Use of ferric citrate in prevention and / or treatment of iron-deficiency anemia in hypermenorrhea patient and / or patient suffering from hypermenorrhea-associated gynecologic disease

Abstract

To provide a prophylactic and / or therapeutic agent for iron-deficiency anemia in a hypermenorrhea patient and / or a patient suffering from a hypermenorrhea-associated gynecologic disease.SOLUTION: According to the present invention, a prophylactic and / or therapeutic agent for iron-deficiency anemia in a hypermenorrhea patient and / or a patient suffering from a hypermenorrhea-associated gynecologic disease can be provided, which contains ferric citrate as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the use of ferric citrate in the prevention and / or treatment of iron deficiency anemia in patients with menorrhagia and / or gynecological disorders associated with menorrhagia. [Background technology]

[0002] Iron is a metal found abundantly in the body, and most of it is used as a component of hemoglobin in red blood cells, functioning to transport oxygen throughout the body. Iron is also essential for cell division and proliferation throughout the body, as well as various metabolic processes. Iron is absorbed from the digestive tract and stored primarily in the liver, but there is no active excretion pathway. Iron deficiency (deficiency) is primarily caused by impaired absorption from the digestive tract, inadequate intake, or blood loss. When the amount of iron in the body decreases, serum ferritin levels, which correlate with the amount of stored iron, decrease. This then leads to "iron deficiency without anemia" (a state in which iron stores are depleted but anemia does not occur). In addition to decreased serum ferritin levels, decreased serum iron and increased total iron-binding capacity (TIBC) lead to decreased transferrin saturation (TSAT). Furthermore, as iron deficiency progresses, "iron deficiency anemia" develops (Non-Patent Document 1). Iron deficiency anemia can cause symptoms of anemia, such as palpitations and shortness of breath, as well as spoon-shaped nails and rotator cuffs. Symptoms of tissue iron deficiency, such as atrophy of the lingual papillae, angular stomatitis, and difficulty swallowing, as well as pica and fatigue, are observed (Non-Patent Document 2), which reduces the quality of life (QOL) of patients.

[0003] Existing oral iron preparations are effective for iron deficiency anemia, excluding malabsorption after gastrectomy and iron-refractory iron deficiency anemia, but they have side effects such as nausea, vomiting, abdominal pain, diarrhea, constipation, and hives. Gastrointestinal symptoms occur in 20-30% of patients (Non-Patent Document 3), and even one severe side effect significantly reduces patient adherence to medication (Non-Patent Document 4). Among the gastrointestinal symptoms, However, the incidence of nausea and vomiting is high, reaching approximately 13% in surveys conducted up until the time of approval of sodium ferrous citrate (Non-Patent Document 5). While intravenous iron preparations have the advantage of reliably providing the necessary iron, they can cause side effects such as headache, fever, nausea, and shock symptoms. Shock symptoms are particularly concerning in medical settings, and several intravenous iron preparations have been voluntarily recalled and subsequently discontinued due to an increase in reports of side effects, including hypersensitivity and shock symptoms. There are also issues with the invasiveness of injections. Furthermore, patients with menorrhagia (heavy menstrual bleeding) require a combination of iron supplementation and hormone therapy. However, decreased adherence due to gastrointestinal side effects, primarily nausea and vomiting, can lead to worsening of the underlying disease and increased risk of pregnancy, necessitating special caution. Gynecological diseases associated with menorrhagia mainly include uterine fibroids, endometriosis, adenomyosis, endometrial polyps, bicornuate uterus, etc. Iron deficiency anemia associated with menorrhagia can sometimes be serious, and there is a need for the development of better therapeutic agents that can be safely used in combination with therapeutic agents for the underlying disease (e.g., hormone combination drugs, etc.) by menorrhagia patients.

[0004] Recently, ferric citrate has been used to treat iron deficiency and anemia in patients with chronic kidney disease (CKD). However, it has been reported that it is useful for diseases other than CKD (Patent Documents 1 and 2). The effectiveness of ferric citrate for iron deficiency anemia has not been established. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2015-535209 [Patent Document 2] International Publication No. 2016 / 141124 [Non-patent literature]

[0006] [Non-Patent Document 1] Bainton DF, Finch CA. Am. J. Med. 1964; 37: 62-70 [Non-patent document 2] Lee GR. Iron deficiency and iron deficiency anemia. In: Wintrobe's Clinical Hematology 10 th ed., Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM eds., Williams and Wilkins, Baltimore; 1999: 979-1010 [Non-patent document 3] Yano, T., Iron intolerance and inability to tolerate iron deficiency anemia, Internal Medicine 2013; 112: 257-261 [Non-patent document 4] Okada, Sadatoshi, Guidelines for the treatment of iron deficiency anemia, Journal of the Japanese Society of Internal Medicine 2010; 99: 1220-1225 [Non-Patent Document 5] Ferromia® Tablets 50 mg / Feromia® Granules 8.3% Pharmaceutical Interview Form 8th Edition Revised June 2014 Summary of the Invention [Problem to be solved by the invention]

[0007] Against this background, there is a strong demand for the development of oral iron preparations that further reduce gastrointestinal side effects, primarily nausea and vomiting, and improve medication adherence, as these preparations are expected to contribute to improving the quality of life of patients with menorrhagia and / or gynecological diseases accompanied by menorrhagia, particularly those who are expected to be treated in combination with hormone therapy.

[0008] An object of the present invention is to provide an agent for the prevention and / or treatment of iron deficiency anemia, which has few side effects such as gastrointestinal symptoms, and can be safely used in combination with hormone therapy, etc. in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia. [Means for solving the problem]

[0009] Under these circumstances, the present inventors have discovered that ferric citrate is useful for the prevention and / or treatment of iron deficiency anemia in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, and that it can be used safely in combination with other drugs (hormonal therapy agents, hemostatic agents, etc.) in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, without reducing efficacy or causing side effects, and have completed the present invention.

[0010] That is, the present invention is as follows. [1] A preventive and / or therapeutic agent for iron deficiency anemia in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising ferric citrate as an active ingredient. [2] A method for preventing and / or treating iron deficiency anemia in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia. [3] Ferric citrate for use in the prevention and / or treatment of iron deficiency anemia in patients with menorrhagia and / or gynecological disorders associated with menorrhagia. [4] Use of ferric citrate for producing an agent for preventing and / or treating iron deficiency anemia in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia. [5] The preventive and / or therapeutic agent according to the above [1], wherein the molar ratio of ferric citrate to citric acid is 1:0.80 to 1:0.92. [6] The method for prevention and / or treatment according to the above item [2], wherein the molar ratio of ferric citrate to citric acid in the ferric citrate is 1:0.80 to 1:0.92. [7] The iron(III) citrate according to [3] above, characterized in that the molar ratio of iron(III) citrate to citric acid is 1:0.80 to 1:0.92. [8] The use according to [4] above, wherein the ferric citrate has a molar ratio of ferric to citric acid of 1:0.80 to 1:0.92. [9] Ferric citrate has a specific surface area of 20 to 45 m 2 / g, and is the prophylactic and / or therapeutic agent according to [5] above.

[10] Ferric citrate has a specific surface area of 20 to 45 m 2 / g, and is the prophylactic and / or therapeutic method according to [6] above.

[11] Ferric citrate has a specific surface area of 20 to 45 m 2 / g, and is the ferric citrate according to [7] above.

[12] Ferric citrate has a specific surface area of 20 to 45 m 2 / g, and is the use according to [8] above.

[13] The prophylactic and / or therapeutic agent according to any one of [1], [5], and [9] above, which is in the form of tablets.

[14] The prophylactic and / or therapeutic method according to any one of [2], [6], and

[10] above, wherein ferric citrate is administered in the form of tablets.

[15] The ferric citrate according to any one of [3], [7], and

[11] above, which is in the form of tablets.

[16] The use according to any one of [4], [8], and

[12] above, wherein ferric citrate is in the form of tablets.

[17] The prophylactic and / or therapeutic agent according to any one of [1], [5], [9], and

[13] above, which is a female patient with menorrhagia and / or a gynecological disease accompanied by menorrhagia who is receiving administration of other drugs that affect the menstrual blood volume.

[18] The prophylactic and / or therapeutic method according to any one of [2], [6],

[10] , and

[14] above, which is a female patient with menorrhagia and / or a gynecological disease accompanied by menorrhagia who is receiving administration of other drugs that affect the menstrual blood volume.

[19] The ferric citrate according to any one of [3], [7],

[11] , and

[15] above, which is a female patient with menorrhagia and / or a gynecological disease accompanied by menorrhagia who is receiving administration of other drugs that affect the menstrual blood volume. ​

[20] The use according to any one of the above [4], [8],

[12] and

[16] , wherein the patient with menorrhagia and / or the patient with gynecological diseases accompanied by menorrhagia is a woman receiving other medication that affects the amount of menstrual blood.

[21] The preventive and / or therapeutic agent according to the above

[17] , wherein the other drug affecting the amount of menstrual blood is a hormone therapy agent or a hemostatic agent.

