (for example, spherical activated carbon) of the present invention, the yield of the spherical sorbent for oral administration to be used can be improved. In addition, the tablet containing the spherical sorbent for oral administration obtained by the production method of the present invention prevents the localization of the spherical sorbent for oral administration and the binding additive, so that the uniformity of the spherical sorbent for oral administration and the binding additive is improved. It is improved. Thus, the hardness of the obtained tablet was improved. In addition, the purification may exhibit excellent adsorption capacity of DL-β-aminoisobutyric acid. That is, according to the tablet manufacturing method of the present invention, compared with the combined method described in Patent Document 3, it is possible to improve the yield of the spherical adsorbent for oral administration in the tablet manufacturing method, and to improve the hardness, It can also be expected to improve the adsorption capacity of DL-β-aminoisobutyric acid.

≪Uniformity of tablet volume ratio≫

It is preferable that the tablet of the present invention has a uniform volume ratio in the tablet. That is, when the tablet of the present invention contains spherical sorbent carbon for oral administration (for example, spherical activated carbon) as an active ingredient when compared with a tablet containing a general compound as an active ingredient, as apparent from FIG. 1 and the like, A void exists between the spherical adsorbents for oral administration. It is conceivable that the hardness or friability of the tablet decreases when there is a portion with a dense void and a portion with a sparse void. In other words, it is conceivable that the hardness or friability of the tablet decreases if there is a variation in the volume ratio of the spherical adsorbent for oral administration and the additive in the tablet. That is, since the volume ratio of the tablet is uniform, the hardness and friability of the tablet can be further improved.

The uniformity of the volume ratio of the tablet 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 in the flat direction of the tablet into 3 equal parts, the volume ratio of a cube consisting of 2 mm on one side located at the center of the length in the flat direction and at the center of the tablet viewed from the top surface When analyzed by an X-ray CT microscope, when the relative standard deviation of the volume fraction of the cube of the three divided bodies is 5% or less, it can be determined that the uniformity of the tablet is high.

As shown in Fig. 1, the tablet has a flat shape, excluding the jingu-shaped pills. Fig. 1(A) shows a flat tablet viewed from the top, and Fig. 1(B) shows a flat tablet viewed from the side. When the tablet is viewed from the top, the tablet often has a shape such as a circle, oval, square, or rectangle as shown in Fig. 1(A), but the tablet has a generally symmetrical shape, and shown in Fig. 1(A). As indicated by the square broken line, it is possible to specify "the cube at the center of the tablet viewed from the top surface". In addition, when the flat tablet is viewed from the side, as shown in Fig. 1(B), the length in the flat direction can be divided into three equal parts. In each of the divided bodies, as indicated by the broken line, ``flat The cube located at the center of the length of the direction can be specified. Therefore, it is possible to specify "three cubes of 2 mm on one side located at the center of the length in the flat direction and at the center of the tablet viewed from the top surface". And when the tablet is a true spherical pill, the "center of the length in the flat direction" and "the center of the tablet viewed from the top" can be specified with the flat direction as an arbitrary direction.

The three cubes described above can be analyzed by an X-ray CT microscope, and the volume fraction of each cube can be calculated. Then, the relative standard deviation of the volume fractions 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 in the flat direction of the tablet is less than 6 mm, three cubes consisting of 2 mm on one side may partially overlap. However, even when three cubes overlap, it is possible to calculate the relative standard deviation of the volume fraction of the cube of the three divided bodies, and when their relative standard deviation is 5% or less, it can be determined that the uniformity of the tablet is high. have.

The relative standard deviation of the volume fraction is preferably 4.7% or less, and even more preferably 4.5% or less. The smaller the relative standard deviation, the better the uniformity and the hardness or the friability of the tablet may 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, 0.5% or more, or 0.7% or more. The range of the relative standard deviation of the volume ratio may be, for example, 0.1 to 5%, 0.5 to 4.7%, or 0.7 to 4.5%.

≪Uniformity of the localization of additives≫

The tablet of the present invention preferably has a uniform distribution of additives in the tablet, i.e., the tablet of the present invention preferably has excellent uniformity of the volume ratio of the additive compared to the tablet containing the conventional spherical activated carbon. . For example, as shown in Fig. 2(B), in a tablet containing spherical activated carbon obtained by a conventional association method, the additive is unevenly distributed in a portion close to the surface of the upper portion of the tablet (the additive is shown in white), The additive uniformity is low. When additives are ubiquitous, it is conceivable that the hardness or friability of the tablet decreases. In other words, if there is a variation in the volume ratio of the additive in the tablet, it is conceivable that the hardness or friability of the tablet decreases. That is, since the volume ratio of the additive is uniform, the hardness and friability of the tablet can be further improved.

