WO2017170762A1 - Tablet containing spherical adsorptive carbon for oral administration - Google Patents

Abstract

The purpose of the present invention is to provide a tablet having sufficient strength and containing spherical adsorptive carbon for oral administration. This purpose is met with a tablet that contains spherical adsorptive carbon for oral administration and a binder additive, wherein the spherical adsorptive carbon for oral administration is coated with the binder additive, the spherical adsorptive carbon for oral administration is bonded together with the coated binder additive, and the hardness of the tablet is 105 N or greater.

Description

Tablet containing spherical adsorption charcoal for oral administration

The present invention relates to a tablet containing spherically adsorbed charcoal for oral administration. According to the present invention, a tablet having excellent hardness can be provided.

Spherical adsorption charcoal for oral administration can be taken orally and can treat kidney and liver dysfunction by adsorbing harmful substances in the digestive tract (Patent Document 1). In order for this orally administered spherical adsorbent charcoal to exhibit the pharmacological effect of adsorbing harmful substances, it is important to maintain the spherical shape of the oral adsorbent spherical adsorbent and maintain its pore structure. The spherically adsorbed charcoal for oral administration is sold, for example, under the trade names “Cremedin (registered trademark) capsule 200 mg” and “Cremedin (registered trademark) fine particle sachet 2 g” (hereinafter referred to as “cremedin”).

The daily dose of cremedin for kidney disease patients is 6 g, and since it is taken in three doses, the dose per dose is 2 g. The volume of 2 g of cremedin fine granules is about 4 cm ³ , and the volume to be taken is never small. Therefore, when taking a 4 cm ³ fine granule, since the spherical activated carbon does not dissolve in water, there is a patient who feels disgusting in the oral cavity and feels disgust.
On the other hand, in the case of capsules of cremedin, there is no crispness in the mouth. However, since a dead volume other than the spherical activated carbon is formed in the capsule, the volume of the capsule increases by about 1.5 times (about 6 cm ³ ) compared to the volume of the fine granule. Specifically, about 0.613 cm ³ of a capsule had to be taken 10 capsules at a time, and there were patients who complained of a high dose.
In addition, there are many patients who can not take fine granules or capsules unless they are mixed with a large amount of water because of the gritty feeling of fine granules or the large dose of capsules. Among patients with kidney disease or renal failure, there are patients whose water intake is restricted, and when these patients take fine granules or capsules, as little water as possible is possible. Patients who inherently need a large amount of water will be in great pain.

Japanese Patent Publication No.62-11611 JP 2006-8602 A International Publication No. 2012/121202

In order to solve the above-mentioned problems, it is conceivable to use a spherical adsorption charcoal for oral administration as a tablet. However, spherical adsorbent charcoal for oral administration, unlike general drugs, cannot be tableted by compression or the like (Patent Document 2). In other words, the spherically adsorbed charcoal for oral administration is very hard like glass, and has poor deformability and brittle properties. could not.
The present inventors have found that tablets containing spherically adsorbed charcoal for oral administration that can be put to practical use can be produced by a kneading method using an additive for particle preparation exhibiting thin film forming ability (Patent Document 3). However, the strength of the obtained tablets was not sufficient.
Accordingly, an object of the present invention is to provide a tablet containing spherically adsorbed charcoal for oral administration having sufficient strength.

As a result of intensive studies on tablets containing spherically-adsorbed charcoal for oral administration having sufficient strength (for example, spherical activated carbon), the present inventors have surprisingly found that spherically-adsorbed charcoal for oral administration is a specific binding additive. It was found that the above-mentioned problem can be solved by a tablet having a hardness of 105 N or more, in which the spherical adsorption charcoal for oral administration is bonded via the coated binding additive. Furthermore, it has been found that the tablets can be obtained by coating orally administered spherical adsorption charcoal with a binding additive, adding a solvent to the coated oral adsorption charcoal, and compression molding.
The present invention is based on these findings.
Therefore, the present invention
[1] Spherical adsorption charcoal for oral administration, propylene glycol alginate, gati gum, carboxyvinyl polymer, carmellose sodium, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind gum, tara gum, corn starch, tragacanth, sodium hyaluronate , Hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, phosphoric acid cross-linked starch, locust bean gum, cold plum powder, fully pregelatinized starch, oxidized starch, and parts A tablet containing at least one binding additive selected from the group consisting of pregelatinized starch, wherein the spherical absorbent for oral administration is used. Charcoal is covered by the binder additive, the and through the coated binder additive bonded each oral administration for spherical adsorptive carbon, and the hardness of the tablet is greater than or equal to 105N, tablets,
[2] The tablet according to [1], wherein the spherical adsorption charcoal for oral administration is spherical activated carbon,
[3] The tablet according to [2], wherein the spherical activated carbon has an average particle size of 0.02 to 1 mm,
[4] The volume ratio of the binding additive of five prisms of 1 mm on one side from the upper surface to the lower surface located at the center when the tablet is viewed from the upper surface and the end of the straight line extending from the center in all directions. When analyzed with an X-ray CT microscope from the upper surface to the lower surface, the ratio of the maximum value and the minimum value of the binding additive volume ratio per 1 mm ³ in 5 prisms is 100 or less, [1] to [3] A tablet according to any one of the above,
[5] In each divided body obtained by dividing the length of the tablet in the flat direction into three equal parts, the cube is located at the center of the length in the flat direction and has a side of 2 mm located at the center of the tablet as viewed from above. When the volume fraction of each is analyzed with an X-ray CT microscope, the relative standard deviation of the volume fraction of the three divided cubes is 5% or less, and the tablet according to any one of [1] to [3], and [6] The volume ratio of the binding additive for five prisms of 1 mm on one side from the upper surface to the lower surface, which is located at the center when the tablet is viewed from the upper surface and at the end of a straight line extending in all directions from the center. When analyzed with an X-ray CT microscope from the upper surface to the lower surface, the ratio of the maximum value and the minimum value of the binding additive volume ratio per mm ³ in 5 prisms is 100 or less, and the length of the tablet in the flat direction In each divided body divided into three equal parts, the length in the flat direction Relative standard deviation of the volume fraction of the three divided cubes when the volume fraction of a cube consisting of 2 mm per side located in the center of the tablet and viewed from the top is analyzed with an X-ray CT microscope [7] (1) 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 / methyl methacrylate copolymer, phosphate cross-linked de Spray or spray a solution containing at least one binder additive selected from the group consisting of pung, locust bean gum, ginger powder, fully pregelatinized starch, oxidized starch, and partially pregelatinized starch onto orally administered spherical adsorbent charcoal A step of dripping and coating orally administered spherical adsorbent charcoal with a binder additive; (2) compression to obtain a molded article by adding a solvent to the coated spherical adsorbent charcoal for oral administration and compression molding. A method for producing a tablet comprising: a molding step; and (3) a step of drying the obtained molded body.
About.