[22] The method for prevention and / or treatment according to the above

[18] , wherein the other drug affecting the amount of menstrual blood is a hormone therapy agent or a hemostatic agent.

[23] The ferric citrate according to

[19] above, wherein the other drug that affects menstrual blood flow is a hormone therapy agent or a hemostatic agent.

[24] The use according to

[20] above, wherein the other drug affecting menstrual flow is a hormone therapy agent or a hemostatic agent.

[25] The preventive and / or therapeutic agent according to any one of [1], [5], [9],

[13] ,

[17] and

[21] above, containing 500 mg or 1000 mg of ferric citrate as an effective daily dose.

[26] The dose of ferric citrate is 500 mg / day or 1000 mg / day. ],

[10] ,

[14] ,

[18] and

[22] .

[27] The dosage of ferric citrate is 500 mg / day or 1000 mg / day. ],

[11] ,

[15] ,

[19] and

[23] .

[28] The dosage of ferric citrate is 500 mg / day or 1000 mg / day. ],

[12] ,

[16] ,

[20] and

[24] .

[29] An agent for improving hemoglobin levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising ferric citrate as an active ingredient.

[30] A method for improving hemoglobin levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[31] Ferric citrate for use in improving hemoglobin levels in patients with menorrhagia and / or gynecological conditions associated with menorrhagia.

[32] Use of ferric citrate for producing an agent for improving hemoglobin levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[33] An agent for improving serum iron levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

[34] A method for improving serum iron levels in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia.

[35] Ferric citrate for use in improving serum iron levels in patients with menorrhagia and / or gynecological disorders associated with menorrhagia.

[36] Use of ferric citrate for producing an agent for improving serum iron levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[37] A serum ferritin level improving agent for patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

[38] A method for improving serum ferritin levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[39] Ferric citrate for use in improving serum ferritin levels in patients with menorrhagia and / or gynecological disorders associated with menorrhagia.

[40] Use of ferric citrate for producing an agent for improving serum ferritin levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[41] A total iron binding capacity (TIBC) improving agent for patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

[42] A method for improving total iron binding capacity (TIBC) in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia.

[43] Ferric citrate for use in improving total iron binding capacity (TIBC) in patients with menorrhagia and / or gynecological conditions associated with menorrhagia.

[44] Use of ferric citrate for producing an agent for improving total iron binding capacity (TIBC) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[45] A transferrin saturation rate (TSAT) improving agent for patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

[46] A method for improving transferrin saturation level (TSAT) in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia.

[47] Ferric citrate for use in improving transferrin saturation (TSAT) in patients with menorrhagia and / or gynecological disorders associated with menorrhagia.

[48] ​​Use of ferric citrate for producing an agent for improving transferrin saturation (TSAT) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[49] An agent for improving mean corpuscular volume (MCV) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

[50] A method for improving mean corpuscular volume (MCV) in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia.

[51] Ferric citrate for use in improving mean corpuscular volume (MCV) in patients with menorrhagia and / or gynecological disorders associated with menorrhagia.

[52] Use of ferric citrate for producing an agent for improving mean corpuscular volume (MCV) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[53] A hepcidin concentration improving agent for patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising ferric citrate as an active ingredient.

[54] Ferric citrate was administered to patients with menorrhagia and / or gynecological disorders associated with menorrhagia. A method for improving hepcidin levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising administering an effective amount of the compound to a subject.

[55] Ferric citrate for use in improving hepcidin levels in patients with menorrhagia and / or gynecological conditions associated with menorrhagia.

[56] Use of ferric citrate for producing an agent for improving hepcidin concentration in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[57] An agent for improving serum soluble transferrin receptor (sTfR) levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

[58] A method for improving serum soluble transferrin receptor (sTfR) levels in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia.

[59] Ferric citrate for use in improving serum soluble transferrin receptor (sTfR) levels in patients with menorrhagia and / or gynecological disorders associated with menorrhagia.

[60] Use of ferric citrate for producing an agent for improving serum soluble transferrin receptor (sTfR) levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[61] An agent for improving C-terminal FGF23 levels (cFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

[62] A method for improving C-terminal FGF23 levels (cFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[63] Ferric citrate for use in improving C-terminal FGF23 levels (cFGF23) in patients with menorrhagia and / or gynecological disorders associated with menorrhagia.

[64] Use of ferric citrate for producing an agent for improving C-terminal FGF23 levels (cFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[65] An agent for improving full-length FGF23 levels (iFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

[66] A method for improving full-length FGF23 levels (iFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising administering an effective amount of ferric citrate to the patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[67] Ferric citrate for use in improving full-length FGF23 levels (iFGF23) in patients with menorrhagia and / or gynecological conditions associated with menorrhagia.

[68] Use of ferric citrate for producing an agent for improving full-length FGF23 levels (iFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[69] The agent according to any one of the above

[29] ,

[33] ,

[37] ,

[41] ,

[45] ,

[49] ,

[53] ,

[57] ,

[61] and

[65] , containing 500 mg or 1000 mg of ferric citrate as an effective amount per day.

[70] The method for improving according to any one of

[30] ,

[0034] ,

[38] ,

[42] ,

[46] ,

[50] ,

[54] ,

[58] ,

[62] and

[66] above, wherein the dosage of ferric citrate is 500 mg / day or 1000 mg / day.

[71] The ferric citrate according to any one of

[31] ,

[0035] ,

[39] ,

[43] ,

[47] ,

[51] ,

[55] ,

[59] ,

[63] and

[67] above, wherein the amount of ferric citrate used is 500 mg / day or 1000 mg / day.

[72] The use of ferric citrate according to any one of

[32] ,

[0036] ,

[40] ,

[44] ,

[48] ,

[52] ,

[56] ,

[60] ,

[64] and

[68] above, wherein the amount of ferric citrate used is 500 mg / day or 1000 mg / day.

[73] A pharmaceutical composition for preventing and / or treating iron deficiency anemia in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising ferric citrate and a pharmaceutically acceptable carrier.

[74] The composition according to

[73] above, wherein the molar ratio of ferric citrate to citric acid is 1:0.80 to 1:0.92.

[75] Ferric citrate is 20-45m 2 The composition according to

[74] above, characterized in that it has a specific surface area of ​​1000 nm / g.

[76] The composition according to any one of the above

[73] to

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

[77] The composition according to any one of

[73] to

[76] above, wherein the patient with menorrhagia and / or the patient with a gynecological disease accompanied by menorrhagia is a woman receiving other medication that affects the amount of menstrual blood.

[78] The composition according to

[77] above, wherein the other drug that affects menstrual blood flow is a hormone therapy agent or a hemostatic agent.

[79] The composition according to any one of the above

[73] to

[78] , which contains 500 mg or 1000 mg of iron(III) citrate as an effective amount per day. [Effects of the Invention]

[0011] The present invention can provide a medicament effective for the prevention and / or treatment of iron deficiency anemia in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia (e.g., uterine fibroids, endometriosis, adenomyosis, endometrial polyps, bicornuate uterus, etc.). The present invention also can provide agents for improving hemoglobin levels, serum iron levels, serum ferritin levels, total iron binding capacity (TIBC), transferrin saturation (TSAT), mean corpuscular volume (MCV), hepcidin levels (hepcidin-25), serum soluble transferrin receptor levels (sTfR), C-terminal FGF23 levels (cFGF23), and full-length FGF23 levels (iFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia. Pharmaceuticals containing the ferric citrate of the present invention as an active ingredient are expected to be used safely without causing side effects or reduced efficacy, even when combined with other drugs (particularly hormone therapy agents and hemostatic agents that affect menstrual blood flow) for the treatment of gynecological diseases accompanied by menorrhagia (primary diseases of menorrhagia), such as uterine fibroids, endometriosis, adenomyosis, endometrial polyps, and bicornuate uterus. Therefore, they are particularly useful for the prevention and / or treatment of iron deficiency anemia in patients with menorrhagia and / or gynecological diseases accompanied by menorrhagia. DETAILED DESCRIPTION OF THE INVENTION

[0012] The definitions used in the present invention are as follows:

[0013] 1. Ferric citrate In the present invention, the "ferric citrate" used as a pharmaceutically active ingredient may be either a hydrate or anhydrous. The form of the "ferric citrate" is not particularly limited.

[0014] The iron(III) citrate used in the present invention can be produced by a method known per se, for example, the method described in the Examples of WO 2012 / 099139, or a method similar thereto.

[0015] One embodiment of the iron(III) citrate used in the present invention is high-purity iron(III) citrate that is substantially free of β-iron hydroxide oxide. The content of β-iron hydroxide oxide in the high-purity iron(III) citrate is preferably less than 6 wt %, more preferably 2.5 wt %, based on the total weight of the high-purity iron(III) citrate. The content of β-iron hydroxide oxide in ferric citrate is preferably in the range below 1.0 wt %, more preferably in the range of 0 to 1 wt %. In this specification, "substantially free of β-iron hydroxide oxide" means that the content of β-iron hydroxide oxide is in the above-mentioned range, and "high-purity ferric citrate" means ferric citrate with a content of β-iron hydroxide oxide in the above-mentioned range. The content of β-iron hydroxide oxide in ferric citrate can be calculated, for example, by powder X-ray diffraction, without any particular limitation.