The uniformity of the volume ratio of the additive of the present invention can be specified, for example, by the following method. X-ray CT microscopy of the volume ratio of the additives of 5 footnotes, one side 1 mm from the upper surface to the lower surface, located at the center of the tablet when viewed from the upper surface and the end of a straight line stretched from the center to the lower surface. When interpreted as, it can be determined 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 1 mm ³ in five footnotes is 100 or less. That is, in the tablet of the present invention, in five footnotes, the ratio of the maximum value and the minimum value of the additive volume ratio is 100 or less. On the other hand, in conventional tablets, in five footnotes, since the ratio of the maximum value and the minimum value of the additive volume ratio exceeds 100, the hardness or friability of the tablet decreases.

As shown in Fig. 3, the tablet has a flat shape, excluding the true spherical pill. Fig. 3(A) shows a flat tablet viewed from the top, and Fig. 3(B) shows a flat tablet viewed from the side. When looking at the tablet from the top, the tablet often has a shape such as a circle, oval, square, or rectangle as shown in FIG. 3(A), but the tablet has a generally symmetrical shape, and shown in FIG. 3(A). As indicated by the square broken line of C, it is possible to specify "the footnote of the central part when viewed from the top surface". In addition, it is possible to specify "the footnote located at the end of a straight line extending from the center in all directions" indicated by the square dashed lines of N, E, S, and W in Fig. 3A. In addition, when the flat tablet is viewed from the side, as indicated by the broken line in Fig. 3(B), the footnotes are located from the top to the bottom in the flat direction of the tablet. Therefore, it is possible to specify "the footnote of the center when viewed from the top surface" and "the footnote located at the end of a straight line extending from the center of the tablet in all directions".

For the above five footnotes, the volume ratio of the additives of each footnote can be calculated by analyzing with an X-ray CT microscope from the upper surface to the lower surface. Then, in any position on the footing, to calculate the volume rate of the additive per 1 mm ^3, it is possible to find the maximum value and Min in the additive volume ratio per 1 mm ^3.

In the present invention, when the ratio of the maximum value and minimum value of the additive volume ratio per 1 mm ^{3 is} 100 or less, it can be determined that the uniformity of the distribution of the additive is high, but the ratio of the maximum value and the minimum value is preferably 99 or less, It is more preferably 98 or less, and even more preferably 96 or less. The smaller the ratio between the maximum value and the minimum value, the better the uniformity of the additive, and the hardness or friability of the tablet can be improved. Therefore, the lower limit of the ratio of the maximum value and the minimum value is most preferably 1 or more, and practically, it may be 2 or more, 4 or more, or 6 or more. The range of the ratio of the maximum value and the minimum value may be, for example, 1 to 100, 2 to 99, 4 to 98, or 6 to 96.

And, depending on the shape of the tablet, the height of the footnotes at the positions of N, E, S, and W may decrease compared to the footnotes at the position of C, but in this case, the additive volume ratio per 1 mm ³ may be measured. By determining the volume ratio of the additive from the upper surface to the lower surface, it is possible to calculate the "ratio of the maximum value and the minimum value of the additive volume ratio".

(X-ray CT microscope)

The X-ray CT microscope that analyzes the volume ratio of tablets and the volume ratio of additives in the present invention provides a planar (2D) or three-dimensional (3D) interior of a material or a sample such as a tablet with high resolution at a submicron level. It is a device that can be observed with ). Microstructures such as materials or tablets can be analyzed with high resolution. For example, as described in this example, it is possible to analyze the volume ratio of a tablet made of spherical activated carbon and an 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 measurement X-ray CT device TDM series: Yamato Scientific Co., Ltd. , Ltd.)” The device has a high resolution of 1 μm or less, and the volume ratio of the tablet or the volume ratio of additives can be calculated using the software attached to the device or image processing software ImageJ.

