Tablets containing ferric citrate

Abstract

To provide a new preparation containing ferric citrate.SOLUTION: Provided is a tablet comprising ferric citrate as a pharmaceutically active ingredient and hydroxypropylcellulose.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a tablet containing ferric citrate as an active pharmaceutical ingredient. [Background technology]

[0002] It is known that capsules containing ferric citrate are effective in treating hyperphosphatemia. Summary of the Invention [Problem to be solved by the invention]

[0003] The objective of this study is to provide a new formulation. It has been found that there are issues with tableting, such as moldability during tableting, cracking, disintegration, and dissolution, when producing tablets containing a high content of ferric citrate as an active ingredient. [Means for solving the problem]

[0004] As a result of extensive research, the present inventors have found that the above-mentioned problems can be solved by providing a tablet containing ferric citrate as a pharmaceutically active ingredient and partially pregelatinized starch, or a tablet containing ferric citrate as a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, with a high content of the pharmaceutically active ingredient. As a result of further intensive research, the inventors discovered that the above problems could be solved by forming a tablet containing (1) ferric citrate, (2) polyvinyl alcohol-polyethylene glycol graft copolymer, and (3) polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and thus completed the present invention.

[0005] That is, the present invention is as follows. [1] A tablet comprising ferric citrate as an active pharmaceutical ingredient and partially pregelatinized starch. [2] The tablet according to [1] above, further comprising low-substituted hydroxypropyl cellulose and / or crystalline cellulose. [3] The tablet according to [1] or [2] above, further comprising trehalose. [4] The tablet according to any one of the above [1] to [3], further comprising a polyvinyl alcohol-polyethylene glycol graft copolymer. [5] The tablet according to any one of the above [2] to [4], wherein the low-substituted hydroxypropyl cellulose and / or crystalline cellulose are contained in a total amount of 5 to 20 parts by mass per 100 parts by mass of ferric citrate in anhydrous equivalent. [6] The tablet according to any one of the above [3] to [5], which contains trehalose in a ratio of 2 to 15 parts by mass per 100 parts by mass of ferric citrate in anhydrous equivalent. [7] A tablet according to any one of the above [4] to [6], which contains 100 parts by mass of ferric citrate in anhydrous equivalent and 2 to 15 parts by mass of polyvinyl alcohol-polyethylene glycol graft copolymer. [8] The tablet according to any one of the above [1] to [7], wherein the anhydrous ferric citrate is contained in an amount of 70 parts by mass or more per 100 parts by mass of the uncoated tablet obtained by removing the water content of the ferric citrate. [9] The tablet according to any one of the above [1] to [8], wherein the partially pregelatinized starch is contained in a ratio of 3 to 20 parts by mass per 100 parts by mass of ferric citrate in anhydrous equivalent.

[10] In the dissolution test using the paddle method of the 15th revised Japanese Pharmacopoeia dissolution test method, the 2nd fluid of the 15th revised Japanese Pharmacopoeia dissolution test is used as the test fluid, and the rotation speed is 50 rpm, the dissolution time is 30 minutes. The tablet according to any one of the above [1] to [9], wherein the dissolution rate of the ferric citrate is 75% or more.

[11] The tablet according to any one of the above [1] to

[10] , which is a preventive or therapeutic agent for hyperphosphatemia.

[12] A tablet comprising ferric citrate as a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, and containing the pharmaceutically active ingredient at a high content.

[13] The tablet according to

[12] above, wherein one of the pharmaceutically acceptable carriers is partially pregelatinized starch.

[0006]

[14] The tablet according to

[12] or

[13] above, wherein the anhydrous ferric citrate is contained in an amount of 70 parts by mass or more per 100 parts by mass of the uncoated tablet excluding the water content of the ferric citrate.

[15] The tablet according to

[13] or

[14] above, which contains 3 to 20 parts by mass of partially pregelatinized starch per 100 parts by mass of ferric citrate in anhydrous equivalent.

[16] A tablet containing ferric citrate as an active pharmaceutical ingredient, in which the dissolution rate of ferric citrate after 30 minutes is 75% or more in a dissolution test using the 2nd fluid of the 15th revised Japanese Pharmacopoeia dissolution test as the paddle method of the 15th revised Japanese Pharmacopoeia dissolution test at a rotation speed of 50 rpm.

[17] The tablet according to any one of the above

[12] to

[15] , wherein in a dissolution test according to the Japanese Pharmacopoeia, 15th Edition, paddle method using the second fluid of the Japanese Pharmacopoeia, 15th Edition, as the test fluid and at a rotation speed of 50 rpm, the dissolution rate of ferric citrate after a dissolution time of 30 minutes is 75% or more.

[18] The tablet according to any one of the above

[12] to

[17] , which is a preventive or therapeutic agent for hyperphosphatemia.

[19] A tablet comprising ferric citrate as an active pharmaceutical ingredient, partially pregelatinized starch, and low-substituted hydroxypropyl cellulose.

[20] The tablet according to

[19] above, further comprising a polyvinyl alcohol-polyethylene glycol graft copolymer.

[21] The tablet according to

[19] or

[20] above, wherein the anhydrous ferric citrate is contained in an amount of 70 parts by mass or more per 100 parts by mass of the uncoated tablet excluding the water content of the ferric citrate.

[22] The tablet according to any one of the above

[19] to

[21] , wherein the partially pregelatinized starch is contained in a ratio of 3 to 20 parts by mass per 100 parts by mass of ferric citrate in anhydrous equivalent.

[23] The tablet according to any one of the above [1] to

[10] ,

[12] to

[17] , and

[19] to

[22] , which is coated.

[24] The tablet according to any one of the above

[19] to

[23] , which is an agent for preventing or treating hyperphosphatemia.

[25] A method for producing tablets, comprising a step of mixing or granulating ferric citrate as an active pharmaceutical ingredient and partially pregelatinized starch.

[26] The manufacturing method according to

[25] above, further comprising the step of adding polyvinyl alcohol-polyethylene glycol graft copolymer and mixing or granulating the mixture.

[27] The method according to

[25] or

[26] above, further comprising the step of adding and mixing low-substituted hydroxypropyl cellulose.

[28] The method according to any one of the above

[25] to

[27] , further comprising a compression molding step.

[29] The method according to any one of the above

[25] to

[28] , further comprising a coating step.

[30] A tablet produced by the production method described in any one of

[25] to

[29] above.

[0007] [30-2] (1) A tablet containing ferric citrate and further containing (2) polyvinyl alcohol-polyethylene glycol graft copolymer and / or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[31] A tablet comprising (1) ferric citrate, (2) polyvinyl alcohol-polyethylene glycol graft copolymer, and (3) polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[32] The tablet according to

[31] above, further comprising one or more selected from the group consisting of low-substituted hydroxypropylcellulose, microcrystalline cellulose, and carboxymethylcellulose.

[33] The tablet according to

[31] or

[32] above, further comprising a lubricant.

[34] The tablet according to

[33] above, wherein the lubricant is calcium stearate and / or magnesium stearate.

[35] The tablet according to any one of

[31] to

[34] above, further comprising crospovidone.

[36] The tablet according to any one of the above

[31] to

[35] , wherein the anhydrous ferric citrate is contained in an amount of 70 parts by mass or more per 100 parts by mass of the uncoated tablet obtained by removing the water content of the ferric citrate.

[37] The tablet according to any one of the above

[31] to

[36] , which is coated.

[38] Use of the tablet according to any one of the above

[31] to

[37] as a preventive or therapeutic agent for hyperphosphatemia.

[39] A tablet comprising ferric citrate as a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, the tablet containing the pharmaceutically active ingredient at a high content.

[40] The tablet according to

[39] above, wherein the pharmaceutically acceptable carrier is polyvinyl alcohol-polyethylene glycol-graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[41] The tablet according to

[39] or

[40] above, further comprising one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose.

[42] The tablet according to any one of the above

[39] to

[41] , further comprising a lubricant.

[43] The tablet according to any one of the above

[39] to

[42] , further comprising crospovidone.

[44] The tablet according to any one of the above

[39] to

[43] , wherein the anhydrous ferric citrate is contained in an amount of 70 parts by mass or more per 100 parts by mass of the uncoated tablet excluding the water content of the ferric citrate.

[45] The tablet according to any one of the above

[39] to

[44] , which is coated.

[46] Use of the tablet according to any one of the above

[39] to

[45] as a preventive or therapeutic agent for hyperphosphatemia.

[47] The tablet according to any one of the above [30-2],

[31] to

[37] , and

[39] to

[45] , wherein in a dissolution test according to the Japanese Pharmacopoeia, Fifteenth Edition, paddle method using the second fluid of the Japanese Pharmacopoeia, Fifteenth Edition, as the test fluid and at a rotation speed of 50 rpm, the dissolution rate of ferric citrate after a dissolution time of 30 minutes is 75% or more.

[48] ​​A method for producing tablets, comprising a step of mixing or granulating ferric citrate as an active pharmaceutical ingredient with polyvinyl alcohol-polyethylene glycol-graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[49] The method according to

[48] above, further comprising the step of adding and mixing low-substituted hydroxypropyl cellulose.

[50] The manufacturing method according to the above

[48] or

[49] , further comprising a compression molding step.

[51] The manufacturing method according to any one of the above

[48] to

[50] , further comprising a coating step.

[0008] In this specification, the above tablets [1] to

[10] ,

[12] to

[17] ,

[19] to

[23] and

[30] are also referred to as tablets (I). In this specification, the above tablets [30-2],

[31] to

[37] ,

[39] to

[45] , and

[47] are also referred to as tablets (II). [Effects of the Invention]

[0009] According to the present invention, a new formulation containing an effective amount of ferric citrate can be provided. [Brief explanation of the drawings]

[0010] [Figure 1A] FIG. 1A shows the results of Test Example 1A for the tablets of Examples 1A and 2A. [Figure 2A] FIG. 2A shows the results of Test Example 1A for the tablets of Examples 3A and 4A. [Figure 3A] FIG. 3A shows the results of Test Example 2A for the tablets of Examples 5A and 6A. [Figure 4A]FIG. 4A shows the results of Test Example 2A for the tablets of Examples 7A and 8A. [Figure 5A] FIG. 5A shows the results of Test Example 3A. [Figure 6A] FIG. 6A shows the results of Test Example 4A. [Figure 7A] FIG. 7A shows the results of Test Example 8A. [Figure 8A] FIG. 8A shows the results of Test Example 9A. [Figure 9A] FIG. 9A shows the results of Test Example 10A. [Figure 1B] FIG. 1B shows the results of Test Example 13B. DETAILED DESCRIPTION OF THE INVENTION

[0011] The definitions used in the present invention are as follows: In the present invention, the "ferric citrate" used as a pharmaceutically active ingredient may be either a hydrate or anhydrous. The form of the "ferric citrate" is not particularly limited.

[0012] The iron(III) citrate used in the present invention can be produced by a method known per se, for example, the method described in WO 2004 / 07444 or a method similar thereto.

[0013] Specifically, for example, iron(III) citrate can be produced by the following steps (a) to (f): The conditions for steps (a) to (f) may be the same as those described in the method of International Publication No. 2004 / 07444. (a) Obtaining ferric chloride hexahydrate, (b) adding sodium hydroxide to ferric chloride hexahydrate at a rate and temperature effective to produce a uniform polyiron oxo suspension; (c) isolating the precipitate from the suspension; (d) adding crystalline citric acid to the precipitate; (e) forming a ferric iron-citric acid solution by heating the precipitate with citric acid; and (f) Precipitating ferric citrate from the ferric-citric acid solution by adding an organic solvent to the solution. Each step may be modified as appropriate.