[0016] One embodiment of the iron(III) citrate used in the present invention is a mixture of iron(III) and citrate. One embodiment of the complex is represented by the molecular formula Fe·x(C6H8O7)·y(H2O). In the above molecular formula, x is preferably 0.75 to 1.10. In another embodiment, x is preferably in the range of 0.78 to 0.95, more preferably in the range of 0.80 to 0.92, and particularly preferably in the range of 0.81 to 0.91. Preferably, y is in the range of 0.75 to 1.15, more preferably in the range of 0.80 to 1.10. is in the range of 1.8 to 3.2, more preferably in the range of 2.4 to 3.1, and particularly preferably 2.7 The molar ratio of ferric iron to citric acid is preferably in the range of 1:0.75 to 1:1.10. 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 1:0.92, 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.

[0017] In one embodiment of the iron(III) citrate used in 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 The specific surface area is in the range of 1 / g. Although there is no limitation on the specific surface area, it can be measured by, for example, a method for measuring the BET surface area using a nitrogen gas adsorption method (relative pressure: 0.05-0.3).

[0018] One embodiment of the iron(III) citrate used in the present invention is in an amorphous form, preferably in the form of an amorphous powder.

[0019] In one embodiment of the iron(III) citrate used in the present invention, the dissolution rate after 15 minutes of dissolution is 80% or more, preferably 85% or more, more preferably 90% or more, and particularly preferably 95% or more, in a dissolution test performed by the paddle method of the Japanese Pharmacopoeia, 15th Edition, using the first fluid of the Japanese Pharmacopoeia, 15th Edition, as the test fluid at a rotation speed of 100 rpm.

[0020] By virtue of the above characteristics, the iron(III) citrate used in the present invention is able to exhibit excellent elution properties.

[0021] 2. An agent for preventing and / or treating iron deficiency anemia in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising ferric citrate as an active ingredient, or a pharmaceutical composition for preventing and / or treating iron deficiency anemia in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising ferric citrate and a pharmaceutically acceptable carrier. The preventive and / or therapeutic agent or pharmaceutical composition containing the iron(III) citrate of the present invention as an active ingredient has the following effects in vivo on both humans and non-human animals suffering from iron deficiency anemia. The present invention can also be applied to the human body. When applied to humans, the preventive and / or therapeutic agent or pharmaceutical composition can be provided in the form of 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.

[0022] By administering the prophylactic and / or therapeutic agent or pharmaceutical composition of the present invention to the above-mentioned subject (patient or test subject), it is possible to prevent and / or treat (ameliorate) iron deficiency anemia. Therefore, the present invention also provides a method for preventing and / or treating (ameliorating) iron deficiency anemia, which comprises administering the prophylactic and / or therapeutic agent or pharmaceutical composition of the present invention to the above-mentioned patient or test subject.

[0023] The prophylactic and / or therapeutic agent or pharmaceutical composition of the present invention can be suitably used to prevent and / or treat (ameliorate) iron deficiency anemia, particularly in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, although the subject is not limited thereto. Iron deficiency anemia is a condition in which blood hemoglobin concentration is reduced, and in which a decrease in serum ferritin levels due to a decrease in iron stores in the body, as well as a decrease in transferrin saturation (TSAT) due to a decrease in serum iron and an increase in total iron binding capacity (TIBC). Therefore, the present invention also provides an agent for improving hemoglobin levels, serum iron levels, serum ferritin levels, total iron binding capacity (TIBC), or transferrin saturation (TSAT) that contains ferric citrate as an active ingredient.

[0024] By using the prophylactic and / or therapeutic agent or pharmaceutical composition of the present invention, iron deficiency anemia can be prevented and / or treated (ameliorated). In this specification, "prevention and / or treatment of iron deficiency anemia" refers to, for example, reducing the hemoglobin concentration in blood to 12 g / dL or more. Increase serum iron levels to the range of 360 μg / dL, decrease total iron binding capacity (TIBC) to the range of less than 360 μg / dL, increase transferrin saturation (TSAT) to the range of 16% or more, and This includes, but is not limited to, increasing serum ferritin levels to a range of 12 ng / mL or greater.

[0025] The preventive and / or therapeutic agent or pharmaceutical composition of the present invention containing iron(III) citrate as an active ingredient may be administered to a subject as the preventive and / or therapeutic agent or pharmaceutical composition itself alone, or may be administered in combination with iron(III) citrate and one or more pharmaceutically acceptable carriers, such as excipients and disintegrants. The composition may also be provided as a pharmaceutical (e.g., formulation) containing additives such as binders, flow agents, lubricants, preservatives, antioxidants, coloring agents, sweeteners, or other materials known to those skilled in the art, and optionally other drugs.

[0026] The present invention also provides use of ferric citrate in the manufacture of a medicament for preventing and / or treating (ameliorating) iron deficiency anemia in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia.

[0027] As used herein, "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that is suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other complications, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Each excipient, such as a carrier, must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0028] A preventive and / or therapeutic agent or pharmaceutical composition (also referred to as "preparation of the present invention") containing the iron(III) citrate of the present invention as an active ingredient can be conveniently provided in a unit dosage form and can be prepared by any method well known in the pharmaceutical arts. Such a method includes the step of mixing iron(III) citrate with one or more accessory ingredients (e.g., additives such as carriers). In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with finely divided solid carriers or liquid carriers or both, and then, if necessary, shaping the product.

[0029] The form (dosage form) of the formulation of the present invention is not limited, but examples thereof include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions. Among these, tablets are preferred.

[0030] Tablets may be made by conventional means, e.g., compression or molding, optionally with one or more of the accessory ingredients described above. Compressed tablets can be prepared by mixing ferric citrate with optional excipients, disintegrants, and / or granules. The mixture is mixed with one or more pharmaceutically acceptable carriers selected from the group consisting of disintegrants, binders, flow agents, lubricants, preservatives, antioxidants, coloring agents, and sweeteners, and compressed in a suitable machine. Tablets may be optionally coated or scored and may be formulated, for example, to provide slow or controlled release of the ferric citrate contained in the formulation. Tablets may optionally be enteric coated, to provide release in parts of the digestive tract other than the stomach.

[0031] Examples of the "excipient" used in the formulation (tablet) of the present invention include microcrystalline cellulose (CEOLUS (grades: PH-101, PH-102, PH-301, PH-302, KG-802, KG-1000, manufactured by Asahi Kasei Chemicals), VIVAPUR (grades: 101, 102, 105, 301, 302, manufactured by JRS Pharma), Emcocel (grades: 50M, 90M, manufactured by JRS Pharma)), lactose, partially pregelatinized starch (e.g., Starch 1500G (manufactured by Colorcon Japan), PCS (manufactured by Asahi Kasei Chemicals)), sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, and gum arabic.

[0032] Examples of the "disintegrant" used in the preparation (tablet) of the present invention include low-substituted hydroxypropylcellulose (e.g., L-HPC (grades: LH-11, LH-21, LH-22, LH-31, LH-32, LH-B1, manufactured by Shin-Etsu Chemical Co., Ltd.)), crospovidone (e.g., Kollidon (grades: CL, CL-F, CL-SF, CL-M, manufactured by BASF), Polyplasdone (grades: XL, XL-10, INF-10, manufactured by ISP)), carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylstarch sodium, and croscarmellose sodium.

[0033] Examples of the "binder" used in the formulation (tablet) of the present invention include polyvinyl alcohol-polyethylene glycol graft copolymer (e.g., Kollicoat IR (manufactured by BASF)), polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (e.g., POVACOAT Type: F (manufactured by Daido Chemical Industry Co., Ltd.)), hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, sucrose, dextrin, starch, pregelatinized starch, gelatin, sodium carboxymethylcellulose, gum arabic, etc.

[0034] Examples of the "fluidizer" used in the formulation (tablet) of the present invention include light anhydrous silicic acid, magnesium stearate (e.g., magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd., Japanese Pharmacopoeia, vegetable-based), magnesium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.), magnesium stearate (manufactured by Mallinckrodt Co., Ltd.)), and the like.

[0035] Examples of the "lubricant" used in the preparation (tablet) of the present invention include magnesium stearate, calcium stearate (e.g., calcium stearate (manufactured by Taihei Chemical Industry Co., Ltd., Japanese Pharmacopoeia, vegetable-based), calcium stearate (manufactured by Nitto Kasei Kogyo Co., Ltd.), calcium stearate (manufactured by Mallinckrodt Co., Ltd.)), sodium stearyl fumarate, stearic acid, talc, etc.

[0036] Examples of the "preservatives" used in the preparation (tablet) of the present invention include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.

