TWI701055B - Tablet containing spherical adsorption carbon for oral administration and its manufacturing method - Google Patents

Abstract

The object of the present invention is to provide a tablet with high yield of spherical adsorbent carbon for oral administration, and high uniformity of spherical adsorbent carbon for oral administration and adhesive additives, and a manufacturing method thereof. The above-mentioned problem can be solved by the following tablet, which is characterized in that the ratio of the maximum value and the minimum value of the additive volume ratio per 1 mm ³ of the prescribed 5 prisms is 100 or less; The relative standard deviation of the volume rate of the cube is 5% or less; or the ratio of the maximum and minimum value of the additive volume rate per 1 mm ³ of the specified 5 prisms is 100 or less, and the volume of the cube of the specified 3 divisions The relative standard deviation of the rate is less than 5%.

Description

Tablet containing spherical adsorption carbon for oral administration and its manufacturing method

The present invention relates to a tablet containing spherical adsorbent carbon for oral administration and a manufacturing method thereof. According to the present invention, it is possible to provide a method for manufacturing a tablet having an excellent yield.

The adsorbent for oral administration can be taken orally, and treats renal dysfunction or liver dysfunction by adsorbing harmful substances in the digestive tract (Patent Document 1). In order to ensure that the spherical adsorption carbon for oral administration exerts the pharmacological effect of adsorbing harmful substances, it is important to maintain the spherical shape of the spherical adsorption carbon for oral administration and maintain its pore structure. The spherical adsorption charcoal for oral administration is sold as a brand name of "Kremezin (registered trademark) capsule 200 mg" and "Kremezin (registered trademark) granular 2 g" (hereinafter referred to as "Kremezin"), for example.

The daily dosage of Kremezin for patients with kidney disease is 6g, which is divided into 3 times, each dosage is 2g. The volume of 2g Kremezin granules is about 4cm ³ , and the volume to take is definitely a lot. Therefore, when taking 4cm ³ fine granules, the spherical activated carbon does not dissolve in water, so there is a rough feeling in the mouth, which some patients will not like.

On the other hand, Kremezin capsules do not produce roughness in the oral cavity. However, an ineffective volume other than the spherical activated carbon is formed in the capsule, so the volume of the capsule is approximately 1.5 times (about 6 cm ³ ) compared with the volume of the fine granule. Specifically, a capsule with a volume of about 0.613 cm ³ must be taken 10 capsules at a time, and some patients complain of taking too much.

In addition, in order to eliminate the roughness of the fine granules, or due to the large amount of capsules taken, many patients have to use a lot of water when taking the granules or capsules. In patients with kidney disease or renal insufficiency, some patients need to control their water intake. When these patients take fine granules or capsules, they require as little water as possible, which will prevent patients who originally need a lot of water. Bring great pain.

【Advanced Technical Literature】 【Patent Literature】

[Patent Document 1] Japanese Patent Publication No. 62-11611

[Patent Document 2] Japanese Patent Laid-Open No. 2006-8602

[Patent Document 3] International Publication No. 2012/121202

In order to solve the problem, the spherical adsorption carbon for oral administration can be made into tablets. However, the spherical adsorption charcoal for oral administration is different from ordinary drugs and cannot be tableted and molded by compression or the like (Patent Document 2). That is, the spherical adsorbent carbon for oral administration is very hard like glass, lacks deformability, and has a fragile nature. If it is punched and molded, the spherical adsorbent carbon for oral administration is destroyed and cannot maintain its spherical shape. .

The inventors of the present invention have discovered that by using a kneading method using an additive for granular preparations with film-forming ability, it is possible to produce practically usable spherical adsorbent carbon-containing materials for oral administration. Tablets (Patent Document 3). However, when using the kneading method to manufacture tablets, the yield of spherical activated carbon is low. In addition, the uniformity of the spherical adsorption carbon for oral administration and the additives for binding of tablets obtained by the kneading method is poor. In addition, the adsorption amount of DL-β-aminoisobutyric acid of tablets obtained by the kneading method may be lower than that of granules or capsules.

Therefore, the object of the present invention is to provide a tablet with high yield of spherical adsorbent charcoal for oral administration and high uniformity of spherical adsorbent charcoal for oral administration and adhesive additives, and a manufacturing method thereof.

The inventors of the present invention conducted in-depth studies on tablets with high yield of spherical adsorbent carbon for oral administration and good uniformity of spherical adsorbent carbon for oral administration and binding additives and the manufacturing method thereof, and surprisingly found , By spraying or dropping the solution containing the adhesive additive onto the spherical adsorption carbon for oral administration, and manufacturing tablets by compression molding method, the yield rate of the spherical adsorption carbon for oral administration can be greatly improved, and then The uniformity of the spherical adsorption charcoal for oral administration and the additives for bonding has also been greatly improved.

The present invention was obtained based on the above knowledge.

Therefore, the present invention relates to a tablet and a method for manufacturing the tablet.

[1] A tablet containing additives and spherical adsorption charcoal for oral administration, characterized in that the center portion of the tablet when observed from above with an X-ray CT microscope, and the location extending from the center to the four directions When analyzing the volume ratio of the additive of 5 prisms with a side length of 1mm from top to bottom at the end of the straight line from top to bottom, the ratio of the maximum and minimum volume ratio of the additive per 1mm ³ of the 5 prisms is Below 100.

[2] A tablet containing additives and spherical adsorption charcoal for oral administration, characterized in that each divided body divided into three equal lengths in the flat direction of the tablet is subjected to X-ray CT When a microscope analyzes the volume ratio of a cube with a side length of 2 mm located at the center of the flat direction length and at the center of the tablet viewed from above, the relative standard deviation of the volume ratio of the cubes of three divided bodies is 5% or less.

[3] A tablet containing additives and spherical adsorption charcoal for oral administration, characterized in that the center portion of the tablet when observed from above with an X-ray CT microscope, and the location extending from the center to the four directions When the volume ratio of the additive of 5 prisms with a side length of 1mm from top to bottom at the end of the straight line is analyzed from top to bottom, the ratio of the maximum and minimum additive volume ratios per 1mm ³ of the 5 prisms is 100 or less; in each of the divided bodies in which the length of the tablet is divided into 3 equal parts, an X-ray CT microscope is used to examine a cube with a side length of 2 mm located in the center of the length in the flat direction and at the center of the tablet viewed from above When analyzing the volume ratio of the three divided cubes, the relative standard deviation of the volume ratio of the cube is 5% or less.