[2] Method for producing tablets

The manufacturing method of the tablet of the present invention includes (1) alginate propylene glycol ester, gati gum, carboxyvinyl polymer, camelose sodium, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind gum, tara gum, corn Starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, phosphate crosslinked starch, locust A solution containing at least one binding additive selected from the group consisting of empty gum, single powder, fully-gelatinized starch, oxidized starch and partially-gelatinized starch is used as a spherical adsorbent for oral administration (for example, spherical activated carbon). Spraying or dropping onto the coated spherical adsorbent for oral administration with an additive for binding, (2) adding a solvent to the coated spherical adsorbent for oral administration, and compression molding to obtain a molded article and ( 3) A step of drying the obtained molded article is included.

As the "binding additive" used in the tablet manufacturing method of the present invention, the binding additive described in the above "[1] tablet containing spherical adsorbent for oral administration" can be used.

≪Coating process (1)≫

The coating process (1) is propylene glycol alginate, gatigum, carboxyvinyl polymer, camelose sodium, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind gum, tara gum, corn starch, tragacanth, Sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, phosphate crosslinked starch, locust bean gum, hanmae powder, A solution containing at least one binding additive selected from the group consisting of fully-gelatinized starch, oxidized starch, and partially-gelatinized starch is sprayed onto spherical sorbent carbon (for example, spherical activated carbon) for oral administration and administered orally. The spherical adsorbent is coated with an additive for binding. As a coating method, a spray method is used. Examples of the spraying method include a top spray method, a tangential spray method, a bottom spray method, or a side spray method.

For example, in the case of the top spray method, a spray solution is prepared by dissolving an additive for binding and other additives in a solvent. Then, for example, a spherical adsorbent for oral administration is put into an electric fluid coating device or a fluidized bed granulating device, and a spray liquid is sprayed from the top.

The solvent used for the spray liquid is not particularly limited, and any organic solvent that can be used as a pharmaceutical additive can be used. For example, water, acetic acid, acetone, anisole, 1-butanol, 2-butanol, and n-acetic acid Butyl, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl Ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1, 2-dichloroe Ten, dichloromethane, N, N-dimethylacetamide, N, N-dimethylformamide, 1, 4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, Methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetraline, toluene, 1, 1, 2-trichloroethene or xylene. In addition, the surfactant is not particularly limited, but alkylallyl polyether alcohol, higher alcohol sulfur oxide, N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate, N-cocoyl-N-methyl amino Sodium ethyl sulfonate, cholesterol, self-emulsifying glycerin monostearate, sucrose fatty acid ester, squalane, stearyl alcohol, polyoxyl stearate 40, cetanol, cetomacrogol 1000, diethyl sebacic acid, sorbitan fatty acid ester, sorbitan Non-sesquioleic acid ester, sodium dodecylbenzenesulfonate, sorbitan trioleic acid, nonylphenoxy polyoxyethylene ethane sulfate ammonium solution, polyoxyethylene octyl phenyl ether, polyoxyethylene oleylamine, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbite 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) cetyl ether, polyoxyethylene (2 EO) lauryl ether sodium sulfate (70%), polyoxyl 35 Castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, acyl of N-palm oil fatty acid L-arginine ethyl-DL-pyrrolidone carboxylate, lauryl dimethylamine oxide solution, lauryl pyrrolidone, sodium lauryl sulfate, lauric acid diethanolamide, lauroyl sacosine sodium, lauromacrogol, Sodium phosphate polyoxyethylene lauryl ether or phosphate polyoxyethylene oleyl ether (8 MOL), etc. are mentioned.

The amount of the binding additive relative to the amount of the solvent is not particularly limited as long as the binding additive is substantially uniformly coated on the spherical sorbent carbon (for example, spherical activated carbon) for oral administration, but with respect to the solvent, the binding additive is It is preferably 0.01 to 100 w/v%, more preferably 0.1 to 50 w/v%, and even more preferably 1 to 15 w/v%.

≪Compression molding process (2)≫

In the compression molding step (2), a solvent is added to the coated spherical adsorbent carbon (for example, spherical activated carbon) for oral administration, and compression molded. For example, by adding a solvent to the coated spherical adsorbent for oral administration, compression molding, and drying, a tablet having a hardness of 105 N or more can be obtained.