[0014] In Tablet (I) and Tablet (II) of the present invention, the ferric citrate is contained in an amount of preferably 70 to 90 parts by mass, more preferably 70 to 85 parts by mass, and particularly preferably 70 to 80 parts by mass, based on 100 parts by mass of the uncoated tablet obtained by removing the water content of the ferric citrate, on an anhydrous basis. In another embodiment, in Tablet (I) and Tablet (II) of the present invention, ferric citrate may be contained in an amount of preferably 70 parts by mass or more, more preferably 80 parts by mass or more, and particularly preferably 85 parts by mass or more, based on 100 parts by mass of the uncoated tablet obtained by removing the water content of the ferric citrate, on an anhydrous basis. In this specification, the term "plain tablet" means, if the tablet is a coated tablet, the plain tablet before coating, and if the tablet is not coated, the tablet itself. Furthermore, in this specification, "containing a high content of the pharmaceutically active ingredient" means that ferric citrate, calculated as an anhydrous form, is contained in an amount of preferably 70 parts by mass or more per 100 parts by mass of the uncoated tablet obtained by removing water from the ferric citrate. According to the present invention, a tablet containing a high content of ferric citrate can be provided, and as a result, the size of the tablet can be reduced and / or the number of tablets to be taken can be reduced, thereby improving medication compliance. The "anhydrous equivalent amount" refers to the amount of iron(III) citrate in solid form. Specifically, the water content of iron(III) citrate is measured by the Karl Fischer method, and the amount of iron(III) citrate in solid form after excluding the water content is measured. For example, in the case of Example 12A, the mass of ferric citrate used as a raw material was 584.1 mg per tablet, and the amount of ferric citrate in the solids (i.e., the amount of ferric citrate on an anhydrous basis) obtained by subtracting 84.1 mg of water measured by the Karl Fischer method from this mass was 500.0 mg. The mass of the "uncoated tablet obtained by subtracting the water content of ferric citrate" in Example 12A was 573.5 mg per tablet, obtained by subtracting 84.1 mg from the total mass of the raw materials for the uncoated tablet, 657.6 mg. Thus, the uncoated tablet of Example 12A contained 87.2 parts by mass of "ferric citrate on an anhydrous basis" per 100 parts by mass of "uncoated tablet obtained by subtracting the water content of ferric citrate." (500.0 mg / 573.5 mg × 100)

[0015] In the tablet (I) of the present invention, the "partially pregelatinized starch" is, for example, starch obtained by heating starch together with water under normal pressure or under pressure to partially pregelatinize starch granules, and then drying the resulting product. Examples of starch raw materials include corn starch, potato starch, and rice starch, with corn starch being preferred. The "partially pregelatinized starch" used in the tablet (I) of the present invention is preferably the partially pregelatinized starch described in Pharmaceutical Additives Standards 2003 (published by Yakuji Nipposha in 2003). The "partially pregelatinized starch" used in the tablet (I) of the present invention can be produced by a known method, but commercially available products may also be used. Examples of commercially available products include Starch 1500G (manufactured by Nippon Colorcon Co., Ltd.) and PCS (manufactured by Asahi Kasei Chemicals Corporation), with Starch 1500G (manufactured by Nippon Colorcon Co., Ltd.) being preferred.

[0016] In tablet (I) of the present invention, the mass ratio of ferric citrate to partially pregelatinized starch is, for example, 3 to 20 parts by mass of partially pregelatinized starch per 100 parts by mass of ferric citrate calculated as anhydrous. Furthermore, the mass ratio of partially pregelatinized starch per 100 parts by mass of ferric citrate calculated as anhydrous may be, for example, 3.5 parts by mass or more, 5.9 parts by mass or more, or 8.2 parts by mass or more. Furthermore, the mass ratio of partially pregelatinized starch per 100 parts by mass of ferric citrate calculated as anhydrous may be, for example, 17.6 parts by mass or less.

[0017] In the tablet (I) of the present invention, low-substituted hydroxypropyl cellulose and / or binder It is preferred that the cellulose contains crystalline cellulose. In the tablet (I) of the present invention, examples of the "low-substituted hydroxypropyl cellulose" include, but are not limited to, low-substituted hydroxypropyl cellulose as defined in the 15th edition of the Japanese Pharmacopoeia. The "low-substituted hydroxypropyl cellulose" used in the tablet (I) of the present invention can be produced by a known method, but commercially available products may also be used. Examples of commercially available products include L-HPC (grades: LH-11, LH-21, LH-22, LH-31, LH-32, LH-B1, manufactured by Shin-Etsu Chemical Co., Ltd.), and LH-11 (manufactured by Shin-Etsu Chemical Co., Ltd.) is preferred.

[0018] In the tablet (I) of the present invention, the term "crystalline cellulose" is a concept that includes microcrystalline cellulose. In the tablet (I) of the present invention, examples of the "crystalline cellulose" include, but are not limited to, the crystalline cellulose defined in the 15th edition of the Japanese Pharmacopoeia. The "crystalline cellulose" used in the tablet (I) of the present invention can be produced by a known method, but commercially available products may also be used. Examples of commercially available products include Ceolus (grades: PH-101, PH-102, PH-301, PH-302, KG-802, KG-1000, manufactured by Asahi Kasei Chemicals), VIVAPUR (grades: 101, 102, 105, 301, 302, manufactured by JRS Pharma), and Emcocel (grades: 50M, 90M, manufactured by JRS Pharma), with Ceolus KG-1000 (manufactured by Asahi Kasei Chemicals) being preferred.

[0019] When low-substituted hydroxypropyl cellulose and / or crystalline cellulose are used in the tablet (I) of the present invention, the mass ratio of ferric citrate to low-substituted hydroxypropyl cellulose and / or crystalline cellulose is, for example, 5 to 20 parts by mass of low-substituted hydroxypropyl cellulose and / or crystalline cellulose per 100 parts by mass of ferric citrate in anhydrous equivalent. Furthermore, the total amount of low-substituted hydroxypropyl cellulose and / or crystalline cellulose per 100 parts by mass of ferric citrate in anhydrous equivalent may be, for example, 8 parts by mass or more, or 10 parts by mass or more. Furthermore, the total amount of low-substituted hydroxypropyl cellulose and / or crystalline cellulose per 100 parts by mass of ferric citrate in anhydrous equivalent may be, for example, 15 parts by mass or less.

[0020] The tablet (I) of the present invention preferably contains trehalose. The "trehalose" used in the tablet (I) of the present invention can be produced by a known method, but commercially available products may also be used, such as trehalose (grades: P, G, manufactured by Asahi Kasei Chemicals).

[0021] When trehalose is used in tablet (I) of the present invention, the mass ratio of ferric citrate to trehalose is, for example, 2 to 15 parts by mass of trehalose per 100 parts by mass of ferric citrate in anhydrous equivalent. Furthermore, the mass ratio of trehalose may be, for example, 5 parts by mass or more per 100 parts by mass of ferric citrate in anhydrous equivalent. Furthermore, the mass ratio of trehalose may be, for example, 12 parts by mass or less per 100 parts by mass of ferric citrate in anhydrous equivalent.

[0022] The tablet (I) of the present invention preferably contains a polyvinyl alcohol-polyethylene glycol graft copolymer. In the tablet (I) of the present invention, examples of the "polyvinyl alcohol-polyethylene glycol graft copolymer" include, but are not limited to, a graft copolymer having an average molecular weight of approximately 45,000, which is composed of 3 mol of polyvinyl alcohol and 1 mol of polyethylene glycol. The "polyvinyl alcohol-polyethylene glycol graft copolymer" used in the tablet (I) of the present invention can be produced by a known method, but commercially available products such as Kollicoat IR (manufactured by BASF) may also be used.

[0023] When a polyvinyl alcohol-polyethylene glycol graft copolymer is used in tablet (I) of the present invention, the mass ratio of ferric citrate to polyvinyl alcohol-polyethylene glycol graft copolymer is, for example, 2 to 15 parts by mass per 100 parts by mass of ferric citrate (anhydrous equivalent). Furthermore, the mass ratio of polyvinyl alcohol-polyethylene glycol graft copolymer may be, for example, 5 parts by mass or more per 100 parts by mass of ferric citrate (anhydrous equivalent). Furthermore, the mass ratio of polyvinyl alcohol-polyethylene glycol graft copolymer may be, for example, 12 parts by mass or less per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0024] In the tablet (I) of the present invention, pharmaceutically acceptable carriers other than the above-mentioned components may also be used as needed. The amount of the pharmaceutically acceptable carriers other than the above-mentioned components used is not particularly limited. In the tablet (I) of the present invention, the "pharmaceutically acceptable carrier" includes carriers commonly used in the field of pharmaceutical formulations, such as additives such as excipients, disintegrants, binders, flow agents, lubricants, preservatives, antioxidants, colorants, and sweeteners. These additives can be used together with the partially pregelatinized starch, if necessary.

[0025] Examples of the "excipient" used in the tablet (I) of the present invention include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, gum arabic, and the like. Examples of the "disintegrant" used in the tablet (I) of the present invention include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylstarch sodium, croscarmellose sodium, crospovidone, etc. Examples of the "binder" used in the tablet (I) of the present invention include hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, sucrose, dextrin, starch, pregelatinized starch, gelatin, sodium carboxymethylcellulose, gum arabic, etc. Examples of the "fluidizer" used in the tablet (I) of the present invention include light anhydrous silicic acid, magnesium stearate, etc. Examples of the "lubricant" used in the tablet (I) of the present invention include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, etc. Examples of the "preservative" used in the tablet (I) of the present invention include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. Examples of the "antioxidant" used in the tablet (I) of the present invention include sodium sulfite, ascorbic acid, etc. Examples of the "coloring agent" used in the tablet (I) of the present invention include food dyes (e.g., Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), β-carotene, and the like. The "sweetening agent" used in the tablet (I) of the present invention includes, for example, saccharin nitrate. Examples of suitable anti-inflammatory agents include sodium, dipotassium glycyrrhizinate, and aspartame.

[0026] As described above, the "polyvinyl alcohol-polyethylene glycol graft copolymer" used in tablet (II) of the present invention includes, but is not limited to, a graft copolymer having an average molecular weight of approximately 45,000, which is composed of 3 mol of polyvinyl alcohol and 1 mol of polyethylene glycol. The "polyvinyl alcohol-polyethylene glycol graft copolymer" used in the tablet (II) of the present invention can be produced by a known method, but commercially available products such as Kollicoat IR (manufactured by BASF) may also be used. In tablet (II) of the present invention, the mass ratio of ferric citrate to polyvinyl alcohol-polyethylene glycol graft copolymer is, for example, 0.01 to 15 parts by mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent). Furthermore, the mass ratio of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent) may be, for example, 0.1 parts by mass or more, or 0.5 parts by mass or more. Furthermore, the mass ratio of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent) may be, for example, 12 parts by mass or less, or 10 parts by mass or less. In tablet (II) of the present invention, the mass ratio of ferric citrate to polyvinyl alcohol-polyethylene glycol graft copolymer is preferably 1 to 12 parts by mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), more preferably 1 to 10 parts by mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), particularly preferably 3 to 6 parts by mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), and even more particularly preferably 3 to 5 parts by mass.

[0027] In tablet (II) of the present invention, the "polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" refers to a copolymer consisting of polyvinyl alcohol, acrylic acid, and methyl methacrylate. The polymerization ratios of each component are not particularly limited as long as they exhibit binding strength as a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. Suitable polymerization ratios are, for example, 75% to 80% by mass of polyvinyl alcohol, 2.0% to 8.0% by mass of acrylic acid, and 17% to 21% by mass of methyl methacrylate. Preferably, the polyvinyl alcohol content is 75% to 80% by mass, 2.5% to 7.5% by mass of acrylic acid, and 17.5% to 20% by mass of methyl methacrylate. The polyvinyl alcohol, which is one of the components of the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer used in the tablet (II) of the present invention, has a degree of polymerization in the range of 400 to 600, preferably in the range of 450 to 550, and a degree of saponification in the range of 85 mol% to 90 mol%, preferably in the range of 86 mol% to 89 mol%. The polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer includes the commercially available POVACOAT (manufactured by Daido Chemical Industry Co., Ltd.), which is a copolymer of polyvinyl alcohol with a degree of polymerization of 500 and a degree of saponification in the range of 86.5 mol% to 89.0 mol% with acrylic acid and methyl methacrylate in mass proportions of 80.0 mass%, 2.5 mass%, and 17.5 mass%, respectively. An example is POVACOAT Type: F.

[0028] In the tablet (II) of the present invention, ferric citrate and polyvinyl alcohol-acrylic acid The mass ratio of the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer to 100 parts by mass of ferric citrate, calculated on an anhydrous basis, is, for example, 0.01 to 10 parts by mass. Furthermore, the mass ratio of the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer to 100 parts by mass of ferric citrate, calculated on an anhydrous basis, may be, for example, 0.1 part by mass or more, or 0.5 part by mass or more. Furthermore, the mass ratio of the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer to 100 parts by mass of ferric citrate, calculated on an anhydrous basis, may be, for example, 8 parts by mass or less, or 6 parts by mass or less. In tablet (II) of the present invention, the mass ratio of ferric citrate to polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is preferably 0.1 to 5 parts by mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate, calculated as anhydrous; more preferably 0.1 to 3 parts by mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate, calculated as anhydrous; particularly preferably 0.5 to 2 parts by mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate, calculated as anhydrous; and even more particularly preferably 1 to 2 parts by mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate, calculated as anhydrous.

