Ferric citrate substantially not containing β-iron oxide hydroxide

Abstract

To provide high purity ferric citrate which substantially does not contain β-iron oxide hydroxide.SOLUTION: Provided is high purity ferric citrate which substantially does not contain β-iron oxide hydroxide, where a content of β-iron oxide hydroxide relative to the total weight is less than 6 wt%; preferably, high purity ferric citrate where a content of β-iron oxide hydroxide is less than 2.5 wt%; and more preferably, high purity ferric citrate where a content of β-iron oxide hydroxide is less than 1.0 wt%.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to high-purity iron(III) citrate and a method for producing the same. [Background technology]

[0002] Patent Document 1 discloses that a ferric organic compound containing a specific ferric citrate is effective in treating hyperphosphatemia, etc. It is described that the present invention is useful for [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Special Publication No. 2006-518391 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a method for producing high-purity iron(III) citrate that is substantially free of β-iron oxide hydroxide, as well as high-purity iron(III) citrate that is substantially free of β-iron oxide hydroxide, and medical uses thereof. [Means for solving the problem]

[0005] As a result of examining various means for solving the above problems, the present inventors have discovered the method described in Patent Document 1. The present inventors have found that the above object can be achieved by modifying the conditions for contacting ferric chloride with sodium hydroxide in the method of claim 1, and have completed the present invention.

[0006] That is, the gist of the present invention is as follows. (1) High-purity ferric citrate that is substantially free of β-iron hydroxide oxide, and The high purity ferric citrate has a beta iron hydroxide oxide content of less than 6% by weight. . (2) The high-purity citric acid according to (1) above, having a β-iron hydroxide oxide content of less than 2.5% by weight. Ferrous iron. (3) The high-purity citric acid according to (1) above, having a β-iron hydroxide oxide content of less than 1.0% by weight. Ferrous iron. (4) Any of the above (1) to (3), wherein the molar ratio of ferric iron to citric acid is 1:0.75 to 1:1.10. Any high purity ferric citrate. (5) The high-purity iron(III) citrate according to (4) above, wherein the molar ratio of iron(III) 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, the first fluid of the 15th revised Japanese Pharmacopoeia dissolution test is used as the test fluid, and the rotation speed is 100 rpm, the dissolution time is 15 minutes. The high-purity iron(III) citrate according to any one of (1) to (5), wherein the elution rate of iron(III) citrate is 80% or more.

[0007] (7) A method for producing a food product comprising the high-purity iron(III) citrate according to any one of (1) to (6) above as an active ingredient. A pharmaceutical composition. (8) A method for treating a skin ulcer comprising the step of administering to a patient a high-purity iron citrate as defined in any one of (1) to (6) above as an active ingredient. A drug for treating or improving hyperphosphatemia. (9) A method for treating a skin ulcer comprising the step of administering to the patient a high-purity iron citrate as defined in any one of (1) to (6) above as an active ingredient. A phosphorus adsorbent. (10) A serum phosphorus-reducing agent comprising, as an active ingredient, the high-purity iron(III) citrate according to any one of (1) to (6). (11) A powder of high-purity iron(III) citrate according to any one of (1) to (6), characterized in that the powder is amorphous. (12) A powder of high-purity iron(III) citrate according to any one of (1) to (6), having a purity of 20 to 45 m 2 / g specific surface area.

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

[0009] (19) The method according to any one of (16) to (18), wherein the iron-containing precipitate is ferrihydrite. (20) Ferric citrate produced by any one of the processes (16) to (19) above. (21) A pharmaceutical composition comprising the iron(III) citrate according to (20) above as an active ingredient. (22) A therapeutic or ameliorating agent for hyperphosphatemia, comprising the iron(III) citrate according to (20) above as an active ingredient. (23) A phosphorus adsorbent containing the iron citrate according to (20) as an active ingredient. (24) A serum phosphorus-reducing agent comprising the iron(III) citrate according to (20) above as an active ingredient.

[0010] (25) A powder of the iron(III) citrate according to (20), which is amorphous. (26) The powder of iron(III) citrate according to (20), having a concentration of 20 to 45 µL. 2 / g specific surface area. (27) The powder of iron(III) citrate according to (25), having a concentration of 20 to 45 μm. 2 / g specific surface area A powder characterized in that (28) A pharmaceutical composition comprising the powder according to any one of (25) to (27) above as an active ingredient. (29) A therapeutic or ameliorating agent for hyperphosphatemia, comprising as an active ingredient any one of the powders according to (25) to (27). (30) The compound according to any one of (7), (14), (21) or (28) for use in the treatment of hyperphosphatemia. A pharmaceutical composition comprising:

[0011] (31) A high-purity iron(III) complex coordinated with citric acid and water, which is substantially free of β-iron hydroxide oxide, and which has a content of β-iron hydroxide oxide of less than 6% by weight based on the total weight of the complex. (32) The high-purity quartz crystal of (31) above, having a β-iron hydroxide oxide content of less than 2.5% by weight. Iron(III) complex with enoic acid and water. (33) The high-purity quartz crystal of (31) above, having a β-iron hydroxide oxide content of less than 1.0% by weight. Iron(III) complex with enoic acid and water. (34) The high-purity iron(III) complex coordinated with citric acid and water according to any one of (31) to (33), wherein a molar ratio of ferric iron to citric acid is 1:0.75 to 1:1.10. (35) The high-purity iron(III) complex coordinated with citric acid and water according to any one of (31) to (33), wherein a molar ratio of ferric iron to citric acid is 1:0.80 to 1:0.92. (36) 20~45 m 2 Any one of the above (31) to (33) has a specific surface area of ​​1 / g and is amorphous. Any of the high purity iron(III) complexes with citric acid and water.

[0012] (37) The 15th revised Japanese Pharmacopoeia dissolution test paddle method, 1st liquid of the 15th revised Japanese Pharmacopoeia dissolution test In a dissolution test with a rotation speed of 100 rpm, the dissolution time was 15 minutes. The above (31) to (36), wherein the dissolution rate of the iron (III) complex coordinated with enoic acid and water is 80% or more. High purity iron(III) complex with citric acid and water. (38) A pharmaceutical composition comprising, as an active ingredient, the high-purity iron(III) complex coordinated with citric acid and water according to any one of (31) to (37). (39) A therapeutic or ameliorating agent for hyperphosphatemia, comprising as an active ingredient the high-purity iron(III) complex coordinated with citric acid and water according to any one of (31) to (37). (40) A phosphorus adsorbent comprising, as an active ingredient, the high-purity iron(III) complex coordinated with citric acid and water according to any one of (31) to (37). (41) A serum phosphorus-reducing agent comprising, as an active ingredient, the high-purity iron(III) complex coordinated with citric acid and water according to any one of (31) to (37).