[4] The tablet according to any one of [1] to [3], wherein the additive is selected from sodium alginate, propylene glycol alginate, carboxymethyl cellulose, and calcium carboxymethyl cellulose , Ghatti gum, carrageenan, carboxyvinyl polymer, sodium carboxymethyl cellulose, xanthan gum, guar gum, quince seed gum, glucomannan, copovidone, gellan gum, gelatin , Tamarind gum, tara gum, dextran, corn starch, tragacanth gum, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan Polysaccharides, poly Vividone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyethylene glycol 6000, ethyl cellulose, methyl cellulose, phosphoric acid cross-linked starch, locust bean Gum, agar, winter plum powder, fully pregelatinized starch, crystalline cellulose sodium methylcellulose, oxidized starch, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sugars, and sugar alcohols Adhesive additives in

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

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

[7] A method for manufacturing a tablet, characterized in that it comprises: (1) a compound selected from sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethyl cellulose, gum ghatti, keratin Chakra gum, carboxyvinyl polymer, sodium carboxymethyl cellulose, xanthan gum, guar gum, quince seed gum, glucomannan, copovidone, gellan gum, gelatin, tamarind gum, other Pull gum, dextran, corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, Polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyethylene glycol 6000, ethyl cellulose, methyl cellulose, phosphoric acid cross-linked starch, locust bean gum, agar , Winter plum powder, fully pregelatinized starch, crystalline cellulose sodium methylcellulose, oxidized starch, low degree of substitution hydroxypropyl cellulose, partially pregelatinized starch, sugars, and sugar alcohols Spray or drop the solution of additives onto the spherical adsorption carbon for oral administration, and cover the manufacturing process of the spherical adsorption carbon for oral administration with the adhesive additive; (2) To the covered oral administration The spherical adsorption carbon is used to add a solvent, and then compression molding is performed to obtain a compression molding process of the molded body; and (3) a process of drying the obtained molded body.

According to the method for manufacturing a tablet containing 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 used can be improved. In addition, the tablet containing spherical adsorbent carbon for oral administration obtained by the manufacturing method of the present invention can prevent the local distribution of spherical adsorbent carbon for oral administration and adhesive additives, and improve the spherical adsorbent carbon for oral administration and The uniformity of bonding additives. Therefore, the hardness of the obtained tablet is improved. In addition, the above-mentioned tablet can show excellent adsorption capacity of DL-β-aminoisobutyric acid. That is, according to the tablet manufacturing method of the present invention, compared with the kneading method described in Patent Document 3, the yield and hardness of the spherical adsorption carbon for oral administration in the tablet manufacturing method can be improved, and it is also expected to improve DL -The adsorption capacity of β-aminoisobutyric acid.

According to the tablet of the present invention, it is possible to provide a tablet that can be reduced in volume compared with a capsule and has improved administrability. That is, in the case of taking capsules, 10 capsules with a volume of about 0.613 cm ³ must be taken at a time. Some patients complain that the dosage is too much. In this regard, the tablet of the present invention can reduce the volume to 65% of the capsule ( Approximately 4cm ³ ), the ease of use is improved. In addition, according to the tablet of the present invention, it is possible to provide a tablet that has improved ingestibility disadvantages such as roughness and astringency compared with fine granules. According to the tablet of the present invention, it is possible to provide a tablet that maintains the spherical shape of the spherical adsorption carbon for oral administration, does not destroy the pore structure, and can fully exhibit the function of the adsorbent for oral administration.

Fig. 1 is a diagram schematically showing the positions of three cubes for analyzing the tablet volume ratio in the tablet of the present invention from the upper surface (A) and the side surface (B).

2 is an X-ray CT microscope (nano3DX) analysis image showing the local distribution of additives in the tablet (A) obtained by the manufacturing method of the present invention and the tablet (B) obtained by the conventional kneading method.

Fig. 3 is a diagram schematically showing the positions of five prisms for analyzing the volume ratio of additives in the tablet of the present invention from the top (A) and the side (B).

Fig. 4 is a graph showing the change when the volume ratio of the additive of the tablet of the present invention is analyzed from top to bottom using an X-ray CT microscope.

Fig. 5 is a photograph showing that the spherical activated carbon manufactured by the kneading method remains in the stirring granulator (A) and adheres to the molding die (B).

Fig. 6 is a graph and a photograph of the difference between the additive and the spherical activated carbon when the volume ratio of the additive is calculated by the analysis software ImageJ based on the 256-level brightness information.

[1] Tablets containing spherical adsorption charcoal for oral administration

The tablet containing spherical adsorption charcoal for oral administration of the present invention contains a binding additive. The above-mentioned adhesive additives are preferably selected from sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethyl cellulose, gum ghatti, carrageenan, carboxyvinyl polymer, sodium carboxymethyl cellulose, Xanthan gum, guar gum, quince seed gum, glucomannan, copovidone, gellan gum, gelatin, tamarind gum, tara gum, dextran, corn starch, tragacanth gum, hyaluronic acid Sodium, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl fiber Vitamin, hypromellose, pullulan, povidone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyethylene glycol 6000, ethyl Cellulose, methyl cellulose, phosphoric acid cross-linked starch, locust bean gum, agar, winter plum powder, fully pregelatinized starch, crystalline cellulose sodium methylcellulose, oxidized starch, low-substituted hydroxypropyl cellulose, part Choose from the group consisting of pregelatinized starch, sugars, and sugar alcohols. In addition, the spherical adsorption carbon for oral administration is preferably spherical activated carbon.

"Spherical adsorption charcoal for oral administration"

Spherical adsorption carbon for oral administration is not particularly limited as long as it is medically usable spherical adsorption charcoal for oral administration, but it is preferably spherical activated carbon for oral administration, that is, spherical activated carbon for oral administration. Activated carbon. In addition, in this specification, as an example of spherical adsorption carbon for oral administration, spherical activated carbon may be used for description.

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 still more preferably 0.05 to 0.80 mm. In addition, 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 still more preferably 0.03 to 1 mm.

The BET specific surface area of the "spherical activated carbon" 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, and even more preferably 1300 m ² /g or more, particularly preferably 1650 m ² /g or more.

The spherical adsorption carbon for oral administration (for example, spherical activated carbon) contained in the tablet maintains its pore structure and exerts the pharmacological effect of adsorbing harmful substances, and its form is preferably a spherical shape that maintains the spherical adsorption carbon for oral administration. . That is, since the adsorption capacity of toxic substances, such as selective adsorption rate, is affected by the diameter, average particle diameter, specific surface area, and pore volume within a specified pore diameter range, it is preferable to maintain the spherical adsorption carbon for oral administration. A spherical shape that is not damaged and affects the diameter or average particle size, and maintains a pore structure that affects the contrast surface area and pore volume. Furthermore, by maintaining the spherical shape, side effects such as constipation can be prevented.

"additive"

The additives used in the tablet of the present invention contain adhesive additives. By containing additives for bonding, tablets with high uniformity and excellent strength can be obtained.

