Ferric citrate that is substantially free of β-iron hydroxide

Abstract

This invention provides high-purity ferric citrate that is substantially free of β-iron hydroxide. [Solution] A high-purity ferric citrate that substantially does not contain β-iron hydroxide, and in which the β-iron hydroxide content is less than 6% by weight relative to its total weight. Preferably, high-purity ferric citrate having a β-iron hydroxide content of less than 2.5% by weight. More preferably, high-purity citric acid II having a β-iron oxide content of less than 1.0% by weight. iron.

Description

[Technical Field]

[0001] This invention relates to high-purity ferric citrate and methods for producing the same. [Background technology]

[0002] Patent Document 1 describes how a ferric organic compound containing a specific ferric citrate can be used in the treatment of hyperphosphatemia, etc. It will be described as being useful for [something]. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Special Publication No. 2006-518391 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] The present invention aims to provide a method for producing high-purity ferric citrate that is substantially free of β-iron oxide hydroxide, as well as high-purity ferric citrate that is substantially free of β-iron oxide hydroxide and its pharmaceutical applications. [Means for solving the problem]

[0005] The present inventors have investigated various means to solve the above problem, and as a result, described in Patent Document 1 We discovered that the above objective can be achieved by modifying the conditions for contacting ferric chloride and sodium hydroxide in the method described above, and thus completed the present invention.

[0006] In other words, the gist of this invention is as follows: (1) High-purity ferric citrate that substantially does not contain β-iron hydroxide, and whose total The high-purity ferric citrate has a β-oxide ferric hydroxide content of less than 6% by weight. . (2) The high-purity citric acid according to (1), wherein the content of β-iron hydroxide is less than 2.5% by weight Ferric iron. (3) The high-purity citric acid according to (1), wherein the content of β-iron hydroxide is less than 1.0% by weight Ferric iron. (4) Any of the high-purity ferric citrates according to (1) to (3), wherein the molar ratio of ferric iron to citric acid is 1:0.75 to 1:1.10 Ferric citrate. (5) The high-purity ferric citrate according to (4), wherein the molar ratio of ferric iron to citric acid is 1:0.80 to 1:0.92 (6) In the dissolution test using the paddle method of the 15th revised Japanese Pharmacopoeia dissolution test method and the 15th revised Japanese Pharmacopoeia dissolution test first solution as the test solution and a rotation speed of 100 rpm, the dissolution rate of ferric citrate at a dissolution time of 15 minutes is 80% or more, and any of the high-purity ferric citrates according to (1) to (5) Ferric citrate.

[0007] (7) A pharmaceutical composition containing any of the high-purity ferric citrates according to (1) to (6) as an active ingredient Pharmaceutical composition. (8) A therapeutic or ameliorating agent for hyperphosphatemia containing any of the high-purity ferric citrates according to (1) to (6) as an active ingredient Hyperphosphatemia therapeutic or ameliorating agent. (9) A phosphorus adsorbent containing any of the high-purity ferric citrates according to (1) to (6) as an active ingredient Phosphorus adsorbent. (10) A serum phosphorus lowering agent containing any of the high-purity ferric citrates according to (1) to (6) as an active ingredient (11) A powder of any of the high-purity ferric citrates according to (1) to (6), characterized by being amorphous (12) A powder of any of the high-purity ferric citrates according to (1) to (6), characterized by having a specific surface area of 20 to 45 m 2 / g

[0008] (13) A powder of the high-purity ferric citrate according to (11), characterized by having a specific surface area of 20 to 45 m 2A powder characterized by having a specific surface area of / g. (14) A pharmaceutical composition containing, as an active ingredient, any of the powders of (11) to (13). (15) A therapeutic or ameliorating agent for hyperphosphatemia containing, as an active ingredient, any of the powders of (11) to (13). (16) A method for producing ferric citrate, comprising the following steps: An iron-containing precipitate forming step of contacting ferric chloride and sodium hydroxide in an aqueous medium for a short time and at a low temperature to form an iron-containing precipitate; A ferric citrate aqueous solution forming step of contacting citric acid and the iron-containing precipitate in an aqueous medium and then heating to form a ferric citrate aqueous solution; A ferric citrate precipitation step of contacting the ferric citrate aqueous solution with an organic solvent to precipitate ferric citrate; The above method comprising the above steps. (17) In the iron-containing precipitate forming step, contacting ferric chloride and sodium hydroxide within 2 hours and at a liquid temperature in the range of 0 to 10 °C, the method of (16) above. (18) In the ferric citrate aqueous solution forming step, contacting citric acid and the iron-containing precipitate at a liquid temperature in the range of 60 to 100 °C, the method of (16) or (17) above.

[0009] (19) The precipitate containing iron is ferrihydrite, any of the methods of (16) to (18) above. (20) Ferric citrate produced by any of the methods of (16) to (19) above. (21) A pharmaceutical composition containing, as an active ingredient, the ferric citrate of (20) above. (22) A therapeutic or ameliorating agent for hyperphosphatemia containing, as an active ingredient, the ferric citrate of (20) above. (23) A phosphorus adsorbent containing, as an active ingredient, the ferric citrate of (20) above. (24) A serum phosphorus lowering agent containing, as an active ingredient, the ferric citrate of (20) above.

[0010] (25) A powder of ferric citrate according to (20), characterized in that it is amorphous. (26) A powder of ferric citrate as described in (20), which is 20 to 45 ml 2 A powder characterized by having a specific surface area of ​​ / g. (27) The ferric citrate powder of (25) above, which is 20-45 m 2 It has a specific surface area of ​​ / g. A powder characterized by the following: (28) A pharmaceutical composition containing any of the powders (25) to (27) above as an active ingredient. (29) A treatment or improvement agent for hyperphosphatemia containing any of the powders (25) to (27) above as an active ingredient. (30) The above (7), (14), (21) or (28) for use in the treatment of hyperphosphatemia A pharmaceutical composition.

[0011] (31) A high-purity iron(III) complex coordinated with citric acid and water that is substantially free of β-iron hydroxide, wherein the content of β-iron hydroxide is less than 6% by weight relative to the total weight thereof. (32) The high-purity, β-iron hydroxide content is less than 2.5% by weight, as described in (31). An iron(III) complex coordinated with enoic acid and water. (33) The high-purity, β-iron hydroxide content is less than 1.0% by weight, as described in (31). An iron(III) complex coordinated with enoic acid and water. (34) A high-purity iron(III) complex coordinated with citric acid and water, having a molar ratio of ferric acid to citric acid of 1:0.75 to 1:1.10, as described in any of (31) to (33). (35) A high-purity iron(III) complex coordinated with citric acid and water, having a molar ratio of ferric acid to citric acid of 1:0.80 to 1:0.92, as described in any of (31) to (33). (36) 20-45 m 2 Having a specific surface area of ​​ / g and being amorphous, the above (31) to (33) A highly pure iron(III) complex coordinated with either citric acid or water.

[0012] (37) Dissolution Test Method of the 15th Revised Japanese Pharmacopoeia, Paddle Method, Solution 1 In an elution test using the test solution and a rotation speed of 100 revolutions / minute, the elution time was 15 minutes. The elution rate of the iron(III) complex coordinated with enoic acid and water is 80% or more, as described in (31) to (36) above. One of the following high-purity iron(III) complexes coordinated with citric acid and water. (38) A pharmaceutical composition containing, as an active ingredient, any of the high-purity iron(III) complexes described in (31) to (37) above, which are coordinated with citric acid and water. (39) A treatment or improvement agent for hyperphosphatemia containing, as an active ingredient, any of the high-purity iron(III) complexes in which citric acid and water are coordinated, as described in (31) to (37). (40) A phosphorus adsorbent containing, as an active ingredient, any of the high-purity iron(III) complexes described in (31) to (37) above, which are coordinated with citric acid and water. (41) A serum phosphorus-lowering agent containing, as an active ingredient, any of the high-purity iron(III) complexes described in (31) to (37) above, which are coordinated with citric acid and water.