According to the tablet containing the spherical adsorption charcoal (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 provide a tablet that can be reduced in volume as compared with a capsule and that has improved dosing properties. That is, in the case of capsules, about 0.613 cm ³ of the capsule had to be taken 10 capsules at a time, and there were patients who complained of the high dose, In the tablet of the invention, the volume can be reduced to 65% (about 4 cm ³ ) in the case of a capsule, and the dosage is improved. Moreover, according to the tablet of this invention, the tablet which improved the defect of taking property, such as a crispness, compared with a fine granule can be provided. According to the tablet of the present invention, it is possible to provide a tablet that maintains the spherical shape of the spherically adsorbed charcoal for oral administration, does not destroy the pore structure, and can fully exhibit the function of the adsorbent for oral administration. is there.

In the tablet of this invention, it is the figure which showed typically the position of three cubes which analyze the volume ratio of a tablet from the upper surface (A) and the side surface (B). It is an analysis image of the X-ray CT microscope (nano3DX) which showed the localization of the additive in the tablet (A) obtained by the manufacturing method of this invention, and the tablet (B) obtained by the conventional kneading | mixing method. In the tablet of this invention, it is the figure which showed typically the position of five prisms which analyze the volume ratio of an additive from the upper surface (A) and the side surface (B). It is the graph which showed the change at the time of analyzing the volume ratio of the additive in the tablet of this invention from the upper surface to the lower surface with the X-ray CT microscope. It is the photograph which showed the residue (A) to the stirring granulator of the spherical activated carbon by a kneading method, and the adhesion (B) to a shaping | molding die. It is the graph and photograph which showed performing the division of an additive and spherical activated carbon when calculating the volume ratio of an additive with analysis software ImageJ based on the brightness information of 256 steps.

[1] Tablet containing spherical adsorption charcoal for oral administration The tablet containing spherical adsorption charcoal for oral administration according to the present invention includes spherical adsorption charcoal for oral administration, propylene glycol alginate, 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 / methyl methacrylate copolymer Selected from the group consisting of: phosphate cross-linked starch, locust bean gum, ginger powder, fully pregelatinized starch, oxidized starch, and partially pregelatinized starch At least one binding additive. The spherical adsorbent charcoal for oral administration is coated with the binding additive, the spherical adsorbent charcoal for oral administration is bonded via the coated binding additive, and the tablet hardness is 105N. That's it.

《Spherical adsorption charcoal for oral administration》
The spherically adsorbed charcoal for oral administration is not particularly limited as long as it is a spherically adsorbed charcoal for oral administration that can be used for medical purposes, but is orally used for oral administration. Spherical activated carbon that can be used is preferred. In addition, in this specification, it demonstrates using spherical activated carbon as an illustration of the spherical adsorption charcoal for oral administration.
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 0.05 to 0. More preferably, it is 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 further preferably 0.03 to 1 mm. preferable.
“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. preferably, further preferably not less than ^{1300m 2 / g, 1650m 2 /} g or more is particularly preferable.

The form of spherically adsorbed charcoal for oral administration (for example, spherical activated carbon) contained in the tablet is the same as that of spherically adsorbed charcoal for oral administration in order to maintain its pore structure and exert the pharmacological effect of adsorbing harmful substances. It is preferable to maintain. That is, the adsorption capacity of toxic substances, such as the selective adsorption rate, is affected by the diameter, average particle diameter, specific surface area, pore volume in a specific pore diameter range, etc. It is desirable that the spherical shape that affects the diameter or average particle diameter is maintained, and the pore structure that affects the specific surface area and pore volume is maintained. Furthermore, side effects such as constipation can be prevented by maintaining the spherical shape.

<Additive for binding>
The binding additive used in the tablet of the present invention is propylene glycol alginate, gati gum, carboxyvinyl polymer, carmellose sodium, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind gum, tara gum, corn starch, tragacanth, hyaluron Sodium acid, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, phosphoric acid cross-linked starch, locust bean gum, cold plum powder, fully pregelatinized starch, oxidized starch, Including partially pregelatinized starch, or combinations thereof. The tablet of the present invention, in which the binding additive is coated on the spherical adsorption charcoal for oral administration, and the binding additive binds the spherical adsorption charcoal for oral administration, has a hardness of 105 N or more.
The tablet of the present invention is characterized by containing the above-mentioned binder additive as an additive, but an additive other than the binder additive (hereinafter sometimes referred to as “other additives”). May be included. That is, the tablet of the present invention may contain a binder additive and other additives as an additive, or may contain only a binder additive. In other words, the additive used in the present invention may be a binder additive and other additives, or may be a binder additive.