[0029] When "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" is used in tablet (II) of the present invention, the mass ratio of ferric citrate to "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" is, for example, 3 to 15 parts by mass of "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" to 100 parts by mass of ferric citrate in anhydrous terms. Furthermore, the amount of "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" may be, for example, 5 parts by mass or more per 100 parts by mass of ferric citrate in anhydrous equivalent. Furthermore, the amount of "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" may be, for example, 12 parts by mass or less per 100 parts by mass of ferric citrate in anhydrous equivalent. When "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" is used in tablet (II) of the present invention, the mass ratio of ferric citrate to "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" is preferably 3 to 10 parts by mass of "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" per 100 parts by mass of ferric citrate (anhydrous equivalent), more preferably 4 to 7 parts by mass of "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" per 100 parts by mass of ferric citrate (anhydrous equivalent), and particularly preferably 5 to 7 parts by mass of "polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer" per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0030] The tablet (II) of the present invention preferably contains one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose.

[0031] "Low-substituted hydroxypropyl cellulose" used in the tablet (II) of the present invention As mentioned above, examples of the low-substituted hydroxypropyl cellulose include, but are not limited to, low-substituted hydroxypropyl cellulose as defined in the 15th edition of the Japanese Pharmacopoeia. The "low-substituted hydroxypropyl cellulose" used in the tablet (II) of the present invention can be produced by a known method, but commercially available products may also be used. Examples of commercially available products include L-HPC (grades: LH-11, LH-21, LH-22, LH-31, LH-32, LH-B1, manufactured by Shin-Etsu Chemical Co., Ltd.), and LH-11 (manufactured by Shin-Etsu Chemical Co., Ltd.) is preferred. When low-substituted hydroxypropyl cellulose is used in tablet (II) of the present invention, the mass ratio of ferric citrate to low-substituted hydroxypropyl cellulose is, for example, 5 to 20 parts by mass of low-substituted hydroxypropyl cellulose per 100 parts by mass of ferric citrate in anhydrous equivalent. Furthermore, low-substituted hydroxypropyl cellulose may be, for example, 8 parts by mass or more, or 10 parts by mass or more per 100 parts by mass of ferric citrate in anhydrous equivalent. Furthermore, low-substituted hydroxypropyl cellulose may be, for example, 15 parts by mass or less per 100 parts by mass of ferric citrate in anhydrous equivalent. When low-substituted hydroxypropyl cellulose is used in tablet (II) of the present invention, the mass ratio of ferric citrate to low-substituted hydroxypropyl cellulose is preferably 6 to 16 parts by mass of low-substituted hydroxypropyl cellulose per 100 parts by mass of ferric citrate in anhydrous equivalent, more preferably 8 to 16 parts by mass of low-substituted hydroxypropyl cellulose per 100 parts by mass of ferric citrate in anhydrous equivalent, and particularly preferably 10 to 14 parts by mass of low-substituted hydroxypropyl cellulose per 100 parts by mass of ferric citrate in anhydrous equivalent.

[0032] In the tablet (II) of the present invention, the term "crystalline cellulose" is a concept that includes microcrystalline cellulose. In the tablet (II) of the present invention, examples of the "crystalline cellulose" include, but are not limited to, the crystalline cellulose defined in the 15th edition of the Japanese Pharmacopoeia. The "crystalline cellulose" used in the tablet (II) of the present invention can be produced by a known method, but commercially available products may also be used. Examples of commercially available products include Ceolus (grades: PH-101, PH-102, PH-301, PH-302, KG-802, KG-1000, manufactured by Asahi Kasei Chemicals), VIVAPUR (grades: 101, 102, 105, 301, 302, manufactured by JRS Pharma), and Emcocel (grades: 50M, 90M, manufactured by JRS Pharma).

[0033] In the tablet (II) of the present invention, the "carboxymethylcellulose" includes, but is not limited to, for example, carboxymethylcellulose defined in the 15th edition of the Japanese Pharmacopoeia. The carboxymethylcellulose used in the tablet (II) of the present invention can be produced by a known method, but commercially available products may also be used. Examples of commercially available products include NS-300 (manufactured by Nichirin Chemical Industry Co., Ltd.), and NS-300 (manufactured by Nichirin Chemical Industry Co., Ltd.) is preferred.

[0034] In the tablet (II) of the present invention, when "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" is used, the mass ratio of ferric citrate to "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" is, for example, 5 to 42 parts by mass in total of "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" per 100 parts by mass of ferric citrate in anhydrous equivalent. The total amount of "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" may be, for example, 8 parts by mass or more. Furthermore, the total amount of "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" may be, for example, 36 parts by mass or less per 100 parts by mass of ferric citrate in anhydrous terms. In the tablet (II) of the present invention, when using "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose," the mass ratio of ferric citrate to "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" is preferably 10 parts by mass to 35 parts by mass of ferric citrate per 100 parts by mass of anhydrous equivalent, "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" as a total amount, more preferably, 20 parts by mass to 35 parts by mass of ferric citrate per 100 parts by mass of anhydrous equivalent, "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" as a total amount, particularly preferably, 25 parts by mass to 32 parts by mass of ferric citrate per 100 parts by mass of anhydrous equivalent, "one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, and carboxymethyl cellulose" as a total amount.

[0035] In tablet (II) of the present invention, "crospovidone" refers to a crosslinked polymer of 1-vinyl-2-pyrrolidone, and examples thereof include, but are not limited to, crospovidone defined in the Pharmaceutical Additives Standards 2003 (published by Yakuji Nipposha in 2003). The crospovidone used in the tablet (II) of the present invention can be produced by a known method, but commercially available products may also be used. Examples of commercially available products include Kollidon (grades: CL, CL-F, CL-SF, CL-M, manufactured by BASF), Polyplasd one (grades: XL, XL-10, INF-10, manufactured by ISP), and Kollidon CL-F (manufactured by BASF) is preferred. When crospovidone is used in tablet (II) of the present invention, the mass ratio of ferric citrate to crospovidone is, for example, 0.01 to 10 parts by mass of crospovidone per 100 parts by mass of ferric citrate in anhydrous equivalent. Furthermore, the mass ratio of crospovidone per 100 parts by mass of ferric citrate in anhydrous equivalent may be, for example, 0.1 part by mass or more, or 0.5 part by mass or more. Furthermore, the mass ratio of crospovidone per 100 parts by mass of ferric citrate in anhydrous equivalent may be, for example, 8 parts by mass or less. When crospovidone is used in tablet (II) of the present invention, the mass ratio of ferric citrate to crospovidone is preferably 0.1 to 6 parts by mass of crospovidone per 100 parts by mass of ferric citrate in anhydrous equivalent, and more preferably 0.5 to 4 parts by mass of crospovidone per 100 parts by mass of ferric citrate in anhydrous equivalent.

[0036] In the tablet (II) of the present invention, a pharmaceutically acceptable carrier other than the above-mentioned components may be used as needed. The amount of the pharmaceutically acceptable carrier other than the above-mentioned components used is not particularly limited. The "pharmaceutically acceptable carrier" used in the tablet (II) of the present invention includes carriers commonly used in the field of pharmaceutical formulations, such as additives such as excipients, disintegrants, binders, flow agents, lubricants, preservatives, antioxidants, colorants, and sweeteners. These additives can be used together with the polyvinyl alcohol-polyethylene glycol graft copolymer and the polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, if desired.

[0037] The "excipient" used in the tablet (II) of the present invention includes, for example, lactose, sucrose, Examples include D-mannitol, D-sorbitol, corn starch, dextrin, trehalose, carboxymethylcellulose calcium, carboxymethylstarch sodium, and gum arabic. Examples of the "disintegrant" used in the tablet (II) of the present invention include carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylstarch sodium, croscarmellose sodium, etc. Examples of the "binder" used in tablet (II) of the present invention include hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, sucrose, dextrin, starch, pregelatinized starch, partially pregelatinized starch, gelatin, sodium carboxymethylcellulose, gum arabic, etc. Examples of the "fluidizer" used in the tablet (II) of the present invention include light anhydrous silicic acid, magnesium stearate, etc. Examples of the "lubricant" used in the tablet (II) of the present invention include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, etc. Examples of the "preservative" used in the tablet (II) of the present invention include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, etc. Examples of the "antioxidant" used in the tablet (II) of the present invention include sodium sulfite, ascorbic acid, etc. Examples of "coloring agents" include food dyes (e.g., Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), β-carotene, and the like. Examples of the "sweetener" used in the tablet (II) of the present invention include saccharin sodium, dipotassium glycyrrhizinate, aspartame, etc.

[0038] The tablet (II) of the present invention preferably contains a lubricant. The lubricant used in the tablet (II) of the present invention is preferably magnesium stearate or calcium stearate. The magnesium stearate used in tablet (II) of the present invention can be produced by known methods, but commercially available products may also be used, such as magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd., Japanese Pharmacopoeia, vegetable-based), magnesium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.), magnesium stearate (manufactured by Mallinckrodt Co., Ltd.), etc. The calcium stearate used in the tablet (II) of the present invention can be produced by known methods, but commercially available products may also be used, such as calcium stearate (manufactured by Taihei Chemical Industry Co., Ltd., Japanese Pharmacopoeia, vegetable-based), calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.), and calcium stearate (manufactured by Mallinckrodt Co., Ltd.). When a lubricant is used in tablet (II) of the present invention, the mass ratio of ferric citrate to lubricant is, for example, 0.01 to 6 parts by mass of lubricant per 100 parts by mass of ferric citrate in anhydrous equivalent. Furthermore, the mass ratio of lubricant per 100 parts by mass of ferric citrate in anhydrous equivalent may be, for example, 0.1 part by mass or more, or 0.5 part by mass or more. Furthermore, the mass ratio of lubricant per 100 parts by mass of ferric citrate in anhydrous equivalent may be, for example, 3 parts by mass or less.

[0039] The tablet of the present invention may be coated with a coating agent, if necessary. As the "coating agent," coating agents commonly used in the field of pharmaceutical preparations can be used, and examples thereof include hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, etc. The coating agent may be mixed with other additives, such as macrogols or plasticizers such as triacetin, light-blocking agents such as titanium oxide, and anti-adhesion agents such as talc, as needed, before use for coating. In addition, Opadry II ( Premix coating agents such as those manufactured by Colorcon may also be used.

[0040] "15th Edition Japanese Pharmacopoeia Dissolution Test First Fluid" is prepared by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water to make 1000 mL. "15th Edition Japanese Pharmacopoeia Dissolution Test Fluid No. 2" is prepared by adding 1 volume of water to 1 volume of phosphate buffer solution, pH 6.8 (dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL). "15th Edition Japanese Pharmacopoeia Disintegration Test Fluid 1" is the same as "15th Edition Japanese Pharmacopoeia Dissolution Test Fluid 1." In a dissolution test of tablets (I) and (II) of the present invention using the paddle method of the Japanese Pharmacopoeia, 15th Edition, dissolution test fluid No. 2 as the test fluid at a rotation speed of 50 rpm, the dissolution rate of ferric citrate after a dissolution time of 30 minutes is preferably 70% or more, more preferably 75% or more. In a disintegration test according to the Japanese Pharmacopoeia, 15th Edition, using the first disintegration test fluid of the Japanese Pharmacopoeia, 15th Edition as the test fluid, the disintegration time of the tablets (I) and (II) of the present invention is preferably 10 minutes or less. Preferably, the time is 5 minutes or less.

[0041] The tablet of the present invention can be used, for example, for the prevention and treatment of hyperphosphatemia.

[0042] The subject to which the tablet of the present invention is administered is mainly humans, but it may also be mammals other than humans (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) The dosage varies depending on the subject, disease, symptoms, administration route, etc.

[0043] The shape of the tablet of the present invention is not particularly limited, and may be, for example, a round tablet, an irregularly shaped tablet (e.g., a capsule-shaped tablet), or the like. Tablets (oval tablets) etc.