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

(Content of additives)

The weight ratio of the spherical adsorbent carbon for oral administration (for example, spherical activated carbon) to the additive is not particularly limited as long as the effect of the present invention can be obtained. For example, the additive is preferably 1 to 35% by weight, more preferably 1.5 to 35. % By weight, 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, a tablet with high uniformity can be obtained. When the amount of the additive is too small, it sometimes becomes difficult to form a tablet. In addition, if there are too many additives, the volume of the tablet may be larger and the dosage of the tablet may be larger.

"Uniformity of Volume Rate of Tablets"

The tablet of the present invention has a uniform volume ratio in the tablet. That is, the tablet of the present invention contains spherical adsorbent carbon (for example, spherical activated carbon) for oral administration as an effective ingredient when compared with a tablet containing a common compound as an active ingredient. Therefore, it is clear from Fig. 1 etc. , There are gaps between the spherical adsorption carbon for oral administration. If there are portions with dense voids and portions with sparse voids, the hardness, abrasion, etc. of the tablet may decrease. In other words, if the volume ratio of the spherical adsorption carbon for oral administration and additives in the tablet is not uniform, the hardness, the degree of abrasion, etc. of the tablet may decrease. That is, the volume ratio of the tablet is uniform, and the hardness and abrasion of the tablet can be improved.

The uniformity of the volume ratio of the tablet of the present invention can be specified by the following method, for example. That is, in each divided body that divides the length of the tablet in the flat direction into 3 equal parts, the volume ratio of a cube with a side length of 2 mm at the center of the length in the flat direction and at the center of the tablet viewed from above is measured with an X-ray CT microscope When parsing, if 3 If the relative standard deviation of the volume ratio of the cube of each divided body is 5% or less, it can be judged that the uniformity of the tablet is good.

As shown in Figure 1, the tablet has a flat shape in addition to the spherical pill. Fig. 1(A) shows the flat tablet viewed from above, and Fig. 1(B) shows the flat tablet viewed from the side. When viewing the tablet from above, most of the tablets are round, oval, quadrilateral, or rectangular as shown in Figure 1(A), but the tablets usually have a symmetrical shape, such as the square dotted line in Figure 1(A) As shown, "the cube in the center of the tablet viewed from above" can be specified. In addition, when viewing a flat tablet from the side, as shown in Figure 1(B), the length in the flat direction can be divided into three equal parts to form divided bodies. In each divided body, as shown by the dotted line, you can specify The length of the central cube". Therefore, it is possible to specify "3 cubes with a side length of 2 mm located at the center of the length in the flat direction and at the center of the tablet viewed from above". In addition, when the tablet is a spherical pill, the flatness direction can be set to any direction, and the "center of the length in the flatness direction" and "the center of the tablet viewed from above" can be designated.

The three cubes can be analyzed using an X-ray CT microscope to calculate the volume ratio of each cube. Moreover, if the calculated relative standard deviation of the volume ratio of the three cubes is less than 5%, it is determined that the uniformity of the tablet is good.

In addition, when the length of the tablet in the flat direction is less than 6 mm, the three cubes with a side length of 2 mm may partially overlap. However, when three cubes overlap, the relative standard deviation of the volume ratio of the three divided cubes can still be calculated. If the relative standard deviation is 5% or less, it can be determined that the uniformity of the tablet is good.

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, the better the uniformity, which can improve the hardness or abrasion of the tablet. Therefore, the lower limit of the relative standard deviation of the volume ratio is most preferably 0% or more, and in actual use, it can be 0.1% or more, 0.3% or more, or 0.4% or more. The range of the relative standard deviation of the volume ratio may be, for example, 0.1 to 5%, 0.3 to 4.7%, or 0.4 to 4.5%.

"The uniformity of local distribution of additives"

In the tablet of the present invention, the distribution of additives in the tablet is uniform, that is, compared with the conventional spherical activated carbon-containing tablets, the uniformity of the volume ratio of the additives in the tablet of the present invention is excellent. For example, as shown in Figure 2(B), in the tablet containing spherical activated carbon obtained by the kneading method in the past, the additives are located near the upper surface of the tablet (the additives are shown in white), and the uniformity of the additives is poor. . When the additives are in a certain place, the hardness or abrasion of the tablet may decrease. In other words, if the volume ratio of the additive in the tablet is not uniform, the hardness or abrasion of the tablet may decrease. That is, the volume ratio of the additive is uniform, and the hardness and abrasion of the tablet can be improved.

The uniformity of the volume ratio of the additive of the present invention can be specified by the following method, for example. Using an X-ray CT microscope to observe the center of the tablet from the top, and the volume ratio of the additive of 5 prisms with a side length of 1 mm from top to bottom at the straight end extending from the center to the square, from top to bottom. In the analysis, if the ratio of the maximum value and the minimum value of the additive volume ratio per 1 mm ³ of the five prisms is 100 or less, it can be determined that the uniformity of the additive distribution is good. That is, in the tablet of the present invention, the ratio of the maximum value and the minimum value of the additive volume ratio of the five prisms is 100 or less. On the other hand, in a conventional tablet, the ratio of the maximum value and the minimum value of the additive volume ratio of the five prisms exceeds 100, so the hardness, abrasion, etc. of the tablet are reduced.

As shown in Fig. 3, the tablet has a flat shape except for the spherical pill. Fig. 3(A) shows the flat tablet viewed from above, and Fig. 3(B) shows the flat tablet viewed from the side. When viewing the tablet from above, most of the tablets are round, oval, quadrilateral, or rectangular as shown in Figure 3(A), but the tablets usually have a symmetrical shape, as shown by the dotted line of C square in Figure 3(A) You can specify "Prism at the center when viewed from above". In addition, it is possible to specify the "prism at the end of a straight line extending from the center to the four directions" shown by the dotted lines in the squares of N, E, S, and W in FIG. 3(A). In addition, when the flat tablet is viewed from the side, as shown by the broken line in FIG. 3(B), the prisms are located from the upper surface to the lower surface of the tablet in the flat direction. Therefore, it is possible to specify "the prism at the center when viewed from above" and "the prism at the end of a straight line extending from the center of the tablet in all directions".

An X-ray CT microscope can be used to analyze the five prisms from top to bottom, and calculate the volume ratio of the additives of each prism. Furthermore, the additive volume ratio per 1 mm ³ can be calculated at any position of the prism, and the maximum and minimum additive volume ratios per 1 mm ³ can be obtained.