[0013] (42) A method for producing an iron(III) complex coordinated with citric acid and water, comprising the following steps: An iron-containing precipitate formation process, in which ferric chloride and sodium hydroxide are brought into contact in an aqueous medium for a short period of time at a low temperature to form an iron-containing precipitate; By contacting citric acid with an iron-containing precipitate in an aqueous medium and then heating it, an aqueous solution of iron(III) complex in which citric acid and water are coordinated is formed. The process of forming an aqueous solution of iron(III) complex; An aqueous solution of an iron(III) complex coordinated with citric acid and water is brought into contact with an organic solvent, and the citric acid and A process for precipitating iron(III) complexes coordinated with water using citric acid and water; The method, including the method described above. (43) In the process of forming iron-containing precipitates, ferric chloride and sodium hydroxide are mixed for 2 hours or less The method of (42) above, wherein contact is made within the range of 0 to 10°C. (44) In the step of forming an aqueous solution of an iron(III) complex coordinated with citric acid and water, citric acid The method of (42) or (43) above, wherein the iron-containing precipitate is brought into contact with the iron-containing precipitate at a liquid temperature in the range of 60 to 100°C. . (45) Any of the methods described in (42) to (44), wherein the iron-containing precipitate is ferrihydrite.

[0014] (46) An iron(III) complex coordinated with citric acid and water, produced by any of the methods described in (42) to (45). (47) Contains the iron(III) complex coordinated with citric acid and water as described in (46) above as an active ingredient. A pharmaceutical composition. (48) A pharmaceutical composition according to (38) or (47) for use in the treatment of hyperphosphatemia. (49) Contains the iron(III) complex coordinated with citric acid and water as described in (46) above as an active ingredient. A treatment or corrective agent for hyperphosphatemia. (50) Contains the iron(III) complex coordinated with citric acid and water as described in (46) above as an active ingredient. Treatment for hyperphosphatemia or phosphate binders. (51) Contains the iron(III) complex coordinated with citric acid and water as described in (46) above as an active ingredient. Treatment for hyperphosphatemia or serum phosphorus-lowering agents. [Effects of the Invention]

[0015] The present invention makes it possible to provide a method for producing high-purity ferric citrate that is substantially free of β-iron oxide hydroxide, as well as high-purity ferric citrate that is substantially free of β-iron oxide hydroxide and its pharmaceutical applications. [Brief explanation of the drawing]

[0016] [Figure 1] This figure shows the IR spectrum of ferric citrate from Example 4. [Figure 2] This figure shows the powder X-ray diffraction spectrum of ferric citrate from Example 4. [Figure 3] This figure shows the results of comparing the elution profiles of ferric citrate from Comparative Examples 1, 11, and 12, and Examples 4, 5, 6, 7, 8, and 9, using the Japanese Pharmacopoeia elution test solution 1 (pH 1.2). [Figure 4] This figure shows the average values ​​(mg phosphorus / day) of phosphorus absorption and urinary phosphorus excretion in the control group and the test group (Example 1) in a phosphorus absorption inhibitory study in rats. [Modes for carrying out the invention]

[0017] 1. Ferric citrate This invention relates to high-purity ferric citrate that is substantially free of β-iron hydroxide. In this specification, "ferric citrate" is a complex of ferric (Fe(III)) and citric acid. One form of this is a complex represented by the molecular formula Fe·x(C6H8O7)·y(H2O). In the formula, x is preferably in the range of 0.75 to 1.10, and more preferably in the range of 0.78 to 0.95. The range is, and more preferably, in the range of 0.80 to 0.92, and especially preferably in the range of 0.81 to 0.91. In another embodiment, x is preferably in the range of 0.75 to 1.15, and more preferably The range of is 0.80 to 1.10. Y is preferably in the range of 1.8 to 3.2, more preferably in the range of 2.4 to 3.1, and particularly preferably in the range of 2.7 to 3.1. Also, ferric acid and citric acid The molar ratio of ferric acid to citric acid is preferably in the range of 1:0.75 to 1:1.10, more preferably in the range of 1:0.78 to 1:0.95, particularly preferably in the range of 1:0.80 to 1:0.92, and especially preferably in the range of 1:0.81 to 1:0.91. In another embodiment, the molar ratio of ferric acid to citric acid is preferably in the range of 1:0.75 to 1:1.15, more preferably in the range of 1:0.80 to 1:1.10. The molar ratio of ferric acid to water is preferably in the range of 1:1.8 to 1:3.2, more preferably in the range of 1:2.4 to 1:3.1, and particularly preferably in the range of 1:2.7 to 1:3.1.

[0018] As will be explained in detail below, the present inventors have found that ferric and grouper can be obtained using the method described in Patent Document 1. We found that when preparing complexes with nic acid, they sometimes contain β-iron hydroxide (β-FeOOH), which is poorly soluble in water, as a byproduct.

[0019] In contrast, the ferric citrate of the present invention, produced by the method described below, is substantially free of β-iron hydroxide. Therefore, the present invention provides a high-purity ferric citrate that is substantially free of β-iron hydroxide. Furthermore, one embodiment of the ferric citrate of the present invention is a high-purity iron(III) complex coordinated with citric acid and water, which is substantially free of β-iron hydroxide. Therefore, the ferric citrate of the present invention comprises a highly pure iron(III) complex coordinated with citric acid and water, substantially free of β-oxidized iron hydroxide. High-purity citric acid of the present invention The ferric iron preferably has a β-iron hydroxide content of less than 6% by weight relative to its total weight. The range is, more preferably 2.5% by weight or less, particularly preferably 1.0% by weight or less, and especially preferably 0 to 1% by weight. In this specification, "Substantially free of β-iron hydroxide" means that the β-iron hydroxide content is within the above range, and "high-purity ferric citrate" means ferric citrate with a β-iron hydroxide content within the above range.

[0020] The content of β-iron hydroxide in ferric citrate is not limited, but for example... It can be calculated by powder X-ray diffraction.

[0021] One embodiment of the present invention, ferric citrate and high-purity ferric citrate, has a specific surface area of, for example, 20 m². 2 / g or more, preferably 20-45 m 2 The range is / g, more preferably 20-40 m 2 / g It is within the range.

[0022] The specific surface area is not limited, but can be measured, for example, by the BET surface area measurement method using nitrogen gas adsorption (relative pressure: 0.05-0.3).

[0023] One embodiment of the ferric citrate and high-purity ferric citrate of the present invention is in an amorphous form, preferably in the form of an amorphous powder. Therefore, the present invention also relates to an amorphous or amorphous powder of ferric citrate or high-purity ferric citrate having the above and the following characteristics. In this specification, "amorphous form" means diffuse in the powder X-ray diffraction spectrum. This means that it exhibits diffraction characteristics of a halo pattern with a maximum.

[0024] Furthermore, in an elution test using the paddle method of the 15th edition of the Japanese Pharmacopoeia elution test, with the 15th edition of the Japanese Pharmacopoeia elution test solution No. 1 as the test solution and a rotation speed of 100 revolutions / minute, the elution rate of the ferric citrate and high-purity ferric citrate of the present invention at an elution time of 15 minutes is 80% or more, preferably 85% or more, more preferably 90% or more, and particularly preferably 95% or more.

[0025] Due to the above-described characteristics, the ferric citrate and high-purity ferric citrate of the present invention can exhibit excellent elution properties.

[0026] 2. Method for producing ferric citrate The present invention also relates to a method for producing ferric citrate. The method of the present invention comprises at least a step of forming an iron-containing precipitate, a step of forming an aqueous solution of ferric citrate, and a step of precipitating ferric citrate. Each step is described below.

[0027] 2-1. Iron-containing precipitate formation process This process aims to form an iron-containing precipitate by contacting ferric chloride and sodium hydroxide in an aqueous medium. Here, "contact" refers to, for example, the dropwise addition of an aqueous sodium hydroxide solution to an aqueous ferric chloride solution, but is not limited to this.

[0028] The iron-containing precipitate formed in this process is preferably a precipitate mainly composed of ferrihydrite, and more preferably an iron-containing precipitate that mainly contains ferrihydrite and substantially does not contain β-iron hydroxide.