[0037] The "antioxidant" used in the preparation (tablet) of the present invention includes, for example, sodium sulfite. sodium, ascorbic acid, etc.

[0038] Examples of the "coloring agent" used in the preparation (tablet) of the present invention include food dyes (e.g., Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), β-carotene, and the like.

[0039] Examples of the "sweetener" used in the preparation (tablet) of the present invention include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and the like.

[0040] Examples of the "coating agent" used in the preparation (tablet) of the present invention include hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, etc. If necessary, the coating agent may be mixed with other additives such as macrogols (e.g., macrogol 6000), plasticizers such as triacetin, light-blocking agents such as titanium oxide, and anti-adhesion agents such as talc before use. Furthermore, premix coating agents such as Opadry II (manufactured by Colorcon) may be used, if necessary, in combination with other additives such as macrogols, plasticizers such as triacetin, and light-blocking agents such as titanium oxide.

[0041] The formulation (tablet) of the present invention preferably contains polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and polyvinyl alcohol-polyethylene glycol graft copolymer as pharmaceutically acceptable carriers, and more preferably further contains microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and crospovidone in addition to these.

[0042] The formulation (tablet) of the present invention contains ferric citrate, calculated as anhydrous, in an amount of preferably 70 to 90 parts by mass, more preferably 70 to 85 parts by mass, and particularly preferably 70 to 80 parts by mass, per 100 parts by mass of the uncoated tablet obtained by removing the water content of the ferric citrate. In another embodiment, the formulation (tablet) of the present invention may contain ferric citrate, calculated on an anhydrous basis, in a ratio of preferably 70 parts by mass or more, more preferably 80 parts by mass or more, and particularly preferably 85 parts by mass or more per 100 parts by mass of the uncoated tablet obtained by removing the water content of the ferric citrate. In this specification, the term "plain tablet" means, if the tablet is a coated tablet, the plain tablet before coating, and if the tablet is not coated, the tablet itself. The formulation of the present invention can provide a tablet containing a high content of ferric citrate, which allows the tablet to be made smaller and / or the number of tablets to be taken to be reduced, thereby improving compliance with administration. The "anhydrous equivalent amount" refers to the amount of iron(III) citrate in solid form. Specifically, the water content of iron(III) citrate is measured by the Karl Fischer method, and the amount of iron(III) citrate in solid form after excluding the water content is measured.

[0043] Suitable specific examples of the formulation (tablet) of the present invention include, but are not limited to, those described in the Examples and Formulation Examples of WO 2012 / 005340, JP 2012-31166 A, and the like.

[0044] When the formulation of the present invention is used to treat or improve iron deficiency anemia, the appropriate dosage of ferric citrate varies from patient to patient. Generally, the dosage is selected to achieve a blood 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 route of administration of ferric citrate, the time of administration, the rate of excretion, the duration of treatment, other drugs used in combination, and the patient's age, sex, weight, condition, general health, and medical history.

[0045] Administration in vivo can be by 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 can be selected by a physician in charge. For example, when administered orally to an adult patient, a suitable dosage of ferric citrate is about 100 mg / day on an anhydrous basis. The daily dose is usually in the range of about 0.25 to 8 g, preferably in the range of about 0.25 to 3 g, more preferably in the range of about 0.25 to 2 g, and particularly preferably in the range of about 0.5 to 1.5 g. Specific examples of suitable daily doses, calculated as anhydrous equivalent, include 0.25 g, 0.5 g, 0.75 g, 1.0 g, 1.25 g, and 1.5 g. The above amount can be administered in one or more divided doses before meals, between meals, and after meals. It can be administered after or with a meal. Among these, administration after a meal is preferred, and administration immediately after a meal is particularly preferred.

[0046] In the present invention, "treatment" means curing or ameliorating a disease or symptom, or suppressing a symptom, and includes "prevention." "Prevention" means preventing the onset of a disease or symptom.

[0047] 3. Patients with menorrhagia and / or gynecological diseases accompanied by menorrhagia The "menorrhagia patient" to whom the medicament (prophylactic and / or therapeutic agent, and pharmaceutical composition) of the present invention is administered refers to a patient (female) who exhibits symptoms of iron deficiency anemia due to blood loss associated with menorrhagia. Furthermore, the "patient with a gynecological disease accompanied by menorrhagia" refers to a patient who, in addition to the menorrhagia patients, suffers from a gynecological disease accompanied by menorrhagia, such as uterine fibroids, endometriosis, adenomyosis, endometrial polyps, or bicornuate uterus. Since most menorrhagia patients have gynecological diseases accompanied by menorrhagia, most of the "menorrhagia patients and / or patients with gynecological diseases accompanied by menorrhagia" of the present invention concomitantly use other drugs (e.g., hormone therapy agents, hemostatic agents, etc.) to treat and / or alleviate the underlying diseases or symptoms, such as uterine fibroids, endometriosis, adenomyosis, endometrial polyps, or bicornuate uterus.

[0048] Examples of the other drugs include hormone therapy agents such as drugs for treating uterine fibroids, drugs for treating endometriosis, drugs for treating adenomyosis, drugs for treating endometrial polyps, drugs for treating bicornuate uterus, and drugs for treating dysmenorrhea, as well as analgesics and hemostatic agents. Specific examples of hormone therapy agents include GnRH agonists, LHRH derivatives, GnRH antagonists, LHRH antagonists, estrogen preparations, progesterone preparations, mixed estrogen / progesterone preparations (e.g., norethisterone / ethinyl estradiol, levonorgestrel / ethinyl estradiol, desogestrel / ethinyl estradiol, drospirenone / ethinyl estradiol, etc.), danazol, etc. Examples of analgesics include NSAIDs such as aspirin, acetaminophen, ibuprofen, diclofenac sodium, and loxoprofen sodium. Examples of hemostatic agents include tranexamic acid, carbazochrome sodium sulfonate hydrate, and Chinese herbal medicines with hemostatic properties (such as Kyukikyogaito).

[0049] In the present invention, "hormonal therapy" refers to a treatment method using hormones or drugs that promote or suppress hormone secretion (collectively referred to as "hormonal therapy agents" in this specification) for various symptoms. Examples of hormone therapy include progesterone therapy, Kaufmann therapy (estrogen-progesterone cyclic therapy), and treatment using pills, and examples of hormone therapy agents used include those described above.

[0050] 4. Iron parameters A healthy person normally stores about 4-5g of iron in their body. About 2.5g of this iron is It is contained in hemoglobin, which carries oxygen through the blood. Most of the remaining iron, about 1.5 to 2.5 g, is It is contained in iron-binding complexes present in all cells, including the bone marrow and the liver and spleen. Of the total body iron content, about 400 mg is available to proteins that use iron in cellular processes, such as oxygen storage (myoglobin) or performing redox reactions that produce energy (cytochrome proteins). In addition to stored iron, a small amount of iron, usually about 3-4 mg, circulates through the blood plasma bound to a protein called transferrin. Due to its toxicity, free soluble ferrous iron (iron(II) or Fe 2+ ) is normally maintained at low concentrations in the body.

[0051] Heavy bleeding due to menorrhagia initially depletes the body's iron stores, and since most of the iron utilized by the body is required for hemoglobin, iron deficiency anemia is the primary clinical symptom in patients with menorrhagia and / or gynecological disorders associated with menorrhagia.

[0052] There are several markers of whole-body iron status that can be measured to determine whether patients with menorrhagia and / or gynecological disorders associated with menorrhagia have sufficient iron stores to maintain health. These markers may relate to circulating iron stores, iron stored in iron-binding complexes, or both, and are generally referred to as iron parameters. Iron parameters include, for example, total iron-binding capacity (TIBC), transferrin saturation (TSAT), serum iron level, liver iron level, spleen iron level, serum ferritin level, hepcidin, serum soluble transferrin receptor (sTfR), etc. Among these, total iron-binding capacity (TIBC), transferrin saturation (TSAT), and serum iron level are generally known as circulating iron stores. Liver iron level, spleen iron level, and serum ferritin level are generally referred to as stored iron or iron stored in iron-binding complexes. Among the above iron parameters, total iron-binding capacity (TIBC), transferrin saturation (TSAT), serum iron level, serum ferritin value, hepcidin, serum soluble transferrin receptor (sTfR), etc. can be examined to diagnose whether menorrhagia patients and / or patients with gynecological diseases accompanied by menorrhagia are in a state of iron deficiency anemia.

[0053] 5. Blood hemoglobin level (Hb) Blood hemoglobin (Hb) refers to the weight of hemoglobin contained in a given volume of blood. The reference (normal) values ​​for blood hemoglobin (Hb) are 13.1 to 16.6 g / dL for men and 12.1 to 14.6 g / dL for women. A blood hemoglobin (Hb) value below 12 g / dL is suspected to be iron deficiency anemia. However, whether or not a patient has iron deficiency anemia cannot be diagnosed solely from blood hemoglobin (Hb) values. A comprehensive assessment is required based on the measurement results of multiple parameters, including total iron-binding capacity (TIBC), transferrin saturation (TSAT), serum iron level, and serum ferritin level, as described below.