(Other additives)
The additives that can be used as additives other than the binding additive (other additives) will be described below.
In general, additives used for pharmaceuticals are described in “Pharmaceutical Additives Dictionary 2016”, and examples thereof include excipients, lubricants, disintegrants, surfactants, and binders. The functions of excipients, lubricants, disintegrants, and binders are not necessarily unitary. For example, crystalline cellulose classified as an excipient often functions as a disintegrant and is directly applied. The tablet method also has a function as a binder for improving moldability. Thus, the respective functions of the excipient, lubricant, disintegrant, and binder may overlap. Although the example of an excipient | filler, a lubricant agent, a disintegrating agent, and a binder is given to the following, the additive which is not classified into these additives may be used as another additive.
Excipients are additives mainly used for bulking (bulking agent) or dilution (diluent), specifically starch, calcium hydrogen phosphate, synthetic aluminum silicate, magnesium trisilicate, etc. Can be mentioned.
In addition, the binder is an additive used to form and bind the active ingredient and bulking agent, maintain the dosage form, prevent damage during the packaging process and transportation, and increase the mechanical strength. It is used for this purpose. Specifically, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, powdered cellulose, hypromellose, methylcellulose, hydroxypropylcellulose, starch, fully pregelatinized starch, partially pregelatinized starch, dextrin, gum arabic, sodium alginate, Examples include tragacanth, purified gelatin, polyvinyl alcohol, and povidone.
Furthermore, when a tablet is taken, the disintegrant is an additive used for wetting in the digestive tract to disintegrate and disperse the preparation into fine particles. Specific examples include carmellose, carmellose calcium, low-substituted hydroxypropylcellulose, hypromellose, powdered cellulose, starch, sodium carboxymethyl starch, and hydroxypropyl starch.
Lubricants are additives that have the function of improving various properties such as powder flowability, filling property, adhesiveness, and moldability in tableting, in order to improve tablet quality and manufacturing efficiency. It is used. Specific examples include sucrose fatty acid ester, talc, magnesium stearate, or stearic acid.
Surfactant includes alkyl allyl polyether alcohol, higher alcohol sulfate, N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate, N-cocoyl-N-methylaminoethyl sodium sulfonate, cholesterol, self-emulsifying type Glyceryl monostearate, sucrose fatty acid ester, squalane, stearyl alcohol, polyoxyl 40 stearate, cetanol, cetomacrogol 1000, diethyl sebacate, sorbitan fatty acid ester, sorbitan sesquioleate, sodium dodecylbenzenesulfonate, trioleic acid Sorbitan, nonylphenoxy polyoxyethylene ethane sulfate ammonium solution, polyoxyethylene octylphenyl ether, polyoxyethylene olei Amine, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbit beeswax, polyoxyethylene nonylphenyl ether , Polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (124) poly Oxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) Tyl ether, polyoxyethylene (2 EO) sodium lauryl ether sulfate (70%), polyoxyl 35 castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glycerin monostearate, mono Sorbitan stearate, sorbitan monolaurate, N-coconut oil fatty acid acyl L-arginine ethyl DL-pyrrolidone carboxylate, lauryl dimethylamine oxide solution, lauryl pyrrolidone, sodium lauryl sulfate, lauric acid diethanolamide, lauroyl sarcosine sodium, lauro macro Galle, sodium phosphate polyoxyethylene lauryl ether or polyoxyethylene oleyl ether phosphate (8MOL)

(Content of binding additive)
The weight ratio of the spherically adsorbed charcoal 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 binding addition in the tablet of the present invention is not limited. The content of the agent is preferably 1% by weight or more, more preferably 1.5% by weight or more, and further preferably 2% by weight or more. If the amount of the binding additive is too small, the hardness of the resulting tablet may be reduced. The upper limit of the binder additive is not limited, but the binder additive is preferably 35% by weight or less, more preferably 30% by weight or less, and further preferably 25% by weight or less. . If there are too many binding additives, the volume of the tablet increases and the dosage of the tablet may increase. The range of the content of the binder additive in the tablet of the present invention is preferably 1 to 35% by weight (or 1 to 25% by weight even if it is 1 to 30% by weight) from the viewpoint that the hardness of the obtained tablet tends to be 105N or more. More preferably 1.5 to 30% by weight (or 1.5 to 25% by weight or 1.5 to 20% by weight), still more preferably 2 to 25% by weight. % (Or 2 to 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 also particularly limited as long as the effects of the present invention can be obtained. Although it is not a thing, Preferably it is 10000 weight part or less with respect to 100 weight part of binder additives, More preferably, it is 1000 weight part or less, More preferably, it is 100 weight part or less. Yes, most preferably 50 parts by weight or less. If the amount of other additives is too large, the hardness of the resulting tablet may be reduced. The lower limit of the weight ratio is not particularly limited, and the content of other additives may be, for example, 0.1 parts by weight or more and 1 part by weight or more with respect to 100 parts by weight of the binding additive. It may be 10 parts by weight or more.

<Coating>
In the tablet of the present invention, spherical adsorption charcoal for oral administration (for example, spherical activated carbon) is coated with the binding additive, and the spherical activated carbon is bound via 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, and in some embodiments, 140 N or more, In some embodiments, it is 160N or more, in some embodiments, 180N or more, and in some embodiments, 200N or more. When the hardness is 105 N or more, the dosage form can be maintained, and damage during the packaging process and transportation can be more effectively prevented. The upper limit of the hardness is not particularly limited, and may be, for example, 500 N or less, 400 N or less, or 350 N or less. The hardness range 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 to 350 N, 140-500N, 140-400N, 140-350N, 160-500N, 160-400N, 160-350N, 180-500N, 180-400N, 180-350N, 200-500N, 200-400N, 200-350N, etc. It is done.

《Other problems with kneading method, means to solve it, and its effect》
When the kneading method which is a conventional method is used, the strength of the obtained tablet is not sufficient, and there are the following problems. That is, when a tablet was produced using the kneading method, the yield of spherical activated carbon was low. Moreover, the tablet obtained by the kneading method had low uniformity of the spherical adsorption charcoal for oral administration and the binding additive. In the tablet obtained by the kneading method, the amount of DL-β-aminoisobutyric acid adsorbed may be lower than that of granules or capsules.
As a result of diligent research on a tablet having a high yield of spherically adsorbed charcoal for oral administration and high uniformity of the spherically adsorbed charcoal for oral administration and a binder and a method for producing the same, the inventors have surprisingly found that By spraying or dropping a solution containing a binding additive onto orally administered spherical adsorbent charcoal and producing tablets by compression molding, the yield of oral adsorbent spherical adsorbent charcoal is drastically improved. It has been found that tablets with dramatically improved uniformity of spherical adsorbent charcoal for administration and additive for binding can be obtained. More specifically, the description will be given below in the description regarding the uniformity of the volume fraction of the tablet or the uniformity of the localization of the additive.
According to the manufacturing method of the tablet containing the spherically-adsorbed charcoal for oral administration (for example, spherical activated carbon) of the present invention, the yield of the spherically-adsorbed charcoal for oral administration to be used can be improved. Moreover, the tablet containing the spherical adsorption charcoal for oral administration obtained by the manufacturing method of the present invention prevents the localization of the spherical adsorption charcoal and binding additive for oral administration, and prevents the localization of the spherical adsorption charcoal and binding additive for oral administration. The uniformity is improved. Therefore, the hardness of the obtained tablet was improved. The tablet can exhibit excellent DL-β-aminoisobutyric acid adsorption ability. That is, according to the tablet manufacturing method of the present invention, compared to the kneading method described in Patent Document 3, the yield of spherically adsorbed charcoal for oral administration in the tablet manufacturing method is improved, and the hardness is improved. Can also be expected to improve the adsorption capacity of DL-β-aminoisobutyric acid.