In the present invention, if the ratio of the maximum value and the minimum value of the additive volume ratio per 1 mm ³ is 100 or less, it can be determined that the uniformity of the additive distribution is good, and 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, which can improve the hardness or abrasion of the tablet. Therefore, the lower limit of the ratio of the maximum value to the minimum value is most preferably 1 or more, and in actual use, it may be 2 or more, 4 or more, or 6 or more. The range of the ratio of the maximum value to the minimum value may be, for example, 1 to 100, 2 to 99, 4 to 98, or 6 to 96.

In addition, depending on the shape of the tablet, the height of the prisms at the positions N, E, S, and W may be lower than the prisms at the C position, but in this case, the volume ratio of the additive per 1 mm ³ can be measured from the top To the following additive volume rate, the "ratio of the maximum and minimum additive volume rate" can be calculated.

(X-ray CT microscope)

The X-ray CT microscope for analyzing the volume ratio of tablets and the volume ratio of additives of the present invention is capable of performing planar (2D) or three-dimensional (2D) or three-dimensional ( 3D) Observation device. It is possible to analyze the fine structure of materials or tablets with high resolution. For example, as described in this example, it is possible to analyze the volume rate of a tablet composed of spherical activated carbon and additives, or analyze only the volume rate of additives.

As the X-ray CT microscope, commercially available "nano3DX (high resolution 3DX ray microscope: Rigaku Co., Ltd." and "three-dimensional measurement X-ray CT device TDM series: Yamato Scientific Co., Ltd." can be used. The device has a high resolution of 1 μm or less Degree, you can use the software attached to the device, or image processing software ImageJ, etc., to calculate the volume rate of the tablet or the volume rate of the additive.

(Adhesive additives)

The adhesive additive used in the tablet of the present invention contains: sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethyl cellulose, gum ghatti, carrageenan, carboxyvinyl polymer, Sodium carboxymethyl cellulose, xanthan gum, guar gum, quince seed gum, glucomannan, copovidone, gellan gum, gelatin, tamarind gum, tara gum, dextran, corn starch , Tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyethylene oxide, polyvinyl alcohol , Polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyethylene glycol 6000, ethyl cellulose, methyl cellulose, phosphoric acid cross-linked starch, locust bean gum, agar, winter plum powder, fully pregelatinized starch , Crystalline cellulose sodium methylcellulose, oxidized starch, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sugars, ethyl sugar alcohols, or combinations thereof. The spherical adsorbent carbon for oral administration is covered with an adhesive additive, and the adhesive additive allows the tablet of the present invention in which each spherical adsorbent carbon for oral administration is bonded to have a hardness of 105 N or more.

(Other additives)

The additives that can be used as additives (other additives) other than the adhesive additives will be described below.

Additives commonly used in pharmaceuticals are described in "Drug Additives Reference 2016", and examples include excipients, lubricants, disintegrating agents, surfactants, and binding agents. The functions of excipients, lubricants, disintegrating agents, and binding agents are not necessarily single. For example, crystalline cellulose classified as excipients also functions as a disintegrating agent in most cases. In addition, it also functions as a disintegrant in direct tableting. The function of the binder to improve the formability can. Therefore, the functions of excipients, lubricants, disintegrating agents, and binders may be repeated. Examples of excipients, lubricants, disintegrating agents, and binders are listed below, but additives that are not classified as these additives can be used as other additives.

Excipients are additives mainly used for augmentation (extender) or dilution (diluent), and specifically include starch, dibasic calcium phosphate, synthetic aluminum silicate, or magnesium trisilicate.

In addition, the binding agent is an additive used to impart binding force to the main drug and extender and to form it. It can be used to maintain the dosage form, prevent damage during packaging and transportation, and improve mechanical strength. Specifically, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, powdered cellulose, hypromellose, methyl cellulose, hydroxypropyl cellulose, starch, Fully pregelatinized starch, partially pregelatinized starch, dextran, acacia, sodium alginate, tragacanth, refined gelatin, polyvinyl alcohol, or povidone, etc.

Furthermore, the disintegrating powder is an additive used to infiltrate the digestive tract when taking a tablet to disintegrate and disperse the preparation into fine particles. Specifically, carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, powdered cellulose, starch, sodium carboxymethyl starch, or hydroxypropyl Base starch, etc.

Lubricants are additives that have the function of improving powder fluidity, filling, adhesion, and moldability during tableting, and can be used to improve tablet quality and manufacturing efficiency. Specifically, sucrose fatty acid ester, talc, magnesium stearate, stearic acid, etc. can be mentioned.

Surfactants include alkyl aryl polyether alcohols, higher alcohol sulfates, N-coconut oil-L-arginine ethyl ester DL-pyrrolidone carboxylate, N-coco oil-N-methyl gum base Sodium ethanesulfonate, cholesterol, self-emulsifying glycerol monostearate, sucrose fatty acid ester, squalane, stearyl alcohol, polyethylene glycol 40 stearate, cetyl alcohol, cetrol 1000, Diethyl sebate, sorbitan fatty acid ester, sorbitan sesquioleate, sodium dodecylbenzene sulfonate, sorbitan trioleate, nonylphenoxy polyoxyethylene Ethane sulfate ammonium liquid, polyoxyethylene octyl phenyl ether, polyoxyethylene oleylamine, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 60, polyoxyethylene stearyl alcohol ether, polyoxyethylene whale Wax alcohol ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitol 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) polyoxy Propylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl alcohol ether, polyoxyethylene (2 EO) sodium laureth ether sulfate (70%), polyethylene glycol 35 castor oil, poly Sorbate 20, Polysorbate 60, Polysorbate 80, Polyethylene Glycol 400, Sorbitan Monooleate, Glycerol Monostearate, Sorbitan Monostearate, Sorbitan Monolaurate, N-coconut oil fatty acid ester L-arginine ethyl ester-DL-pyrrolidone carboxylate, lauryl dimethyl amine oxide liquid, lauryl pyrrolidone, sodium lauryl sulfate, lauric acid diethanolic acid Gum, sodium lauryl sarcosinate, lauryl alcohol, sodium laureth phosphate or oleyl alcohol polyoxyethylene ether phosphate (8MOL), etc.

(Content of bonding additives)

The weight ratio of spherical adsorbent carbon (for example, spherical activated carbon) for oral administration to the adhesive additive is not particularly limited as long as the effect of the present invention can be obtained, but the content of the adhesive additive of the tablet of the present invention is preferably 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 bonding additive is too small, the hardness of the obtained tablet may decrease. The upper limit of the adhesive additive is not limited, but the adhesive additive is preferably 35% by weight or less, more preferably 30% by weight or less, and still more preferably 25% by weight or less. If there are too many additives for bonding, the volume of the tablet may be larger and the dosage of the tablet may be larger. From the viewpoint that the hardness of the obtained tablet is easily 105N or more, the content of the adhesive additive of 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) ), more preferably 1.5 to 30% by weight (alternatively, 1.5 to 25% by weight or 1.5 to 20% by weight), and even more preferably 2 to 25% by weight (or, 2 to 20% by weight or 2 to 17% by weight) % Can also).