Examples of the solvent include an organic solvent, water, or a mixture thereof. The volume ratio of the organic solvent and water in the mixture of the organic solvent and water is not particularly limited, but is preferably 5:95 to 95:5, more preferably 15:85 to 85:15, and even more preferably Is 30:70~70:30. By being in the said range, water can permeate|penetrate into the binding additive covering the spherical adsorbent 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 is obtained, for example, acetic acid, acetone, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl Methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2- Methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1, 2-dichloroethene, dichloromethane, N, N-dimethylacetamide, N, N-dimethylformamide, 1, 4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl Cyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1, 1, 2-trichloroethene, xylene, and the like.

≪Drying process (3)≫

In the tablet manufacturing method of the present invention, the obtained molded article is dried. The drying method is not limited as long as the solvent of the molded article evaporates, and examples thereof include freeze drying, vacuum drying, air drying, natural drying, or heat drying.

For example, in the case of heat drying, the heating temperature is not particularly limited, but, for example, 50 to 200°C is preferable and 80 to 180°C is preferable. The heating time is also 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, it is possible to shorten the heating time, and those skilled in the art can appropriately determine the heating temperature and the heating time.

In addition, the moisture content of the tablet 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 specifically described by examples, but these do not limit the scope of the present invention.

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

A porous spherical carbonaceous material was obtained in the same manner as in Example 1 of Japanese Patent No. 3522708 (Japanese Patent Laid-Open No. 2002-308785). The specific operation is as follows.

68 kg of petroleum pitch (softening point = 210°C; quinoline insoluble content = 1% by weight or less; H/C atomic ratio = 0.63) and 32 kg of naphthalene were put into a pressure-resistant vessel with an internal volume of 300 L with a stirring blade, After performing melt mixing at 180°C, cooling to 80 to 90°C and extruding were performed to obtain a string-shaped molded body. Subsequently, this string-shaped molded article was crushed so that the ratio between the diameter and the length was about 1 to 2.

Dissolving 0.23% by weight of polyvinyl alcohol (saponification degree = 88%) and adding the crushed product to an aqueous solution heated to 93° C., spheroidizing by stirring and dispersing, and cooling by substituting the aqueous solution of polyvinyl alcohol with water, After cooling at 20°C for 3 hours, solidification of the pitch and precipitation of naphthalene crystals were performed to obtain a slurry of a spherical pitch formed body.

After most of the water was removed by filtration, naphthalene in the pitch formed body was extracted and removed with n-hexane of about 6 times the weight of the spherical pitch shaped body. The thus-obtained porous spherical pitch was heated to 235°C using a fluidized bed while passing through heated air, and then maintained at 235°C for 1 hour and oxidized to obtain a porous spherical oxidized pitch that is infusible to heat.

Subsequently, the porous spherical oxidized pitch was activated in a nitrogen gas atmosphere containing 50 vol% of water vapor using a fluidized bed at 900° C. for 170 minutes to obtain a porous spherical activated carbon. Oxidation treatment was performed at 470°C for 3 hours and 15 minutes in a mixed gas atmosphere of nitrogen and oxygen having an oxygen concentration of 18.5 vol%, and then reduction treatment was performed at 900°C for 17 minutes in a nitrogen gas atmosphere in a fluidized bed to obtain a porous spherical carbonaceous material. Got it. The thus obtained porous spherical carbonaceous substance was used as spherical activated carbon in the following pharmacological test examples.

The main properties 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 15000 nm in pore diameter determined by the mercury intrusion method);

Average particle diameter=350 μm;

Total acidic groups=0.67 meq/g;

Total basic groups=0.54 meq/g;

Crush strength=31.2 MPa; And

Distortion ratio (歪率) = 0.7% when a pressure of 2 MPa is applied.

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

A porous spherical carbonaceous material (surface-modified spherical activated carbon) was obtained in the same manner as in the method described in Example 1 of JP 2005-314416 A. The specific operation is as follows.