[0029] The ferric chloride used in this process may be in the form of anhydrous or hydrated form, or in the form of an aqueous solution thereof. Any form of ferric chloride can be used in the method of the present invention.

[0030] The aqueous medium used in this process is preferably water. In this case, this process forms an aqueous solution containing an iron-containing precipitate, preferably a precipitate mainly composed of ferrihydrite. The aqueous medium is preferably substantially free of components other than citric acid and the precipitate.

[0031] The ferric chloride and sodium hydroxide used in this process may be of the usual purity commonly used in this industry. The molar ratio of ferric chloride to sodium hydroxide is preferably in the range of 1:1 to 1:5, and more preferably in the range of 1:2 to 1:4.

[0032] In the solution of this process, the concentration of ferric acid contained in ferric chloride is preferably in the range of 2 to 6% by weight, and more preferably in the range of 3 to 5% by weight. The concentration of sodium hydroxide is preferably in the range of 5 to 15% by weight, and more preferably in the range of 9 to 11% by weight.

[0033] The inventors investigated conditions for suppressing the formation of β-iron oxide hydroxide and found that by contacting ferric chloride and sodium hydroxide for a short time at a low temperature, it is possible to form an iron-containing precipitate that mainly contains ferrihydrite and substantially does not contain β-iron oxide hydroxide.

[0034] In this process, the contact time between ferric chloride and sodium hydroxide is no more than 3 hours. It is preferable that the contact period be within 2 hours, more preferably within 1 hour, and particularly preferable within 30 minutes. Furthermore, the temperature at which ferric chloride and sodium hydroxide are brought into contact (liquid temperature) is preferably 15°C or lower, more preferably 10°C or lower, and particularly preferable to be in the range of 0 to 10°C.

[0035] Therefore, in this process, the conditions for contacting ferric chloride and sodium hydroxide are preferably a time of 3 hours or less and a liquid temperature of 15°C or lower, preferably a liquid temperature of 10°C or lower or in the range of 0 to 10°C, more preferably a time of 2 hours or less and a liquid temperature of 15°C or lower, even more preferably a time of 2 hours or less and a liquid temperature of 10°C or lower, particularly preferably a time of 2 hours or less and a liquid temperature in the range of 0 to 10°C, and especially preferably a time of 1 hour or less and a liquid temperature in the range of 0 to 10°C.

[0036] In this process, the final pH of the mixture obtained by contacting ferric chloride and sodium hydroxide is preferably in the range of 8 to 10.

[0037] By carrying out this process under the above conditions, it is possible to suppress the formation of β-iron hydroxide and form a precipitate that is substantially free of β-iron hydroxide.

[0038] 2-2. Washing Process The method of the present invention may include a washing step of washing the iron-containing precipitate one to three times before the ferric citrate aqueous solution formation step described below.

[0039] In this process, it is preferable to wash the iron-containing precipitates with an aqueous medium. The aqueous medium is preferably purified water that is substantially free of other components.

[0040] Furthermore, this process is preferably carried out at a temperature in the range of 10 to 30°C.

[0041] By carrying out this process under the above conditions, it is possible to improve the purity of the resulting ferric citrate.

[0042] 2-3. Process for forming ferric citrate aqueous solution The purpose of this process is to form an aqueous solution of ferric citrate by contacting citric acid with the iron-containing precipitate obtained in the above process in an aqueous medium. Here, "contact" includes, but is not limited to, the reaction between the iron-containing precipitate and the aqueous citric acid solution.

[0043] The aqueous medium used in this process is preferably water. In this case, an aqueous solution of ferric citrate is formed by this process. It is preferable that the above aqueous medium substantially contains no components other than citric acid and the precipitate.

[0044] The citric acid used in this process may be of the usual purity commonly used in this industry. The molar ratio of ferric acid to citric acid contained in the iron-containing precipitate is preferably in the range of 1:1.0 to 1:1.5, and more preferably in the range of 1:1.2 to 1:1.3. In another embodiment, the molar ratio of ferric acid to citric acid contained in the iron-containing precipitate is preferably in the range of 1:1.0 to 1:3.0, and more preferably in the range of 1:1.0 to 1:1.6.

[0045] In the solution obtained in this process, the concentration of citric acid is preferably in the range of 10 to 40% by weight, and more preferably in the range of 20 to 30% by weight.

[0046] In this process, citric acid and an iron-containing precipitate are brought into contact in a medium to form a mixture, and then the mixture is heated to form an aqueous solution of ferric citrate. In this process, the heating temperature is preferably in the range of 60 to 100°C, and preferably in the range of 70 to 90°C. It is more preferable that the temperature be at liquid temperature. Furthermore, the heating time is preferably in the range of 1 to 3 hours, and more preferably in the range of 1.5 to 2.5 hours.

[0047] Therefore, in this process, the conditions for forming the ferric citrate aqueous solution are particularly preferably such that the mixture is heated at the above liquid temperature for 1 to 3 hours.

[0048] By carrying out this process under the above conditions, it becomes possible to form an aqueous solution containing ferric citrate in high yield.

[0049] 2-4. Ferric citrate precipitation process The purpose of this process is to precipitate ferric citrate by contacting an aqueous solution of ferric citrate with an organic solvent.

[0050] The organic solvents that can be used in this process are not limited, but examples include water-miscible organic solvents such as acetone. Acetone or aqueous acetone is preferred.

[0051] The organic solvent used in this process may be of a standard purity commonly used in this industry. The amount of organic solvent used should be in the range of 300 to 500 parts by weight per 100 parts by weight of ferric citrate aqueous solution. It is preferable that the amount is in the range of 350 to 450 parts by weight, and more preferably in the range of 350 to 450 parts by weight.

[0052] In this step, ferric citrate is precipitated by contacting an aqueous solution of ferric citrate with an organic solvent under the above conditions. In this step, the precipitation temperature is preferably in the range of 15 to 35°C, and more preferably in the range of 20 to 30°C. Furthermore, the precipitation time is preferably in the range of 0.5 to 2 hours, and more preferably in the range of 0.5 to 1 hour.

[0053] The ferric citrate obtained by the above method may be used in its original form for the desired application, but in some cases, the precipitated ferric citrate may be further dried. For example, it can be dried by the method described in Patent Document 1.

[0054] By carrying out this process under the above conditions, it becomes possible to precipitate high-purity ferric citrate in high yield.

[0055] 3. Pharmaceutical uses of ferric citrate 3-1. Pharmaceutical Compositions The pharmaceutical composition of the present invention, containing ferric citrate as an active ingredient, in vivo This product can be applied to any human or non-human animal having the diseases or disorders described below. When applied to humans, it can be provided in the form of a pharmaceutical composition or a formulation as described below. When applied to non-human animals, the target non-human animals are not limited to, but are preferably, for example, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, or monkeys.

[0056] By applying the pharmaceutical composition or formulation of the present invention to the above-mentioned subjects (patients or test subjects), it becomes possible to treat or improve the diseases or disorders described below. Therefore, the present invention also provides a method for treating or improving the following diseases or disorders, which includes administering the pharmaceutical composition or formulation of the present invention to the above-mentioned patients or test subjects.

[0057] The pharmaceutical compositions of the present invention can be used, for example, to inhibit the absorption of ingested phosphates in patients, or to treat or improve hyperphosphatemia. Therefore, the present invention also provides a hyperphosphatemia treatment or improvement agent containing ferric citrate as an active ingredient. Alternatively, the present invention also provides a serum phosphorus lowering agent containing ferric citrate as an active ingredient.

[0058] The ferric citrate of the present invention has a high specific surface area and high phosphorus adsorption capacity. Therefore, the present invention also provides a phosphorus adsorbent containing the ferric citrate of the present invention as an active ingredient.

[0059] By using the pharmaceutical composition or formulation of the present invention, it is possible to treat or improve the above-mentioned diseases or disorders. In this specification, "treatment of hyperphosphatemia" is synonymous with "improvement of hyperphosphatemia," and means, for example, reducing the serum phosphorus concentration to the range of 3.5 to 6.0 mg / dL, but is not limited thereto.