<Uniformity of tablet volume ratio>
The tablet of the present invention preferably has a uniform volume ratio in the tablet. That is, the tablet of the present invention, when compared with a tablet containing a general compound as an active ingredient, contains spherically-adsorbed charcoal for oral administration (for example, spherical activated carbon) as an active ingredient. As described above, there is a gap between the spherical adsorbents for oral administration. If there are a portion where the voids are dense and a portion where the voids are rough, the hardness or friability of the tablet may be reduced. In other words, if there is a variation in the volume ratio of the spherically adsorbed charcoal for oral administration and additives in the tablet, the hardness or friability of the tablet may decrease. That is, when 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 divided body obtained by dividing the length in the flat direction of the tablet into three equal parts, the volume of a cube consisting of 2 mm per side located at the center of the length in the flat direction and at the center of the tablet as viewed from the upper surface When the rate is analyzed with an X-ray CT microscope, it can be determined that the uniformity of the tablet is high when the relative standard deviation of the volume ratios of the three divided cubes is 5% or less.
As shown in FIG. 1, a tablet has a flat shape except for a spherical pill. FIG. 1A shows a flat tablet viewed from the top, and FIG. 1B shows a flat tablet viewed from the side. When the tablet is viewed from the top, the tablet often exhibits a circular shape as shown in FIG. 1A, or an elliptical shape, a rectangular shape, or a rectangular shape, but the tablet usually has a symmetrical form, As shown by a square broken line in FIG. 1A, it is possible to specify “the center cube of the tablet as viewed from above”. Moreover, when a 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, and each divided object is indicated by a broken line. Thus, it is possible to specify “a cube located at the center of the length in the flat direction”. Therefore, it is possible to specify “three cubes each having a side of 2 mm and positioned at the center of the length in the flat direction and positioned at the center of the tablet as viewed from the upper surface”. When the tablet is a spherical pill, it is possible to specify “the center of the length in the flat direction”, “the center of the tablet viewed from the top surface”, etc., with the flat direction as an arbitrary direction.
The three cubes can be analyzed by an X-ray CT microscope, and the volume ratio of each cube can be calculated. And the relative standard deviation of the volume ratio of the obtained three cubes is calculated, and when a relative standard deviation is 5% or less, it determines with the uniformity of a tablet being high.
When the length of the tablet in the flat direction is less than 6 mm, the three cubes each having a side of 2 mm may partially overlap. However, even if the three cubes overlap, it is possible to calculate the relative standard deviation of the volume fraction of the three divided cubes, and when their relative standard deviation is 5% or less, It can be determined that the uniformity of the tablet is high.
The relative standard deviation of the volume ratio is preferably 4.7% or less, more preferably 4.5% or less. As the relative standard deviation is smaller, the uniformity is improved and the hardness or friability of the tablet can be improved. Therefore, the lower limit of the relative standard deviation of the volume ratio is most preferably 0% or more, and may be practically 0.1% or more, may be 0.5% or more, or may be 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 additive localization》
The tablet of the present invention preferably has a uniform distribution of the additive within the tablet, that is, the tablet of the present invention is excellent in the uniformity of the volume ratio of the additive compared to the tablet containing the conventional spherical activated carbon. It is preferable. For example, as shown in FIG. 2B, in the tablet containing spherical activated carbon obtained by the conventional kneading method, the additive is unevenly distributed near the surface of the upper part of the tablet (the additive is shown in white). The uniformity of the additive is low. If the additive is unevenly distributed, the hardness or friability of the tablet may be reduced. In other words, if there is a variation in the volume ratio of the additive in the tablet, the hardness or friability of the tablet may decrease. 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 by, for example, the following method. X-ray volume ratio of the additive of five prisms of 1 mm on each side from the upper surface to the lower surface located at the center when the tablet is viewed from the upper surface and the end of a straight line extending in all directions from the center from the upper surface to the lower surface When analyzed with a CT microscope, when the ratio of the maximum value and the minimum value of the additive volume ratio per 1 mm ³ in five prisms is 100 or less, it is determined that the uniformity of the additive distribution is high. it can. That is, in the tablet of the present invention, the ratio of the maximum value and the minimum value of the additive volume ratio is 100 or less in the five prisms. On the other hand, in the conventional tablet, since the ratio of the maximum value and the minimum value of the additive volume ratio exceeds 100 in the five prisms, the hardness or friability of the tablet decreases.
As shown in FIG. 3, the tablet has a flat shape except for a spherical pill. FIG. 3A shows a flat tablet viewed from the top, and FIG. 3B shows a flat tablet viewed from the side. When the tablet is viewed from the top, the tablet often has a circular shape as shown in FIG. 3A or an elliptical shape, a rectangular shape, or a rectangular shape, but the tablet usually has a symmetrical form, As shown by the square broken line C in FIG. 3A, it is possible to specify “the prism in the center when viewed from the top”. Further, it is possible to specify “a prism positioned at the end of a straight line extending in all directions from the center” shown by square broken lines N, E, S, and W in FIG. When the flat tablet is viewed from the side, as shown by the broken line in FIG. 3B, the prism is located from the upper surface to the lower surface in the flat direction of the tablet. Therefore, it is possible to specify “a prism at the center when viewed from the top surface” and “a prism positioned at the end of a straight line extending in all directions from the center of the tablet”.
The above five prisms can be analyzed from the upper surface to the lower surface with an X-ray CT microscope, and the volume fraction of the prism additive can be calculated respectively. Then, the additive volume ratio per 1 mm ³ can be calculated at any position of the prism and the maximum value and the minimum value of the additive volume ratio per 1 mm ³ can be obtained.
In the present invention, when 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 high. The ratio of the minimum values is preferably 99 or less, more preferably 98 or less, and still more preferably 96 or less. The smaller the ratio between the maximum value and the minimum value, the more uniform the additive, and the hardness or friability of the tablet can be improved. Therefore, the lower limit of the ratio between the maximum value and the minimum value is most preferably 1 or more, and may be 2 or more in practical use, may be 4 or more, and may be 6 or more. The range of the ratio between the maximum value and the minimum value may be, for example, 1 to 100, 2 to 99, 4 to 98, or 6 to 96.
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 prism at the position C. In this case, the additive volume per mm ³ By determining the additive volume ratio from the upper surface to the lower surface where the rate can be measured, it is possible to calculate the “ratio between the maximum value and the minimum value of the additive volume ratio”.

(X-ray CT microscope)
The X-ray CT microscope for analyzing the volume ratio of the tablet and the additive in the present invention is a two-dimensional (2D) or three-dimensional (submicron level) high-resolution image of the interior of a sample such as a material or tablet. It is an apparatus that can be observed in 3D). A fine structure such as a material or a tablet 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 an additive.
As the X-ray CT microscope, commercially available “nano3DX (high-resolution 3DX-ray microscope: Rigaku Corporation)” and “three-dimensional measurement X-ray CT apparatus TDM series: Yamato Scientific Co., Ltd.” can be used. The volume ratio of the tablet or the additive volume ratio can be calculated using software attached to the apparatus or image processing software ImageJ.