In addition, the tablet of the present invention may contain other additives as an additive. The weight ratio of the adhesive additive to other additives is not particularly limited as long as the effects of the present invention can be obtained, but it is preferably relative to 100 parts by weight of the adhesive additive. The additive is preferably 10000 parts by weight or less, more preferably 1000 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 much, the hardness of the obtained tablet may decrease. In addition, the lower limit of the above-mentioned weight ratio is not particularly limited, and the content of other additives relative to 100 parts by weight of the adhesive additive may be, for example, 0.1 parts by weight or more, 1 part by weight or more, or 10 parts by weight or more.

〔2〕Method for manufacturing tablets

The manufacturing method of the tablet of the present invention includes the following manufacturing process: (1) It contains selected from sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethyl cellulose, gum ghatti, carrageenan, Carboxy vinyl polymer, sodium carboxymethyl cellulose, xanthan gum, guar gum, quince seed gum, glucomannan, copovidone, gellan gum, gelatin, tamarind gum, tara gum, grape Glycan, corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyethylene oxide Alkyl, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyethylene glycol 6000, ethyl cellulose, methyl cellulose, phosphoric acid cross-linked starch, locust bean gum, agar, winter plum powder, Adhesive additives in the group consisting of fully pregelatinized starch, crystalline cellulose methylcellulose sodium, oxidized starch, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sugars, and sugar alcohols Spray or drop onto the spherical adsorbent carbon for oral administration (for example, spherical activated carbon), and cover the manufacturing process of the spherical adsorbent carbon for oral administration with adhesive additives; (2) To the covered oral administration The spherical adsorption carbon is used to add a solvent, and then compression molding is performed to obtain a compression molding process of the molded body; and (3) a process of drying the obtained molded body.

As the "adhesive additive" used in the method of manufacturing the tablet of the present invention, the adhesive additive described in the section "[1] Tablets containing spherical adsorption carbon for oral administration" can be used.

"Covering Process (1)"

Covering method (1) will contain selected from sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethyl cellulose, gum ghatti, carrageenan, carboxyvinyl polymer, carboxymethyl cellulose Sodium, xanthan gum, guar gum, quince seed gum, glucomannan, copovidone, gellan gum, gelatin, tamarind gum, tara gum, dextran, corn starch, tragacanth, Sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol- Acrylic acid-methyl methacrylate copolymer, polyethylene glycol 6000, ethyl cellulose, methyl cellulose, phosphoric acid cross-linked starch, locust bean gum, agar, winter plum powder, fully pregelatinized starch, crystalline cellulose The solution of adhesive additives in the group consisting of sodium base cellulose, oxidized starch, low degree of substitution hydroxypropyl cellulose, partially pregelatinized starch, sugars, and sugar alcohols is sprayed onto spherical adsorption charcoal for oral administration (For example, spherical activated carbon), the spherical adsorbent carbon for oral administration is covered with adhesive additives. As the covering method, a spray method is used. Examples of the spray method include a top spray method, a tangential spray method, a bottom spray method, or a side spray method.

For example, when using the top spray method, the adhesive additives and other additives are dissolved in the solvent to prepare the spray liquid. Then, for example, the spherical adsorbent carbon for oral administration is put into a rotary flow coating device or a fluidized bed granulation device, and spray liquid mist is sprayed from the upper part.

The solvent used for spraying is not particularly limited. All organic solvents that can be used as pharmaceutical additives can be used. For example, water, acetic acid, acetone, anisole, 1-butanol, 2-butanol can be used. , N-butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfene, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, acetic acid Methyl ester, 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-di Vinyl chloride, dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, methyl Amide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, N-methyl pyrrolidone, nitromethane, pyridine, cyclobutylene, tetralin, toluene, 1, 1,2-Trichloroethylene or xylene, etc. In addition, the surfactant is not particularly limited, and examples include alkyl aryl polyether alcohols, higher alcohol sulfates, N-coconut oil-L-arginine ethyl ester DL-pyrrolidone carboxylate, and N-coco oil Sodium-N-methylaminoethanesulfonate, cholesterol, self-emulsifying glycerol monostearate, sucrose fatty acid ester, squalane, stearyl alcohol, polyethylene glycol 40 stearate, cetyl alcohol , Polycetol 1000, diethyl sebanoate, sorbitan fatty acid ester, sorbitan sesquioleate, sodium dodecylbenzene sulfonate, sorbitan trioleate, nonane Base phenoxy polyoxyethylene ethane sulfate ammonium liquid, polyoxyethylene octyl phenyl ether, polyoxyethylene oleylamine, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 60, polyoxyethylene stearin Alcohol ether, polyoxyethylene cetyl alcohol ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitol beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) ) Glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (124) polyoxypropylene (39) glycol, poly Ethylene oxide (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl alcohol ether, polyoxyethylene (2 EO) sodium laureth ether sulfate (70%), polyethylene Glycol 35 castor oil, polysorbate 20, polysorbate 60, polysorbate 80, polyethylene glycol 400, sorbitan monooleate, glycerol monostearate, sorbitan monostearate Ester, sorbitan monolaurate, N-coconut oil fatty acid Base L-arginine ethyl ester. DL-pyrrolidone carboxylate, lauryl dimethyl amine oxide solution, lauryl pyrrolidone, sodium lauryl sulfate, diethanolamide laurate, sodium lauryl sarcosinate, lauryl alcohol, polyoxyethylene lauryl ether phosphate Sodium or oleyl alcohol polyoxyethylene ether phosphate (8MOL), etc.

The amount of the adhesive additive relative to the amount of the solvent is not particularly limited as long as the adhesive additive substantially uniformly covers the spherical adsorbent carbon for oral administration (for example, spherical activated carbon). The amount of the adhesive additive is preferably 0.01 to 100w/v%, more preferably 0.1 to 50w/v%, still more preferably 1 to 15w/v%.

"Compression Molding Process (2)"

The compression molding process (2) adds a solvent to the covered spherical adsorption carbon (for example, spherical activated carbon) for oral administration, and then performs compression molding. For example, a solvent is added to the covered spherical adsorption carbon for oral administration, and after compression molding, a tablet with a strength of 105N or more can be obtained by drying.

As the solvent, an organic solvent, water, or a mixture thereof can be mentioned. The volume ratio of the organic solvent to the water in the mixed liquid 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 still more preferably 30:70 to 70 : 30. Within this range, the adhesive additive that covers the spherical adsorption carbon for oral administration can be saturated with water.