[0060] 3-2. Pharmaceutical preparations A pharmaceutical composition containing ferric citrate produced by the method of the present invention, i.e., the high-purity ferric citrate of the present invention, as an active ingredient may be administered to a subject alone, or the high-purity ferric citrate of the present invention may be administered with the compound and one or more pharmaceutically acceptable compounds. The present invention may also be provided as a pharmaceutical (e.g., a formulation) comprising a carrier, excipient, disintegrant, binder, fluidizer, diluent, filler, buffer, auxiliary, stabilizer, preservative, lubricant, solvent, solubilizer, suspending agent, isotonic agent, analgesic agent, or other material known to those skilled in the art, and optionally other drugs. Therefore, the present invention not only provides the above-mentioned pharmaceutical composition, but also provides the high-purity ferric citrate of the present invention together with one or more pharmaceutically acceptable carriers, excipients, disintegrants, binders, The present invention provides a method for manufacturing pharmaceuticals, which may include mixing with fluidizing agents, diluents, fillers, buffers, auxiliary agents, stabilizers, preservatives, lubricants, solvents, solubilizers, suspending agents, isotonic agents, analgesics, or other materials known to those skilled in the art, and optionally with other drugs.

[0061] Furthermore, the present invention also provides the use of the high-purity ferric citrate of the present invention in the manufacture of pharmaceuticals for treating or improving the above-mentioned diseases or disorders.

[0062] In this specification, “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form suitable for use in contact with the tissues of a subject (e.g., human) that does not cause excessive toxicity, irritation, allergic reactions, or complications, in proportion to a reasonable benefit-to-risk ratio, within the bounds of sound medical judgment. Each carrier, excipient, etc., must also be “acceptable” in the sense that it can coexist with the other components of the formulation.

[0063] The formulation can be provided as a unit dosage form as appropriate and can be prepared by any method well known in the pharmaceutical technology field. Such a method involves the high-purity ferric citrate of the present invention and one or more The process includes mixing the above-mentioned auxiliary components (e.g., carriers). Generally, the formulation is made of the active compound and It is prepared by uniformly and tightly mixing a finely ground solid carrier, a liquid carrier, or both, and then, if necessary, shaping the product.

[0064] The form (dosage form) of the formulation is not limited, but examples include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, or suspensions.

[0065] The tablets may be mixed with one or more of the above-mentioned auxiliary components by conventional means, such as compression or compounding. It can be manufactured in various forms. The compressed tablets contain the high-purity ferric citrate of the present invention, optionally with one or more binders (e.g., povidone, gelatin, acacia gum, sorbitol, etc.). The tablets may be prepared by mixing them with lagacanth, hydroxypropyl methylcellulose; fillers or diluents (e.g., microcrystalline cellulose, lactose); lubricants (e.g., calcium stearate, talc, silica); disintegrants (e.g., crospovidone, sodium starch glycolate, cross-linked sodium carboxymethylcellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); and preservatives (e.g., p-methyl hydroxybenzoate, p-propyl hydroxybenzoate, sorbic acid) and compressing them in a suitable machine. The tablets may optionally be coated or incised, and may also be formulated to provide, for example, sustained or controlled release of ferric citrate contained in the formulation. The tablets may optionally be enterically coated so that they are released in parts of the gastrointestinal tract other than the stomach.

[0066] 3-3. Treatment method When the pharmaceutical composition or formulation of the present invention is used for the treatment or improvement of the above-mentioned diseases or disorders, the appropriate dosage of the high-purity ferric citrate of the present invention will, of course, vary depending on the patient. Generally, the dosage is selected to achieve a local concentration at the site of action that achieves the desired effect without substantially causing harmful side effects. Here, the dosage level selected depends on various factors including, but not limited to, for example, the activity of ferric citrate, the route of administration, the time of administration, the excretion rate, the duration of treatment, other drugs used in combination, and the patient's age, sex, weight, disease state, general health, and medical history.

[0067] In vivo administration can be carried out once, continuously, or intermittently (e.g., by divided administration at appropriate intervals) throughout the entire treatment process. The one or more administrations can be carried out at dosage levels and patterns selected by the treating physician. For example, when orally administering to an adult patient, a suitable dosage of ferric citrate is usually in the range of about 1 to 8 g per day. The above amount can be administered in one or more divided doses.

Example

Example

[0068] Hereinafter, the present invention will be further specifically described using examples. However, the technical scope of the present invention is not limited to these examples.

[0069] 1. Preparation of ferric citrate Example 1: Iron-containing precipitate formation step 60.5 kg (6.7 kg as Fe 3+ ; 120.0 mol) of an aqueous solution of ferric chloride was placed in a reaction vessel and diluted with 102.9 kg of purified water to obtain an aqueous solution of ferric chloride containing 4.1 wt% Fe 3+ . This salt An aqueous solution of ferric chloride was cooled to a liquid temperature of 0-5°C. 139.6 kg of a 10 wt% NaOH aqueous solution, which had been pre-cooled to 0-5°C, was added dropwise to the ferric chloride aqueous solution over 120 minutes while maintaining a liquid temperature of 0-4.2°C, until the final pH was 9.05. After the dropwise addition was complete, the resulting mixture was given a pH of 1.6-3.8. The mixture was stirred for 1 hour at a temperature of °C (liquid temperature). The pH was measured and confirmed to be in the range of 8.0 to 10.0.

[0070] Washing process The mixture obtained in the above process was washed with 120 kg of purified water while being filtered. 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, and the ferrihydrite was the main component. An iron-containing precipitate was obtained as a component (wet solid (2): 53.26 kg).

[0071] 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 citric acid aqueous solution. 53.26 kg of wet solid (2) obtained in the above process and 67.64 kg of the citric acid The acid solution was placed in a reaction vessel and slowly stirred at a stirring speed of approximately 67 rpm for 70 minutes at room temperature (approximately 25°C) to form a mixture. Then, the mixture was slowly stirred under conditions such that the temperature difference between the mixture (liquid temperature) and the ambient temperature was in the range of 0 to 15°C until the temperature of the mixture (liquid temperature) reached 80°C. The mixture was then heated to a higher temperature. After that, the mixture was stirred at a liquid temperature of 80.1-84.0°C for 120 minutes, and then Ferihai An iron-containing precipitate, mainly composed of hydrite, was dissolved. After confirming that the iron-containing precipitate, mainly composed of ferrihydrite, had dissolved, the mixture was cooled to a temperature in the range of 20-30°C. Insoluble matter in the resulting mixture was removed by filtration to obtain an aqueous solution of ferric citrate (118.0 kg).

[0072] Ferric citrate precipitation process 471.8 kg of 95% by weight acetone (acetone containing 5% by weight water) was placed in the reaction vessel. The 118.0 kg of ferric citrate aqueous solution obtained in the above process was added dropwise to 95% by weight acetone in a reaction vessel while stirring for 25 minutes. After the addition was complete, the resulting mixture was stirred for 40 minutes at a liquid temperature of 21.1–22.2°C. The resulting mixture was filtered to obtain a precipitate containing ferric citrate (wet solid (3): 74.08 kg). The obtained 74.08 kg of wet solid (3) was dried to obtain the desired high-purity ferric citrate in powder form (yield: 25.86 kg; yield: 78.86%).

[0073] Example 2: The ferric citrate in Example 2 was prepared in the same manner as in Example 4, except that in the iron-containing precipitate formation step of Example 4, an aqueous NaOH solution was added dropwise to an aqueous ferric chloride solution over 165 minutes while maintaining a liquid temperature of 4.0 to 4.7°C, to a final pH of 9.20 (yield: 136.03 kg; yield: 85.3%).

[0074] Example 3: The ferric citrate in Example 3 was prepared in the same manner as in Example 4, except that in the iron-containing precipitate formation step of Example 4, an aqueous NaOH solution was added dropwise to an aqueous ferric chloride solution over 165 minutes while maintaining a liquid temperature of 4.0 to 4.7°C, to a final pH of 9.20 (yield: 136.42 kg; yield: 84.7%).