220 g of deionized exchanged water and 58 g of methyl cellulose were placed in a 1 L separable flask, and 105 g of styrene and 57% of purity divinylbenzene (57% of divinylbenzene and 43% of ethyl Vinylbenzene) 184 g, 2, 2'-azobis (2, 4-dimethylvaleronitrile) 1.68 g, and 1-butanol 63 g as a porogen were appropriately added, and then the system was replaced with nitrogen gas. , This ideal system was stirred at 200 rpm, heated to 55°C, and then maintained as it is for 20 hours. The obtained resin was filtered, dried with a rotary evaporator, and 1-butanol was removed by distillation from the resin with a vacuum dryer, and then dried under reduced pressure at 90° C. for 12 hours to form a sphere having an average particle diameter of 180 μm. To obtain a porous synthetic resin. 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 put into a reaction tube equipped with a perforated plate, and an infusible treatment was performed in a vertical tube furnace (縱型管狀爐). Incompatibility conditions were 3 L/min, dry air was flowed from the bottom of the reaction tube toward the top, the temperature was raised to 260°C at 5°C/h, and then maintained at 260°C for 4 hours to obtain a spherical porous oxidized resin. The spherical porous oxidized resin was heat-treated at 600°C for 1 hour in a nitrogen atmosphere, and then activated for 10 hours at 820°C 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 further subjected to oxidation treatment in a fluidized bed at 470°C for 3 hours and 15 minutes in a mixed gas atmosphere of nitrogen and oxygen having an oxygen concentration of 18.5 vol%, and then reduction treatment at 900°C for 17 minutes in a nitrogen gas atmosphere in a fluidized bed. Thus, a surface-modified spherical activated carbon was obtained.

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 15000 nm in pore diameter determined by the mercury intrusion method);

Average particle diameter=111 μm (Dv50);

Total acidic groups=0.59 meq/g;

Total basic groups=0.61 meq/g;

Bulk density=0.50 g/cm ³ ;

Crush strength=436.5 MPa; And

Distortion when applying a pressure of 2 MPa = 0.2%.

In addition, in this specification, although the example in which the tablet was produced using the spherical activated carbon obtained in Production Example 2 is not described, the tablet of the present invention can be obtained similarly to the spherical activated carbon obtained in Production Example 1.

<<Example 1>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 1 was sprayed. Then, it dried and obtained 535.5 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (6:4) in a ratio of 1.2 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 15 mm. The hardness of the obtained tablet was 230 N. Table 2 shows the composition of the obtained tablets.

[Table 1]

[Table 2]

<<Example 2>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 3 was sprayed. Thereafter, it was dried to obtain 512.5 g of a coated product. The obtained coating was filled into a Teflon (registered trademark) mold (diameter 12 mm, depth 10.2 mm, R 16 mm), and water was added in a ratio of 0.9 mL to 1 g of the coating. Thereafter, the upper portion was lightly compressed with a molding rod attached to a stirrer to clean the tablet surface, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 124 N. Table 4 shows the composition of the obtained tablets.

[Table 3]

[Table 4]

<<Example 3>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 5 was sprayed. Then, it dried and obtained 506.8 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (5:5) in a ratio of 1.4 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 173 N. Table 6 shows the composition of the obtained tablets.

[Table 5]

[Table 6]

<<Example 4>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 7 was sprayed. Then, it dried and obtained 564.4 g of a coated article. The obtained coated product was molded after adding an ethanol/water mixture (6:4) in a ratio of 1.1 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 216 N. Table 8 shows the composition of the obtained tablets.

[Table 7]

[Table 8]

<<Example 5>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 9 was sprayed. Then, it dried and obtained 530.8 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (2:8) in a ratio of 1.2 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 137 N. Table 10 shows the composition of the obtained tablets.

[Table 9]

[Table 10]

<<Example 6>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 11 was sprayed. Then, it dried and obtained 497.8 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (5:5) in a ratio of 1.1 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 121 N. Table 12 shows the composition of the obtained tablets.

[Table 11]

[Table 12]

<<Example 7>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 13 was sprayed. Then, it dried and obtained 518.1 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (4:6) in a ratio of 1.0 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 123 N. Table 14 shows the composition of the obtained tablets.

[Table 13]

[Table 14]

<<Example 8>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 15 was sprayed. Then, it dried and obtained 537.3 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (1:9) in a ratio of 1.4 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 171 N. Table 16 shows the composition of the obtained tablets.

[Table 15]

[Table 16]

<<Example 9>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 17 was sprayed. Then, it dried and obtained 525.2 g of a coating product. The obtained coated product was molded after adding an ethanol/water mixture (1:9) in a ratio of 1.3 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 122 N. Table 18 shows the composition of the obtained tablets.

[Table 17]

[Table 18]

<<Example 10>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 19 was sprayed. Then, it dried and obtained 622.6 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (1:9) at a ratio of 0.6 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 162 N. Table 20 shows the composition of the obtained tablets.

[Table 19]

[Table 20]

<<Example 11>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 21 was sprayed. Then, it dried and obtained 506.0 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (5:5) at a ratio of 0.9 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 175 N. Table 22 shows the composition of the obtained tablets.