[2] Tablet production method The tablet production method of the present invention includes (1) propylene glycol alginate, 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 / methyl methacrylate copolymer, phosphate cross-linked starch, locust bean gum, cold plum powder, complete alpha For oral administration a solution comprising at least one binding additive selected from the group consisting of modified starch, oxidized starch, and partially pregelatinized starch Spraying or dripping onto spherical adsorbent charcoal (for example, spherical activated carbon), coating the spherical adsorbent for oral administration with a binder additive, (2) adding a solvent to the coated spherical adsorbent for oral administration, And the compression molding process of obtaining a molded object by compression molding, and (3) the process of drying the obtained molded object are included.
As the “binding additive” used in the method for producing a tablet of the present invention, the binding additive described in the section “[1] Tablets containing orally administered spherical adsorption charcoal” can be used.

<< Coating process (1) >>
Coating method (1) consists of propylene glycol alginate, gati gum, carboxyvinyl polymer, carmellose sodium, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind gum, tara gum, corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose, From hydroxypropylcellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, phosphoric acid cross-linked starch, locust bean gum, ginger powder, fully pregelatinized starch, oxidized starch, and partially pregelatinized starch A solution containing at least one binding additive selected from the group consisting of spherical adsorbents for oral administration (for example, spherical activated carbon) And fog coating for oral administration spherical adsorptive carbon in binder additive. A spraying method is used as the coating method. Examples of the spraying method include a top spray method, a tangential spray method, a bottom spray method, and a side spray method.
For example, in the case of the top spray method, a binder additive and other additives are dissolved in a solvent to prepare a spray solution. Then, for example, spherically adsorbed charcoal for oral administration is charged into a tumbling fluidized coating device or a fluidized bed granulator, and sprayed from above.
The solvent used in 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, 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, methylbutylketone, methylcyclohexane, N-methylpyrrolidone Nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene or xylene. Further, the surfactant is not particularly limited, but alkylallyl polyether alcohol, higher alcohol sulfate, N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate, N-cocoyl-N-methylamino Sodium ethyl sulfonate, cholesterol, self-emulsifying glyceryl monostearate, sucrose fatty acid ester, squalane, stearyl alcohol, polyoxyl 40 stearate, cetanol, cetomacrogol 1000, diethyl sebacate, sorbitan fatty acid ester, sorbitan sesquioleate , Sodium dodecylbenzenesulfonate, sorbitan trioleate, nonylphenoxy polyoxyethylene ethane sulfate ammonium solution, polyoxyethylene octylphenyl Ether, polyoxyethylene oleylamine, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbite beeswax, poly Oxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxy Ethylene (124) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene 10) Polyoxypropylene (4) cetyl ether, polyoxyethylene (2 EO) sodium lauryl ether sulfate (70%), polyoxyl 35 castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, monoolein Sorbitan acid, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, N-coconut oil fatty acid acyl L-arginine ethyl DL-pyrrolidone carboxylate, lauryl dimethylamine oxide solution, lauryl pyrrolidone, sodium lauryl sulfate, lauric acid Diethanolamide, lauroyl sarcosine sodium, lauromacrogol, sodium phosphate polyoxyethylene lauryl ether or phosphate polyoxyethylene oleyl ether 8MOL), and the like can be given.
The amount of the binder additive relative to the solvent amount is not particularly limited as long as the binder additive is almost uniformly coated on the spherically adsorbed carbon for oral administration (for example, spherical activated carbon). On the other hand, the binder additive is preferably 0.01 to 100 w / v%, more preferably 0.1 to 50 w / v%, still 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 adsorption charcoal for oral administration (for example, spherical activated carbon), and compression molding is performed. For example, a tablet having a hardness of 105 N or more can be obtained by adding a solvent to the coated spherical adsorption charcoal for oral administration, drying after compression molding.
Examples of the solvent include an organic solvent, water, or a mixture thereof. The volume ratio of the organic solvent to 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. More preferably 30:70 to 70:30. By being the said range, water can be made to osmose | permeate the binding additive which coat | covers the spherical adsorption charcoal for oral administration.

(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, n-acetic acid n- 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-dichloroethene, dichloromethane, N, N-dimethylacetate Amide, N, N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, Examples include sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

<< Drying process (3) >>
In the manufacturing method of the tablet of this invention, the obtained molded object is dried. Although a drying method is not limited as long as the solvent of a molded object evaporates, For example, freeze-drying, reduced pressure drying, ventilation drying, natural drying, or heat drying can be mentioned.
For example, in the case of heat drying, the heating temperature is not particularly limited, but is preferably 50 to 200 ° C., for example, and preferably 80 to 180 ° C. The heating time is not particularly limited, but is preferably 10 minutes to 3 hours, and more preferably 30 minutes to 2 hours.
However, when the heating temperature is high, the heating time can be shortened, and those skilled in the art can appropriately determine the heating temperature and the heating time.
The water 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.

Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.

<< Production Example 1: Production of Porous Spherical Carbonaceous Material >>
A porous spherical carbonaceous material was obtained in the same manner as described 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-based pitch (softening point = 210 ° C .; quinoline insoluble content = 1 wt% or less; H / C atomic ratio = 0.63) and 32 kg of naphthalene are charged into a pressure-resistant container having an internal volume of 300 L with a stirring blade. After melt mixing at 180 ° C., the mixture was cooled to 80 to 90 ° C. and extruded to obtain a string-like molded body. Next, the string-like molded body was crushed so that the ratio of diameter to length was about 1-2.
The crushed material was put into an aqueous solution in which 0.23% by weight of polyvinyl alcohol (degree of saponification = 88%) was dissolved and heated to 93 ° C., and spheroidized by stirring and dispersing. Was replaced by water and cooled at 20 ° C. for 3 hours to solidify the pitch and precipitate naphthalene crystals to obtain a spherical pitch formed body slurry.
After most of the water was removed by filtration, naphthalene in the pitch formed body was extracted and removed with n-hexane, which was about 6 times the weight of the spherical pitch formed body. The porous spherical pitch obtained in this way was heated to 235 ° C. through heated air using a fluidized bed, and then oxidized by holding at 235 ° C. for 1 hour, so that it was infusible to heat. A porous spherical oxide pitch was obtained.
Subsequently, the porous spherical oxidized pitch was activated at 900 ° C. for 170 minutes in a nitrogen gas atmosphere containing 50 vol% of water vapor using a fluidized bed to obtain porous spherical activated carbon. Then, oxidation treatment is 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 is performed at 900 ° C. for 17 minutes in a fluidized bed under nitrogen gas atmosphere A porous spherical carbonaceous material was obtained. The porous spherical carbonaceous material thus obtained was used as spherical activated carbon in the following pharmacological test examples.
The main characteristics of the obtained carbonaceous material are as follows.
Specific surface area = 1300 m ² / g (BET method);
Pore volume = 0.08 mL / g
(Pore volume in the range of 20 to 15000 nm pore diameter determined by mercury porosimetry);
Average particle size = 350 μm;
Total acidic groups = 0.67 meq / g;
Total basic groups = 0.54 meq / g;
Crushing strength = 31.2 MPa; and strain rate when a pressure of 2 MPa is applied = 0.7%.