[0075] Example 4: Iron-containing precipitate formation process 639.5 kg (Fe 3+ As an example, 67.3 kg (1205 mol) of ferric chloride aqueous solution is placed in a reaction vessel and diluted with 1002 kg of purified water to form 4.1 wt% Fe 3+ An aqueous solution of ferric chloride containing this salt was obtained. The ferric chloride aqueous solution was cooled to a liquid temperature of 0-5°C. 1467.9 kg of a 10 wt% NaOH aqueous solution, which had been pre-cooled to 0-5°C, was added to the ferric chloride aqueous solution while maintaining a liquid temperature of 3.5-8.0°C. The solution was then added dropwise over 120 minutes until the final pH was 9.22. After the addition was complete, the resulting mixture was stirred for 1 hour at a temperature of 3.7–4.7°C (liquid temperature). The pH was measured, and the pH of the mixture was in the range of 8.0–10.0. I confirmed that something was true.

[0076] Washing process The mixture obtained in the above process was washed with 2000 L of purified water while being filtered. The filtered iron-containing crude precipitate (wet solid (1): 628.02 kg), mainly composed of ferrihydrite, was 1627.0 Washed with 25 minutes of stirring in 1 kg of purified water. This suspension was filtered again, and the ferrihydrite was removed. An iron-containing precipitate, which was the main component, was obtained (wet solid (2): 530.75 kg).

[0077] Ferric citrate aqueous solution formation process 289.30 kg (1506 mol) of citric acid was dissolved in 389.0 kg of purified water to make 678.3 kg of citric acid. An aqueous acid solution was prepared. 530.75 kg of the wet solid (2) obtained in the above step and 678.3 kg of the citric acid aqueous solution were placed in a reaction vessel and slowly stirred at a stirring speed of approximately 50 rpm for 69 minutes at room temperature (approximately 25°C) to form a mixture. Then, the mixture was slowly stirred under conditions such that the difference between the temperature of the mixture (liquid temperature) and the ambient temperature was in the range of 0 to 15°C until the temperature of the mixture (liquid temperature) reached 80°C. The mixture was heated to a higher temperature. Then, the mixture was stirred at a liquid temperature of 80.0-81.9°C for 120 minutes, and the ferrih An iron-containing precipitate mainly composed of idolite was dissolved. After confirming that the iron-containing precipitate mainly composed of ferrihydrite had dissolved, the mixture was cooled to a temperature in the range of 20-30°C. Insoluble matter in the resulting mixture was removed by filtration to obtain an aqueous solution of ferric citrate (1226.5 kg).

[0078] Ferric citrate precipitation process 2453 kg of acetone was placed in the reaction vessel. 613.2 kg of citrate obtained in the above process An aqueous solution of ferric citrate was added dropwise to acetone in the reaction vessel while stirring for 45 minutes. After the addition was complete, the resulting mixture was stirred for 40 minutes at a liquid temperature of 24.0-24.6°C. The resulting mixture was filtered to obtain a precipitate containing ferric citrate (wet solid (3): 425.17 kg). The wet solid (3) was dried to obtain the desired high-purity ferric citrate in powder form (yield: 154.21 kg; yield: 91.7%).

[0079] Example 5: The ferric citrate in Example 5 was prepared in the same manner as in Example 4, except that in the iron-containing precipitate formation step of Example 4, an aqueous NaOH solution was added dropwise to an aqueous ferric chloride solution over 120 minutes while maintaining a liquid temperature of 3.5 to 8.0°C, to a final pH of 9.22 (yield: 154.61 kg; yield: 91.9%).

[0080] Example 6: The ferric citrate in Example 6 was prepared in the same manner as in Example 4, except that in the iron-containing precipitate formation step of Example 4, an aqueous NaOH solution was added dropwise to an aqueous ferric chloride solution over 115 minutes while maintaining a liquid temperature of 2.6 to 7.5°C, to a final pH of 9.09 (yield: 154.68 kg; yield: 91.5%).

[0081] Example 7: The ferric citrate in Example 7 was prepared in the same manner as in Example 4, except that in the iron-containing precipitate formation step of Example 4, an aqueous NaOH solution was added dropwise to an aqueous ferric chloride solution over 115 minutes while maintaining a liquid temperature of 2.6 to 7.5°C, to a final pH of 9.09 (yield: 156.09 kg; yield: 92.3%).

[0082] Example 8: The ferric citrate in Example 8 was prepared in the same manner as in Example 4, except that in the iron-containing precipitate formation step of Example 4, an aqueous NaOH solution was added dropwise to an aqueous ferric chloride solution over 162 minutes while maintaining a liquid temperature of 2.4 to 8.6°C, to a final pH of 9.21 (yield: 150.43 kg; yield: 92.1%).

[0083] Example 9: The ferric citrate in Example 9 was prepared in the same manner as in Example 4, except that in the iron-containing precipitate formation step of Example 4, an aqueous NaOH solution was added dropwise to an aqueous ferric chloride solution over 162 minutes while maintaining a liquid temperature of 2.4 to 8.6°C, to a final pH of 9.21 (yield: 152.30 kg; yield: 92.8%).

[0084] Example 10: The ferric citrate in Example 10 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was added dropwise to a ferric chloride aqueous solution over 118 minutes while maintaining a liquid temperature of 2.6-7.6°C, and the final pH was determined. Except for setting the ratio to 9.13, the preparation was carried out in the same manner as in Example 4 (Yield: 149.47 kg; Yield: 88.4%). .

[0085] Example 11: The ferric citrate in Example 11 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was added dropwise to a ferric chloride aqueous solution over 118 minutes while maintaining a liquid temperature of 2.6-7.6°C, and the final pH was determined. Except for setting the ratio to 9.13, the preparation was carried out in the same manner as in Example 4 (Yield: 150.47 kg; Yield: 89.0%). .

[0086] Example 12: The ferric citrate in Example 12 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 105 minutes while maintaining a liquid temperature of 0 to 7.3°C, and the final pH was adjusted to 8.98 (yield: 146.06 kg; yield: 87.7%).

[0087] Example 13: The ferric citrate in Example 13 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 105 minutes while maintaining a liquid temperature of 0 to 7.3°C, to a final pH of 8.98 (yield: 146.56 kg; yield: 88.0%).

[0088] Example 14: The ferric citrate in Example 14 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 74 minutes while maintaining a liquid temperature of 1.3 to 8.3°C, and the final pH was adjusted to 8.91 (yield: 146.01 kg; yield: 88.7%).

[0089] Example 15: The ferric citrate in Example 15 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 74 minutes while maintaining a liquid temperature of 1.3 to 8.3°C, to a final pH of 8.91 (yield: 146.23 kg; yield: 89.6%).

[0090] Example 16: The ferric citrate in Example 16 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 91 minutes while maintaining a liquid temperature of 2.5 to 8.4°C, to a final pH of 9.64 (yield: 142.30 kg; yield: 86.2%).

[0091] Example 17: The ferric citrate in Example 17 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 91 minutes while maintaining a liquid temperature of 2.5 to 8.4°C, to a final pH of 9.64 (yield: 144.60 kg; yield: 86.5%).

[0092] Example 18: The ferric citrate in Example 18 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was added dropwise to a ferric chloride aqueous solution over 117 minutes while maintaining a liquid temperature of 1.9-8.0°C, and the final pH was determined. Except for setting the ratio to 8.40, the preparation was carried out in the same manner as in Example 4 (Yield: 138.93 kg; Yield: 86.8%). .

[0093] Example 19: The ferric citrate in Example 19 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was added dropwise to a ferric chloride aqueous solution over 117 minutes while maintaining a liquid temperature of 1.9-8.0°C, and the final pH was determined. Except for setting the ratio to 8.40, the preparation was carried out in the same manner as in Example 4 (Yield: 132.89 kg; Yield: 83.2%). .

[0094] Example 20: The ferric citrate in Example 20 was used in the iron-containing precipitate formation step of Example 4, in the NaOH aqueous solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 77 minutes while maintaining a liquid temperature of 1.4 to 8.3°C, to a final pH of 8.61 (yield: 146.18 kg; yield: 87.8%).