[0013] (42) A method for producing an iron(III) complex coordinated with citric acid and water, comprising the steps of: an iron-containing precipitate forming step of contacting ferric chloride with sodium hydroxide in an aqueous medium for a short period of time at a low temperature to form an iron-containing precipitate; The iron-containing precipitate is contacted with citric acid in an aqueous medium, and then heated to form an aqueous solution of an iron (III) complex in which citric acid and water are coordinated. Iron (III) complex aqueous solution formation process; The aqueous solution of iron(III) complex coordinated with citric acid and water is contacted with an organic solvent to obtain the citric acid and a step of precipitating an iron(III) complex coordinated with citric acid and water; The method comprising: (43) In the iron-containing precipitate formation process, ferric chloride and sodium hydroxide are mixed for 2 hours or more. The process according to (42), wherein the contact is carried out at a liquid temperature within the range of 0 to 10°C. (44) In the step of forming an aqueous solution of iron(III) complex containing citric acid and water, and the iron-containing precipitate are contacted at a liquid temperature in the range of 60 to 100° C. . (45) The method according to any one of (42) to (44), wherein the iron-containing precipitate is ferrihydrite.

[0014] (46) An iron(III) complex coordinated with citric acid and water, which is produced by any one of the processes (42) to (45) above. (47) The iron(III) complex coordinated with citric acid and water according to (46) is contained as an active ingredient. A pharmaceutical composition for (48) The pharmaceutical composition according to (38) or (47) for use in treating hyperphosphatemia. (49) The iron(III) complex coordinated with citric acid and water according to (46) is contained as an active ingredient. A drug for treating or improving hyperphosphatemia. (50) The iron(III) complex coordinated with citric acid and water according to (46) above is contained as an active ingredient. Treatment for hyperphosphatemia or phosphate binders. (51) The iron(III) complex coordinated with citric acid and water according to (46) is contained as an active ingredient. Treatment for hyperphosphatemia or serum phosphorus lowering agents. Effect of the Invention

[0015] The present invention makes it possible to provide a method for producing high-purity iron(III) citrate that is substantially free of β-iron oxide hydroxide, as well as high-purity iron(III) citrate that is substantially free of β-iron oxide hydroxide, and medical uses thereof. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows an IR spectrum of the iron(III) citrate of Example 4. [Diagram 2] FIG. 1 shows an X-ray powder diffraction spectrum of the iron(III) citrate of Example 4. [Diagram 3] FIG. 1 shows the results of comparing the dissolution profiles of the ferric citrates of Comparative Examples 1, 11 and 12, and Examples 4, 5, 6, 7, 8 and 9 in the Japanese Pharmacopoeia Dissolution Test No. 1 Fluid (pH 1.2). [Figure 4] FIG. 2 is a graph showing the average phosphorus absorption amount and urinary phosphorus excretion amount (mg phosphorus / day) of the control group and the test group (Example 1) in a phosphorus absorption inhibitory effect test in rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] 1. Ferric citrate The present invention relates to high-purity iron(III) citrate that is substantially free of β-iron hydroxide oxide. As used herein, "ferric citrate" refers to a complex of ferric iron (Fe(III)) and citric acid. One embodiment of the complex is 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, more preferably in the range of 0.78 to 0.95. In another embodiment, x is preferably in the range of 0.75 to 1.15, more preferably 0.80 to 0.92, and particularly preferably 0.81 to 0.91. is in the range of 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. In addition, ferric iron and citric acid The molar ratio of ferric iron 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 particularly preferably in the range of 1:0.81 to 1:0.91. In another embodiment, the molar ratio of ferric iron 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 iron 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 described in detail below, the present inventors have synthesized ferric iron and quercetin by the method described in Patent Document 1. It was found that when complexes with phosphoric acid were prepared, the complexes sometimes contained poorly water-soluble β-iron hydroxide oxide (β-FeOOH) as a by-product.

[0019] In contrast, the iron(III) citrate of the present invention produced by the method described below is substantially free of β-iron hydroxide oxide. Therefore, the present invention provides high-purity iron(III) citrate that is substantially free of β-iron hydroxide oxide. One embodiment of the iron(III) citrate of the present invention is a high-purity iron(III) complex that is substantially free of β-iron hydroxide oxide and is coordinated with citric acid and water. Therefore, the iron(III) citrate of the present invention includes a high-purity iron(III) complex that is substantially free of β-iron hydroxide oxide and is coordinated with citric acid and water. The ferric iron has a content of β-iron hydroxide of preferably less than 6% by weight based on the total weight of the ferric iron. The range is preferably 2.5% by weight or less, more preferably 1.0% by weight or less, and particularly preferably 0 to 1% by weight. "Substantially free of β-iron hydroxide oxide" means that the content of β-iron hydroxide oxide is within the above-mentioned range, and "high-purity ferric citrate" means ferric citrate whose content of β-iron hydroxide oxide is within the above-mentioned range.

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

[0021] In one embodiment of the iron(III) citrate and high-purity iron(III) citrate of the present invention, the specific surface area is, for example, 20 m 2 / g or more, preferably 20 to 45 m 2 / g, more preferably 20 to 40 m 2 / g The range is.

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

[0023] One embodiment of the iron(III) citrate and high-purity iron(III) 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 iron(III) citrate or high-purity iron(III) citrate having the above and following characteristics. In this specification, the term "amorphous form" refers to a form in which the powder X-ray diffraction spectrum shows a diffuse pattern. This means that it exhibits the diffraction characteristics of a halo pattern with a local maximum.

[0024] Furthermore, in a dissolution test according to the paddle method of the Japanese Pharmacopoeia, 15th Edition, using the first fluid of the dissolution test of the Japanese Pharmacopoeia, 15th Edition as the test fluid at a rotation speed of 100 rpm, the ferric citrate and high-purity ferric citrate of the present invention have a dissolution rate of 80% or more, preferably 85% or more, more preferably 90% or more, and particularly preferably 95% or more after 15 minutes of dissolution.