<< Production Example 2: Production 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-A-2005-314416. The specific operation is as follows.
220 g of deionized water and 58 g of methylcellulose were placed in a 1 L separable flask, and 105 g of styrene, 184 g of 57% divinylbenzene (57% divinylbenzene and 43% ethylvinylbenzene), 2,2′-azobis. After adding 1.68 g of (2,4-dimethylvaleronitrile) and 63 g of 1-butanol as porogen, the inside of the system was replaced with nitrogen gas, and this two-phase system was stirred at 200 rpm and heated to 55 ° C. And then kept for 20 hours. The obtained resin was filtered and dried on a rotary evaporator. Then, 1-butanol was removed from the resin by distillation in a vacuum dryer, and then dried under reduced pressure at 90 ° C. for 12 hours. A spherical particle having an average particle size of 180 μm was obtained. A porous synthetic resin was obtained. The specific surface area of the porous synthetic resin was about 90 m ² / g.
100 g of the obtained spherical porous synthetic resin was charged into a reaction tube with a mesh dish and subjected to infusibilization treatment in a vertical tubular furnace. The infusibilizing condition is that a spherical porous oxide resin is obtained by flowing dry air from the lower part of the reaction tube to the upper part at 3 L / min, raising the temperature to 260 ° C. at 5 ° C./h, and holding at 260 ° C. for 4 hours. Got. After heat treatment of spherical porous oxidized resin at 600 ° C. for 1 hour in a nitrogen atmosphere, activation treatment was performed at 820 ° C. for 10 hours in a nitrogen gas atmosphere containing 64.5 vol% of water vapor using a fluidized bed. Obtained. The obtained spherical activated carbon was further oxidized 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 in a fluidized bed under a nitrogen gas atmosphere 900 Reduction treatment was carried out at 17 ° C. 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 = 1763 m ² / g (BET method);
Pore volume = 0.05 mL / g
(Pore volume in the range of 20 to 15000 nm pore diameter determined by mercury porosimetry);
Average particle size = 111 μm (Dv50);
Total acidic groups = 0.59 meq / g;
Total basic group = 0.61 meq / g;
Bulk density = 0.50 g / cm ³ ;
Crushing strength = 436.5 MPa; and strain rate when a pressure of 2 MPa is applied = 0.2%.
In addition, in this specification, although the Example which produced the tablet using the spherical activated carbon obtained in manufacture example 2 is not described, it is similar to the spherical activated carbon obtained in manufacture example 1 of this invention. Tablets can be obtained.

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

<< Example 2 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 3 was sprayed. Thereafter, it was dried to obtain 512.5 g of a coated product. The obtained coated product was filled in a mold made of Teflon (registered trademark) (diameter 12 mm, depth 10.2 mm, R16 mm), and water was added at a ratio of 0.9 mL to 1 g of the coated product. A tablet with a diameter of 12 mm was obtained by lightly compressing with a forming rod attached to a stirrer to prepare a tablet surface and drying. The obtained tablet had a hardness of 124N. Table 4 shows the composition of the obtained tablets.

Example 3
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 5 was sprayed. Thereafter, it was dried to obtain 506.8 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (5: 5) at a ratio of 1.4 mL to 1 g of the coated product, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 173N. Table 6 shows the composition of the obtained tablets.

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

Example 5
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 9 was sprayed. Thereafter, it was dried to obtain 530.8 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (2: 8) at a ratio of 1.2 mL to 1 g of the coated product, and dried to form a tablet with a diameter of 12 mm. Obtained. The obtained tablet had a hardness of 137N. Table 10 shows the composition of the obtained tablets.

Example 6
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 11 was sprayed. Thereafter, it was dried to obtain 497.8 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (5: 5) at a ratio of 1.1 mL to 1 g of the coated product, and dried to obtain a tablet having a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 121N. Table 12 shows the composition of the obtained tablets.

Example 7
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 13 was sprayed. Thereafter, it was dried to obtain 518.1 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (4: 6) at a ratio of 1.0 mL to 1 g of the coated product, and dried to form a tablet with a diameter of 12 mm. Obtained. The obtained tablet had a hardness of 123N. Table 14 shows the composition of the obtained tablets.

Example 8
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 15 was sprayed. Thereafter, it was dried to obtain 537.3 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (1: 9) at a ratio of 1.4 mL to 1 g of the coated product, and dried to obtain a tablet having a diameter of 12 mm. Obtained. The hardness of the obtained tablet was 171N. Table 16 shows the composition of the obtained tablets.

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

Example 10
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 19 was sprayed. Thereafter, it was dried to obtain 622.6 g of a coated product. Using a low-pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The obtained tablet had a hardness of 162N. Table 20 shows the composition of the tablets obtained.

Example 11
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 21 was sprayed. Then, it dried and obtained the coated product 506.0g. Using a low pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The obtained tablet had a hardness of 175N. Table 22 shows the composition of the obtained tablets.

<< Example 12 >>
305 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 23 was sprayed. Thereafter, it was dried to obtain 336.3 g of a coated product. Using a low-pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 133N. Table 24 shows the composition of the obtained tablets.

Example 13
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 25 was sprayed. Thereafter, it was dried to obtain 548.3 g of a coated product. Using a low pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (1: 9) at a ratio of 1.2 mL to 1 g of the coated product, and dried to form a tablet having a diameter of 12 mm. Obtained. The hardness of the obtained tablet was 201N. Table 26 shows the composition of the obtained tablets.

<< Example 14 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01) and sprayed with the formulation shown in Table 27 was sprayed. Thereafter, it was dried to obtain 557.2 g of a coated product. Using a low pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (1: 9) at a ratio of 1.2 mL to 1 g of the coated product, and dried to form a tablet having a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 114N. Table 28 shows the composition of the obtained tablets.