[Table 21]

[Table 22]

<<Example 12>>

305 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 23 was sprayed. Then, it dried and obtained 336.3 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (4:6) at a ratio of 1.4 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 133 N. Table 24 shows the composition of the obtained tablets.

[Table 23]

[Table 24]

<<Example 13>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 25 was sprayed. Then, it dried and obtained 548.3 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (1:9) in a ratio of 1.2 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 201 N. Table 26 shows the composition of the obtained tablets.

[Table 25]

[Table 26]

<<Example 14>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 27 was sprayed. Then, it dried and obtained 557.2 g of a coating product. The obtained coated product was molded after adding an ethanol/water mixture (1:9) in a ratio of 1.2 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 114 N. Table 28 shows the composition of the obtained tablets.

[Table 27]

[Table 28]

<<Example 15>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 29 was sprayed. Then, it dried and obtained 524.0 g of a coating product. The obtained coated product was molded after adding an ethanol/water mixture (1:9) in a ratio of 1.1 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 105 N. Table 30 shows the composition of the obtained tablets.

[Table 30]

<<Example 16>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 31 was sprayed. Then, it dried and obtained 543.5 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (4:6) in a ratio of 1.1 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 290 N. Table 32 shows the composition of the obtained tablets.

[Table 31]

[Table 32]

<<Example 17>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 33 was sprayed. Then, it dried and obtained 531.9 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (5:5) in a ratio of 1.2 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 133 N. Table 34 shows the composition of the obtained tablets.

[Table 33]

[Table 34]

<<Example 18>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 35 was sprayed. Then, it dried and obtained 543.3 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (4:6) at a ratio of 1.2 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 343 N. Table 36 shows the composition of the obtained tablets.

[Table 35]

[Table 36]

<<Example 19>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 37 was sprayed. Then, it dried and obtained 502.9 g of a coating product. The obtained coated product was molded after adding an ethanol/water mixture (6:4) at a ratio of 1.4 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 134 N. Table 38 shows the composition of the obtained tablets.

[Table 37]

[Table 38]

<<Example 20>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 39 was sprayed. Then, it dried and obtained 500.4 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (6:4) at a ratio of 1.4 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 187 N. Table 40 shows the composition of the obtained tablets.

[Table 39]

[Table 40]

<<Example 21>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 41 was sprayed. Then, it dried and obtained 508.9 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (6:4) in a ratio of 1.1 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 222 N. Table 42 shows the composition of the obtained tablets.

[Table 41]

[Table 42]

<<Example 22>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 43 was sprayed. Then, it dried and obtained 530.8 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (6:4) at a ratio of 1.4 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 162 N. Table 44 shows the composition of the obtained tablets.

[Table 43]

[Table 44]

<<Example 23>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 45 was sprayed. Then, it dried and obtained 552.0 g of a coating product. The obtained coated product was molded after adding an ethanol/water mixture (1:9) in a ratio of 1.1 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 227 N. Table 46 shows the composition of the obtained tablets.

[Table 45]

[Table 46]

<<Example 24>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 47 was sprayed. Then, it dried and obtained 545.5 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (6:4) in a ratio of 1.1 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 110 N. Table 48 shows the composition of the obtained tablets.

[Table 47]

[Table 48]

<<Example 25>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 49 was sprayed. Then, it dried and obtained 516.4 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (1:9) at a ratio of 1.0 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 141 N. Table 50 shows the composition of the obtained tablets.

[Table 49]

[Table 50]

<<Example 26>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 51 was sprayed. Then, it dried and obtained 533.3 g of a coated product. The obtained coated product was molded after adding an ethanol/water mixture (6:4) at a ratio of 1.4 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 125 N. Table 52 shows the composition of the obtained tablets.

[Table 51]

[Table 52]

<<Example 27>>

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 53 was sprayed. Then, it dried and obtained 520.7 g of a coating product. The obtained coated product was molded after adding an ethanol/water mixture (2:8) at a ratio of 0.9 mL to 1 g of the coated product using a low pressure molding machine, and dried to obtain a tablet having a diameter of 12 mm. The hardness of the obtained tablet was 110 N. Table 54 shows the composition of the obtained tablets.