[0095] Example 21: The ferric citrate in Example 21 was used in the iron-containing precipitate formation step of Example 4, in the NaOH aqueous solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 77 minutes while maintaining a liquid temperature of 1.4 to 8.3°C, to a final pH of 8.61 (yield: 145.92 kg; yield: 89.3%).

[0096] Example 22: The ferric citrate in Example 22 was used in the iron-containing precipitate formation step of Example 4, in an aqueous NaOH solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 76 minutes while maintaining a liquid temperature of 2.2 to 9.1°C, to a final pH of 9.08 (yield: 156.90 kg; yield: 93.7%).

[0097] Example 23: The ferric citrate in Example 23 was used in the iron-containing precipitate formation step of Example 4, in the NaOH aqueous solution. The solution was prepared in the same manner as in Example 4, except that it was added dropwise to an aqueous solution of ferric chloride over 76 minutes while maintaining a liquid temperature of 2.2 to 9.1°C, to a final pH of 9.08 (yield: 153.60 kg; yield: 90.4%).

[0098] Example 24: Iron-containing precipitate formation process 186.2 g(Fe 3+ Using 24.6 g (0.440 mol) of ferric chloride aqueous solution as the starting material, NaOH aqueous solution is added dropwise to the ferric chloride aqueous solution over 100 minutes while maintaining a liquid temperature of 3.0 to 5.3°C. Then, except that the final pH was set to 9.08, an iron-containing precipitate was obtained from the mixture prepared in the same manner as in Example 4. The above iron-containing precipitate was divided into four equal parts and used as raw material for the ferric citrate aqueous solution formation process. In this case, citric acid is Fe 3+ Except for the amount of 1.00 equivalent used, the ferric citrate solution from Example 4 was used. By preparing the solution in the same manner as in the solution formation step and the ferric citrate precipitation step, the desired high-purity ferric citrate was obtained (yield: 24.76 g; yield: 90.6%).

[0099] Example 25: The ferric citrate in Example 25 was obtained using the iron-containing precipitate from Example 20, and in the ferric citrate aqueous solution formation step of Example 20, citric acid was replaced with Fe 3+ The preparation was carried out in the same manner as in Example 20, except that the amount was set to 2.50 equivalents (yield: 26.79 g; yield: 93.7%).

[0100] Example 26: The ferric citrate in Example 26 was obtained using the iron-containing precipitate from Example 20, and in the ferric citrate aqueous solution formation step of Example 20, citric acid was replaced with Fe 3+ The preparation was carried out in the same manner as in Example 20, except that the amount was set to 2.50 equivalents (yield: 26.88 g; yield: 93.8%).

[0101] Example 27: The ferric citrate in Example 27 was obtained using the iron-containing precipitate from Example 20, and in the ferric citrate aqueous solution formation step of Example 20, citric acid was replaced with Fe 3+ The preparation was carried out in the same manner as in Example 20, except that 3.00 equivalents were used (yield: 27.96 g; yield: 94.4%).

[0102] Example 28: The ferric citrate in Example 28 was prepared by adding an aqueous NaOH solution to an aqueous ferric chloride solution dropwise over 89 minutes while maintaining a liquid temperature of 2.3 to 6.3°C during the iron-containing precipitate formation process of Example 20, resulting in a final pH of 9. 13. And in the step of forming an aqueous ferric citrate solution, citric acid is Fe 3+ The preparation was carried out in the same manner as in Example 20, except that the amount was set to 1.10 equivalents (yield: 37.05 g; yield: 94.8%).

[0103] Example 29: The ferric citrate in Example 29 was prepared by adding an aqueous NaOH solution to an aqueous ferric chloride solution dropwise over 97 minutes while maintaining a liquid temperature of 0-5.9°C during the iron-containing precipitate formation step of Example 20, to a final pH of 9.25, and by adding citric acid to the ferric citrate aqueous solution during the ferric citrate aqueous solution formation step. 3+The preparation was carried out in the same manner as in Example 20, except that the amount was 1.25 equivalents (yield: 37.98 g; yield: 93.5%).

[0104] Example 30: The ferric citrate in Example 30 was prepared by adding an aqueous NaOH solution to an aqueous ferric chloride solution dropwise over 91 minutes while maintaining a liquid temperature of 3.1 to 6.3°C during the iron-containing precipitate formation step of Example 20, to a final pH of 9.21, and by adding citric acid to the ferric citrate aqueous solution during the ferric citrate aqueous solution formation step. 3+ The preparation was carried out in the same manner as in Example 20, except that the amount was 1.40 equivalents (yield: 37.15 g; yield: 94.5%).

[0105] Example 31: The ferric citrate in Example 31 was prepared by adding an aqueous NaOH solution to an aqueous ferric chloride solution over 90 minutes while maintaining a liquid temperature of 3.7 to 5.4°C during the iron-containing precipitate formation step of Example 20, to a final pH of 9.28, and by adding citric acid to the ferric citrate aqueous solution during the ferric citrate aqueous solution formation step. 3+ The preparation was carried out in the same manner as in Example 20, except that the amount was 1.55 equivalents (yield: 37.69 g; yield: 96.8%).

[0106] Comparative Example 1-4 It was prepared according to the method described in Patent Document 1. However, the iron-containing precipitate formation method of the present invention The conditions for the corresponding process were modified to the conditions shown in Table 3 below.

[0107] Comparative Example 11 We used commercially available ferric citrate for food additives (manufactured by Kanto Chemical Co., Ltd.; manufacturing lot number: 901X1445; manufacturing date: January 2007). This ferric citrate is made from ferric sulfate and ammonia water. It is prepared by reacting ferric hydroxide with citric acid, concentrating the resulting solution into a syrup, thinly coating it onto a glass plate, and drying it until it peels off as small flakes (from the Commentary on the Official Compendium of Food Additives).

[0108] Comparative Example 12 We used commercially available ferric citrate that conforms to food additive standards (SIGMA, Technical Grade; manufacturing lot number: 048K0125; manufacturing date: June 2008). This ferric citrate is comparative It is prepared by the same method as described in Comparative Example 11.

[0109] 2. Compositional analysis of ferric citrate For comparative examples 11 and 12, and ferric citrate in Examples 1 to 31, ferric citrate was prepared using a conventional method. The amounts of (titration method), citric acid (liquid chromatography), and water (Karl Fischer method, coulometry, standard test method code B-021) were measured. The results are shown in Tables 1A and 1B.

[0110] [Table 1A]

[0111] [Table 1B]

[0112] As shown in Table 1A, in comparative examples 11 and 12, the average molar ratio of ferric acid to citric acid was 1:1.10, and the average molar ratio of ferric acid to water was 1:2.70.

[0113] In contrast, as shown in Table 1B, in the ferric citrate of Examples 1 to 31, ferric, ku The amounts of ferric acid and water were 17.6-21.4% by weight, 58.6-66.5% by weight, and 16.5-19.4% by weight, respectively, relative to the total weight of ferric citrate, and there were no significant differences in the measurement results for each example. The molar ratio of ferric acid to citric acid determined from the above measurements was 1:0.796-1:1.098, and the molar ratio of ferric acid to water was 1:2.412-1:3.021.

[0114] When the maximum and minimum molar ratios of Examples 1 to 31 were applied to the molecular formula "Fe·x(C6H8O7)·y(H2O)", the range of x was 0.796 to 1.098, and the range of y was 2.412 to 3.021.

[0115] 3. Elemental analysis of ferric citrate The elemental composition of ferric citrate from Comparative Examples 11 and 12, and Examples 1 to 23, was determined by conventional methods. Analysis was performed to measure the amounts of carbon, hydrogen, and oxygen. The results are shown in Tables 2A and 2B.

[0116] [Table 2A]

[0117] [Table 2B]

[0118] As shown in Table 2A, in Comparative Examples 11 and 12, the average values ​​of the composition ratios of ferric to carbon, ferric to hydrogen, and ferric to oxygen were 1:6.7, 1:10.6, and 1:10.2, respectively. That was the case.