[0054] 6. Total iron binding capacity (TIBC) Total iron-binding capacity (TIBC) is a measure of blood's ability to bind iron to the protein transferrin. TIBC is typically measured by collecting a blood sample and measuring the maximum amount of iron the sample can carry. Therefore, TIBC is an indirect measurement of transferrin, the protein that transports iron in the blood. The reference (normal) value for total iron-binding capacity (TIBC) is 250-385 μg / dL for men and 260-420 μg / dL for women. When menorrhagia patients and / or patients with gynecological disorders accompanied by menorrhagia experience iron deficiency due to bleeding, the body attempts to resolve the iron deficiency by increasing iron absorption from the gastrointestinal tract or increasing the amount of transferrin in the blood to efficiently transport iron. Therefore, menorrhagia patients and / or patients with gynecological disorders accompanied by menorrhagia exhibit high TIBC values ​​when they are in a state of iron deficiency anemia. If the TIBC value is 360 μg / dL or higher, it is iron deficiency anemia. The diagnosis is made in combination with the measurement of other parameters.

[0055] 7. Transferrin Saturation Rate (TSAT) In addition to stored iron, a small amount of iron, usually about 3-4 mg, is stored in the blood as a protein called transferrin. It circulates through the blood plasma bound to the protein transferrin. Therefore, serum iron levels can be expressed as the amount of iron circulating in the blood bound to the protein transferrin. Transferrin contains one or two ferric iron (iron(III) or Fe 3+ Transferrin saturation (TSAT) is a glycoprotein produced by the liver that can bind to iron ions. It is the most common and dynamic carrier of iron in the blood and is therefore an essential component of the body's ability to transport iron stores for systemic use. Transferrin saturation (TSAT) is measured as a percentage and calculated as the ratio of serum iron to total iron-binding capacity (TIBC) multiplied by 100. This value indicates how much serum iron is actually bound relative to the total amount of transferrin available for binding iron. Normal TSAT values ​​are approximately 15-50% for men and 12-45% (around 30%) for women. When patients with menorrhagia and / or gynecological disorders associated with menorrhagia have iron deficiency anemia, TSAT values ​​usually decrease significantly due to the reduced amount of iron available for transferrin binding. A TSAT value of 16% or less is suspected, but a diagnosis is made in combination with other parameters.

[0056] 8. Serum iron level Serum iron levels can be expressed as the amount of iron circulating in the blood bound to the protein transferrin (i.e., the amount of iron contained in serum). The reference (normal) serum iron level is 60-210 μg / dL for men and 50-170 μg / dL for women. When patients with menorrhagia and / or gynecological diseases associated with menorrhagia are in a state of iron deficiency anemia, their serum iron levels decrease significantly.

[0057] 9. Serum ferritin levels Ferritin binds to iron and exists as stored iron throughout the body, such as in the liver, spleen, and bone marrow. When the iron in the serum decreases, ferritin supplies iron to transferrin, and when it increases, it receives iron from transferrin and stores it. Since serum ferritin levels are known to correlate well with the amount of stored iron (serum ferritin 1 ng / ml corresponds to 8-10 mg of stored iron), By examining changes in serum ferritin levels, it is possible to observe the decrease or increase in iron stores in the body. The reference (normal) serum ferritin level is 20-250 ng / mL for men and 5-120 ng / mL for women. When menorrhagia patients and / or patients with gynecological diseases accompanied by menorrhagia are in a state of iron deficiency anemia, serum ferritin levels decrease significantly. If the serum ferritin level is less than 12 ng / mL, iron deficiency anemia is suspected, but a diagnosis is made by combining the results of other parameters.

[0058] 10.Mean corpuscular volume (MCV) MCV indicates the size of red blood cells in the blood. When the MCV value is low, the body is less able to transport oxygen throughout the body, making it more likely to experience symptoms of anemia (microcytic anemia) such as shortness of breath and dizziness. The standard (normal) MCV value is 82.7-101.6 fL for men and 79-100 fL for women. If the value is less than 80 fL, iron deficiency anemia is suspected, but in combination with the results of other parameters, The diagnosis is made by a combination of factors.

[0059] 11. Hepcidin (hepcidin-25) Hepcidin is secreted in response to iron overload and its concentration decreases in iron deficiency. Therefore, elevated hepcidin-25 levels are an indicator for the treatment of iron deficiency anemia. Elevated hepcidin-25 levels have been shown to contribute to infection defense and protection of inflamed tissues.

[0060] 12. Serum soluble transferrin receptor (sTfR) The transferrin receptor is said to be a membrane protein essential for the uptake of iron into cells by binding to transferrin, an iron transport protein in serum, but some of it is released into the serum. Most of it is released from erythroblasts, which are the center of erythropoiesis, and serum soluble transferrin receptor (sTfR) concentration is clinically useful for determining the total amount of erythroblast production. It is useful for investigating signs of recovery of blood function. sTfR is elevated in patients with iron deficiency anemia, but in patients with anemia due to chronic disease, the level is normal, so a decrease in sTfR is an indicator of treatment for iron deficiency anemia.

[0061] 13. Fibroblast growth factor (FGF) 23 (C-terminal FGF23 (cFGF23), full-length FGF23 (iFGF23)) FGF23 is produced mainly by bone cells and binds to the Klotho-FGF receptor complex. It is a hormone that exerts effects such as reducing the concentration of phosphorus and 1,25-hydroxyvitamin D. In iron deficiency, the transcription of FGF23 is enhanced and the degradation of FGF23 is also enhanced, and when iron deficiency improves, a decrease in cFGF23 is observed. Elevated FGF23 is associated with a risk of heart failure. It is known that cFGF23 contributes to an increase in blood cholesterol, and a decrease in cFGF23 levels is expected to contribute to a reduction in the risk of heart failure.

[0062] 14. Diagnostic criteria for iron deficiency anemia in patients with menorrhagia and / or gynecological disorders associated with menorrhagia The revised Guidelines for the Treatment of Anemia with Proper Use of Iron Supplements [Third Edition], 2015, compiled by the Treatment Guidelines Preparation Committee of the Japanese Iron Bioscience Society, includes the diagnostic criteria for iron deficiency anemia shown in Table 1 below. In this specification, menorrhagia patients and / or patients with gynecological diseases accompanied by menorrhagia were diagnosed according to the diagnostic criteria in Table 1, and test subjects with iron deficiency anemia were selected.

[0063] [Table 1]

[0064] As shown in the Examples below, it has been confirmed that the preparation of the present invention is effective in preventing and / or treating iron deficiency anemia in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia. Specifically, administration of the preparation of the present invention improved hemoglobin levels, serum iron levels, serum ferritin levels, total iron-binding capacity (TIBC), and transferrin saturation capacity (TSAT) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, regardless of the dosage. Furthermore, it has been confirmed that the preparation can be used safely without causing side effects or reduced efficacy, even when used in combination with other drugs (particularly hormone therapy agents, hemostatic agents, etc. that affect menstrual blood flow) for the treatment of gynecological diseases accompanied by menorrhagia, such as uterine fibroids, endometriosis, adenomyosis, endometrial polyps, and bicornuate uterus. [Example]

[0065] The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[0066] Example 1 A 7-week administration study of ferric citrate (development code: JTT-751) in patients with iron deficiency anemia ( Phase II clinical trial)

[0067] (Clinical trial design) This study was a three-period multicenter safety and efficacy clinical trial. The first period was the observation period (Day -40 to Day -1), and the second period was the treatment period (Day 1 to Day 48). The first period was the first follow-up period (days 49 to 63) (efficacy and safety evaluation period), and the second period was the follow-up period (days 49 to 63) (efficacy and safety evaluation period). Safety and efficacy evaluations were conducted using a multicenter, placebo-controlled, randomized, double-blind, parallel-group comparative study.

[0068] The observation start date will be set between 39 and 14 days (Days -40 to -15) before the day before the start of study drug administration (Week 0) after written consent is obtained from the subject. The following survey (Table 2) will be conducted on the observation start date to confirm eligibility.

[0069] [Table 2]

[0070] Week 0 refers to the name of the observation day before the start of administration of the investigational drug (Day -1). Week 0 is listed in the table below. Investigate item 3.

[0071] [Table 3]

[0072] The start date of observation and subsequent observation dates will be based on this date. This is the first day of administration of the investigational drug, and is considered to be Day 1.

[0073] Week 3 refers to the name of the observation date three weeks later (21st day). In Week 3, the items in Table 4 below will be investigated.

[0074] [Table 4]

[0075] Week 7 refers to the name of the observation day 7 weeks later (49th day). The items in Table 5 below will be investigated on Week 7.

[0076] [Table 5]

[0077] F-up Visit refers to the name of the observation day 9 weeks after Week 0 (63rd day). The items in Table 6 below will be investigated 9 weeks after Week 0.