[0025] By having the above-mentioned characteristics, the iron(III) citrate and high-purity iron(III) citrate of the present invention are able to exhibit excellent elution characteristics.

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

[0027] 2-1. Iron-containing precipitate formation process The purpose of this step is to contact ferric chloride with sodium hydroxide in an aqueous medium to form an iron-containing precipitate. Here, "contact" includes, for example, but is not limited to, dropping an aqueous sodium hydroxide solution into an aqueous ferric chloride solution.

[0028] The iron-containing precipitate formed in this step is preferably a precipitate containing ferrihydrite as a main component, and more preferably an iron-containing precipitate containing ferrihydrite as a main component and substantially free of β-iron hydroxide oxide.

[0029] The ferric chloride used in this step 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 step is preferably water. In this case, an aqueous solution containing an iron-containing precipitate, preferably a precipitate mainly composed of ferrihydrite, is formed by this step. The aqueous medium preferably does not substantially contain any components other than citric acid and the precipitate.

[0031] The ferric chloride and sodium hydroxide used in this step may have a purity that is commonly used in the art. 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 step, the concentration of ferric contained in the ferric chloride is preferably in the range of 2 to 6% by weight, more preferably in the range of 3 to 5% by weight, and the concentration of sodium hydroxide is preferably in the range of 5 to 15% by weight, more preferably in the range of 9 to 11% by weight.

[0033] The present inventors have investigated conditions for suppressing the formation of β-iron hydroxide oxide and have found that by contacting ferric chloride with sodium hydroxide for a short period of time at a low temperature, it is possible to form an iron-containing precipitate that contains ferrihydrite as a main component and is substantially free of β-iron hydroxide oxide.

[0034] In this process, the time for contacting ferric chloride with sodium hydroxide is within 3 hours. Preferably, the time is within 2 hours, more preferably within 2 hours, even more preferably within 1 hour, and particularly preferably within 30 minutes. The temperature (liquid temperature) at which ferric chloride and sodium hydroxide are brought into contact with each other is preferably 15°C or lower, more preferably 10°C or lower, and particularly preferably in the range of 0 to 10°C.

[0035] Therefore, in this step, the conditions for contacting ferric chloride with sodium hydroxide are a time of 3 hours or less and a liquid temperature of 15°C or less, preferably a liquid temperature of 10°C or less 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 less, even more preferably a time of 2 hours or less and a liquid temperature of 10°C or less, 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 step, the final pH of the mixture obtained by contacting ferric chloride with sodium hydroxide is preferably in the range of 8-10.

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

[0038] 2-2. Cleaning process The method of the present invention may include a washing step of washing the iron-containing precipitate one to three times prior to the step of forming an aqueous iron citrate solution described below.

[0039] In this step, the iron-containing precipitate is preferably washed with an aqueous medium, which is preferably purified water substantially free of other components.

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

[0041] By carrying out this step under the above conditions, it is possible to improve the purity of the resulting iron(III) citrate.

[0042] 2-3. Ferric citrate aqueous solution formation process The purpose of this step is to contact the iron-containing precipitate obtained in the above step with citric acid in an aqueous medium to form an aqueous solution of iron(III) citrate. Here, "contact" refers to, for example, but is not limited to, reacting the iron-containing precipitate with an aqueous citric acid solution.

[0043] The aqueous medium used in this step is preferably water. In this case, an aqueous solution of iron(III) citrate is formed by this step. It is preferable that the aqueous medium does not substantially contain any components other than citric acid and the precipitate.

[0044] The citric acid used in this step may have a normal purity commonly used in the art. The molar ratio of ferric iron 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 iron 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 step, 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 step, citric acid and the iron-containing precipitate are brought into contact with each other in a medium to form a mixture, and then the mixture is heated to form an aqueous solution of iron(III) citrate. In this step, the heating temperature is preferably in the range of 60 to 100°C, and more preferably in the range of 70 to 90°C. 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 step, the conditions for forming the aqueous solution of iron(III) citrate are particularly preferably such that the mixture is heated at the above liquid temperature for 1 to 3 hours.

[0048] By carrying out this step under the above conditions, it is possible to form an aqueous solution containing iron(III) citrate in high yield.

[0049] 2-4. Ferric citrate precipitation process The purpose of this step is to bring an aqueous solution of iron(III) citrate into contact with an organic solvent to precipitate iron(III) citrate.

[0050] The organic solvent that can be used in this step is not limited, but may be, for example, a water-miscible organic solvent such as acetone, preferably acetone or hydrous acetone.

[0051] The organic solvent used in this step may have a purity that is commonly used in the art. The amount of the organic solvent used is in the range of 300 to 500 parts by weight per 100 parts by weight of the aqueous solution of ferric citrate. It is preferable that the content is in the range of 350 to 450 parts by weight.

[0052] In this step, the aqueous solution of iron(III) citrate is contacted with an organic solvent under the above conditions to precipitate iron(III) citrate. 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. 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 iron(III) citrate obtained by the above method may be used as it is for the desired purpose, but in some cases, the precipitated iron(III) citrate may be further dried by the method described in Patent Document 1.

[0054] By carrying out this step under the above conditions, it is possible to precipitate high-purity iron(III) citrate in high yield.

[0055] 3. Medicinal Uses of Ferric Citrate 3-1. Pharmaceutical Composition The pharmaceutical composition containing the iron(III) citrate of the present invention as an active ingredient has the following properties in vivo: The present invention can be applied to both humans and non-human animals with the diseases or disorders described below. When applied to humans, the present invention can be provided in the form of a pharmaceutical composition or a formulation described below. When applied to non-human animals, the target non-human animals are preferably, but not limited to, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, or monkeys.

[0056] By applying the pharmaceutical composition or preparation of the present invention to the above-mentioned subject (patient or test subject), it becomes possible to treat or ameliorate the diseases or disorders described below. Therefore, the present invention also provides a method for treating or ameliorating the following diseases or disorders, which comprises administering the pharmaceutical composition or preparation of the present invention to the above-mentioned patient or test subject.

[0057] The pharmaceutical composition of the present invention can be used, for example and without limitation, to inhibit the absorption of ingested phosphate in a patient or to treat or ameliorate hyperphosphatemia. Thus, the present invention also provides an agent for treating or ameliorating hyperphosphatemia, which contains ferric citrate as an active ingredient. Alternatively, the present invention also provides a serum phosphorus-lowering agent, which contains ferric citrate as an active ingredient.