[Table 53]

[Table 54]

≪Comparative Example 1≫

20 g of spherical activated carbon obtained in Preparation 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 obtained mixture was kneaded using a spatula so that lumps of additives did not occur. The prepared mixture (slurry) was filled into a mold (12 mm in diameter, 10.2 mm in depth), rubbed with a spatula, and lightly compressed with a molding rod attached to a stirrer to clean the tablet surface. Tablets were obtained by drying for each mold. The hardness of the tablet was 69 N.

≪Comparative Example 2≫

500 g of spherical activated carbon obtained in Production Example 1 was put into an electric fluid coating apparatus (MP-01), and the spray liquid of the formulation shown in Table 55 was sprayed. Then, it dried and obtained 523.5 g of a coated product. Using a low-pressure molding machine, an ethanol/water mixture (6:4 and 7:3) was added at a ratio of 1.1 mL and 1.2 mL to 1 g of the coated product, and then molded and dried to obtain a tablet having a diameter of 15 mm.

Table 56 shows the hardness of the obtained tablets. Table 57 shows the composition of the obtained tablets.

[Table 55]

[Table 56]

*1 Since the molding was very soft and it was difficult to transfer, the examination was stopped.

*2 Not reviewed.

[Table 57]

≪Hardness of tablet type composition≫

To measure the hardness of the tablet-type composition, the thickness of the tablet-type composition sample was measured using a tablet hardness tester (TBH320TD, manufactured by ERWEKA), and after inputting the measured value to the hardness tester, the measurement was performed at room temperature. Measurement conditions are shown below. The results of the hardness measurement are summarized and shown in Tables 59 to 64 together with the composition of the tablet. In the table, "the main drug" means spherical activated carbon.

[Table 58]

This operation was performed at n=1.

[Table 59]

[Table 60]

[Table 61]

[Table 62]

[Table 63]

[Table 64]

≪Interpretation of recovery rate≫

The recovery rate of the coated article in Examples or Comparative Examples was analyzed. The recovery rate (%) of the coated article is calculated as the amount of the obtained coated article/the theoretical amount of the coated article × 100. The higher the recovery rate, the better the yield of the spherical adsorbent for oral administration.

≪Example 1≫

For Example 1, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 65]

≪Example 2≫

For Example 2, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 66]

≪Example 3≫

For Example 3, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 67]

≪Example 4≫

For Example 4, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 68]

≪Example 5≫

For Example 5, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 69]

≪Example 6≫

For Example 6, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 70]

≪Example 7≫

For Example 7, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 71]

≪Example 8≫

For Example 8, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 72]

≪Example 9≫

For Example 9, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 73]

≪Example 10≫

For Example 10, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 74]

≪Example 13≫

For Example 13, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 75]

≪Example 15≫

For Example 15, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 76]

≪Example 16≫

For Example 16, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 77]

≪Example 17≫

For Example 17, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 78]

≪Example 18≫

For Example 18, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 79]

≪Example 19≫

For Example 19, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 80]

≪Example 22≫

For Example 22, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 81]

≪Example 23≫

For Example 23, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 82]

≪Example 24≫

For Example 24, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 83]

≪Example 25≫

For Example 25, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 84]

≪Example 26≫

For Example 26, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 85]

≪Example 27≫

For Example 27, the following table shows the recovery rate of the coated article. As a result of analyzing the obtained tablets with an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88 were obtained.

[Table 86]

≪Comparative Example 1≫

For Comparative Example 1, the obtained tablets were analyzed by an X-ray CT microscope to obtain the results of the volume ratio of the tablets shown in Table 87 and the volume ratio of the additives in the tablets shown in Table 88.

≪Analysis of the volume ratio of tablets in an X-ray CT microscope≫

For the tablet of 2 lots obtained in Example 1 and the tablet of 3 lots obtained in Comparative Example 1, the inside of the tablet was analyzed under the following conditions using an X-ray CT microscope nano3DX (Co., Ltd.) did.

Source: Mo

Voltage: 50 kV

Current: 24 mA

Pixel size: 8.64 μm/voxel

Number of shots: 1200

Shooting time: about 3 hours

Using the attached analysis software, the volume fraction of a cube having a side of 2 mm in the upper, middle and lower portions of the tablet divided into three was calculated. The RSDs of the volume fractions of the three cubes of the two-lot tablets obtained in Example 1 were 1.0 and 2.4, and the tablets of the present invention had high uniformity (Table 87).

For each one lot of tablets obtained in Examples 2 to 27, the inside of the tablet was analyzed under the following conditions using an X-ray CT microscope TDM1000H-II (2K) (Yamato Chemical Co., Ltd.).