[0078] [Table 6]

[0079] (Sample collection) Blood and urine samples will be collected from subjects and used for efficacy, safety, and other investigations. Sample collection and processing procedures will follow the "Procedure for Sample Processing." In addition, to confirm the selection and discontinuation criteria for subjects, the "Procedure for Simple Measurement of Hb Levels" will be followed. A small amount of blood is drawn from the fingertip.

[0080] (Target subjects) Patients with iron deficiency anemia

[0081] (Selection criteria) Written consent will be obtained from prospective participants before the first examination on the first day of observation. Patients who meet the following criteria will be included in the study. (1) Japanese patients who are aged 20 to 65 at the time of consent and who are able to receive outpatient treatment (2) Hb values ​​on the first day of observation and at Week 0 (HemoCue® Hb 201 DM analyzer at the clinical trial site) Patients whose blood pressure (measured using a lyser) is 7.0 g / dL or more but less than 11.0 g / dL, with a difference of 1.0 g / dL or less (3) TIBC ≥ 360 μg / dL or serum ferritin < 12 ng / mL on the first day of observation patient

[0082] (exclusion criteria) (1) Patients who are judged by the investigator or sub-investigator to have anemia whose primary cause is not iron deficiency (e.g., mean corpuscular volume (MCV) of 85 fL or more on the observation start date) (2) Patients with a serum phosphorus concentration of less than 2.5 mg / dL on the first day of observation (3) If you have a bleeding focus that could be causing iron deficiency, you must have had significant bleeding within the 8 weeks prior to Week 0. Patients on inconsistent treatment that may have a significant effect (e.g., patients on estrogen-progesterone combination drugs whose dosing pattern for the last two cycles prior to Week 0 has not been consistent) (4) For premenopausal female patients, one of the last two menstrual cycles before Week 0 is 25 days or longer. Patients not less than 1 day (5) Patients with liver dysfunction (e.g., aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 100 IU / L on the first day of observation) or type C liver dysfunction Patients with chronic hepatitis (6) Patients with gastrointestinal diseases such as acute peptic ulcer, chronic ulcerative colitis, and regional enteritis (excluding chronic gastritis) (7) Patients with paroxysmal nocturnal hemoglobinuria (8) Patients with a history of hypersensitivity to iron-containing preparations (9) Patients with a history of gastric or duodenectomy (excluding endoscopic resection such as polypectomy) (10) Patients with malignant tumors (including hematological malignancies) or those with a history of malignant tumors within 5 years prior to the start of observation Patients with (11) Serious damage to the brain, liver, kidneys, heart, lungs, digestive system, blood, endocrine system, metabolic system, and mental system. Patients with comorbidities (12) Patients who received intravenous iron within 4 weeks before the start of observation (13) Patients who received a blood transfusion or donated blood within 12 weeks before the start of observation (14) Patients who have received erythropoiesis-stimulating agents, anabolic hormones, testosterone enanthate, or mepitiostane within 12 weeks prior to the start of observation. (15) Patients with a history of severe drug allergies such as anaphylactic shock (16) Patients with a history of or concurrent drug or alcohol dependence (17) Patients who have received other investigational drugs (or test drugs) or investigational devices (or test devices) within 12 weeks prior to the start of observation, or who have participated in and received treatment in an interventional clinical study (a medical procedure beyond normal medical practice that is carried out for research purposes) (18) Patients who have previously received JTT-751 in a clinical trial or Riona ( Patients who have previously been treated with 250 mg tablets of Benzene. (19) Patients who are pregnant, breastfeeding, or possibly pregnant (if the investigator or subinvestigator cannot rule out the possibility of pregnancy based on the pregnancy test on the first day of observation or the interview at Week 0), or who will use appropriate contraception from the time of obtaining consent until 9 weeks after Week 0 or the test after discontinuation. Patients of childbearing potential who did not give informed consent. For male patients, Week 0 after starting the study drug administration Patients who did not agree to use appropriate contraception until 9 weeks after discontinuation or until the examination after discontinuation (20) Patients who are otherwise deemed inappropriate as subjects by the investigator or clinical trial co-investigator.

[0083] (investigational drug) Ferric citrate (development code: JTT-751) is administered in tablet (caplet) form. Each tablet contains 250 mg of ferric citrate.

[0084] (Dosage, administration method, and administration period of investigational drug) The dose of JTT-751 tablets is 0 mg / day (placebo), 250 mg / day, 500 mg / day, 1000 mg / day, or 1500 mg / day of ferric citrate. JTT-751 tablets 250 mg or JTT-751 placebo tablets 3 times a day (2 tablets each time) immediately after each meal The formulation and number of tablets used for each administration period in each administration group are shown in Table 7 below.

[0085] [Table 7]

[0086] The study drug will be administered for 7 weeks from the day after the Week 0 visit to the day before the Week 7 visit. However, the medication should not be taken on the designated visit day of Week 3.

[0087] (Medications prohibited for use in combination) Use of the following drugs from the start of observation until 9 weeks after Week 0 or the end of the investigation at the time of discontinuation is prohibited. (1) Oral and intravenous iron preparations (2) Erythropoiesis-stimulating factor preparations (3) Anabolic hormones, testosterone enanthate, mepitiostane (4) Medicines intended to improve the absorption of oral iron preparations (5) Medicines for the treatment of hyperphosphatemia (6) Drugs not approved in Japan and other investigational drugs (or experimental drugs)

[0088] (Concomitant Therapy) The following therapies will be administered from the start of observation until 9 weeks after Week 0 or the end of the investigation at the time of discontinuation. is prohibited. (1) Surgical treatment for bleeding lesions causing iron deficiency (2) Blood transfusion (3) Blood donation (4) Supplements whose primary purpose is to replenish iron or improve iron absorption (5) Medical devices not approved in Japan and investigational devices (or test devices)

[0089] (Restricted concomitant use of drugs) (1) 9 weeks after Week 0 from the start of observation or at the time of discontinuation, except for drugs specified as prohibited concomitant drugs Medications that have been administered since before the start of observation may be used until the end of the study, but as a general rule, they should not be started or discontinued, and their dosage and administration should not be changed. However, this does not apply if they are used for the purpose of treating acute illnesses or adverse events. However, for medications that clearly affect menstrual blood flow (estrogen-progesterone combination drugs, progesterone preparations, progesterone-releasing systems, GnRH agonist preparations, danazol preparations, etc.), they should not be started, discontinued, or their dosage and administration changed. (2) During the administration period of the investigational drug, care should be taken to avoid administering the following medications at the same time, such as by leaving as much time between administrations as possible. 1) Thyroid hormone preparations (levothyroxine, etc.) 2) Quinolone antibacterial agents (ciprofloxacin, etc.) 3) Tetracycline antibiotics (tetracycline, etc.) 4) Cefdinir 5) Anti-Parkinson's disease medications (benserazide, levodopa, etc.) 6) Eltrombopag Olamine 7) Antacids (aluminum hydroxide gel, synthetic aluminum silicate, etc.)

[0090] (Efficacy evaluation items) (1) Primary endpoint Change in blood hemoglobin (Hb) levels from Week 0 to the end of administration (2) Secondary endpoints 1) Red blood cell-related test values ​​on each observation day and the change from Week 0 2) Iron-related test values ​​on each observation day and changes from Week 0 3) The rate of achieving the target Hb value (female: 12.0 g / dL or more, male: 13.0 g / dL or more) on each observation day 4) The rate of achieving an improvement in Hb levels of 1.0 g / dL or more and 2.0 g / dL or more from Week 0 on each observation day Achievement rate of over 5) Average daily change in Hb levels from Week 0 to each observation day

[0091] (Safety evaluation items) (1) Adverse events, side effects (subjective symptoms, objective findings) (2) Vital signs (blood pressure, pulse rate, weight, body temperature) (3) Standard 12-lead electrocardiogram (4) Clinical tests (hematological tests, blood biochemistry tests, blood coagulation tests, urinalysis)

[0092] (Adverse Events) An adverse event is any untoward medical occurrence that occurs in a subject who has been administered an investigational drug, and does not necessarily mean only those that have a clear causal relationship to the administration of the investigational drug. In other words, an adverse event is any untoward or unintended sign (including abnormalities in clinical test values), symptom, or illness that occurs when an investigational drug is administered, regardless of whether or not it has a causal relationship to the investigational drug. The principal investigator or subinvestigator must report any of the following subjective symptoms, objective findings, clinical tests, vital signs, and changes in standard 12-lead electrocardiograms: This is considered an adverse event. (1) In the case of subjective symptoms and objective findings, if "new abnormalities" are observed between the start of administration of the investigational drug and 9 weeks after Week 0 or the end of testing after discontinuation, compared to before the start of administration of the investigational drug, If. (2) Due to the worsening of the subject's symptoms (complications, etc.) that were present before the start of the study drug administration, new medical issues occurred between the start of the study drug administration and 9 weeks after Week 0 or the end of the post-discontinuation examination. When an event (such as the addition or increase in the dose of concomitant medication) occurs or is deemed necessary, or when the principal investigator or co-investigator determines that the worsening of these symptoms is a medical deterioration. (3) When the principal investigator or sub-investigator determines that a new abnormality is found in clinical tests, vital signs, or a standard 12-lead electrocardiogram between the start of administration of the investigational drug and 9 weeks after Week 0 or the end of testing after discontinuation, or that an abnormality that was found before the start of administration of the investigational drug has worsened, is a clinical problem. The period for investigating adverse events is from the start of administration of the study drug to 9 weeks after Week 0 or at the end of the examination after discontinuation. Until then. The severity of adverse events will be assessed on a three-point scale (Grade 1, Grade 2, and Grade 3 will be interpreted as mild, moderate, and severe, respectively) based on the following criteria: <Reference standards> Mild: No interference with daily living activities Moderate: Decreased or affected activities of daily living Severe: Disabling activities of daily living or death