(Organic solvent)

The organic solvent that can be used in the production method is not particularly limited as long as the effects of the present invention can be obtained. For example, acetic acid, acetone, anisole, 1-butanol, 2-butanol, and n-butyl acetate can be cited. , Tert-butyl methyl ether, cumene, dimethyl sulfide, 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-dichloroethylene, methylene chloride, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane Cyclo, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, N-methylpyrrolidone, nitromethane, Pyridine, cyclobutylene, tetralin, toluene, 1,1,2-trichloroethylene or xylene, etc.

"Drying Process (3)"

In the method for producing a tablet of the present invention, the obtained molded body is dried. The drying method is not limited as long as the solvent of the molded body evaporates. For example, freeze drying, reduced-pressure drying, air-blast drying, natural drying, or heat drying can be cited.

For example, when heating and drying are used, the heating temperature is not particularly limited. For example, it is preferably 50 to 200°C, and preferably 80 to 180°C. 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 higher, the heating time can be shortened, and those skilled in the industry can appropriately determine the heating temperature and heating time.

In addition, the moisture content of the tablet obtained by the drying process (3) is not particularly limited, and 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 through examples, but the description is not intended to limit the scope of the present invention.

"Production Example 1: Production of Porous Spherical Carbonaceous Material"

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

Put 68kg of petroleum-based asphalt (softening point 210℃; quinoline insoluble matter below 1% by weight; H/C atomic ratio 0.63) and 32kg naphthalene into a pressure vessel with a stirring blade and an inner volume of 300L, at 180℃ After being melt-mixed, it is cooled to 80 to 90°C and extruded to obtain a rope-shaped molded body. Next, the rope-shaped molded body is broken into a ratio of about 1 to 2 in diameter to length.

The crushed material is added to an aqueous solution that dissolves 0.23% by weight of polyvinyl alcohol (88% of saponification degree) and is heated to 93°C. After stirring and dispersing to spheroidize, it is cooled by replacing the polyvinyl alcohol aqueous solution with water. Cooled at 20°C for 3 hours to solidify the pitch and crystallize naphthalene to obtain a spherical pitch molded body paste.

After removing most of the water by filtration, the naphthalene in the pitch molded body is extracted and removed with n-hexane, which weighs about 6 times the weight of the spherical pitch molded body. While using the fluid bed The porous spherical pitch was heated to 235°C by passing heated air, and then kept at 235°C for 1 hour to oxidize to obtain porous spherical oxidized pitch that does not melt when heated.

Then, the porous spherical oxidized pitch was activated for 170 minutes at 900°C using a fluid bed in a nitrogen environment containing 50 vol% water vapor to obtain porous spherical activated carbon, and then the fluid bed was used at an oxygen concentration of 18.5 vol% The porous spherical activated carbon was oxidized at 470°C for 3 hours and 15 minutes in a mixed gas environment of nitrogen and oxygen, and then reduced in a fluid bed at 900°C for 17 minutes in a nitrogen environment to obtain porous balls Like carbonaceous material. In the following pharmacological test examples, the porous spherical carbonaceous material thus obtained was used as the spherical activated carbon.

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

Specific surface area 1300m ² /g (BET method); pore volume 0.08mL/g

(The pore diameter calculated by mercury intrusion method is the pore volume in the range of 20 to 15000nm); the average particle size is 350μm; the total acid base is 0.67meq/g; the total base is 0.54meq/g; the crush strength is 31.2MPa; And the deformation rate when 2MPa pressure is applied is 0.7%.

"Production Example 2: Production of Porous Spherical Carbonaceous Material"

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

Put 220g of deionized exchange water and 58g of methylcellulose into a 1L separable flask, and add 105g of styrene and 184g of divinylbenzene (57% divinylbenzene and 43%) with a purity of 57% into the separable flask. Of vinyl ethyl benzene), 1.68g of 2,2'-azobis(2,4-dimethylvaleronitrile), and 63g of 1-butanol as a pore-forming agent, then replace the inside of the system with nitrogen to The two-phase system was stirred at 200 rpm, and after heating to 55°C, the state was maintained for 20 hours. The obtained resin was filtered, dried with a rotary evaporator, 1-butanol was removed from the resin by distillation using a vacuum dryer, and then dried under reduced pressure at 90°C for 12 hours to obtain a ball with an average particle diameter of 180μm Shape porous synthetic resin. The specific surface area of the porous synthetic resin is approximately 90 m ² /g.

Put 100 g of the obtained spherical porous synthetic resin into a reaction tube with a porous disk, and perform a non-melting treatment in a vertical tubular furnace. The non-melting conditions were as follows. Dry air was flowed from the lower part of the reaction tube to the upper part at 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. After the spherical porous oxide resin is heat-treated at 600°C for 1 hour in a nitrogen environment, using a fluid bed, an activation treatment is performed at 820°C for 10 hours in a nitrogen environment containing 64.5vol% water vapor to obtain a spherical shape. Activated carbon. Furthermore, a fluid bed was used to oxidize the obtained spherical activated carbon at 470°C for 3 hours and 15 minutes in a mixed gas environment of nitrogen and oxygen with an oxygen concentration of 18.5 vol%, and then a fluid bed was used at 900°C in a nitrogen environment. The reduction treatment was carried out for 17 minutes to obtain surface-modified spherical activated carbon.

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

Specific surface area 1763m ² /g (BET method); pore volume 0.05mL/g

(The pore diameter is the pore volume in the range of 20 to 15000nm, as determined by mercury intrusion method); average particle size 111μm (Dv50); total acid groups 0.59meq/g; total bases 0.61meq/g; bulk density 0.50 g/cm ³ ; crushing strength 436.5MPa; and the deformation rate when 2MPa pressure is applied 0.2%.

In addition, in this specification, although there is no description of an example of producing a tablet using the spherical activated carbon obtained in Production Example 2, the tablet 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 spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 1 was sprayed. Then, it dried to obtain 535.5 g of mulch. After adding an ethanol/water mixed solution (6:4) at a ratio of 1 g of the covering product to 1.2 mL to the obtained covering product, it was molded using a low-pressure forming machine and dried to obtain tablets with a diameter of 15 mm.

Table 2 shows the recovery rate of the covering product. The recovery rate (%) of mulch is calculated by the amount of mulch obtained/theoretical amount of mulch×100. The higher the above recovery rate, the higher the harvest rate of the spherical adsorption charcoal for oral administration.

After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 2"

500 g of the spherical activated carbon obtained in Production Example 1 was put into the rotary flow coating device (MP-01), and the spray mist of the prescription shown in Table 3 was sprayed. Then, it dried to obtain 751.78 g of mulch. Corresponds to 1.2 of the obtained coverings with 1g coverings After adding an ethanol/water mixed solution (6:4) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 4 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 3"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 5 was sprayed. Then, it dried to obtain 512.5 g of mulch. Fill the obtained coverings into Teflon (registrar Standard) Forming mold (diameter 12mm, depth 10.2mm, R16mm), after adding water at a ratio of 1g covering to 0.9mL, gently compress it with a molding rod attached to the mixer to trim the surface of the tablet and dry it , Thereby obtaining tablets with a diameter of 12 mm.