[0044] The method for producing the tablet of the present invention will be described below, but is not limited thereto. The method for producing tablet (I) of the present invention includes a step of granulating or mixing ferric citrate as a pharmaceutically active ingredient with partially pregelatinized starch, followed by compression molding by a method known per se to produce the tablet of the present invention. Specifically, the following method is exemplified. 1. Granulation or mixing process The ferric citrate is granulated or mixed with the partially pregelatinized starch. The granulation or mixing method is not particularly limited, and any method known per se in the pharmaceutical field may be used. In the case of granulation, examples include fluidized bed granulation. Specifically, for example, a fluidized bed granulator can be used to granulate the mixture while spraying a suspension of partially pregelatinized starch in purified water onto ferric citrate. After granulation, the mixture is dried to obtain dry granules. The obtained dry granules may be sized as necessary. Furthermore, necessary additives may be added at any stage of this process, followed by granulation or mixing. 2. Compression molding process A lubricant can be added to the obtained granulated product (for example, granules) or mixture, and the mixture can be compressed to obtain the tablet of the present invention. The method for compressing tablets is not particularly limited, but for example, a screw universal testing machine, a rotary tablet press, etc. may be used. The compression force is not particularly limited as long as it is sufficient to give the tablet sufficient strength, but a tensile strength of 1 N / mm 2 More than 2N / mm is preferable, and the tensile strength is 2N / mm 2 More specifically, in the case of a capsule-shaped tablet having a major axis of 14.8 mm and a minor axis of 6.8 mm, the tablet hardness is preferably 60 N or more, and more preferably 90 N or more. The lubricant may be added by either an internal mixing method or an external lubrication method. Furthermore, necessary additives may be added at any stage of this process. Furthermore, the tablets may be coated with a coating agent after compression.

[0045] When tablet (I) of the present invention contains one or more components selected from the group consisting of low-substituted hydroxypropyl cellulose, crystalline cellulose, trehalose, and polyvinyl alcohol-polyethylene glycol graft copolymer, the components may be added at any stage and by any method, but a preferred addition method is to add the components to granules obtained by granulating ferric citrate with partially pregelatinized starch. For example, when tablet (I) of the present invention contains polyvinyl alcohol-polyethylene glycol graft copolymer, the component may be added at any stage and by any method, but a preferred addition method is to granulate ferric citrate with partially pregelatinized starch, to obtain granules, and then add polyvinyl alcohol-polyethylene glycol graft copolymer to the granules and granulate the resulting mixture.

[0046] The method for producing tablet (II) of the present invention includes a step of granulating or mixing ferric citrate as a pharmaceutically active ingredient with polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, followed by compression molding by a method known per se to produce the tablet of the present invention. Specifically, the following method is exemplified. 1. Granulation or mixing process The ferric citrate is granulated or mixed with polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. The granulation or mixing method is not particularly limited, and any method known in the pharmaceutical field may be used. For example, fluidized bed granulation is used for granulation. Specifically, for example, a fluidized bed granulator can be used to granulate the mixture while spraying a solution of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer dissolved in purified water onto ferric citrate. After granulation, the mixture is dried to obtain dry granules. The resulting dry granules may be sized as needed. Furthermore, necessary additives may be added at any stage of this process, followed by granulation or mixing. 2. Compression molding process A lubricant can be added to the obtained granulated product (for example, granules) or mixture, and the mixture can be compressed to obtain the tablet of the present invention. The method for compressing tablets is not particularly limited, but for example, a screw universal testing machine, a rotary tablet press, etc. may be used. The compression force is not particularly limited as long as it is sufficient to give the tablet sufficient strength, but a tensile strength of 1 N / mm 2 More than 1.5N / mm is preferable. 2 The above is more preferable. The method of adding the lubricant may be an internal mixing method or an external lubrication method. Furthermore, necessary additives may be added at any stage of this process. Furthermore, the tablet may be coated with a coating agent after compression.

[0047] When tablet (II) of the present invention contains crystalline cellulose, this component may be added at any stage and by any method, but a preferred method of adding crystalline cellulose is to add it to granules obtained by granulating ferric citrate with polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. Alternatively, crystalline cellulose may be added to ferric citrate and granulated with polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. For example, when the tablet (II) of the present invention contains low-substituted hydroxypropyl cellulose and / or carboxymethyl cellulose, the components may be added at any stage and by any method. However, a preferred method of addition is to add ferric citrate to polyvinyl alcohol-polyethylene glycol-graft copolymer and polyvinyl alcohol-acrylic acid-methacrylic acid. For example, the additive may be added to granules obtained by granulating the additive together with the methyl copolymer.

[0048] The manufacturing method of the tablets of the present invention will be explained in more detail with reference to the following examples, but the present invention is not limited to these examples. During manufacturing, the order of mixing the additives and the mixing conditions may be changed as appropriate. When changing the content of ferric citrate per tablet, the mass of each additive may also be changed according to the mass of ferric citrate. In the examples where magnesium stearate was used as an external lubricant, the amount of magnesium stearate was considered to be zero. [Example]

[0049] Reference example 1-1 Partially pregelatinized starch (Starch 1500G, manufactured by Colorcon Japan) was dispersed in purified water using a propeller mixer, and then uniformly dispersed using a handy homomixer. Purified water was then added to prepare a binding solution with a concentration of 10% by mass.

[0050] Reference example 1-2 Hydroxypropyl cellulose (HPC L, manufactured by Nippon Soda) was dissolved in purified water using a propeller mixer to prepare a binding solution with a concentration of 5% by mass.

[0051] Reference example 1-3 Pregelatinized starch (Amycol C, manufactured by Nippon Starch Chemical Co., Ltd.) was dispersed in purified water using a propeller mixer, and then uniformly dispersed using a handy homomixer. Purified water was then added to prepare a binding solution with a concentration of 5% by mass.

[0052] Reference example 1-4 Partially pregelatinized starch (Starch 1500G, manufactured by Colorcon Japan) was dispersed in purified water using a propeller mixer, and the dispersion was sieved through a stainless steel sieve with 250 μm openings. Purified water was then added to prepare a binding solution with a concentration of 10% by mass.

[0053] Example 1A 450 g of ferric citrate (383.9 g on anhydrous basis) was placed in a tumbling fluidized bed granulation dryer (MP-01, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 135 g of the binding solution of Reference Example 1-1 was sprayed onto the granules at a rate of 4 to 5 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain "sized powder a." The obtained "granulated powder a" (618 mg) was analyzed by magnesium stearate (Japanese Pharmacopoeia Using a vegetable-based lubricant (manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, the tablets were molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 3, 4, 5, or 7.5 kN to obtain circular tablets with a diameter of 12 mm.

[0054] Example 2A 450 g of ferric citrate (383.9 g on anhydrous basis) was placed in a tumbling fluidized bed granulation dryer (MP-01, manufactured by Powrex), the air volume was set to bring the ferric citrate into a moderately fluidized state, and 270 g of the binding solution of Reference Example 1-2 was sprayed onto the granules at a rate of 4 to 5 g per minute at an inlet air temperature of 60°C. The granules were then dried at an inlet air temperature of 60°C to obtain dried granules. The obtained dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain "sized powder b." The obtained "granulated powder b" (618 mg) was analyzed for magnesium stearate ( Using a vegetable-based lubricant (manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, the tablets were molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 5, 7, or 10 kN to obtain circular tablets with a diameter of 12 mm.

[0055] Example 3A 450 g of ferric citrate (383.9 g on anhydrous basis) was placed in a tumbling fluidized bed granulation dryer (MP-01, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 315 g of the binding solution of Reference Example 1-1 was sprayed onto the granules at a rate of 4 to 5 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain "sized powder c." The obtained "granulated powder c" (642 mg) was analyzed for magnesium stearate (Japanese Pharmacopoeia Using a vegetable-based lubricant (manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, the tablets were molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 4, 5, or 7.5 kN to obtain circular tablets with a diameter of 12 mm.

[0056] Example 4A 450 g of ferric citrate (383.9 g on anhydrous basis) was placed in a tumbling fluidized bed granulation dryer (MP-01, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 630 g of the binding solution of Reference Example 1-3 was sprayed onto the granules at a rate of 4 to 5 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain "sized powder d." The obtained "granulated powder d" (642 mg) was analyzed for magnesium stearate (Japanese Pharmacopoeia Using a vegetable-based lubricant (manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, the tablets were molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 3, 4, or 5 kN to obtain circular tablets with a diameter of 12 mm.

[0057] Test Example 1A (Moldability Test) To investigate the tensile strength (hardness / fracture area) of the tablets at each compression pressure, the tablet hardness (N) of the tablets obtained in Examples 1A to 4A was measured using a tablet hardness tester (6D, manufactured by Schleuniger), and the tensile strength was calculated by dividing the obtained value by the fracture area (tablet diameter (mm) x tablet thickness (mm)). Tensile strength (N / mm) against compressive pressure (kN) 2 ) are plotted and shown in Figures 1A and 2A.

[0058] Example 5A Using 618 mg of the "sized powder a" obtained in Example 1A and magnesium stearate (Japanese Pharmacopoeia, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machine Co., Ltd.) was used to measure a tensile strength of approximately 2 N / mm at a compression speed of 20 mm / min. 2 The mixture was compressed under a pressure such that the tablet size was 12 mm, giving circular tablets (each tablet containing 18 mg of partially pregelatinized starch).

[0059] Example 6A Using 618 mg of the "sized powder b" obtained in Example 2A and magnesium stearate (Japanese Pharmacopoeia, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machine Co., Ltd.) was used to measure a tensile strength of approximately 2 N / mm at a compression speed of 20 mm / min. 2 The mixture was compressed under a pressure such that the tablet size was 12 mm, giving circular tablets (each tablet containing 18 mg of hydroxypropyl cellulose).

[0060] Example 7A Using 642 mg of the "sized powder c" obtained in Example 3A, magnesium stearate (Japanese Pharmacopoeia, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machine Co., Ltd.) was used to measure a tensile strength of approximately 2 N / mm at a compression speed of 20 mm / min. 2 The tablets are compressed to a pressure that will give them a diameter of 12 mm (partial aluminum per tablet). The resulting product contained 42 mg of cellulose-modified starch.

[0061] Example 8A Using 642 mg of the "sized powder d" obtained in Example 4A and magnesium stearate (Japanese Pharmacopoeia, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machine Co., Ltd.) was used to measure a tensile strength of approximately 2 N / mm at a compression speed of 20 mm / min. 2 The mixture was compressed under a pressure such that the tablet size was 12 mm, giving circular tablets (each tablet containing 42 mg of pregelatinized starch).

[0062] Test Example 2A (Dissolution Test) The tablets obtained in Examples 5A to 8A were subjected to a dissolution test under the conditions shown in Table 1A to evaluate the dissolution characteristics.

[0063] [Table 1A]

[0064] The results are shown in Figures 3A and 4A.

[0065] Example 9A 450 g of ferric citrate (383.9 g on anhydrous basis) was placed in a tumbling fluidized bed granulation dryer (MP-01, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 225 g of the binding solution of Reference Example 1-1 was sprayed onto the granules at a rate of 4 to 5 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain "sized powder e." The obtained "granulated powder e" (630 mg) was analyzed for magnesium stearate (Japanese Pharmacopoeia Using a 50kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) with an external lubricant (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.), the tensile strength was measured at a compression speed of 20mm / min and was approximately 2N / mm. 2 The mixture was compressed under a pressure such that the tablet size was 12 mm, giving circular tablets (each tablet containing 30 mg of partially pregelatinized starch).

[0066] Example 10A 450 g of ferric citrate (383.9 g in anhydrous equivalent) was placed in a tumbling fluidized bed granulation dryer (MP-01, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 675 g of the binding solution of Reference Example 1-1 was sprayed onto the granules at a rate of 4 to 5 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain "sized powder f." The obtained "granulated powder f" (690 mg) was analyzed for magnesium stearate (Japanese Pharmacopoeia Using a vegetable-based lubricant (manufactured by Taihei Chemical Industry Co., Ltd.) as an external lubricant, the tablets were molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines Co., Ltd.) at a compression speed of 20 mm / min and a compression pressure such that the tablet hardness was approximately 140 N, yielding capsule-shaped tablets (each tablet containing 90 mg of partially pregelatinized starch) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0067] Example 11A 450 g of ferric citrate (383.9 g on anhydrous basis) was placed in a tumbling fluidized bed granulator dryer (MP-01, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 450 g of the binding solution of Reference Example 1-1 was sprayed onto the granules at a rate of 4 to 5 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The resulting dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain 483.9 g of "sized powder." 462 g of the obtained "sized powder" and 4.76 g of magnesium stearate (Japanese Pharmacopoeia, vegetable-based, Taihei Chemical Industry Co., Ltd.) were mixed in a 2 L container using a turbulator mixer for 3 minutes to obtain a tablet powder. This tablet powder was then compressed using a rotary tablet press (Collect 12HUK, Kikusui Seisakusho Co., Ltd.) at a compression pressure of 140-150 N to obtain capsule-shaped tablets with a major axis of 17.5 mm and a minor axis of 8 mm (each tablet containing 60 mg of partially pregelatinized starch).