[0093] (statistical analysis) (1) Efficacy analysis set The efficacy analysis set will consist of the largest analysis set (FAS: Full Analysis Set) and an analysis set consisting of cases that comply with the clinical trial protocol (PPS: Per Protocol Set). Furthermore, because Hb levels begin to increase after 1 to 2 weeks of oral iron administration, patients who received the investigational drug for less than 1 week were excluded from the FAS analysis population. 1) FAS Cases in which the investigational drug was administered for at least one week and efficacy surveys were conducted at least once 2) PPS Cases that conformed to the clinical trial protocol, had a compliance rate of 75% or more, and had an efficacy evaluation at Week 7 (including an evaluation at the time of discontinuation conducted on the observation day corresponding to Week 7). (2) Safety analysis set The safety analysis set refers to patients who received the investigational drug and underwent at least one safety investigation. (3) Handling of calculation items The baseline value is the reference value used to calculate the amount of change and rate of change in test values, and to analyze changes (abnormal clinical test values, etc.). The baseline value is the test value measured before the start of administration of the investigational drug and closest to Week 0. (4) Analysis method 1) Significance level The significance level for tests of efficacy survey items will be set at 5% on both sides. When examining imbalances between treatment groups, a two-sided significance level of approximately 15% will be used as a guideline, and no adjustment for multiplicity will be performed. 2) Method of calculating descriptive statistics For count values, frequency counting is performed to calculate the number of cases and percentages. For quantitative values, the number of cases (N), mean (Mean), standard deviation (SD), median (Median), minimum (Min), and maximum (Max) are calculated. 3) Breakdown of the number of subjects Number of consented subjects, randomized subjects, unrandomized subjects, treated subjects, untreated subjects by PPS, FAS, and safety analysis set The frequency of cases of administration, cases of administration completed, cases of administration not completed, cases of clinical trial completed, cases of clinical trial not completed, and reasons for clinical trial not completed will be tabulated by administration group, and the breakdown of the number of subjects will be confirmed. In addition, for cases of discontinuation, a list of discontinuation cases will be created and the details of discontinuation will be examined. 4) Subject background The analysis populations will be the PPS, FAS, and safety analysis population. Descriptive statistics will be calculated for quantitative data (age in years, height, weight, blood pressure, pulse rate, and body temperature) by treatment group. Counts will be tabulated for counts by treatment group (sex, menopausal status (if female), previous history of iron administration and route of administration, medical history, complications, and primary disease). In order to confirm imbalances between treatment groups in subject background items, analysis of variance was performed for quantitative values, and Fisher's exact test was performed for count values ​​and categorical variables when there were two categories. If there are three or more categories, a chi-square test is performed. 5) Effectiveness For the FAS and PPS, descriptive statistics will be calculated by treatment group for the baseline values ​​of efficacy endpoints. Categories will also be created for each efficacy endpoint and frequency tabulations will be performed. Metrics used for stratification in subgroup analysis will also be frequency tabulated for the categories used in the subgroup analysis. However, details of the subgroup analysis will be specified in the statistical analysis plan. To confirm imbalances between treatment groups at baseline in efficacy endpoints, analysis of variance will be performed on quantitative values, and Fisher's exact test will be performed on count values ​​and categorical variables if there are two categories, and chi-square test will be performed if there are three or more categories.Descriptive statistics of test values ​​and changes on each observation day will be calculated by treatment group for the FAS. The mean values ​​for each treatment group were the placebo group (μ1), the 250 mg group (μ2), and the 500 mg group (μ3). ), 1000 mg group (μ4), and 1500 mg group (μ5). Assuming that the following hypotheses were tested using Williams' test (one-sided significance level 2.5%), the results are The lowest dose that is more effective than the Sebo group will be determined (primary analysis). (hypothesis) Comprehensive null hypothesis: The mean values ​​(μ) of each group are equal. H0: μ1=μ2=μ3=μ4=μ5 Alternative hypothesis: The mean value of the 1500 mg group is at least greater than the mean value of the placebo group. H1: μ1 ≦ μ2 ≦ μ3 ≦ μ4 ≦ μ5 (where at least one “≦” is “<”) 6) Safety The analysis population will be the safety analysis population, and adverse events and side effects that occur during the study treatment will be compiled and evaluated. Safety will be evaluated using the number of cases (incidence rate) of adverse events and side effects as the main indicator using MedDRA preferred terms (PTs) and system organ classes (SOCs). Descriptive statistics were calculated for vital signs, standard 12-lead electrocardiograms, and clinical test results, and count values ​​were calculated. In addition, for items for which test values ​​cannot be obtained, safety will be examined based on the investigator's findings, etc. Examination of abnormal test values: For abnormal values ​​that conflict with the "standards for abnormal values ​​related to clinical test items, etc." established by the clinical trial sponsor, the number of cases (incidence rate) that occurred will be calculated by administration group. 7) Other surveys Regarding medication status, the analysis populations were the FAS, PPS, and safety analysis population. The compliance rate at each time point will be calculated for each group and frequency tabulated. For the safety analysis population, frequency tabulation will be performed for the number of cases administered the investigational drug, the period, and the dose, and the exposure status of the safety analysis population will be examined. The period will be the actual exposure period excluding the washout period. Regarding menstrual status, the frequency of menorrhagia during the clinical trial period will be counted by administration group. In addition, descriptive statistics will be calculated for the duration of menstruation during the clinical trial period by administration group.

[0094] (Evaluation of effectiveness) Blood hemoglobin (Hb), serum iron, serum ferritin, total iron binding capacity (TIBC), transferrin saturation (TSAT), and mean corpuscular volume (MCV) were examined. The examinations were conducted on the first day of the examination, Week 0, Week 3, Week 7, at the end of administration, and at the examination 9 weeks after Week 0. Tests for serum hepcidin (hepcidin-25), hepcidin levels (hepcidin-25), and serum soluble transferrin receptor (sTfR) levels were performed at Week 0, Week 3, Week 7, and at the end of administration, respectively. Tests for C-terminal FGF23 levels (cFGF23) and full-length FGF23 levels (iFGF23) were performed at Week 0, Week 7, and at the end of administration, respectively. The following describes the changes in blood hemoglobin (Hb) levels and other parameters following administration of JTT-751 tablets, based on the test (measurement) results. However, the following describes the results of the Phase II clinical trial for iron-deficiency anemia patients described above, focusing on patients with menorrhagia and / or gynecological disorders associated with menorrhagia.

[0095] (Blood hemoglobin level (Hb)) Table 8 shows the change in blood hemoglobin (Hb) levels from baseline to the end of administration of ferric citrate (JTT-751 tablets) and the results of the Williams test.

[0096] [Table 8]

[0097] The results in Table 8 confirmed that the blood hemoglobin levels in the ferric citrate (JTT-751 tablets) group increased significantly compared to the placebo group, regardless of the dosage, and that the blood hemoglobin levels in the JTT-751 tablets group improved to near baseline (or above baseline). Furthermore, it was confirmed that the blood hemoglobin levels increased with increasing dosage of ferric citrate (JTT-751 tablets).

[0098] The blood hemoglobin levels in the ferric citrate (JTT-751 tablets) and placebo groups were measured at the start of observation, Week 0, Week 3, Week 7, the end of administration, and at the examination 9 weeks after Week 0. The changes in bin values ​​(Hb) are shown in Tables 9 to 11.

[0099] [Table 9]

[0100] [Table 10]

[0101] [Table 11]

[0102] According to the results in Tables 9 to 11, no change in blood hemoglobin levels over time was observed in the placebo group, but in the JTT-751 tablet group, blood hemoglobin levels increased as JTT-751 tablets were continuously administered at Week 0, Week 3, and Week 7. Furthermore, no decrease in blood hemoglobin levels was observed 9 weeks after Week 0 (2 weeks after the end of administration).

[0103] (serum iron level) The changes in serum iron levels in the ferric citrate (JTT-751 tablets) and placebo groups at Week 0, Week 3, Week 7, the end of administration, and at the examination 9 weeks after Week 0 are shown in the table below. 12-13.