Example 15
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 29 was sprayed. Thereafter, it was dried to obtain 524.0 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (1: 9) at a ratio of 1.1 mL to 1 g of the coated product, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 105N. Table 30 shows the composition of the obtained tablets.

<< Example 16 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 31 was sprayed. Thereafter, it was dried to obtain 543.5 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (4: 6) at a ratio of 1.1 mL to 1 g of the coated product, and dried to form a tablet with a diameter of 12 mm. Obtained. The obtained tablet had a hardness of 290N. Table 32 shows the composition of the obtained tablets.

<< Example 17 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 33 was sprayed. Thereafter, it was dried to obtain 531.9 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (5: 5) at a ratio of 1.2 mL to 1 g of the coated product, and dried to form a 12 mm diameter tablet. Obtained. The resulting tablet had a hardness of 133N. Table 34 shows the composition of the obtained tablets.

<< Example 18 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 35 was sprayed. Thereafter, it was dried to obtain 543.3 g of a coated product. Using a low-pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 343N. Table 36 shows the composition of the obtained tablets.

Example 19
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 37 was sprayed. Thereafter, it was dried to obtain 502.9 g of a coated product. Using a low-pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 134N. Table 38 shows the composition of the obtained tablets.

<< Example 20 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 39 was sprayed. Thereafter, it was dried to obtain 500.4 g of a coated product. Using a low-pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 187N. Table 40 shows the composition of the obtained tablets.

<< Example 21 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 41 was sprayed. Thereafter, it was dried to obtain 508.9 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (6: 4) at a ratio of 1.1 mL to 1 g of the coated product, and dried to form a tablet with a diameter of 12 mm. Obtained. The obtained tablet had a hardness of 222N. Table 42 shows the composition of the obtained tablets.

<< Example 22 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 43 was sprayed. Thereafter, it was dried to obtain 530.8 g of a coated product. Using a low-pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The obtained tablet had a hardness of 162N. Table 44 shows the composition of the obtained tablets.

<< Example 23 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 45 was sprayed. Thereafter, it was dried to obtain 552.0 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (1: 9) at a ratio of 1.1 mL to 1 g of the coated product, and dried to form a tablet with a diameter of 12 mm. Obtained. The obtained tablet had a hardness of 227N. Table 46 shows the composition of the obtained tablets.

<< Example 24 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 47 was sprayed. Thereafter, it was dried to obtain 545.5 g of a coated product. Using a low-pressure molding machine, the resulting coated product was molded after adding an ethanol / water mixture (6: 4) at a ratio of 1.1 mL to 1 g of the coated product, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 110N. Table 48 shows the composition of the obtained tablets.

Example 25
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 49 was sprayed. Then, it dried and obtained 516.4g of coated articles. Using a low pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 141N. Table 50 shows the composition of the obtained tablets.

<< Example 26 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 51 was sprayed. Thereafter, it was dried to obtain 533.3 g of a coated product. Using a low-pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 125N. Table 52 shows the composition of the obtained tablets.

Example 27
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 53 was sprayed. Thereafter, it was dried to obtain 520.7 g of a coated product. Using a low-pressure molding machine, the resulting 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, and dried to form a tablet with a diameter of 12 mm. Obtained. The resulting tablet had a hardness of 110N. Table 54 shows the composition of the obtained tablets.

<< Comparative Example 1 >>
20 g of spherical activated carbon obtained in Production Example 1, 1.2 g of pullulan and 0.18 g of sodium lauryl sulfate were uniformly dispersed in a beaker, and 24 mL of purified water was further added. The resulting mixture was kneaded using a spatula so that the additive could not be spoiled. The prepared kneaded material (slurry) was filled in a mold (diameter 12 mm, depth 10.2 mm), scraped off with a spatula, and lightly compressed with a molding rod attached to a stirrer at the top to prepare the tablet surface. A tablet was obtained by drying the entire mold. The tablet hardness was 69N.

<< Comparative Example 2 >>
500 g of the spherical activated carbon obtained in Production Example 1 was put into a tumbling fluidized coating apparatus (MP-01), and a spray liquid having a formulation shown in Table 55 was sprayed. Thereafter, it was dried to obtain 523.5 g of a coated product. Using a low pressure molding machine, ethanol / water mixtures (6: 4 and 7: 3) were added at a ratio of 1.1 mL and 1.2 mL to 1 g of the coated product, and then molded and dried. A 15 mm tablet was obtained.
Table 56 shows the hardness of the obtained tablets. Table 57 shows the composition of the obtained tablets.

 

 

<< Hardness of tablet-type composition >>
The hardness of the tablet-type composition was measured at room temperature after measuring the thickness of the tablet-type composition sample using a tablet hardness meter (TBH320TD, manufactured by ERWEKA) and inputting the measured value into the hardness meter. The measurement conditions are shown below. The results of the hardness measurement are shown in Tables 59 to 64 together with the tablet composition and the like. In the table, “main agent” means spherical activated carbon.

 

《Analysis of recovery rate》
The recovery rate of the coated product in the examples or comparative examples was analyzed. The recovery rate (%) of the coated product is calculated by the amount of the obtained coated product / theoretical amount of the coated product × 100. The higher the recovery rate, the higher the yield of the spherically adsorbed charcoal for oral administration.

Example 1
The recovery rate of the coated product is shown in the following table for Example 1. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

 

Example 2
For Example 2, the recovery rate of the coated product is shown in the following table. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 3
The recovery rate of the coated product is shown in the following table for Example 3. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 4
The recovery rate of the coated product is shown in the following table for Example 4. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 5
The recovery rate of the coated product is shown in the following table for Example 5. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 6
The recovery rate of the coated product is shown in the following table for Example 6. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 7
The recovery rate of the coated product is shown in the following table for Example 7. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 8
The recovery rate of the coated product is shown in the following table for Example 8. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 9
For Example 9, the recovery rate of the coated product is shown in the following table. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 10
The recovery rate of the coated product is shown in the following table for Example 10. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 13
The recovery rate of the coated product is shown in the following table for Example 13. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 15
For Example 15, the recovery rate of the coated product is shown in the following table. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 16
The recovery rate of the coated product is shown in the following table for Example 16. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

<< Example 17 >> For Example 17, the recovery rate of the coated product is shown in the following table. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 18
For Example 18, the recovery rate of the coated product is shown in the following table. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 19
The recovery rate of the coated product is shown in the following table for Example 19. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

<< Example 22 >>
The recovery rate of the coated product is shown in the following table for Example 22. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 23
About Example 23, the recovery rate of a coated product is shown in the following table. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 24
For Example 24, the recovery rate of the coated product is shown in the following table. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 25
The recovery rate of the coated product is shown in the following table for Example 25. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 26
The recovery rate of the coated product is shown in the following table for Example 26. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

Example 27
The recovery rate of the coated product is shown in the following table for Example 27. When the obtained tablet was analyzed with an X-ray CT microscope, the results of the tablet volume ratio shown in Table 87 and the additive volume ratio in the tablet shown in Table 88 were obtained.