Sailor: W

Voltage: 50 kV

Current: 0.085 mA

Pixel size: 12.7 μm/voxel

Number of shots: 700-1500 shots (optionally set according to the thickness of the tablet)

Shooting time: 10 minutes

Using the analysis software ImageJ, the volume fraction of a cube having a side of 2 mm in the upper, middle and lower portions of the tablet divided into three was determined (Table 87).

[Table 87]

≪Analysis of the volume ratio of additives in tablets in X-ray CT microscope≫

About the tablet obtained in the Example, the inside of a tablet was analyzed under the following conditions using the X-ray CT microscope TDM1000H-II(2K) (Yamato Chemical Co., Ltd.).

Sailor: W

Voltage: 40 kV (Example 1, Comparative Example 1), 50 kV (Examples 2 to 27)

Current: 0.095 mA (Example 1, Comparative Example 1), 0.085 mA (Examples 2 to 27)

Pixel size: 15.9 μm/voxel (Example 1), 14.4 μm/voxel (Comparative Example 1), 12.7 μm/voxel (Examples 2 to 27)

Number of shots: 700-1500 shots (optionally set according to the thickness of the tablet)

Shooting time: 30 minutes (Example 1, Comparative Example 1), 10 minutes (Examples 2 to 27)

For each of the tablets of Examples 1 to 27 and Comparative Example 1, the volume ratio of the additives of the five footnotes C, N, E, S, and W in FIG. 3 was calculated by the analysis software ImageJ. Based on the information on the brightness of 256 levels in the obtained image, since the distribution of the number of pixels of brightness equivalent to the spherical activated carbon takes a normal distribution, it is determined that the brightness is equal to or greater than the average value of the brightness plus 2.5 times the standard deviation. It was defined as an additive, and the ratio of the number of pixels was the additive area ratio, and the ratio of the number of pixels of the additive when the image was accumulated by a number corresponding to a predetermined thickness was the additive volume ratio (Fig. 6). Table 88 shows the values of the maximum and minimum values of the additive volume ratio in each footnote, and the ratio of the maximum and minimum values in the five footnotes. In addition, the variation from the upper surface to the lower surface of the additive area ratio and volume ratio at the position C of Comparative Example 1 is shown in FIG. 4.

As shown in Fig. 4, the volume ratio of the additive of the tablet obtained by the conventional associative method varied greatly between the upper and lower surfaces of the tablet.

[Table 88]

Industrial availability

The tablet of the present invention can be used as an adsorbent for oral administration for the treatment or prevention of kidney disease, or as an adsorbent for treatment or prevention of liver disease.

Claims (7)

A tablet comprising a spherical adsorbent for oral administration, a binding additive, and a surfactant,
The binding additive is pullulan, the content of the binding additive in the tablet is 2% by weight to 17% by weight,
The spherical sorbent for oral administration is coated with the binding additive and the surfactant, and each spherical sorbent for oral administration is bound through the coated binding additive, and the hardness of the tablet is 140 N to 350 N,
The volume ratio of the additive for binding of five footnotes, which is 1 mm from the upper surface to the lower surface, located at the center of the tablet when viewed from the upper surface and at the end of a straight line stretched from the center to the lower surface is X from the upper surface to the lower surface. When analyzed by a line CT microscope, the ratio of the maximum value and minimum value of the volume ratio of the binding additive per 1 mm ³ in five footnotes is 100 or less,
In each of the divided bodies obtained by dividing the length in the flat direction of the tablet into three equal parts, the volume ratio of a cube consisting of 2 mm on one side located at the center of the length in the flat direction and at the center of the tablet viewed from the top is X When analyzed with a line CT microscope, the relative standard deviation of the volume fraction of the cube of the three divisions is 5% or less,
The spherical sorbent carbon for oral administration is a spherical activated carbon,
The tablet, wherein the spherical activated carbon has an average particle diameter of 0.02 mm to 1 mm. delete delete delete delete (1) spraying a solution containing pullulan and a surfactant onto a spherical sorbent for oral administration to coat the spherical sorbent for oral administration with an additive for binding;
(2) a compression molding step of adding a solvent to the coated spherical adsorbent for oral administration and compression molding to obtain a molded article; And
(3) Step of drying the obtained molded article
A method for producing a tablet according to claim 1 comprising a. delete

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