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

[0059] By using the pharmaceutical composition or preparation 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, but not limited to, lowering serum phosphorus concentration to a range of 3.5 to 6.0 mg / dL.

[0060] 3-2. Pharmaceutical preparations The iron(III) citrate produced by the method of the present invention, i.e., a pharmaceutical composition containing the high-purity iron(III) citrate of the present invention as an active ingredient, may be administered to a subject by itself, but it is also possible to administer the high-purity iron(III) citrate of the present invention in combination with one or more pharma- ceutical acceptable salts. The present invention can also be provided as a medicine (e.g., a formulation) containing a carrier, excipient, disintegrant, binder, fluidizing agent, diluent, filler, buffer, auxiliary, stabilizer, preservative, lubricant, solvent, solubilizing agent, suspending agent, isotonicity agent, soothing agent or other materials known to those skilled in the art, and optionally other drugs. Therefore, the present invention not only provides the above-mentioned pharmaceutical compositions, but also provides a pharmaceutical composition comprising the high-purity iron(III) citrate of the present invention, in combination with one or more pharma- ceutical acceptable carriers, excipients, disintegrants, binders, The present invention provides a method for preparing a pharmaceutical preparation, comprising mixing with a flow agent, a diluent, a filler, a buffer, an adjuvant, a stabilizer, a preservative, a lubricant, a solvent, a solubilizing agent, a suspending agent, an isotonicity agent, a soothing agent or other materials known to those skilled in the art, and optionally with other drugs.

[0061] The present invention also provides use of the high-purity iron(III) citrate of the present invention in the manufacture of a medicament for treating or ameliorating the above-mentioned diseases or disorders.

[0062] As used herein, "pharmaceutical acceptable" means a compound, material, composition, and / or dosage form suitable for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic response or complications, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0063] The formulations may conveniently be provided in unit dosage form and may be prepared by any method well known in the pharmaceutical art. Such methods include combining the high purity iron(III) citrate of the present invention with one or more The formulation generally comprises the step of mixing the active compound with the above accessory ingredients (e.g., carriers). They are prepared by uniformly and intimately admixing finely divided solid carriers, or liquid carriers, or both, and then, if necessary, shaping the product.

[0064] Examples of the formulation form (dosage form) include, but are not limited to, oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions.

[0065] Tablets may be made by conventional means, e.g., compression or molding, optionally with one or more of the accessory ingredients mentioned above. The compressed tablets can be prepared by mixing the high purity iron(III) citrate of the present invention with, optionally, one or more binders (e.g., povidone, gelatin, gum acacia, sorbitol, tetanylate, etc.). The tablets may be prepared by mixing with a filler or diluent (e.g., microcrystalline cellulose, lactose); a lubricant (e.g., calcium stearate, talc, silica); a disintegrant (e.g., crospovidone, sodium starch glycolate, cross-linked sodium carboxymethylcellulose); a surfactant or dispersant or wetting agent (e.g., sodium lauryl sulfate); and a preservative (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid) and compressing in a suitable machine. The tablets may be optionally coated or scored, and may be formulated to provide a slow or controlled release of, for example, the ferric citrate contained in the formulation. The tablets may be optionally enteric coated to provide release in parts of the digestive tract other than the stomach.

[0066] 3-3. Treatment method When the pharmaceutical composition or preparation 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 iron(III) citrate of the present invention will naturally vary from patient to patient. In general, the dosage is selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial adverse side effects. Here, the selected dosage level depends on various factors including, but not limited to, the activity of the iron(III) citrate, the route of administration, the time of administration, the rate of excretion, the duration of treatment, other drugs used in combination, and the age, sex, weight, pathology, general health, and medical history of the patient.

[0067] In vivo administration can be in one dose, continuous or intermittent (e.g., daily) throughout the entire course of treatment. The single or multiple doses may be administered at appropriate intervals. The dosage level and pattern may be selected by the physician in charge. For example, when administered orally to an adult patient, a suitable dosage of ferric citrate is usually about 1 to 8 g per day. The above amount can be administered in one or more doses. EXAMPLES

[0068] The present invention will be described in more detail below with reference to examples, although 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 process 60.5 kg(Fe 3+ A ferric chloride solution (6.7 kg; 120.0 mol) was placed in a reaction vessel and diluted with 102.9 kg of purified water to obtain a solution of 4.1% by weight of Fe. 3+ An aqueous solution of ferric chloride containing this salt was obtained. The aqueous solution of ferric chloride was cooled to a liquid temperature of 0 to 5° C. 139.6 kg of a 10 wt % NaOH aqueous solution, which had been cooled to a liquid temperature of 0 to 5° C. in advance, was added dropwise to the aqueous solution of ferric chloride over a period of 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 diluted with water and diluted with water to adjust the final pH to 1.6 to 3.8. The mixture was stirred for 1 hour at a temperature (liquid temperature) of ° C. The pH of the mixture was measured and confirmed to be in the range of 8.0 to 10.0.

[0070] Cleaning process The mixture obtained in the above step was washed with 120 kg of purified water while filtering. The iron-containing crude precipitate (wet solid (1): 70.52 kg) mainly composed of ferrihydrite was filtered and washed in 162.7 kg of purified water for 55 minutes by stirring. This suspension was filtered again to separate the iron-containing crude precipitate mainly composed of ferrihydrite. 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 an aqueous citric acid solution. The mixture was then slowly stirred at room temperature (about 25°C) for 70 minutes at a stirring speed of about 67 rpm to form a mixture. The mixture was then slowly stirred under conditions such that the difference between the temperature of the mixture (liquid temperature) and the outside 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 stirred at a temperature of 80.1 to 84.0°C for 120 minutes to obtain ferrihydrite. The iron-containing precipitate, the main component of which was ferrihydrite, was dissolved. After it was confirmed that the iron-containing precipitate, the main component of which was ferrihydrite, had dissolved, the mixture was cooled so that the liquid temperature of the mixture was in the range of 20 to 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 wt % acetone (acetone containing 5 wt % water) was charged to the reaction vessel. 118.0 kg of the aqueous solution of ferric citrate obtained in the above step was added dropwise to 95 wt % acetone in a reaction vessel over a period of 25 minutes while stirring. After completion of the dropwise addition, 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 ferric citrate (wet solid (3): 74.08 kg). The resulting 74.08 kg of wet solid (3) was dried to obtain the desired high purity ferric citrate as a powder (yield: 25.86 kg; yield: 78.86%).