[0068] The component compositions of the tablets of Examples 1A to 4A, 6A, and 8A are shown in Table 2A. The content (%) of ferric citrate (anhydrous equivalent) in the uncoated tablets and the mass of partially pregelatinized starch, hydroxypropyl cellulose, or pregelatinized starch per 100 parts by mass of ferric citrate (anhydrous equivalent) are shown in Table 3A.

[0069] [Table 2A]

[0070] [Table 3A]

[0071] The component compositions of the tablets of Examples 5A, 7A, and 9A to 11A are shown in Table 4A. The content (%) of ferric citrate (anhydrous equivalent) in the uncoated tablets and the mass of partially pregelatinized starch per 100 parts by mass of ferric citrate (anhydrous equivalent) are also shown in Table 5A.

[0072] [Table 4A]

[0073] [Table 5A]

[0074] Test Example 3A (Dissolution Test) The tablets obtained in Examples 5A, 7A, 9A, 10A, and 11A were subjected to a dissolution test under the conditions shown in Table 1A of Test Example 2A to evaluate their dissolution properties. The results of the dissolution test are shown in Figure 5A.

[0075] Example 12A 19.2757 kg of ferric citrate (16.5 kg on anhydrous basis) was placed in a fluidized bed granulation dryer (WSG-60, Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 19,800 g of the binding solution of Reference Example 1-4 was sprayed onto the granules at a rate of 170-200 g per minute at an inlet air temperature of 70°C. After granulation, the granules were dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a screen with 1143 μm openings in a screen mill (U20 type, Powrex). The above procedure was repeated three times and then mixed to obtain "sized powder h." 1300.4 g of calcium stearate was added to 62.0441 kg of the obtained "sized powder h" and mixed, and the resulting mixture was molded in a rotary tablet press (Collect 12HUK, manufactured by Kikusui Seisakusho) at a compression pressure such that the tablet hardness was 150 N or more, yielding plain tablets (capsule-shaped tablets) with a major axis of 17.5 mm and a minor axis of 8 mm. 10.38 kg of uncoated tablets were coated with a coating solution prepared by mixing 1770 g of Opadry II (manufactured by Colorcon Japan), 30 g of yellow ferric oxide, and 10,200 g of purified water using an automatic coating machine (HCT-60N, manufactured by Freund Corporation), to obtain tablets with a coating layer of approximately 30 mg per tablet. The component composition of the tablet of Example 12A is shown in Table 6A. The content (%) of ferric citrate (anhydrous equivalent) in the uncoated tablet and the mass of partially pregelatinized starch per 100 parts by mass of ferric citrate (anhydrous equivalent) are shown in Table 7A.

[0076] [Table 6A]

[0077] [Table 7A]

[0078] Test Example 4A (Dissolution Test) The tablets (coated tablets) obtained in Example 12A were subjected to a dissolution test under the conditions shown in Table 8A to evaluate the dissolution properties.

[0079] [Table 8A]

[0080] The results are shown in Figure 6A.

[0081] Example 13A 17.667 kg of ferric citrate (15 kg on anhydrous basis) was placed in a fluidized bed granulation dryer (WSG-60, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 18,000 g of the binding solution of Reference Example 1-4 was sprayed onto the granules at a rate of 120 to 170 g per minute at an inlet air temperature of 70°C. After granulation, the granules were dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a screen with 813 μm openings in a screen mill (U20 type, manufactured by Powrex). The above procedure was repeated twice and then mixed to obtain "sized powder i." 607.5 g of calcium stearate was added to 27.9027 kg of the obtained "sized powder i" and mixed to obtain "tablet powder j." The obtained "tablet powder j" (662.4 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 60 mg of partially pregelatinized starch) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0082] Example 14A 7.618 g of "tabletting powder j" obtained in Example 13A and 0.345 g of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a Turbula mixer for 3 minutes to obtain "tabletting powder k." 692.4 mg of this "tabletting powder k" was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 60 mg of partially pregelatinized starch and 30 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0083] Example 15A 7.618 g of "tabletting powder j" obtained in Example 13A and 0.690 g of crystalline cellulose (CEOLUS KG-1000, manufactured by Asahi Kasei Chemicals) were mixed in a 50 mL container for 3 minutes using a Turbula mixer to obtain "tabletting powder 1." 722.4 mg of this "tablet powder 1" was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 60 mg of partially pregelatinized starch and 60 mg of crystalline cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0084] The component compositions of the tablets of Examples 13A to 15A are shown in Table 9A. The content (%) of ferric citrate (anhydrous equivalent) in the uncoated tablets, and the parts per 100 parts by mass of ferric citrate (anhydrous equivalent) are also shown in Table 9A. The mass of pregelatinized starch and the mass of low-substituted hydroxypropyl cellulose and crystalline cellulose relative to 100 parts by mass of ferric citrate (anhydrous equivalent) are shown in Table 10A.

[0085] [Table 9A]

[0086] [Table 10A]

[0087] Test Example 5A (Moldability Test) The tablets obtained in Examples 13A to 15A were visually inspected for cracks. Tablet hardness was measured using a tablet hardness tester (6D, manufactured by Schleuniger). Tablet moldability test results are shown in Table 11A.

[0088] [Table 11A]

[0089] Example 16A 497.1 g of ferric citrate (425 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, Powrex Corporation). The air volume was adjusted to ensure adequate fluidization of the ferric citrate. 510 g of the binding solution from Reference Example 1-1 was sprayed onto the granules at a rate of 4-5 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The resulting dried granules were sieved through a 710 μm stainless steel sieve to obtain a sized powder. 10.3168 g of the sized powder and 0.96 g of low-substituted hydroxypropyl cellulose (LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container for 5 minutes using a turbulator mixer, and then 0.216 g of calcium stearate (Japanese Pharmacopoeia, vegetable-based, Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain "tablet powder m." 718.3 mg of this "tablet powder m" was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 60 mg of partially pregelatinized starch and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0090] Reference example 2 35 g of trehalose (Trehalose P, manufactured by Asahi Kasei Chemicals) and 70 g of partially pregelatinized starch (Starch 1500G, manufactured by Colorcon Japan) were dissolved or dispersed in purified water using a propeller mixer, and then purified water was added to make a total weight of 700 g. This solution was sieved through a stainless steel sieve with 250 μm openings to prepare a binding solution.

[0091] Example 17A 438.6 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, Powrex Corporation). The air volume was adjusted to ensure adequate fluidization of the ferric citrate. 450 g of the binding solution from Reference Example 2 was sprayed onto the granules at a rate of 5 to 6.5 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 10.7968 g of the sized powder and 0.48 g of low-substituted hydroxypropyl cellulose (LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, followed by the addition of 0.216 g of calcium stearate (Japanese Pharmacopoeia, vegetable-based, Taihei Chemical Industry Co., Ltd.) and mixing for 3 minutes using the turbulator mixer to obtain "Tableting Powder n." 718.3 mg of this "tabletting powder n" was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 60 mg of partially pregelatinized starch, 30 mg of low-substituted hydroxypropyl cellulose, and 30 mg of trehalose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0092] Reference example 3 35 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 70 g of partially pregelatinized starch (Starch 1500G, manufactured by Colorcon Japan) were dissolved or dispersed in purified water using a propeller mixer, and then purified water was added to make a total volume of 700 g. This liquid was sieved through a stainless steel sieve with 250 μm openings to prepare a binding solution.

[0093] Example 18A 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, Powrex Corporation). The air volume was adjusted to ensure adequate fluidity of the ferric citrate. 450 g of the binding solution from Reference Example 3 was sprayed onto the granules at a rate of 5-6 g per minute at an inlet air temperature of 70°C. The granules were then dried at an inlet air temperature of 70°C to obtain dried granules. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 15.1228 g of the sized powder and 0.66 g of low-substituted hydroxypropyl cellulose (LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container for 5 minutes using a turbulator mixer, and then 0.297 g of calcium stearate (Japanese Pharmacopoeia, vegetable-based, Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain "tablet powder 0." 730.9 mg of this "tablet powder o" was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 60 mg of partially pregelatinized starch, 30 mg of low-substituted hydroxypropyl cellulose, and 30 mg of polyvinyl alcohol-polyethylene glycol graft copolymer) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0094] Reference example 4 Polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) was dissolved in purified water using a propeller mixer, and purified water was then added to prepare a binding solution with a concentration of 10% by mass.

[0095] Example 19A 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulation dryer (MP-01, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 225 g of the binding solution of Reference Example 1-4 was sprayed at a rate of 5 to 6 g per minute at an inlet air temperature of 70°C, followed by spraying 225 g of the binding solution of Reference Example 4 to granulate, followed by further drying at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain "sized powder p." 13.148 g of the obtained "sized powder p" and 1.2 g of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, and then 0.27 g of calcium stearate (Japanese Pharmacopoeia, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using a turbulator mixer to obtain "tablet powder q." 730.9 mg of this "tablet powder q" was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 30 mg of partially pregelatinized starch, 60 mg of low-substituted hydroxypropyl cellulose, and 30 mg of polyvinyl alcohol-polyethylene glycol graft copolymer) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0096] The component compositions of the tablets of Examples 16A to 19A are shown in Table 12A. Table 13A also shows the ferric citrate (anhydrous equivalent) content (%) in the uncoated tablets, the mass of partially pregelatinized starch per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of low-substituted hydroxypropyl cellulose and crystalline cellulose per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of trehalose per 100 parts by mass of ferric citrate (anhydrous equivalent), and the mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0097] [Table 12A]

[0098] [Table 13A]

[0099] Test Example 6A (Moldability Test) The tablets obtained in Examples 16A to 19A were inspected for cracks using a stereomicroscope (SZH, manufactured by Olympus) at a magnification of 15. Tablet hardness was also measured using a tablet hardness tester (6D, manufactured by Schleuniger).

[0100] Test Example 7A (Disintegration Test) The tablets obtained in Examples 16A to 19A were subjected to a disintegration test under the conditions shown in Table 14A to evaluate their disintegration properties.

[0101] [Table 14A]

[0102] The results of Test Examples 6A and 7A are shown in Table 15A.

[0103] [Table 15A]

[0104] Example 20A 23.476 kg of ferric citrate (20 kg on anhydrous basis) was placed in a fluidized bed granulation dryer (WSG-60, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 24,000 g of the binding solution of Reference Example 1-4 was sprayed onto the granules at a rate of 170 to 230 g per minute at an inlet air temperature of 70°C. After granulation, the granules were dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a screen with 1,143 μm openings in a screen mill (U20 type, manufactured by Powrex) to obtain "sized powder r." 46.952 kg of ferric citrate (40 kg on anhydrous basis) was placed in a fluidized bed granulation dryer (WSG-60, manufactured by Powrex), the air volume was set so that the ferric citrate was in a moderately fluidized state, and 48,000 g of the binding solution of Reference Example 1-4 was sprayed onto the granules at a rate of 130 to 250 g per minute at an inlet air temperature of 70°C. After granulation, the granules were dried at an inlet air temperature of 70°C to obtain dried granules. The obtained dried granules were sieved through a screen with 1,143 μm openings in a screen mill (U20 type, manufactured by Powrex) to obtain "sized powder S." To the obtained "sized powder r" (24.6610 kg) and "sized powder s" (25.7972 kg) was added 2340 g of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.), and the mixture was mixed for 277 seconds at 26 revolutions per minute in a W-type mixer (W-200, manufactured by Tokuju Kosakusho), after which 1053 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and the mixture was mixed for 92 seconds at 26 revolutions per minute in a W-type mixer (W-200, manufactured by Tokuju Kosakusho) to obtain tablet powder. The obtained tablet powder was molded using a rotary tablet press (Collect 12HUK, manufactured by Kikusui Seisakusho) at a compression pressure such that the tablet hardness was 150 N or more, to obtain uncoated tablets (capsule-shaped tablets) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0105] Example 21A 11.0916 kg of the uncoated tablets obtained in Example 20A were coated with a coating solution obtained by mixing 1080 g of hypromellose (TC-5M, manufactured by Shin-Etsu Chemical Co., Ltd.), 360 g of titanium oxide (Titanium (IV) Oxide extra pure, manufactured by Merck), 180 g of talc (Hifiller #17, manufactured by Matsumura Sangyo Co., Ltd.), 180 g of Macrogol 6000 (Macrogol 6000P, manufactured by NOF Corp.), and 12,600 g of purified water using an automatic coating machine (HCT-60N, manufactured by Freund Corporation), to obtain tablets with a coating layer of approximately 25 mg per tablet.