Table 6 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 4"

500 g of the spherical activated carbon obtained in Production Example 1 was put into the rotary flow coating device (MP-01), and the spray mist of the prescription shown in Table 7 was sprayed. Then, dry After drying, 500.0 g of mulch was obtained. After adding an ethanol/water mixture (4:6) at a ratio of 1 g of the covering product to 1.9 mL to the obtained covering product, it was molded using a low-pressure molding machine and dried to obtain a tablet with a diameter of 12 mm.

Table 8 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 5"

500 g of the spherical activated carbon obtained in Production Example 1 was put into the rotary flow coating device (MP-01), and the spray mist of the prescription shown in Table 9 was sprayed. Then, it dried to obtain 506.8 g of mulch. Corresponds to 1.4 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (5:5) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 10 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 6"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 11 was sprayed. Then, it dried to obtain 564.4 g of mulch. Corresponds to 1.1 of the obtained coverings with 1g coverings After adding an ethanol/water mixed solution (6:4) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 12 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 7"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 13 was sprayed. Then, drying was performed to obtain 530.8 g of a covering product. Corresponds to 1.2 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (2:8) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 14 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 8"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 15 was sprayed. Then, it dried to obtain 497.8 g of mulch. Corresponds to 1.1 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (5:5) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 16 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 9"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 17 was sprayed. Then, it dried to obtain 518.1 g of mulch. Corresponds to 1.0 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (4:6) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 18 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 10"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 19 was sprayed. Then, it dried to obtain 537.3 g of mulch. Corresponds to 1.4 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (1:9) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 20 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 11"

500 g of the spherical activated carbon obtained in Production Example 1 was put into the rotary flow coating device (MP-01), and the spray mist of the prescription shown in Table 21 was sprayed. Then, it dried to obtain 525.2 g of mulch. Cope with 1.3 of the obtained covering with 1g covering After adding an ethanol/water mixture (1:9) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 22 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 12"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 23 was sprayed. Then, it dried to obtain 622.6 g of mulch. 1g of coverings corresponds to 0.6 of the obtained coverings After adding an ethanol/water mixture (1:9) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 24 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 13"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 25 was sprayed. Then, it dried to obtain 548.3 g of mulch. Corresponds to 1.2 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (1:9) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 26 shows the recovery rate of the cover product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 14"

500 g of the spherical activated carbon obtained in Production Example 1 was put into the rotary flow coating device (MP-01), and the spray mist of the prescription shown in Table 27 was sprayed. Then, it dried and obtained 524.0g of mulches. Corresponds to 1.1 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (1:9) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 28 shows the recovery rate of the cover product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 15"

500 g of the spherical activated carbon obtained in Production Example 1 was put into the rotary flow coating device (MP-01), and the spray mist of the prescription shown in Table 29 was sprayed. Then, it dried to obtain 543.5 g of mulch. Corresponds to 1.1 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (4:6) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 30 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 16"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 31 was sprayed. Then, it dried to obtain 531.9 g of mulch. Corresponds to 1.2 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (5:5) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 32 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 17"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 33 was sprayed. Then, it dried to obtain 543.3 g of mulch. Corresponds to 1.2 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (4:6) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 34 shows the recovery rate of the cover product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 18"

500 g of the spherical activated carbon obtained in Production Example 1 was put into the rotary flow coating device (MP-01), and the spray mist of the prescription shown in Table 35 was sprayed. Then, it dried to obtain 502.9 g of mulch. Corresponds to 1.4 of the obtained coverings with 1g coverings After adding an ethanol/water mixed solution (6:4) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 36 shows the recovery rate of the cover product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 19"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 37 was sprayed. Then, drying was performed to obtain 515.4 g of a covering product. Corresponds to 1.2 of the obtained coverings with 1g coverings After adding an ethanol/water mixed solution (6:4) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 38 shows the recovery rate of the cover product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 20"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 39 was sprayed. Then, drying was performed to obtain 530.8 g of a covering product. Corresponds to 1.4 of the obtained coverings with 1g coverings After adding an ethanol/water mixed solution (6:4) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 40 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 21"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 41 was sprayed. Then, it dried to obtain 552.0 g of mulch. Corresponds to 1.1 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (1:9) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 42 shows the recovery rate of the covering. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 22"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 43 was sprayed. Then, it dried to obtain 490.6 g of mulch. Corresponds to 1.1 of the obtained coverings with 1g coverings After adding an ethanol/water mixed solution (6:4) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 44 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 23"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 45 was sprayed. Then, it dried to obtain 545.5 g of mulch. Corresponds to 1.1 of the obtained coverings with 1g coverings After adding an ethanol/water mixed solution (6:4) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 46 shows the recovery rate of the cover product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 24"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 47 was sprayed. Then, it dried to obtain 516.4 g of mulch. Corresponds to 1.0 of the obtained coverings with 1g coverings After adding an ethanol/water mixture (1:9) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 48 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 25"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and spray mist of the prescription shown in Table 49 was sprayed. Then, it dried to obtain 533.3 g of mulch. Corresponds to 1.4 of the obtained coverings with 1g coverings After adding an ethanol/water mixed solution (6:4) in a ratio of mL, it was molded using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 50 shows the recovery rate of the covering product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Example 26"

500 g of spherical activated carbon obtained in Production Example 1 was put into a rotary flow coating device (MP-01), and a spray mist of the prescription shown in Table 51 was sprayed. Then, it dried to obtain 520.7 g of mulch. Corresponds to 0.9 for 1g of the obtained coverings After adding an ethanol/water mixture (2:8) in a ratio of mL, molding was performed using a low-pressure molding machine and dried to obtain tablets with a diameter of 12 mm.

Table 52 shows the recovery rate of the cover product. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Comparative Example 1"

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

"Comparative Example 2"

20 g of spherical activated carbon, 1.2 g of pullulan, and 0.18 g of sodium lauryl sulfate obtained in Production Example 1 were uniformly dispersed in a beaker, and then 24 mL of purified water was added. Use a spatula to knead the obtained mixture to avoid agglomeration of additives. The prepared kneaded mixture (paste) was filled into a molding die (diameter 12mm, depth 10.2mm), scraped flat with a spatula, and lightly compressed with a molding rod attached to the mixer to trim the surface of the tablet. Each molding die is dried to obtain tablets. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of the tablets shown in Table 54 and the volume ratio of additives in the tablets shown in Table 55 were obtained.