[0073] Example 2: The iron(III) citrate of 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 a period of 165 minutes while maintaining the liquid temperature at 4.0 to 4.7°C, and the final pH was adjusted to 9.20 (yield: 136.03 kg; yield: 85.3%).

[0074] Example 3: The iron(III) citrate of 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 a period of 165 minutes while maintaining the liquid temperature at 4.0 to 4.7°C, and the final pH was adjusted to 9.20 (yield: 136.42 kg; yield: 84.7%).

[0075] Example 4: Iron-containing precipitate formation process 639.5 kg(Fe 3+ A ferric chloride solution (67.3 kg; 1205 mol) was placed in a reaction vessel and diluted with 1002 kg of purified water to obtain a solution of 4.1% by weight of Fe. 3+ An aqueous solution of ferric chloride containing this salt was obtained. The aqueous solution of ferric chloride was cooled to a liquid temperature of 0 to 5° C. 1467.9 kg of a 10% by weight aqueous NaOH solution that had been cooled to a liquid temperature of 0 to 5° C. in advance was added to the aqueous solution of ferric chloride while maintaining the liquid temperature at 3.5 to 8.0° C. The mixture was added dropwise over 120 minutes, and the final pH was adjusted 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 found to be in the range of 8.0 to 10.0. I confirmed that there is.

[0076] Cleaning process The mixture obtained in the above step was filtered and washed with 2000 L of purified water. The iron-containing crude precipitate (wet solid (1): 628.02 kg) mainly composed of ferrihydrite was separated by filtration and diluted with 1627.0 The suspension was washed with stirring in 100 kg of purified water for 25 minutes. The suspension was filtered again to remove ferrihydrite. A precipitate containing iron as the main component was obtained (wet solid (2): 530.75 kg).

[0077] Ferric citrate aqueous solution formation process Dissolve 289.30 kg (1506 mol) of citric acid in 389.0 kg of purified water to obtain 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 aqueous citric acid solution were placed in a reaction vessel and slowly stirred at room temperature (about 25°C) for 69 minutes at a stirring speed of about 50 rpm to form a mixture. Next, the mixture was slowly stirred under conditions such that the difference between the temperature of the mixture (liquid temperature) and the outside 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 stirred at a temperature of 80.0 to 81.9°C for 120 minutes to obtain ferriha The iron-containing precipitate, the main component of which was ferrihydrite, was dissolved. After it was confirmed that the iron-containing precipitate, the main component of which was ferrihydrite, had dissolved, the mixture was cooled so that the liquid temperature of the mixture was in the range of 20 to 30° C. Insoluble matter in the resulting mixture was removed by filtration to obtain an aqueous solution of ferric citrate (1,226.5 kg).

[0078] Ferric citrate precipitation process 2453 kg of acetone was charged into the reactor. 613.2 kg of citric acid fraction obtained in the above process was added. The diferric aqueous solution was added dropwise to the acetone in the reaction vessel over a period of 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 ferric citrate (wet solid (3): 425.17 kg). The wet solid (3) was dried to obtain the desired high-purity iron(III) citrate as a powder (yield: 154.21 kg; yield: 91.7%).

[0079] Example 5: The iron(III) citrate of 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 a period of 120 minutes while maintaining the liquid temperature at 3.5 to 8.0°C, and the final pH was adjusted to 9.22 (yield: 154.61 kg; yield: 91.9%).

[0080] Example 6: The iron(III) citrate of 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 a period of 115 minutes while maintaining the liquid temperature at 2.6 to 7.5°C, and the final pH was adjusted to 9.09 (yield: 154.68 kg; yield: 91.5%).

[0081] Example 7: The iron(III) citrate of 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 a period of 115 minutes while maintaining the liquid temperature at 2.6 to 7.5°C, and the final pH was adjusted to 9.09 (yield: 156.09 kg; yield: 92.3%).

[0082] Example 8: The iron(III) citrate of 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 a period of 162 minutes while maintaining the liquid temperature at 2.4 to 8.6°C, and the final pH was adjusted to 9.21 (yield: 150.43 kg; yield: 92.1%).

[0083] Example 9: The iron(III) citrate of 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 a period of 162 minutes while maintaining the liquid temperature at 2.4 to 8.6°C, and the final pH was adjusted to 9.21 (yield: 152.30 kg; yield: 92.8%).

[0084] Example 10: The iron citrate of Example 10 was prepared by adding an aqueous NaOH solution to the iron-containing precipitate forming step of Example 4. Add dropwise to the ferric chloride solution over 118 minutes while maintaining the liquid temperature at 2.6 to 7.6°C, and adjust the final pH It was prepared in the same manner as in Example 4, except that the amount was 9.13 (yield: 149.47 kg; yield: 88.4%). .

[0085] Example 11: The iron citrate of Example 11 was prepared by adding an aqueous NaOH solution to the iron-containing precipitate forming step of Example 4. Add dropwise to the ferric chloride solution over 118 minutes while maintaining the liquid temperature at 2.6 to 7.6°C, and adjust the final pH It was prepared in the same manner as in Example 4, except that the amount was 9.13 (yield: 150.47 kg; yield: 89.0%). .

[0086] Example 12: The iron(III) citrate of Example 12 was prepared by adding an aqueous NaOH solution to the iron-containing precipitate forming step of Example 4. The preparation was carried out in the same manner as in Example 4, except that the above was added dropwise to an aqueous solution of ferric chloride over a period of 105 minutes while maintaining the liquid temperature at 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 iron(III) citrate of Example 13 was prepared by adding an aqueous NaOH solution to the iron-containing precipitate forming step of Example 4. The same preparation method as in Example 4 was used except that the above was added dropwise to an aqueous solution of ferric chloride over a period of 105 minutes while maintaining the liquid temperature at 0 to 7.3°C to adjust the final pH to 8.98 (yield: 146.56 kg; yield: 88.0%).

[0088] Example 14: The iron citrate of Example 14 was prepared by adding an aqueous NaOH solution to the iron-containing precipitate forming step of Example 4. The same preparation method as in Example 4 was used except that the above was added dropwise to an aqueous solution of ferric chloride over a period of 74 minutes while maintaining the liquid temperature at 1.3 to 8.3°C to adjust the final pH to 8.91 (yield: 146.01 kg; yield: 88.7%).