[0106] Example 22A 361.57 g of the "sized powder p" obtained in Example 19A and 33.0 g of low-substituted hydroxypropyl cellulose (LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed for 5 minutes using a turbulator mixer, and then 7.425 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using a turbulator mixer to obtain a tablet powder. This tablet powder was molded using a rotary tablet press (Collect 12HUK, Kikusui Seisakusho Co., Ltd.) at a compression pressure of 150 N or more to obtain uncoated tablets (capsule-shaped tablets) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0107] Example 23A For the uncoated tablets (146.2 g) obtained in Example 22A, 30 g of hypromellose (TC-5M, manufactured by Shin-Etsu Chemical Co., Ltd.) and titanium oxide (Titanium (IV) Oxide extraneous The tablets were coated with a coating solution prepared by mixing 10 g of talc (High Filler #17, Matsumura Sangyo Co., Ltd.), 5 g of Macrogol 6000 (Macrogol 6000P, NOF Corp.), and 350 g of purified water using an automatic coating machine (HC-LABO, Freund Corp.), to give tablets with a coating layer of approximately 25 mg per tablet. The component compositions of the tablets of Examples 20A to 23A are shown in Table 16A. The content (%) of ferric citrate (anhydrous equivalent) in the uncoated tablets and the amount of ferric citrate (anhydrous equivalent) per 100 parts by mass are shown in Table 16A. The mass of partially pregelatinized starch, the mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), and the masses of low-substituted hydroxypropyl cellulose and crystalline cellulose per 100 parts by mass of ferric citrate (anhydrous equivalent) are shown in Table 17A.

[0108] [Table 16A]

[0109] [Table 17A]

[0110] Test Example 8A (Dissolution Test) The tablets (plain tablets) obtained in Examples 17A, 18A, 20A, and 22A were subjected to a dissolution test under the conditions shown in Table 8A to evaluate the dissolution properties. The results are shown in Figure 7A.

[0111] Test Example 9A (Dissolution Test) The tablets (coated tablets) obtained in Examples 21A and 23A were subjected to a dissolution test under the conditions shown in Table 8A to evaluate the dissolution properties. The results are shown in Figure 8A.

[0112] Test Example 10A (Dissolution Test) The tablets (coated tablets) obtained in Example 12A were subjected to a dissolution test under the conditions shown in Table 18A to evaluate the dissolution properties.

[0113] [Table 18A]

[0114] The results are shown in Figure 9A.

[0115] Example 1B Hydroxypropyl cellulose (HPC L, manufactured by Nippon Soda) was dissolved in purified water using a propeller mixer to prepare a binding solution with a concentration of 5% by mass. 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, manufactured by Powrex Corporation), 450 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 13.8028 g of the sized powder and 1.32 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, and then 0.297 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. The obtained tablet powder (700.9 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 30 mg of hydroxypropyl cellulose and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0116] Example 2B Hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water using a propeller mixer to prepare a binding solution with a concentration of 5% by mass. 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, manufactured by Powrex Corporation), 450 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 13.8028 g of the sized powder and 1.32 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, and then 0.297 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. The obtained tablet powder (700.9 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 30 mg of hypromellose and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0117] Example 3B Polyvinylpyrrolidone K30 (Kollidon 30, manufactured by BASF) was dissolved in purified water using a propeller mixer to prepare a binding solution with a concentration of 10% by mass. 448.1 g of ferric citrate (375 g in anhydrous equivalent) was placed in a tumbling fluidized bed granulator (MP The mixture was placed in a 500-μm stainless steel sieve (-01, manufactured by Powrex), granulated by spraying with 450 g of the binding solution, and then dried. The resulting dried granules were sieved through a 500 μm mesh stainless steel sieve to obtain a sized powder. 14.4628 g of the sized powder and 1.32 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, and then 0.297 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tableting powder. The obtained tablet powder (730.9 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 60 mg of polyvinylpyrrolidone K30 and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0118] Example 4B Polyvinylpyrrolidone K90 (Kollidon 90F, manufactured by BASF) was dissolved in purified water using a propeller mixer to prepare a binding solution with a concentration of 4% by mass. 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, Powrex Corporation), 562.5 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 12.548 g of the sized powder and 1.2 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, and then 0.27 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. The obtained tablet powder (700.9 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 30 mg of polyvinylpyrrolidone K90 and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0119] Example 5B Pregelatinized starch (Amycol C, manufactured by Nippon Starch Chemical Co., Ltd.) was dispersed in purified water using a propeller mixer, and purified water was added to prepare a binding solution with a concentration of 5% by mass, which was then sieved through a stainless steel sieve with 250 μm openings. 438.6 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, Powrex Corporation), 450 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 710 μm stainless steel sieve to obtain a sized powder. 9.8368 g of the sized powder and 0.96 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, followed by the addition of 0.216 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) and mixing for 3 minutes using the turbulator mixer to obtain a tablet powder. The obtained tablet powder (688.3 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 30 mg of pregelatinized starch and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0120] Example 6B Polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) was dissolved in purified water using a propeller mixer to prepare a binding solution with a concentration of 15% by mass. 497.1 g of ferric citrate (425 g in terms of anhydrous form) was placed in a tumbling fluidized bed granulator (MP-01, manufactured by Powrex), and 340 g of the above-mentioned binding solution was sprayed onto it to granulate, followed by drying. The resulting dried granules were sieved through a stainless steel sieve with 710 μm openings to obtain a sized powder. 14.1856 g of the sized powder and low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shinko) were added. After mixing 1.32 g of calcium stearate (Etsu Chemical Industry Co., Ltd.) in a 50 mL container for 5 minutes using a turbulator mixer, 0.297 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using a turbulator mixer to obtain tablet powder. The resulting tablet powder (718.3 mg) was compressed using a 50 kN screw-type universal testing machine (SC-50HJ, Tokyo Testing Machine Co., Ltd.) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 60 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0121] Example 7B Polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) was dissolved in purified water using a propeller mixer to prepare a binding solution with a concentration of 5% by mass. 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, Powrex Corporation), 270 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 12.308 g of the sized powder and 1.2 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, followed by the addition of 0.27 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) and mixing for 3 minutes using the turbulator mixer to obtain a tablet powder. The obtained tablet powder (688.9 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 18 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0122] The component compositions of the tablets of Examples 1B to 7B are shown in Table 1B. Table 2B also shows the ferric citrate (anhydrous equivalent) content (%) in the uncoated tablets, the masses of hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone K30 and K90, pregelatinized starch, polyvinyl alcohol-polyethylene glycol graft copolymer, or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), and the mass of low-substituted hydroxypropyl cellulose per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0123] [Table 1B]

[0124] [Table 2B]

[0125] Example 8B A binder solution was prepared by adding 21.0 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 14.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) to 315.0 g of purified water and dissolving them using a propeller mixer. 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, Powrex Corporation), 225 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 12.548 g of the sized powder and 1.2 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, and then 0.27 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. The resulting tablet powder (700.9 mg) was compacted using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 18 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 12 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0126] Example 9B A binder solution was prepared by adding 6.0 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 12.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) to 282.0 g of purified water and dissolving them using a propeller mixer. 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, manufactured by Powrex Corporation), 225 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 12.308 g of the sized powder and 1.2 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, and then 0.27 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. The obtained tablet powder (688.9 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 6 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 12 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0127] Example 10B A binder solution was prepared by adding 14.0 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 7.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) to 329.0 g of purified water and dissolving them using a propeller mixer. 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, manufactured by Powrex Corporation), 225 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 12.308 g of the sized powder and 1.2 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, and then 0.27 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. The obtained tablet powder (688.9 mg) was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 12 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0128] Example 11B A binder solution was prepared by adding 21.0 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 7.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) to 322.0 g of purified water and dissolving them using a propeller mixer. 448.1 g of ferric citrate (375 g on anhydrous basis) was placed in a tumbling fluidized bed granulator (MP-01, Powrex Corporation), 225 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, and then dried. The resulting dried granules were sieved through a 500 μm stainless steel sieve to obtain a sized powder. 31.07 g of the sized powder and 3.0 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 100 mL container for 5 minutes using a turbulator mixer, and then 0.675 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using a turbulator mixer to obtain a tablet powder. The resulting tablet powder (694.9 mg) was compacted using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 18 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0129] Example 12B A binder solution was prepared by adding 28.0 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 7.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) to 315.0 g of purified water and dissolving them using a propeller mixer. 448.1 g of ferric citrate (375 g in terms of anhydrous form) was placed in a tumbling fluidized bed granulator (MP-01, manufactured by Powrex), 225 g of the above-mentioned binding solution was sprayed onto it to granulate, and then dried. The resulting dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain a sized powder. 12.548 g of the sized powder and 1.2 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a Turbula mixer for 5 minutes, and then 0.27 g of calcium stearate (Japanese Pharmacopoeia, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were added. g of the powder was added and mixed in a turbulator mixer for 3 minutes to obtain a tablet powder. 700.9 mg of the resulting tablet powder was molded using a 50 kN screw-type universal testing machine (SC-50HJ, Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0130] The component compositions of the tablets of Examples 8B to 12B are shown in Table 3B. Table 4B also shows the ferric citrate (anhydrous equivalent) content (%) in the uncoated tablets, the mass of polyvinyl alcohol-polyethylene glycol-graft copolymer or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), and the mass of low-substituted hydroxypropyl cellulose per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0131] [Table 3B]

[0132] [Table 4B]

[0133] Test Example 1B (Rough specific volume of sized powder) The sized powders obtained in Examples 1B to 12B were allowed to flow into a 100 mL stainless steel measuring container until they overflowed. Then, the excess sized powder that had accumulated at the top of the container was carefully scraped off, and the mass of 100 mL of sized powder was measured.

[0134] Test Example 2B (Moldability Test) The tablets obtained in Examples 1B to 12B were inspected for cracks using a stereomicroscope (SZH, manufactured by Olympus) at a magnification of 15. Tablet hardness was also measured using a tablet hardness tester (6D, manufactured by Schleuniger).

[0135] Test Example 3B (Disintegration Test) The tablets obtained in Examples 1B to 12B were subjected to a disintegration test under the conditions shown in Table 5B to evaluate their disintegration properties.

[0136] [Table 5B]

[0137] The results of Test Examples 1B, 2B and 3B are shown in Table 6B.

[0138] [Table 6B]

[0139] Example 13B A binder solution was prepared by adding 1600 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 400 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) to 24,667 g of purified water and dissolving them using a propeller mixer. 17,922 g of ferric citrate (15,000 g in anhydrous equivalent) was placed in a fluidized bed granulation dryer (WSG-30, Powrex), and 12,000 g of the above-mentioned binding solution was sprayed onto the granules to granulate them, followed by drying. The resulting dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain a sized powder.