"Comparative Example 3"

20 g of spherical activated carbon, 9.36 g of pullulan and 1.40 g of sodium lauryl sulfate obtained in Production Example 1 were uniformly dispersed in a beaker, and then 28 mL of purified water was added. Use a spatula to knead the obtained mixture to avoid agglomeration of additives. The prepared kneaded mixture (paste) was filled into a molding die (diameter 12mm, depth 10.2mm), scraped flat with a spatula, and lightly compressed with a molding rod attached to the mixer to trim the surface of the tablet. Each molding die is dried to obtain tablets. After analyzing the obtained tablets using an X-ray CT microscope, the results of the volume ratio of additives in the tablets shown in Table 55 were obtained.

In the kneading method of Comparative Example 1, as shown in FIG. 5, the spherical activated carbon remained on the mixer or adhered to the molding die, so the yield was 87.8%. However, in the manufacturing method of the present invention of Example 1, , The harvest rate of spherical activated carbon is 100.2%, which is a drastic improvement.

"Analysis of the Volume Ratio of Tablets Using X-ray CT Microscopes"

The insides of the two batches of tablets obtained in Example 1 and the three batches of tablets obtained in Comparative Example 2 were analyzed under the following conditions using an X-ray CT microscope nano3DX (Rigaku Corporation).

Line source: Mo

Voltage: 50kV

Current: 24mA

Pixel size: 8.64μm/voxel

Number of shots: 1200

Shooting time: about 3 hours

Using the attached analysis software, the volume ratio of a cube with a side length of 2 mm in the upper, middle, and lower parts of the tablet divided into three parts was calculated. 3 obtained in Comparative Example 2 The relative standard deviations (RSD) of the volume ratios of 3 cubes of tablets of each batch are as high as 5.5%, 7.1% and 5.3%. On the other hand, the RSD of the volume ratio of the 3 cubes of the 2 batches of tablets obtained in Example 1 were 1.0% and 2.4%, and the tablet of the present invention had good uniformity (Table 54).

Using an X-ray CT microscope TDM1000H-II (2K) (Daiwa Scientific Co., Ltd.), the inside of each batch of tablets obtained in Example 2 to Example 26 was analyzed under the following conditions.

Line source: W

Voltage: 50kV (Example 2 to Example 26)

Current: 0.080A (Example 2), 0.085mA (Example 3 to Example 26)

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

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

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

Using the analysis software ImageJ, the volume ratio of a cube with a side length of 2 mm in the upper, middle, and lower parts of the tablet divided into three parts was obtained. According to the 256-level brightness information in the obtained image, the spherical activated carbon and additives are separated from the voids through automatic threshold calculation based on Otsu’s method, and the spherical activated carbon and the spherical activated carbon and the amount equivalent to the thickness of 2mm are accumulated in the image. The ratio of the number of pixels of the additive was defined as the volume ratio (Table 54).

"Analysis of Additive Volume Rate of Tablets Using X-ray CT Microscope"

The insides of the tablets obtained in Examples 1 to 26 and the tablets obtained in Comparative Examples 2 and 3 were analyzed using the X-ray CT microscope TDM1000H-II (2K) (Daiwa Scientific Co., Ltd.) under the following conditions.

Line source: W

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

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

Pixel size: 15.9μm/voxel (Example 1), 14.4μm/voxel (Comparative Example 2), 17.5μm/voxel (Example 2, Comparative Example 3), 12.7μm/voxel (Example 3 to Example 26)

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

Shooting time: 30 minutes (Example 1, Comparative Example 2), 20 minutes (Example 2, Comparative Example 3), 10 minutes (Example 3 to Example 26)

The analysis software ImageJ was used to calculate the C, N, and E of FIG. 3 for each 1 tablet of Example 1, Example 3 to Example 26, and Comparative Example 2, and each of 3 tablets of Example 2 and Comparative Example 3. The volume ratio of the additives of 5 prisms of, S, and W. According to the 256-level brightness information of the obtained image, the distribution of the number of pixels corresponding to the brightness of the spherical activated carbon is a regular distribution. Therefore, the average value of the brightness plus the standard deviation of 2.5 times or more of the brightness is defined as an additive. The ratio of the number of pixels is set as the additive area ratio, and the image of the additive when the image is accumulated by the number corresponding to the specified thickness The ratio of prime numbers was set as the additive volume ratio (Figure 6). Table 55 shows the maximum and minimum values of the additive volume rate of each prism, and the ratio of the maximum and minimum values of the five prisms. In addition, the change in the area ratio and volume ratio of the additive at the position C of Comparative Example 2 from the top to the bottom is shown in FIG. 4.

As shown in Fig. 4, the additive volume ratio of the tablet obtained by the past kneading method varies greatly from the top to the bottom of the tablet.

Claims (1)

A method for manufacturing a tablet, which is a method for manufacturing a tablet containing additives and spherical adsorption carbon for oral administration, characterized in that the center part of the tablet when viewed from above with an X-ray CT microscope, And the additive volume ratio of 5 prisms with a side length of 1mm from top to bottom at the end of a straight line extending from the center to the four directions. When analyzed from top to bottom, the volume ratio of the additive per 1mm ³ of the 5 prisms is the largest The ratio of the value to the minimum value is 100 or less. In each divided body that divides the length in the flat direction of the tablet into three equal parts, an X-ray CT microscope is used to examine the slice located at the center of the length in the flat direction and viewed from above. When the volume ratio of a cube with a side length of 2 mm at the center of the agent is analyzed, the relative standard deviation of the volume ratio of the cube of the three divided bodies is 5% or less, and the additive is 1 to 1 to the spherical adsorption carbon for oral administration. 35 wt%, and the manufacturing method of the tablet includes the following process: (1) will contain selected from sodium alginate, propylene glycol alginate, calcium carboxymethyl cellulose, gum ghatti, carrageenan, carboxyl Ethylene polymer, sodium carboxymethyl cellulose, xanthan gum, guar gum, quince seed gum, glucomannan, copovidone, gellan gum, gelatin, tamarind gum, tara gum, dextran Sugar, corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyethylene oxide , Polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyethylene glycol 6000, ethyl cellulose, phosphoric acid cross-linked starch, locust bean gum, agar, winter plum powder, fully pregelatinized starch, A solution of adhesive additives in the group consisting of crystalline cellulose methylcellulose sodium, oxidized starch, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and sugars is sprayed onto spherical adsorption charcoal for oral administration Above, the process of covering the spherical adsorbent carbon for oral administration with adhesive additives; (2) Adding a solvent to the covered spherical adsorbent carbon for oral administration, and then compressing and molding to obtain a compression molding process And (3) the process of drying the obtained molded body.

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