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

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

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

[0092] Example 18: The iron(III) citrate of Example 18 was prepared by adding an aqueous NaOH solution to the iron-containing precipitate forming step of Example 4. Add dropwise to the ferric chloride solution over 117 minutes while maintaining the liquid temperature at 1.9 to 8.0°C, and the final pH It was prepared in the same manner as in Example 4, except that the pH was 8.40 (yield: 138.93 kg; yield: 86.8%). .

[0093] Example 19: The iron(III) citrate of Example 19 was prepared by adding an aqueous NaOH solution to the iron-containing precipitate forming step of Example 4. Add dropwise to the ferric chloride solution over 117 minutes while maintaining the liquid temperature at 1.9 to 8.0°C, and the final pH It was prepared in the same manner as in Example 4, except that the pH was 8.40 (yield: 132.89 kg; yield: 83.2%). .

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

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

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

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

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

[0099] Example 25: The iron(III) citrate of Example 25 was prepared by using the iron-containing precipitate obtained in Example 20, and by replacing citric acid with Fe in the step of forming an aqueous iron(III) citrate solution in Example 20. 3+ It was prepared in the same manner as in Example 20, except that 2.50 equivalents were used relative to the amount of the compound (yield: 26.79 g; yield: 93.7%).

[0100] Example 26: The iron(III) citrate of Example 26 was prepared by using the iron-containing precipitate obtained in Example 20, and by replacing citric acid with Fe in the step of forming an aqueous iron(III) citrate solution in Example 20. 3+ It was prepared in the same manner as in Example 20, except that 2.50 equivalents were used relative to the amount of the compound (yield: 26.88 g; yield: 93.8%).

[0101] Example 27: The iron(III) citrate of Example 27 was prepared by using the iron-containing precipitate obtained in Example 20, and by replacing citric acid with Fe in the step of forming an aqueous iron(III) citrate solution in Example 20. 3+ It was prepared in the same manner as in Example 20, except that 3.00 equivalents were used relative to the amount of the compound (yield: 27.96 g; yield: 94.4%).

[0102] Example 28: The ferric citrate of Example 28 was prepared by adding an aqueous NaOH solution dropwise to an aqueous ferric chloride solution over a period of 89 minutes while maintaining the liquid temperature at 2.3 to 6.3°C in the iron-containing precipitate formation step of Example 20, until the final pH was 9. 13, and in the step of forming an aqueous solution of ferric citrate, citric acid is added to Fe 3+ It was prepared in the same manner as in Example 20, except that 1.10 equivalents were used relative to the amount of the compound (yield: 37.05 g; yield: 94.8%).

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

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

[0105] Example 31: The iron(III) citrate of Example 31 was prepared by the following procedure: in the iron-containing precipitate forming step of Example 20, an aqueous NaOH solution was added dropwise to an aqueous ferric chloride solution over a period of 90 minutes while maintaining the liquid temperature at 3.7 to 5.4°C to adjust the final pH to 9.28; and in the aqueous ferric citrate solution forming step, citric acid was added to the aqueous ferric chloride solution to adjust the final pH to 9.28. 3+ It was prepared in the same manner as in Example 20, except that 1.55 equivalents of the compound were used (yield: 37.69 g; yield: 96.8%).

[0106] Comparative Example 1-4 The iron-containing precipitate was prepared according to the method described in Patent Document 1. The conditions of the steps corresponding to those described above were modified to those shown in Table 3 below.

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

[0108] Comparative Example 12 We used commercially available ferric citrate (SIGMA, Technical Grade; manufacturing lot number: 048K0125; manufacturing date: June 2008) that complies with food additive standards. Prepared by a method similar to that described in Comparative Example 11.

[0109] 2. Compositional Analysis of Ferric Citrate The ferric citrates of Comparative Examples 11 and 12 and Examples 1 to 31 were extracted with ferric citrate in a conventional manner. The amount of citric acid (by titration), the amount of citric acid (by liquid chromatography) and the amount of water (by Karl Fischer coulometry, standard test method code B-021) were measured. The results are shown in Tables 1A and B.

[0110] [Table 1]

[0111] [Table 2]

[0112] As shown in Table 1A, in the iron(III) citrates of Comparative Examples 11 and 12, the average molar ratio of iron(III) to citric acid was 1:1.10, and the average molar ratio of iron(III) to water was 1:2.70.

[0113] In contrast, as shown in Table 1B, in the iron(III) citrates of Examples 1 to 31, iron(III) and citrate(III) were The amounts of citric 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 between Examples. The molar ratio of ferric to citric acid determined from the above measurements was 1:0.796-1:1.098, and the molar ratio of ferric to water was 1:2.412-1:3.021.

[0114] When the maximum and minimum values ​​of the 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 iron(III) citrates of Comparative Examples 11 and 12 and Examples 1 to 23 were subjected to elemental analysis by a conventional method. The carbon, hydrogen and oxygen contents were measured, and the results are shown in Tables 2A and 2B.

[0116] [Table 3]

[0117] [Table 4]

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

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

[0120] 4. Infrared absorption spectrum measurement of ferric citrate For the ferric citrates of Examples 1 to 23, the infrared absorption spectrum was measured by the potassium bromide tablet method. The IR spectrum of the iron(III) citrate of Example 4 is shown in FIG.

[0121] As shown in FIG. 1, the IR spectrum of the ferric citrate of Example 4 shows a peak at 1608 cm -1 Nearby A strong absorption at 1717 cm is suspected to be due to the C=O stretching vibration of the dissociated carbonium ion of enoic acid. -1 It is speculated that this is due to the C=O stretching vibration of the undissociated carboxylic acid of citric acid. Weak absorption was observed. In addition, the iron citrate of the other examples and the iron citrate of Example 4 The IR spectrum showed a similar pattern to that of ferric iron, and absorption bands of similar intensity were observed near the above wavenumbers.

[0122] 5. Chemical structure analysis of ferric citrate As described above, from the results of the composition analysis, elemental analysis, and infrared absorption spectrum, Examples 1 to 31 The chemical structure of ferric citrate is a 1:1 molar ratio of ferric iron to trivalent citric acid in the form of a normal salt. Instead, it is Fe x(C6H8O7) y(H2O), where x is between 0.796 and 1.098 and y is between 2.412 and 3.021. It was revealed that the compound was in the form of a complex of

[0123] 6. Powder X-ray diffraction of ferric citrate For the iron citrate of Example 4, the powder X-ray diffraction spectrum was obtained by powder X-ray diffraction measurement. The results are shown in Figure 2.