[0140] Example 14B 12.548 g of the sized powder obtained in Example 13B and 1.2 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a Turbula mixer for 5 minutes, and then calcium stearate (Japanese Pharmacopoeia 0.27 g of vegetable-based lactic acid bacteria (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes in a turbulator mixer to obtain tablet powder. 700.9 mg of the resulting tablet powder was compressed using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of low-substituted hydroxypropyl cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0141] Example 15B 13.8028 g of the sized powder obtained in Example 13B and 1.32 g of carboxymethylcellulose (NS-300, Nichirin Chemical Industry Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 5 minutes, followed by the addition of 0.297 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) and mixing for 3 minutes using a turbulator mixer to obtain a tablet powder. 700.9 mg of the resulting tablet powder was molded using a 50 kN screw-type universal testing machine (SC-50HJ, Tokyo Testing Machine Co., Ltd.) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of carboxymethylcellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0142] Example 16B 25.096 g of the sized powder obtained in Example 13B, 1.68 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.), and 0.72 g of crystalline cellulose (CEOLUS KG-1000, manufactured by Asahi Kasei Chemicals Corporation) were mixed in a 100 mL container for 5 minutes using a turbulator mixer, and then 0.54 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. The resulting tablet powder (700.9 mg) was compacted using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, 42 mg of low-substituted hydroxypropyl cellulose, and 18 mg of crystalline cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0143] Example 17B 25.096 g of the sized powder obtained in Example 13B, 1.20 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.), and 1.20 g of crystalline cellulose (CEOLUS KG-1000, manufactured by Asahi Kasei Chemicals Corporation) were mixed in a 100 mL container for 5 minutes using a turbulator mixer, and then 0.54 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. The resulting tablet powder (700.9 mg) was compacted using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, 30 mg of low-substituted hydroxypropyl cellulose, and 30 mg of crystalline cellulose) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0144] Example 18B 12.548 g of the sized powder obtained in Example 13B and crospovidone (Kollidon 1.2 g of calcium stearate (CL, BASF) was mixed in a 50 mL container for 5 minutes using a turbulator mixer, and then 0.27 g of calcium stearate (Japanese Pharmacopoeia, vegetable-based, Taihei Chemical Industry) was added and mixed for 3 minutes using a turbulator mixer to obtain tablet powder. The resulting tablet powder (700.9 mg) was compressed using a 50 kN screw-type universal testing machine (SC-50HJ, Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of crospovidone) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0145] Example 19B 12.548 g of the sized powder obtained in Example 13B and partially pregelatinized starch (Sta After mixing 1.2 g of calcium stearate (Japanese Pharmacopoeia, vegetable-based, Taihei Chemical Industry Co., Ltd.) in a 50 mL container using a turbulator mixer for 5 minutes, 0.27 g of calcium stearate (Japanese Pharmacopoeia, vegetable-based, Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using a turbulator mixer to obtain tablet powder. The resulting tablet powder (700.9 mg) was compressed using a 50 kN screw-type universal testing machine (SC-50HJ, Tokyo Testing Machine Co., Ltd.) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of partially pregelatinized starch) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0146] Example 20B 12.548 g of the sized powder obtained in Example 13B and 1.2 g of pregelatinized starch (SWELSTAR PD-1, manufactured by Asahi Kasei Chemicals) were mixed in a 50 mL container for 5 minutes using a turbulator mixer, followed by 0.27 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industries) and mixing for 3 minutes using a turbulator mixer to obtain a tablet powder. 700.9 mg of the resulting tablet powder was molded using a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machines) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 60 mg of pregelatinized starch) with a major axis of 17.5 mm and a minor axis of 8 mm. The component compositions of the tablets of Examples 14B to 20B are shown in Table 7B. Table 8B also shows the ferric citrate (anhydrous equivalent) content (%) in the uncoated tablets, the mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), and the mass of low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, crystalline cellulose, crospovidone, partially pregelatinized starch, or pregelatinized starch per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0147] [Table 7B]

[0148] [Table 8B]

[0149] Test Example 4B (Moldability Test) The tablets obtained in Examples 14B to 20B were examined for cracks using a stereomicroscope (SZH, manufactured by Olympus) at a magnification of 15. Tablet hardness was also measured using a tablet hardness tester (6D, manufactured by Schleuniger).

[0150] Test Example 5B (Disintegration Test) The disintegration properties of the tablets obtained in Examples 14B to 20B were evaluated in the same manner as in Test Example 3B. The results of Test Examples 4B and 5B are shown in Table 9B.

[0151] [Table 9B]

[0152] Example 21B 13.8028 g of the sized powder obtained in Example 13B and 1.32 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 50 mL container using a turbulator mixer for 10 minutes, followed by 0.297 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) and mixing for 3 minutes to obtain a tablet. 700.9 mg of the resulting tablet was molded using a 50 kN screw-type universal testing machine (SC-50HJ, Tokyo Testing Machine Co., Ltd.) at a compression speed of 20 mm / min and a compression pressure of 10 kN to obtain uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, 60 mg of low-substituted hydroxypropyl cellulose, and 13.5 mg of calcium stearate) with a major axis of 17.5 mm and a minor axis of 8 mm.

[0153] Example 22B The same procedure as in Example 21B was carried out, except that magnesium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was used instead of calcium stearate, to prepare citrate. Uncoated tablets containing ferric acid (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, 60 mg of low-substituted hydroxypropyl cellulose, and 13.5 mg of magnesium stearate) were obtained.

[0154] Example 23B Sodium stearyl fumarate (PRUV, JRS) instead of calcium stearate The same procedure as in Example 21B was carried out, except that ferric citrate-containing uncoated tablets (capsule-shaped tablets, each containing 24 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 6 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, 60 mg of low-substituted hydroxypropyl cellulose, and 13.5 mg of sodium stearyl fumarate) were obtained.

[0155] Example 24B Instead of calcium stearate, stearic acid (NAA-180P-1, NOF Corp.) When compression molding was carried out in the same manner as in Example 21B except that powder was used, adhesion of powder (binding) to the die wall surface after molding was observed.

[0156] Example 25B Compression molding was performed in the same manner as in Example 21B, except that talc (High Filler #17, manufactured by Matsumura Sangyo) was used instead of calcium stearate. After molding, powder adhesion (binding) was observed on the die wall surface. The component compositions of the tablets of Examples 21B to 25B are shown in Table 10B. Table 11B also shows the ferric citrate (anhydrous equivalent) content (%) in the uncoated tablets, the mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), and the mass of low-substituted hydroxypropyl cellulose per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0157] [Table 10B]

[0158] [Table 11B]

[0159] Test Example 6B (Tablet ejection pressure) When the tablets compressed in Examples 21B to 23B were discharged from the die, the tablets in the die were pushed out at a speed of 20 mm / min using the same punch used during molding with a 50 kN screw-type universal testing machine (SC-50HJ, manufactured by Tokyo Testing Machinery Co., Ltd.), and the discharge pressure was measured.

[0160] Test Example 7B (Moldability Test) The tablets obtained in Examples 21B to 23B were examined for cracks using a stereomicroscope (SZH, manufactured by Olympus) at a magnification of 15. Tablet hardness was also measured using a tablet hardness tester (6D, manufactured by Schleuniger).

[0161] Test Example 8B (Disintegration Test) The disintegration properties of the tablets obtained in Examples 21B to 23B were evaluated in the same manner as in Test Example 3B. The results of Test Examples 6B, 7B and 8B are shown in Table 12B.

[0162] [Table 12B]

[0163] Example 26B A binder solution was prepared by adding 84 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 21 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) to 1,295 g of purified water and dissolving them using a propeller mixer. 398.2g of ferric citrate (325g in anhydrous form) and crystalline cellulose (Ceolas 56.8 g of the granules (PH-102, Asahi Kasei Chemicals) were placed in a tumbling fluidized bed granulator dryer (MP-01, Powrex), 260 g of the binding solution was sprayed onto them to granulate, and then dried. The resulting dried granules were sieved through a stainless steel sieve with 500 μm openings to obtain a sized powder.

[0164] Example 27B 211.7 g of the sized powder obtained in Example 26B and 17.4 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, Shin-Etsu Chemical Co., Ltd.) were mixed in a 2 L container using a turbulator mixer for 10 minutes, followed by 3.94 g of calcium stearate (Japanese Pharmacopoeia, plant-based, Taihei Chemical Industry Co., Ltd.) and mixing for 3 minutes using the turbulator mixer to obtain a tablet powder. This tablet powder was compressed using a rotary tablet press (Collect 12HUK, Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 900 kgf / punch to obtain capsule-shaped tablets measuring 14.8 mm in major axis, 6.8 mm in minor axis, and weighing 401.8 mg (each tablet containing 12 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 3 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 30 mg of low-substituted hydroxypropyl cellulose).

[0165] Example 28B 211.7 g of the sized powder obtained in Example 26B, 17.4 g of low-substituted hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.), and 2.9 g of crospovidone (Kollidon CL-F, manufactured by BASF) were mixed in a 2 L container using a turbulator mixer for 10 minutes, and then 3.94 g of calcium stearate (Japanese Pharmacopoeia, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 3 minutes using the turbulator mixer to obtain a tablet powder. This tableting powder was compressed using a rotary tableting machine (Collect 12HUK, Kikusui Seisakusho) at a tableting pressure of 900 kgf / punch to obtain capsule-shaped tablets with a major axis of 14.8 mm, a minor axis of 6.8 mm, and a mass of 406.8 mg (each tablet containing 12 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 3 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, 30 mg of low-substituted hydroxypropyl cellulose, and 5 mg of crospovidone).

[0166] The component compositions of the tablets of Examples 27B and 28B are shown in Table 13B. Table 14B also shows the ferric citrate (anhydrous equivalent) content (%) in the uncoated tablets, the mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of low-substituted hydroxypropyl cellulose per 100 parts by mass of ferric citrate (anhydrous equivalent), and the mass of crospovidone per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0167] [Table 13B]

[0168] [Table 14B]

[0169] Test Example 9B (Moldability Test) The tablets obtained in Examples 27B and 28B were examined for cracks using a stereomicroscope (SZH, manufactured by Olympus) at a magnification of 15. Tablet hardness was also measured using a tablet hardness tester (6D, manufactured by Schleuniger).

[0170] Test Example 10B (Disintegration Test) The disintegration properties of the tablets obtained in Examples 27B and 28B were evaluated in the same manner as in Test Example 3B.

[0171] The results of Test Examples 9B and 10B are shown in Table 15B.

[0172] [Table 15B]

[0173] The method for producing the ferric citrate used in Example 29B is as follows. (Lot AW) Iron-containing precipitate formation process 639.5kg(Fe 3+ 67.3 kg (1205 mol) of ferric chloride solution was placed in a reaction vessel and diluted with 1002 kg of purified water to give a 4.1 mass % Fe 3+ An aqueous ferric chloride solution containing the compound (I) was obtained. This aqueous ferric chloride solution was cooled to a liquid temperature of 0 to 5°C. 1467.9 kg of a 10 mass % aqueous sodium hydroxide solution, which had been cooled to a liquid temperature of 0 to 5°C, was added dropwise to the aqueous ferric chloride solution over 120 minutes while maintaining the liquid temperature at 3.5 to 8.0°C, to adjust the final pH to 9.22. After the dropwise addition was completed, the resulting mixture was stirred for 1 hour at a temperature (liquid temperature) of 3.7 to 4.7°C. The pH of the mixture was measured and confirmed to be in the range of 8.0 to 10.0. Cleaning process The mixture obtained in the above step was filtered and washed with 2000 L of purified water. The filtered iron-containing crude precipitate (wet solid (1): 628.02 kg) mainly composed of ferrihydrite was stirred and washed in 1627.0 kg of purified water for 25 minutes. This suspension was filtered again to obtain an iron-containing precipitate mainly composed of ferrihydrite (wet solid (2): 530.75 kg). Ferric citrate aqueous solution formation process 289.30 kg (1506 mol) of citric acid was dissolved in 389.0 kg of purified water to prepare 678.3 kg of an aqueous citric acid solution. 530.75 kg of the wet solid (2) obtained in the above step and 678.3 kg of the aqueous citric acid solution were placed in a reaction vessel and slowly stirred at room temperature (approximately 25°C) for 69 minutes at a stirring speed of approximately 50 rpm to form a mixture. The mixture was then slowly heated to a temperature of 80°C, with the temperature difference between the mixture (liquid temperature) and the external temperature being within a range of 0 to 15°C. The mixture was then stirred for 120 minutes at a liquid temperature of 80.0 to 81.9°C to dissolve the iron-containing precipitate, primarily composed of ferrihydrite. After confirming that the iron-containing precipitate, primarily composed of ferrihydrite, had dissolved, the mixture was cooled so that the liquid temperature was within a range of 20 to 30°C. The insoluble matter in the resulting mixture was removed by filtration to obtain an aqueous solution of ferric citrate (1226.5 kg). Ferric citrate precipitation process 2,453 kg of acetone was placed in a reaction vessel. 613.2 kg of the aqueous solution of iron(III) citrate obtained in the above step was added dropwise to the acetone in the reaction vessel over 45 minutes with stirring. After the addition was completed, the resulting mixture was stirred for 40 minutes at a liquid temperature of 24.0 to 24.6°C. The resulting mixture was filtered to obtain a precipitate containing iron(III) citrate (wet solid (3): 425.17 kg). The resulting 425.17 kg of wet solid (3) was dried to obtain the desired high-purity iron(III) citrate (yield: 154.21 kg; yield: 91.7%).

[0174] (Lot AX): Ferric citrate (Lot AX) was prepared in a manner similar to that used for Lot AW (yield: 154.61 kg; yield: 91.9%).