[0119] In contrast, as shown in Table 2B, in Examples 1 to 23, the composition ratio of ferric to carbon, The average composition ratios of ferric iron to hydrogen and ferric iron to oxygen are 1:5.09 and 1:9.30, respectively. The ratio was 1:8.56. When the average of the above compositional ratios is applied to the molecular formula "Fe·x(C6H8O7)·y(H2O)", which is one form of ferric citrate, the average compositional formula is "FeC 5.09 H 9.30 O 8.56 The result was calculated as follows, and the average molecular weight was calculated to be 263.33.

[0120] 4. Measurement of the infrared absorption spectrum of ferric citrate For ferric citrate from Examples 1-23, the infrared absorption spectrum was measured using the potassium bromide tablet method. The IR spectrum was measured. The IR spectrum of ferric citrate from Example 4 is shown in Figure 1.

[0121] As shown in Figure 1, the IR spectrum of ferric citrate from Example 4 shows 1608 cm⁻¹. -1 Nearby A strong absorption, presumably originating from the C=O stretching vibration of the dissociated carbonium ion of enoic acid, occurred at 1717 cm⁻¹. -1 It is presumed that this originates from the C=O stretching vibration of the non-dissociated carboxylic acid of citrate in the vicinity. Weak absorption was observed. Also, the ferric citrate in the other examples and the citric acid in Example 4 were also observed. It exhibited an IR spectral pattern similar to that of ferric iron, and absorption bands of similar intensity were observed around the aforementioned wavenumbers.

[0122] 5. Chemical structure analysis of ferric citrate As described above, based on the results of compositional analysis, elemental analysis, and infrared absorption spectroscopy, Examples 1-31 The chemical structure of ferric citrate is a normal salt form in which the molar ratio of ferric to trivalent citric acid is 1:1. Instead, Fe·x(C6H8O7)·y(H2O) (where x is 0.796 to 1.098 and y is 2.412 to 3.021) It was revealed that this is a complex form of a certain compound.

[0123] 6. Powder X-ray diffraction of ferric citrate The powder X-ray diffraction spectrum of ferric citrate from Example 4 was obtained by powder X-ray diffraction measurement. The following measurements were taken. Cobalt was used as the cathode. The results are shown in Figure 2.

[0124] As shown in Figure 2, the powder X-ray diffraction spectrum of ferric citrate in Example 4 shows a diffuse polarity. Because it showed a large halo pattern, the ferric citrate in Example 4 is amorphous (amorphous powder) It was determined to be the end.

[0125] 7. Identification and quantification of β-iron oxide hydroxide. For ferric citrate in Examples 1-31, the impurities, specifically β-iron hydroxide, were qualitatively and quantitatively analyzed. For analysis, the diffraction angle around 40-41° was observed using powder X-ray diffraction (cobalt tube). The peak area of ​​the diffraction peak is measured using an automated integration method, and the following formula is obtained: β-iron oxide hydroxide content (weight %) = (Q T / Q S ) x 0.025 x CF [In the formula, Q T This is the peak plane of the diffraction peak around a diffraction angle of 40-41° obtained from 2.5% β-iron hydroxide. It is a product; Q S This is the peak area of ​​the diffraction peak obtained from the sample at a diffraction angle of approximately 40-41°; CF represents the content (by weight) of β-iron hydroxide standard substance. The amount of β-oxidized iron hydroxide (by weight) relative to the total weight of the ferric citrate sample was calculated using an external standard method.

[0126] The operating conditions for powder X-ray diffraction are as follows: Target: Co X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scanning range: 2θ = 38~44° Step: 2θ = 0.01671° Average time / step: 1000 s Fixed divergence slit: 1 / 2° Rotation speed: 60 revolutions per minute Receiving filter: Fe filter Scanning axis: Goniometer Anti-scatter slit: 1°

[0127] Test Example 1: Investigation of sodium hydroxide addition conditions In the process of forming iron-containing precipitates, the effects of temperature and time during the addition of sodium hydroxide on the formation of β-iron oxide hydroxide and the resulting solubility of ferric citrate were investigated. Ferric citrate for Examples 1 to 31 was prepared according to the method described in 1 above.

[0128] As a comparative example, comparative examples 1 to 4 of citric acid dinitrate were prepared according to the method described in Patent Document 1. Iron was prepared.

[0129] For ferric citrate of Comparative Examples 1-4 and Examples 1-31, the presence or absence of peaks derived from β-oxygenated iron hydroxide by the above powder X-ray diffraction method, and the solubility in the 15th Revised Japanese Pharmacopoeia Dissolution Test Solution 1 (JP Dissolution Test Solution 1) at 30 minutes, based on the paddle method of the 15th Revised Japanese Pharmacopoeia Dissolution Test (JP Dissolution Test Solution 1) ( The paddle method (100 rotations, 600 mg / 900 ml) was used to evaluate the UV-Vis absorption spectrum of the solution (calculated based on the absorbance at the maximum wavelength). The results are shown in Table 3.

[0130] [Table 3]

[0131] As shown in Table 3, in the iron-containing precipitate formation process, ferric chloride and sodium hydroxide and The reaction temperature (liquid temperature) is preferably 15°C or lower, more preferably 10°C or lower, and particularly preferably in the range of 0 to 10°C.

[0132] In the process of forming iron-containing precipitates, the dropping time of sodium hydroxide should be within 3 hours. It is preferable that the interval be within 2 hours, more preferably within 1 hour, and particularly preferable that it be within 30 minutes.

[0133] Therefore, in the iron-containing precipitate formation process, the dropping conditions for sodium hydroxide are, for example, within 3 hours and at 15°C or below, preferably at 10°C or below or in the range of 0 to 10°C, and 2 hours It is more preferable that the temperature is within a certain period and below 15°C, and more preferably within 2 hours and below 10°C. More preferably, the time is within 2 hours and the temperature (liquid temperature) is in the range of 0 to 10°C, and particularly preferably, the time is within 1 hour and the temperature is in the range of 0 to 10°C.

[0134] Test Example 2: Quantitative Determination of β-Iron Oxide Hydroxide For comparative examples 1-4 and examples 1, 4, 5, 6, 7 and 10-23, the β-oxidation of ferric citrate relative to the total weight of the sample was determined by the above-described powder X-ray diffraction method. The amount of iron hydroxide (weight %) was calculated. The results are shown in Table 4.

[0135] [Table 4]

[0136] 8. Dissolution profile of Solution 1 in the Japanese Pharmacopoeia dissolution test. For Comparative Examples 1, 11, and 12, and Examples 4, 5, 6, 7, 8, and 9, the elution profiles of ferric citrate were compared using the 15th Revised Japanese Pharmacopoeia Dissolution Test Solution 1 (pH 1.2) based on the paddle method of the 15th Revised Japanese Pharmacopoeia Dissolution Test (paddle method, 100 rotations, 600 mg / 900 ml). Note that for Comparative Example 1, and Examples 4, 5, 6, 7, 8, and 9, the ferric citrate was... The pulverized sample prepared according to the method described above was used. The results are shown in Figure 3.

[0137] As shown in Figure 3, one aspect of the present invention is ferric citrate, which is used in the Japanese Pharmacopoeia elution test solution 1 (pH 1.2, The ferric citrate exhibits an elution behavior in which 95% or more by weight of ferric citrate is eluted within 15 minutes, preferably within 10 minutes, in the paddle method (100 rotations, 600 mg / 900 ml). Furthermore, the elution rate at 15 minutes is 80% or more, preferably 85% or more, more preferably 90% or more, and particularly preferably 95% or more.

[0138] 9. Measurement of specific surface area Regarding comparative examples 11 and 12, and ferric citrate from examples 1, 4, 5, 6, 7 and 10-23, The specific surface area (BET surface area) was measured using the nitrogen gas adsorption method (relative pressure: 0.05-0.3). The results were obtained. This is shown in Table 5.