[0124] As shown in FIG. 2, the powder X-ray diffraction spectrum of the ferric citrate of Example 4 shows a diffuse polar Since a halo pattern with large diameters was observed, the ferric citrate of Example 4 was amorphous (amorphous powder). It was determined that the

[0125] 7. Identification of β-iron hydroxide oxide and quantification of β-iron hydroxide oxide Qualitative and quantitative analysis of β-iron hydroxide, which is a contaminant, for the ferric citrates of Examples 1 to 31 In order to analyze the results, the diffraction angle of 40 to 41° was observed by powder X-ray diffraction (cobalt tube). The peak areas of the diffraction peaks were measured by an automatic integration method to obtain the following formula: Amount of β-iron hydroxide oxide (wt%) = (Q T / Q S ) x 0.025 x CF [In the formula, Q T The peak surface of the diffraction peak at a diffraction angle of 40 to 41° obtained from 2.5% β-iron hydroxide oxide is is the product; Q S is the peak area of ​​the diffraction peak obtained from the sample at a diffraction angle of about 40 to 41°; CF is the content (wt%) of β-iron hydroxide oxide standard. The amount of β-iron hydroxide oxide (wt %) in the iron(III) citrate sample relative to the total weight of the sample was calculated by the external standard method using

[0126] The operating conditions for the powder X-ray diffraction method 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: Gonio Anti-scatter slit: 1°

[0127] Test Example 1: Examination of sodium hydroxide addition conditions In the iron-containing precipitate formation process, the effects of the temperature and time when sodium hydroxide is added on the production of β-iron hydroxide oxide and the solubility of the resulting ferric citrate were investigated. The iron(III) citrates of Examples 1 to 31 were prepared according to the method described in 1 above.

[0128] As comparative examples, the distillation of citric acid in Comparative Examples 1 to 4 was carried out according to the method described in Patent Document 1. Iron was prepared.

[0129] The ferric citrates of Comparative Examples 1 to 4 and Examples 1 to 31 were examined for the presence or absence of peaks derived from β-iron hydroxide oxide by the powder X-ray diffraction method described above, and the solubility ( The UV-visible absorption spectrum of the solution was measured using the paddle method at 100 rotations and 600 mg / 900 ml, and the absorbance at the maximum wavelength was used as the basis for the evaluation. The results are shown in Table 3.

[0130] [Table 5]

[0131] As shown in Table 3, in the iron-containing precipitate formation step, ferric chloride, 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 iron-containing precipitate formation process, the sodium hydroxide drop time is within 3 hours. It is preferable that the time is within 2 hours, more preferably within 1 hour, and particularly preferably within 30 minutes.

[0133] Therefore, in the iron-containing precipitate forming step, the conditions for dropping sodium hydroxide are, for example, within 3 hours and at 15° C. or lower, preferably at 10° C. or lower or in the range of 0 to 10° C., and more preferably within 2 hours. It is more preferable that the temperature is within 2 hours and 15°C or lower, and more preferable that the temperature is within 2 hours and 10°C or lower. It is more preferable that the temperature (liquid temperature) is within 2 hours and within the range of 0 to 10°C, and it is particularly preferable that the temperature is within 1 hour and within the range of 0 to 10°C.

[0134] Test Example 2: Quantitative determination of β-iron hydroxide oxide For the iron(III) citrates of Comparative Examples 1 to 4 and Examples 1, 4, 5, 6, 7, and 10 to 23, the ratio of β-oxidation to the total weight of the iron(III) citrate samples was measured by the above-mentioned powder X-ray diffraction method. The amount of iron hydroxide (wt%) was calculated, and the results are shown in Table 4.

[0135] [Table 6]

[0136] 8. Dissolution Profile in the First Fluid of the Japanese Pharmacopoeia Dissolution Test The ferric citrates of Comparative Examples 1, 11 and 12 and Examples 4, 5, 6, 7, 8 and 9 were compared for their dissolution profiles in the first fluid of the Japanese Pharmacopoeia, 15th Edition dissolution test (first fluid of the Japanese Pharmacopoeia dissolution test) (pH 1.2) based on the paddle method of the Japanese Pharmacopoeia, 15th Edition dissolution test (paddle method, 100 rotations, 600 mg / 900 ml). The crushed sample prepared according to the above method was used. The results are shown in Figure 3.

[0137] As shown in FIG. 3, one embodiment of the iron(III) citrate of the present invention is soluble in the first fluid of the Japanese Pharmacopoeia dissolution test (pH 1.2, This is ferric citrate that exhibits a dissolution behavior in which 95% by weight or more of the ferric citrate is dissolved within 15 minutes, preferably within 10 minutes (paddle method, 100 rpm, 600 mg / 900 ml).The dissolution rate in 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 the iron(III) citrates of Comparative Examples 11 and 12 and Examples 1, 4, 5, 6, 7, and 10 to 23, The specific surface area (BET surface area) was measured by nitrogen gas adsorption method (relative pressure: 0.05-0.3). As shown in Table 5.

[0139] [Table 7]

[0140] 10. Pharmacological testing Usage example 1: Inhibition of phosphorus absorption in rats The phosphorus absorption inhibitory effect of ferric citrate (Example 1) was examined in rats. Groups of 8 to 9 male SD rats were each given 1.1% or 3.2% by weight of the ferric citrate of Example 1 based on the total weight of the feed. The rats were fed a diet containing ferric citrate for 7 days. The control group was fed a diet containing ferric citrate. The rats were fed a diet that did not contain ferric citrate. Feces and urine were collected every day during the administration period. The phosphorus concentrations in the collected feces and urine samples were measured, and the fecal and urinary phosphorus excretion amounts were calculated. The phosphorus intake amount was calculated by subtracting the amount of ferric citrate from the food intake amount, and multiplying the result by the phosphorus content in the feed. The phosphorus absorption amount was calculated by subtracting the fecal phosphorus excretion amount from the phosphorus intake amount. The average phosphorus absorption amount and urinary phosphorus excretion amount (mg phosphorus / day) for the control and test groups 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, BASF) and 0.42 kg of polyvinyl alcohol-acrylic acid-methacrylic acid A methyl copolymer (POVACOAT Type: F, manufactured by Daido Chemical Industry Co., Ltd.) was added to 25.9 kg of purified water and then dissolved using a propeller mixer to prepare a binding solution.