[0175] Example 29B A binder solution was prepared by adding 1.680 kg of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 0.42 kg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) to 25.9 kg of purified water and dissolving them using a propeller mixer. A mixture of 19.1624 kg each of lot AW and lot AX ferric citrate (38.3248 kg total; 30 kg anhydrous equivalent) and 3.4591 kg of microcrystalline cellulose (Ceolus PH-102, Asahi Kasei Chemicals) was placed in a fluidized bed granulation dryer (WSG-60, Powrex), granulated by spraying 24.0 kg of the above-mentioned binding solution, and then dried. The resulting dried granules were sieved through a screen mill (U20 type, Powrex) with 1143 μm openings to obtain a sized powder. The resulting sized powder (41.4048 kg) was mixed with low-substituted hydroxypropyl cellulose (LH 3.42 kg of crospovidone (Kollidon CL-F, BASF) was added and mixed in a W-type mixer (TCW-100, Tokuju Manufacturing Co., Ltd.) at 29 revolutions per minute for 310 seconds, followed by addition of 0.7752 kg of calcium stearate (Japanese Pharmacopoeia calcium stearate, vegetable-based, Taihei Chemical Industry Co., Ltd.) and mixing in a W-type mixer (TCW-100, Tokuju Manufacturing Co., Ltd.) at 29 revolutions per minute for 104 seconds to obtain a tablet powder. This tablet powder was compressed in a rotary tablet press (Collect 12HUK, Kikusui Manufacturing Co., Ltd.) at a tableting pressure of 950 kgf / punch to obtain capsule-shaped uncoated tablets with a major axis of 14.8 mm, a minor axis of 6.8 mm, and a mass of 405 mg. The resulting uncoated tablets (12.15 kg) were coated with a coating solution prepared by mixing 600 g of hypromellose (TC-5M, Shin-Etsu Chemical Co., Ltd.), 200 g of titanium oxide (Titanuim(IV) Oxide extra pure, Merck KGaA), 100 g of talc (Hifiller #17, Matsumura Sangyo Co., Ltd.), 100 g of Macrogol 6000 (Macrogol 6000P, NOF Corp.), and 7000 g of purified water using an automatic coating machine (HCT-60N, Freund Corp.). Each tablet contained 12 mg of polyvinyl alcohol-polyethylene glycol-graft copolymer, 3 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, 30 mg of low-substituted hydroxypropyl cellulose, and 5 mg of crospovidone. The composition of the tablet of Example 29B is shown in Table 16B. Table 17B also shows the ferric citrate (anhydrous equivalent) content (%) in the uncoated tablet, the mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of low-substituted hydroxypropyl cellulose and crystalline cellulose per 100 parts by mass of ferric citrate (anhydrous equivalent), and the mass of crospovidone per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0176] [Table 16B]

[0177] [Table 17B]

[0178] The method for producing the ferric citrate used in Example 30B is as follows.

[0179] (Lot AR): Iron-containing precipitate formation process 60.5kg(Fe3+ A ferric chloride aqueous solution (6.7 kg; 120.0 mol) was placed in a reaction vessel and diluted with 102.9 kg of purified water to give a 4.1% by mass Fe 3+ An aqueous ferric chloride solution containing the compound (I) was obtained. This aqueous ferric chloride solution was cooled to a liquid temperature of 0 to 5°C. 139.4 kg of a 10 mass % aqueous sodium hydroxide solution, which had been cooled to a liquid temperature of 0 to 5°C, was added dropwise to the aqueous ferric chloride solution over 120 minutes while maintaining the liquid temperature at 0 to 4.2°C, to adjust the final pH to 9.05. After the dropwise addition was completed, the resulting mixture was stirred for 1 hour at a temperature (liquid temperature) of 1.6 to 3.8°C. The pH of the mixture was measured and confirmed to be in the range of 8.0 to 10.0. Cleaning process The mixture obtained in the above step was filtered and washed with 120 kg of purified water. The filtered iron-containing crude precipitate (wet solid (1): 70.52 kg) mainly composed of ferrihydrite was stirred and washed in 162.7 kg of purified water for 55 minutes. This suspension was filtered again to obtain an iron-containing precipitate mainly composed of ferrihydrite (wet solid (2): 53.26 kg). . Ferric citrate aqueous solution formation process 28.9 kg (150.5 mol) of citric acid was dissolved in 38.74 kg of purified water to prepare 67.64 kg of an aqueous citric acid solution. 53.26 kg of the wet solid (2) obtained in the above step and 67.64 kg of the aqueous citric acid solution were placed in a reaction vessel and slowly stirred at room temperature (approximately 25°C) for 70 minutes at a stirring speed of approximately 67 rpm to form a mixture. The mixture was then slowly heated to a temperature of 80°C, with the temperature difference between the mixture (liquid temperature) and the external temperature being within a range of 0 to 15°C. The mixture was then stirred at a temperature of 80.1 to 84.0°C for 120 minutes to dissolve the iron-containing precipitate, primarily composed of ferrihydrite. After confirming that the iron-containing precipitate, primarily composed of ferrihydrite, had dissolved, the mixture was cooled so that the temperature of the mixture was within a range of 20 to 30°C. The insoluble matter in the resulting mixture was removed by filtration to obtain an aqueous solution of ferric citrate (118.0 kg). Ferric citrate precipitation process 471.8 kg of 95% by weight acetone (acetone containing 5% by weight water) was placed in a reaction vessel. 118.0 kg of the aqueous iron(III) citrate solution obtained in the above step was added dropwise to the 95% by weight acetone in the reaction vessel over 25 minutes with stirring. After the addition was completed, the resulting mixture was stirred for 40 minutes at a liquid temperature of 21.1 to 22.2°C. The resulting mixture was filtered to obtain a precipitate containing iron(III) citrate (wet solid (3): 74.08 kg). The resulting 74.08 kg of wet solid (3) was dried to obtain the desired high-purity iron(III) citrate (yield: 25.86 kg; yield: 78.86%).

[0180] (Lot BD): The ferric citrate of lot BD was prepared in the same manner as that of lot AW (yield: 156.09 kg; yield: 92.3%), except that in the iron-containing precipitate formation step of lot AW, "aqueous sodium hydroxide solution was added dropwise to the aqueous ferric chloride solution over 115 minutes while maintaining the solution temperature at 2.6 to 7.5°C to adjust the final pH to 9.09," instead of "aqueous sodium hydroxide solution was added dropwise to the aqueous ferric chloride solution over 120 minutes while maintaining the solution temperature at 3.5 to 8.0°C to adjust the final pH to 9.22."

[0181] (Lot BE): The ferric citrate of lot BE was prepared in the same manner as that of lot AW (yield: 150.43 kg; yield: 92.1%), except that in the iron-containing precipitate formation step of lot AW, "aqueous sodium hydroxide solution was added dropwise to the aqueous ferric chloride solution over 162 minutes while maintaining the solution temperature at 2.4 to 8.6°C to adjust the final pH to 9.21," instead of "aqueous sodium hydroxide solution was added dropwise to the aqueous ferric chloride solution over 120 minutes while maintaining the solution temperature at 3.5 to 8.0°C to adjust the final pH to 9.22."

[0182] (Lot BF): The ferric citrate of lot BF was prepared in the same manner as that of lot AW (yield: 152.30 kg; yield: 92.8%), except that in the iron-containing precipitate formation step of lot AW, "aqueous sodium hydroxide solution was added dropwise to the aqueous ferric chloride solution over 162 minutes while maintaining the solution temperature at 2.4 to 8.6°C to adjust the final pH to 9.21," instead of "aqueous sodium hydroxide solution was added dropwise to the aqueous ferric chloride solution over 120 minutes while maintaining the solution temperature at 3.5 to 8.0°C to adjust the final pH to 9.22."

[0183] Example 30B 1.6800 kg of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 0.05 kg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.). 4201 kg of the product was added to 25.9 kg of purified water and then dissolved using a propeller mixer to prepare a binding solution. A total of 36.9687 kg (30 kg in anhydrous equivalent) of a mixture of 9.2540 kg of lot AR, 9.4352 kg of lot BD, 9.1210 kg of lot BE, and 9.1585 kg of lot BF as ferric citrate, and 4.8808 kg of microcrystalline cellulose (Ceolas PH-102, manufactured by Asahi Kasei Chemicals) were placed in a fluidized bed granulation dryer (WSG-60, manufactured by Powrex), 24.0 kg of the above-mentioned binding solution was sprayed onto the mixture, and the mixture was dried. The resulting dried granules were sieved through a 1143 μm mesh screen in a screen mill (U20 type, manufactured by Powrex) to obtain a sized powder. To the obtained sized powder (41.4670 kg), 3.4200 kg of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) and 0.5700 kg of crospovidone (Kollidon CL-F, manufactured by BASF) were added, and the mixture was mixed for 310 seconds at 29 revolutions per minute in a W-type mixer (TCW-100, manufactured by Tokuju Kosakusho). Then, 0.7752 kg of calcium stearate (Japanese Pharmacopoeia calcium stearate vegetable, manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 104 seconds at 29 revolutions per minute in a W-type mixer (TCW-100, manufactured by Tokuju Kosakusho). This tableting powder was compressed with a rotary tableting machine (Collect 12HUK, manufactured by Kikusui Seisakusho) at a tableting pressure of 1000 kgf / punch to obtain capsule-shaped uncoated tablets with a major axis of 14.8 mm, a minor axis of 6.8 mm, and a mass of 405.6 mg. The resulting uncoated tablets (324.3 g) were coated with a coating solution prepared by mixing 60 g of hypromellose (TC-5M, Shin-Etsu Chemical Co., Ltd.), 20 g of titanium oxide (Titanuim(IV) Oxide extra pure, Merck KGaA), 10 g of talc (High Filler #17, Matsumura Sangyo Co., Ltd.), 10 g of Macrogol 6000 (Macrogol 6000P, NOF Corp.), and 700 g of purified water using an automatic coating machine (HC-LABO, Freund Corporation). Each tablet contained 12 mg of polyvinyl alcohol-polyethylene glycol graft copolymer, 3 mg of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, 30 mg of low-substituted hydroxypropyl cellulose, and 5 mg of crospovidone. The composition of the tablet of Example 30B is shown in Table 18B. Table 19B also shows the ferric citrate (anhydrous equivalent) content (%) in the uncoated tablet, the mass of polyvinyl alcohol-polyethylene glycol graft copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer per 100 parts by mass of ferric citrate (anhydrous equivalent), the mass of low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose per 100 parts by mass of ferric citrate (anhydrous equivalent), and the mass of crospovidone per 100 parts by mass of ferric citrate (anhydrous equivalent).

[0184] [Table 18B]

[0185] [Table 19B]

[0186] Test Example 11B (Moldability Test) The tablets (plain tablets) obtained in Examples 29B and 30B were examined for cracks using a stereomicroscope (SZH, manufactured by Olympus) at a magnification of 15. Tablet hardness was also measured using a tablet hardness tester (6D, manufactured by Schleuniger).

[0187] Test Example 12B (Disintegration Test) The tablets (plain tablets and coated tablets) obtained in Examples 29B and 30B were evaluated for disintegration properties in the same manner as in Test Example 3B.

[0188] The results of Test Examples 11B and 12B are shown in Table 20B.

[0189] [Table 20B]

[0190] Test Example 13B (Dissolution test) The coated tablets obtained in Examples 29B and 30B were subjected to a dissolution test under the conditions shown in Table 21B to evaluate their dissolution properties.

[0191] [Table 21B]

[0192] The results are shown in Figure 1B. [Industrial Applicability]

[0193] According to the present invention, a new tablet containing ferric citrate can be provided.

Claims

1. A tablet comprising ferric citrate as an active pharmaceutical ingredient and hydroxypropyl cellulose.

2. 2. The tablet according to claim 1, wherein the anhydrous ferric citrate is contained in an amount of 70 parts by mass or more per 100 parts by mass of the uncoated tablet obtained by removing water from the ferric citrate.

3. 3. The tablet according to claim 1, wherein the hydroxypropyl cellulose is contained in a ratio of 3.5 parts by mass to 100 parts by mass of ferric citrate in anhydrous equivalent.

4. The tablet according to any one of claims 1 to 3, wherein the dissolution rate of ferric citrate after 30 minutes is 50% or more in a dissolution test performed by the paddle method of the Japanese Pharmacopoeia, 15th Edition, using the second fluid of the Japanese Pharmacopoeia, 15th Edition, as the test fluid at a rotation speed of 50 rpm.

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