<< Comparative Example 1 >>
About the comparative example 1, when the obtained tablet was analyzed with the X-ray CT microscope, the result of the volume ratio of the tablet shown in Table 87 and the additive volume ratio in a tablet shown in Table 88 was obtained.

<< Analysis of tablet volume fraction by X-ray CT microscope >>
About 2 lots of tablets obtained in Example 1 and 3 lots of tablets obtained in Comparative Example 1, the inside of the tablets was analyzed using the X-ray CT microscope nano3DX (Rigaku Corporation) under the following conditions.

Radiation source: Mo
Voltage: 50kV
Current: 24 mA
Pixel size: 8.64 μm / voxel
Number of shots: 1200 shots Shooting time: about 3 hours
Using the attached analysis software, the volume ratio of a cube having a side of 2 mm in the upper part, middle part, and lower part of the tablet divided into three parts was determined. The RSD of the volume ratio of 3 cubes of the 2 lots of tablets obtained in Example 1 were 1.0 and 2.4, and the tablet of the present invention had high uniformity (Table 87). .

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

Radiation source: W
Voltage: 50kV
Current: 0.085 mA
Pixel size: 12.7 μm / voxel
Number of shots: 700 to 1500 (arbitrarily set according to tablet thickness)
Shooting time: 10 minutes
Using analysis software ImageJ, the volume ratio of a cube having a side of 2 mm in the upper part, the middle part, and the lower part of the tablet divided into three parts was obtained. (Table 87).

<< Analysis of tablet additive volume fraction by X-ray CT microscope >>
About the tablet obtained in the Example, the inside of a tablet was analyzed on condition of the following using X-ray CT microscope TDM1000H-II (2K) (Yamato Scientific Co., Ltd.).

Radiation source: 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 to 1500 (arbitrarily set according to tablet thickness)
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 ratios of the additives of the five prisms C, N, E, S, and W in FIG. 3 were calculated by analysis software ImageJ. Since the distribution of the number of pixels corresponding to the spherical activated carbon has a normal distribution based on the information on the brightness of 256 levels in the obtained image, 2.5 times the standard deviation was added to the average value of the brightness. If the value is greater than the value, the additive is defined as the additive, the ratio of the number of pixels is the additive area ratio, and the ratio of the number of pixels of the additive when this image is integrated by the number corresponding to the predetermined thickness The volume ratio was taken (FIG. 6). Table 88 shows the maximum and minimum values of the additive volume fraction in each prism and the ratio of the maximum and minimum values in the five prisms. Moreover, the fluctuation from the upper surface to the lower surface of the additive area ratio and the volume ratio at the position C in Comparative Example 1 is shown in FIG.
As shown in FIG. 4, the additive volume ratio of the tablet obtained by the conventional kneading method varied greatly between the upper surface and the lower surface of the tablet.

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

Claims (7)

1. Spherical adsorption charcoal for oral administration, as well as propylene glycol alginate, gati gum, carboxyvinyl polymer, carmellose sodium, xanthan gum, guar gum, glucomannan, copolyvidone, gelatin, tamarind gum, tara gum, corn starch, tragacanth, sodium hyaluronate, hydroxyethyl cellulose , Hydroxypropylcellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, phosphoric acid cross-linked starch, locust bean gum, cold plum powder, fully pregelatinized starch, oxidized starch, and partially pregelatinized starch A tablet containing at least one binding additive selected from the group consisting of: Wherein it is coated by binder additives, the and through the coated binder additive bonded each oral administration for spherical adsorptive carbon, and the hardness of the tablet is greater than or equal to 105N, tablets.
2. The tablet according to claim 1, wherein the spherically adsorbed charcoal for oral administration is spherical activated carbon.
3. The tablet according to claim 2, wherein the spherical activated carbon has an average particle size of 0.02 to 1 mm.
4. The volume ratio of the binding additive of five prisms with a side of 1 mm from the upper surface to the lower surface located at the center when the tablet is viewed from the upper surface and the end of the straight line extending in all directions from the center is measured from the upper surface to the lower surface. The ratio of the maximum value and the minimum value of the binding additive volume ratio per 1 mm ³ in 5 prisms when the analysis is performed with an X-ray CT microscope over 100, is 100 or less. The tablet described.
5. In each divided body obtained by dividing the length of the tablet in the flat direction into three equal parts, the volume ratio of a cube consisting of 2 mm per side located at the center of the length in the flat direction and at the center of the tablet as viewed from above The tablet according to any one of claims 1 to 3, wherein the relative standard deviation of the volume fraction of the cubes of the three divided bodies is 5% or less when analyzed by an X-ray CT microscope.
6. The volume ratio of the binding additive of five prisms with a side of 1 mm from the upper surface to the lower surface located at the center when the tablet is viewed from the upper surface and the end of the straight line extending in all directions from the center is measured from the upper surface to the lower surface. The ratio of the maximum value and the minimum value of the binding additive volume ratio per 1 mm ³ in the five prisms is 100 or less when analyzed with an X-ray CT microscope.
   In each divided body obtained by dividing the length of the tablet in the flat direction into three equal parts, the volume ratio of a cube consisting of 2 mm per side located at the center of the length in the flat direction and at the center of the tablet as viewed from above The tablet according to any one of claims 1 to 3, wherein the relative standard deviation of the volume fraction of the cubes of the three divided bodies is 5% or less when analyzed by an X-ray CT microscope.
7. (1) Propylene glycol alginate, 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, Selected from the group consisting of hypromellose, pullulan, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, phosphate cross-linked starch, locust bean gum, ginger powder, fully pregelatinized starch, oxidized starch, and partially pregelatinized starch A solution containing at least one binding additive is sprayed or dropped onto a spherical adsorption charcoal for oral administration to obtain a spherical adsorption for oral administration. Step of coating with binder additive,
   (2) A compression molding step for obtaining a molded body by adding a solvent to the coated spherical adsorption charcoal for oral administration and compression molding, and (3) a step of drying the obtained molded body,
   The manufacturing method of the tablet containing this.

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