[0142] 38.3248 kg (30 kg on anhydrous basis) of ferric citrate (produced in Examples 4 and 5) Of these, 19.1624 kg each was mixed) and 3.4591 kg of crystalline cellulose (Ce The mixture (Olas PH-102, Asahi Kasei Chemicals) was placed in a fluidized bed granulation dryer (WSG-60, Powrex), 24.0 kg of the binding liquid was sprayed onto the mixture to granulate it, and then dried. The resulting dried granules were then dried using a scrub machine. The powder was sieved through a 1143 μm mesh screen in a lean mill (U20 type, Powrex) and sized to a granular powder. obtained.

[0143] To the obtained 41.4048 kg of sized powder, 3.42 kg of low-substituted hydroxypropylcellulose (LH-11, Shin-Etsu Chemical Co., Ltd.) and 0.57 kg of crospovidone (Kollidon CL-F, BASF) were added, and the mixture was mixed for 310 seconds at 29 revolutions per minute using a W-type mixer (TCW-100, Tokuju Manufacturing Co., Ltd.). , 0.7752 kg of calcium stearate (Japanese Pharmacopoeia calcium stearate, vegetable, The mixture was mixed for 104 seconds at 29 revolutions per minute using a W-type mixer (TCW-100, manufactured by Tokuju Manufacturing Co., Ltd.) to obtain tablet powder. The tablet powder was compressed using a rotary tablet press (Correct 12HUK, manufactured by Kikusui Manufacturing Co., Ltd.) with a tableting pressure of 950 kgf / punch to obtain tablets with a major axis of 14.8 mm, a minor axis of 6.8 mm, and a mass of 405 mg. As a result, capsule-shaped uncoated tablets of

[0144] The obtained uncoated tablets (12.15 kg) were coated with an automatic coating machine (HCT-60N, Freund Corporation). The mixture was prepared by mixing 600 g of hypromellose (TC-5M, Shin-Etsu Chemical Co., Ltd.), 200 g of titanium oxide (Titanium(IV) Oxide extra pure, Merck Co., Ltd.), and 100 g of talc (Hifiller #17, Matsumura Sangyo Co., Ltd.). The tablets were coated with a coating solution obtained by mixing 100 g of Macrogol 6000 (Macrogol 6000P, NOF Corp.) and 7000 g of purified water to produce tablets with a coating film of approximately 18 mg per 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 hydroxypropylcellulose, and 5 mg of crospovidone per tablet). obtained. The component compositions of the rough tablets and coated tablets of Formulation Example 1 are shown in Table 6.

[0145] [Table 8] [Industrial Applicability]

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

Claims

1. 1. High-purity iron(III) citrate that is substantially free of beta-iron hydroxide oxide, the content of beta-iron hydroxide oxide being less than 6% by weight based on the total weight of the high-purity iron(III) citrate.

2. 2. The high purity ferric citrate of claim 1, having a beta-iron hydroxide oxide content of less than 2.5% by weight.

3. 2. The high purity iron(III) citrate of claim 1, having a beta iron hydroxide oxide content of less than 1.0% by weight.

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

10. High purity ferric citrate.

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

92. iron.

6. The 15th revised Japanese Pharmacopoeia dissolution test paddle method is used. The 15th revised Japanese Pharmacopoeia dissolution test first fluid is the test fluid. In the dissolution test with the rotation speed set at 100 rpm, the dissolution time was 15 minutes.

6. The high-purity iron(III) citrate according to any one of claims 1 to 5, wherein the elution rate of diiron is 80% or more.

7. A pharmaceutical composition comprising the high-purity iron(III) citrate according to any one of claims 1 to 6 as an active ingredient. thing.

8. A method for treating hyperphosphatemia comprising the high-purity iron(III) citrate according to any one of claims 1 to 6 as an active ingredient. A drug for treating or improving symptoms.

9. The high-purity iron(III) citrate powder according to any one of claims 1 to 6, which is amorphous. A powder characterized by:

10. The high-purity iron(III) citrate powder according to any one of claims 1 to 6, having a concentration of 20 to 45 m 2 / g ratio table A powder characterized by having an area.

11. The high purity iron(III) citrate powder of claim 9, having a concentration of 20 to 45 m 2 / g specific surface area A powder characterized by:

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

13. 12. A therapeutic or ameliorating agent for hyperphosphatemia, comprising the powder according to any one of claims 9 to 11 as an active ingredient.

14. A method for producing iron(III) citrate, comprising the steps of: an iron-containing precipitate forming step of contacting ferric chloride with sodium hydroxide in an aqueous medium for a short period of time at a low temperature to form an iron-containing precipitate; a step of forming an aqueous solution of iron(III) citrate, comprising contacting citric acid with the iron-containing precipitate in an aqueous medium and then heating the mixture to form an aqueous solution of iron(III) citrate; a ferric citrate precipitating step of contacting an aqueous solution of ferric citrate with an organic solvent to precipitate ferric citrate; The method comprising:

15. The method according to claim 14, wherein in the iron-containing precipitate forming step, ferric chloride and sodium hydroxide are contacted for 2 hours or less at a liquid temperature in the range of 0 to 10°C.

16. In the iron citrate aqueous solution formation process, citric acid and the iron-containing precipitate are heated to a temperature of 60 to 100°C. The method according to claim 14 or 15, wherein the contacting is carried out at a liquid temperature within the range of 100° C. to 200° C.

17. 17. The method of 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 comprising the iron(III) citrate of claim 18 as an active ingredient.

20. 20. An agent for treating or ameliorating hyperphosphatemia, comprising the iron(III) citrate of claim 18 as an active ingredient.

21. 19. The iron(III) citrate powder of claim 18, characterized in that it is amorphous.

22. The iron(III) citrate powder of claim 18, having a concentration of 20 to 45 ml 2 It is characterized by having a specific surface area of ​​ / g. Characterized by: powder.

23. The iron(III) citrate powder of claim 21, having a concentration of 20 to 45 ml 2 It is characterized by having a specific surface area of ​​ / g. Characterized by: powder.

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

25. A method for treating or improving hyperphosphatemia, comprising the powder according to any one of claims 21 to 23 as an active ingredient. Agent.

26. 25. The pharmaceutical composition of claim 7, 12, 19 or 24 for use in the treatment of hyperphosphatemia.

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