[0139] [Table 5]

[0140] 10. Pharmacology Test Example of use 1: Inhibition of phosphorus absorption in rats The phosphorus absorption inhibitory effect of ferric citrate (Example 1) was investigated in rats. Eight to nine male SD rats were given either 1.1% or 3.2% by weight of ferric citrate (Example 1) relative to the total weight of the feed. The subjects were given a diet containing ferric citrate for 7 days. The control group received ferric citrate. Feed free of phosphorus was administered. Fecal and urine samples were collected daily during the administration period. The phosphorus concentration in the collected fecal and urine samples was measured, and the amount of phosphorus excreted in the feces and urine was calculated. Phosphorus intake was calculated by multiplying the amount obtained by subtracting the amount of ferric citrate from the amount of feed consumed by the phosphorus content in the feed, and phosphorus absorption was calculated by subtracting the amount of phosphorus excreted in the feces from the amount of phosphorus intake. The average values ​​(mg phosphorus / day) of phosphorus absorption and urinary phosphorus excretion for the control group and the test group are shown in Figure 4.

[0141] 11. Formulation Testing Formulation example 1: 250 mg tablet 1.680 kg of polyvinyl alcohol / polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF) and 0.42 kg of polyvinyl alcohol / acrylic acid / methacrylic acid A methyl copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industries) was added to 25.9 kg of purified water, and then dissolved using a propeller mixer to prepare the binder.

[0142] 38.3248 kg (30 kg on an anhydrous basis) of ferric citrate (produced in Examples 4 and 5) (A mixture of 19.1624 kg each of the above) and 3.4591 kg of crystalline cellulose ( Oras PH-102 (manufactured by Asahi Kasei Chemicals) was placed in a fluid bed granulator (WSG-60, manufactured by Powrec), and 24.0 kg of the aforementioned binding solution was sprayed onto it for granulation, followed by drying. The resulting dried granules were then processed. The granules were sieved through a screen with a mesh size of 1143 μm using a lean mill (U20 type, manufactured by Powrec) to form a sieved powder. I obtained it.

[0143] To the obtained 41.4048 kg of whole grain powder, 3.42 kg of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) and 0.57 kg of crospovidone (Kollidon CL-F, manufactured by BASF) were added, and the mixture was mixed for 310 seconds at 29 revolutions per minute using a W-type mixer (TCW-100, manufactured by Tokuju Kogyosho). , 0.7752 kg calcium stearate (Japanese Pharmacopoeia calcium stearate, plant-derived, (Manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed for 104 seconds at 29 revolutions per minute using a W-type mixer (TCW-100, manufactured by Tokuju Kogyosho Co., Ltd.) to obtain tablet powder. This tablet powder was compressed into tablets using a rotary tablet press (Collect 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) at a compression pressure of 950 kgf / punch, resulting in tablets with a long diameter of 14.8 mm, a short diameter of 6.8 mm, and a mass of 405 mg. A capsule-shaped tablet was obtained.

[0144] The obtained 12.15 kg of uncoated tablets were then coated using an automatic coating machine (HCT-60N, manufactured by Freund Industrial Co., Ltd.). In addition, 600 g of hypromellose (TC-5M, manufactured by Shin-Etsu Chemical Co., Ltd.), 200 g of titanium dioxide (Titanium(IV) Oxide extra pure, manufactured by Merck), and 100 g of talc (High Filler #17, manufactured by Matsumura Sangyo Co., Ltd.) are used. Tablets are coated with a coating solution obtained by mixing 100 g of Macrogol 6000 (Macrogol 6000P, manufactured by NOF Corporation) and 7000 g of purified water, resulting in tablets with a coating film of approximately 18 mg per tablet (each tablet contains 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). I obtained it. Table 6 shows the component composition of the crude tablet and the coated tablet of Formulation Example 1.

[0145] [Table 6] [Industrial applicability]

[0146] The method of the present invention makes it possible to provide ferric citrate with a reduced amount of β-iron hydroxide, and high-purity ferric citrate with excellent elution characteristics.

Claims

1. The high-purity ferric citrate that substantially does not contain β-iron hydroxide, wherein the β-iron hydroxide content is less than 6% by weight relative to its total weight.

2. The high-purity ferric citrate according to claim 1, wherein the β-iron hydroxide content is less than 2.5% by weight.

3. The high-purity ferric citrate according to claim 1, wherein the β-iron hydroxide content is less than 1.0% by weight.

4. The high of any one of claims 1 to 3, wherein the molar ratio of ferric acid to citric acid is 1:0.75 to 1:1.

10. Pure ferric citrate.

5. The high-purity ferric citrate according to claim 4, wherein the molar ratio of ferric citrate to citric acid is 1:0.80 to 1:0.

92. iron.

6. The 15th Revised Japanese Pharmacopoeia Dissolution Test Method, paddle method, uses Solution 1 of the 15th Revised Japanese Pharmacopoeia as the test solution. In an elution test with a rotation speed of 100 revolutions / minute, the elution time for citrate was 15 minutes. A high-purity ferric citrate according to any one of claims 1 to 5, wherein the elution rate of ferric citrate is 80% or more.

7. A pharmaceutical composition containing high-purity ferric citrate according to any one of claims 1 to 6 as an active ingredient. thing.

8. A hyperphosphatemia containing high-purity ferric citrate according to any one of claims 1 to 6 as an active ingredient A treatment or improvement agent for a symptom.

9. A high-purity ferric citrate powder according to any one of claims 1 to 6, wherein it is amorphous. A powder characterized by the following:

10. A high-purity ferric citrate powder according to any one of claims 1 to 6, wherein the amount is 20 to 45 mg. 2 Ratio table of / g A powder characterized by having an area.

11. The high-purity ferric citrate powder according to claim 9, wherein 20 to 45 mg 2 Having a specific surface area of ​​ / g A powder characterized by the following:

12. A pharmaceutical composition containing the powder of any one of claims 9 to 11 as an active ingredient.

13. A treatment or improvement agent for hyperphosphatemia containing the powder according to any one of claims 9 to 11 as an active ingredient.

14. A method for producing ferric citrate, comprising the following steps: Iron-containing precipitate formation process: In which ferric chloride and sodium hydroxide are brought into contact in an aqueous medium for a short period of time at a low temperature to form an iron-containing precipitate; A ferric citrate aqueous solution formation step involves contacting citric acid with an iron-containing precipitate in an aqueous medium, and then heating it to form a ferric citrate aqueous solution; A ferric citrate precipitation process involves contacting an aqueous solution of ferric citrate with an organic solvent to precipitate ferric citrate; The method, including the method described above.

15. The method of claim 14, wherein, in the iron-containing precipitate formation step, ferric chloride and sodium hydroxide are brought into contact for no more than 2 hours at a liquid temperature in the range of 0 to 10°C.

16. In the ferric citrate aqueous solution formation process, citric acid and iron-containing precipitate are heated in the range of 60 to 100°C. The method according to claim 14 or 15, wherein contact is made at a liquid temperature within the specified range.

17. The method according to any one of claims 14 to 16, wherein the iron-containing precipitate is ferrihydrite. 。

18. Ferric citrate produced by the method of any one of claims 14 to 17.

19. A pharmaceutical composition containing ferric citrate as an active ingredient according to claim 18.

20. A treatment or improvement agent for hyperphosphatemia containing ferric citrate as an active ingredient according to claim 18.

21. A powder of ferric citrate according to claim 18, characterized in that it is amorphous.

22. The ferric citrate powder according to claim 18, wherein 20 to 45 mg 2 It has a specific surface area of ​​ / g. A powder that is characteristic of something.

23. The ferric citrate powder according to claim 21, wherein 20 to 45 mg 2 It has a specific surface area of ​​ / g. A powder that is characteristic of something.

24. A pharmaceutical composition containing the powder of any one of claims 21 to 23 as an active ingredient.

25. Treatment or improvement of hyperphosphatemia containing the powder of any one of claims 21 to 23 as an active ingredient Agent.

26. A pharmaceutical composition according to claim 7, 12, 19, or 24 for use in the treatment of hyperphosphatemia.

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