[0104] [Table 12]

[0105] [Table 13]

[0106] According to the results in Tables 12 and 13, no change in serum iron levels over time was observed in the placebo group, but in the JTT-751 tablet group, serum iron levels increased to a normal value of approximately 50 μg / dL as JTT-751 tablets were continuously administered at Week 0, Week 3, and Week 7. In the JTT-751 tablet 1000 mg group and the JTT-751 tablet 1500 mg group, serum iron levels improved to normal values ​​at Week 3.

[0107] (serum ferritin level) The changes in serum ferritin levels in the ferric citrate (JTT-751 tablets) and placebo groups were measured at Week 0, Week 3, Week 7, at the end of administration, and at the examination 9 weeks after Week 0. , as shown in Tables 14-15.

[0108] [Table 14]

[0109] [Table 15]

[0110] According to the results in Tables 14 and 15, no change in serum ferritin levels over time was observed in the placebo group, but in the JTT-751 tablet group, as JTT-751 tablets were continuously administered from Week 0 to Week 3, serum ferritin levels increased to the normal range of 12 to 30 ng / mL. showed.

[0111] (Total Iron Binding Capacity (TIBC)) Baseline total iron binding capacity (TIBC) in the ferric citrate (JTT-751 tablets) and placebo groups at Week 0, Week 3, Week 7, end of administration, and at the visit 9 weeks after Week 0 The transition from the line (value at Week 0) is shown in Tables 16 to 17.

[0112] [Table 16]

[0113] [Table 17]

[0114] According to the results in Tables 16 and 17, no change in total iron binding capacity (TIBC) over time was observed in the placebo group, but in the JTT-751 tablet group, TIBC also decreased as JTT-751 tablets were continuously administered at Week 0, Week 3, and Week 7.

[0115] (Transferrin saturation rate (TSAT)) Tables 18 and 19 show the changes from baseline (value at Week 0) in transferrin saturation (TSAT) for the ferric citrate (JTT-751 tablets) and placebo groups at Week 0, Week 3, Week 7, the end of administration, and the examination 9 weeks after Week 0.

[0116] [Table 18]

[0117] [Table 19]

[0118] According to the results in Tables 18 and 19, no change in transferrin saturation rate (TSAT) over time was observed in the placebo group, but in the JTT-751 tablet group, changes were observed at Week 0, Week 3, and Week 4. 7 Furthermore, as JTT-751 tablets were administered continuously, transferrin saturation rate (TSAT) also increased (up to approximately 17%).

[0119] (Mean corpuscular volume (MCV)) Mean corpuscular volume (MCV) in the ferric citrate (JTT-751 tablets) and placebo groups was measured at the start of observation, Week 0, Week 3, Week 7, the end of administration, and at the examination 9 weeks after Week 0. The trends in product values ​​(MCV) are shown in Table 20.

[0120] [Table 20]

[0121] According to the results in Table 20, the placebo group showed no significant change in mean corpuscular volume (MCV) over time. However, in the JTT-751 tablet group, mean corpuscular volume (MCV) increased as JTT-751 tablets were administered continuously from Week 0 to Week 7, and at the end of administration, The values ​​were close to normal.

[0122] (Hepcidin concentration (hepcidin-25)) Table 21 shows the time course of hepcidin-25 concentrations at Week 0, Week 3, Week 7, and at the end of administration in the ferric citrate (JTT-751 tablets) administration group and the placebo administration group.

[0123] [Table 21]

[0124] According to the results in Table 21, no changes in hepcidin-25 concentration over time were observed in the placebo group. However, in the JTT-751 tablet group, hepcidin-25 concentrations increased as JTT-751 tablets were continuously administered at Week 0, Week 3, and Week 7.

[0125] (Serum soluble transferrin receptor (sTfR) concentration) Table 22 shows the time course of serum soluble transferrin receptor (sTfR) concentrations at Week 0, Week 3, Week 7, and at the end of administration in the ferric citrate (JTT-751 tablets) and placebo groups.

[0126] [Table 22]

[0127] According to the results in Table 22, no change in serum soluble transferrin receptor (sTfR) concentration over time was observed in the placebo group, but in the JTT-751 tablet group, serum soluble transferrin receptor (sTfR) concentration decreased as JTT-751 tablets were continuously administered at Week 0, Week 3, and Week 7.

[0128] (C-terminal FGF23 level (cFGF23)) Table 23 shows the changes in C-terminal FGF23 levels (cFGF23) over time at Week 0, Week 7, and at the end of administration in the ferric citrate (JTT-751 tablets) administration group and the placebo administration group.

[0129] [Table 23]

[0130] According to the results in Table 23, no change in C-terminal FGF23 levels (cFGF23) over time was observed in the placebo group, but in the JTT-751 tablet group, the C-terminal FGF23 levels (cFGF23) decreased with continued administration of JTT-751 tablets.

[0131] (Full-length FGF23 value (iFGF23)) Table 24 shows the time course of full-length FGF23 levels (iFGF23) at Week 0, Week 7, and at the end of administration in the ferric citrate (JTT-751 tablets) administration group and the placebo administration group.

[0132] [Table 24]

[0133] According to the results in Table 24, in the placebo group, the change in full-length FGF23 (iFGF23) level over time was However, in the JTT-751 tablet 1000 mg and 1500 mg groups, the full-length FGF23 level (iFGF23) decreased and improved as JTT-751 tablets were continuously administered.

[0134] These results confirmed that the ferric citrate (JTT-751 tablets) administration group showed a significant improvement in blood hemoglobin (Hb) levels, iron parameters, and other parameters (serum iron level, serum ferritin level, total iron binding capacity (TIBC), transferrin saturation (TSAT), mean corpuscular volume (MCV), hepcidin concentration (hepcidin-25), serum soluble transferrin receptor concentration (sTfR), C-terminal FGF23 level (cFGF23), and full-length FGF23 level (iFGF23)) that play important roles in the prevention and / or treatment of iron deficiency anemia in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia.

[0135] (Safety evaluation) All subjects in the clinical trials were iron-deficiency anemia patients. In particular, patients with gynecological disorders associated with menorrhagia (e.g., uterine fibroids, endometriosis, adenomyosis, endometrial polyps, bicornuate uterus) required concomitant use of other medications for the treatment of the underlying disease (especially those affecting menstrual flow). In the JTT-751 tablet group in the clinical trials, concomitant use of medications affecting menstrual flow, including carbazochrome sodium sulfonate (a hemostatic agent), norethisterone-ethinyl estradiol (low-dose birth control pills, a dysmenorrhea treatment), Transamin (a hemostatic agent), levonorgestrel-ethinyl estradiol (oral contraceptives), desogestrel-ethinyl estradiol (oral contraceptives), and drospirenone-ethinyl estradiol (a dysmenorrhea treatment), resulted in no reported adverse events.

[0136] Based on the above results, ferric citrate (JTT-751 tablets) is a drug that affects menstrual blood flow. Even when used in combination with other drugs, it can be safely administered to patients with menorrhagia and / or gynecological disorders accompanied by menorrhagia, and various iron parameters, blood hemoglobin (Hb), mean corpuscular volume (MCV), and C-terminal FGF23 (cFGF23) can be improved without reducing the efficacy of the drug. It was confirmed that the numerical level of [Industrial Applicability]

[0137] The present invention can provide a pharmaceutical agent effective for preventing and / or treating iron deficiency anemia in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia. The present invention also can provide an agent for improving hemoglobin levels, serum iron levels, serum ferritin levels, total iron binding capacity (TIBC), transferrin saturation (TSAT), mean corpuscular volume (MCV), hepcidin levels (hepcidin-25), serum soluble transferrin receptor levels (sTfR), C-terminal FGF23 levels (cFGF23), and full-length FGF23 levels (iFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia. The pharmaceuticals containing the ferric citrate of the present invention as an active ingredient can be used safely without causing side effects or reduced efficacy, even when used in combination with other drugs (particularly hormone therapy agents, hemostatic agents, etc. that affect menstrual blood flow) for the treatment of primary diseases that cause menorrhagia, such as uterine fibroids, endometriosis, adenomyosis, endometrial polyps, and bicornuate uterus, and are therefore particularly useful for the prevention and / or treatment of iron deficiency anemia in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, for whom medication adherence is important due to the risk of worsening the primary disease or pregnancy.

[0138] This application is based on Japanese Patent Application No. 2017-179533, the contents of which are incorporated in their entirety herein. It is something.

Claims

1. 1. A preventive and / or therapeutic agent for iron deficiency anemia in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising ferric citrate as an active ingredient.

2. 2. The preventive and / or therapeutic agent according to claim 1, wherein the ferric citrate has a molar ratio of ferric to citric acid of 1:0.80 to 1:0.

92.

3. The preventive and / or therapeutic agent according to claim 1 or 2, which is in the form of a tablet.

4. The preventive and / or therapeutic agent according to any one of claims 1 to 3, wherein the patient with menorrhagia and / or the patient with a gynecological disease accompanied by menorrhagia is a woman receiving administration of another drug that affects the amount of menstrual blood.

5. The preventive and / or therapeutic agent according to claim 4, wherein the other drug that affects the amount of menstrual blood is a hormone therapeutic agent or a hemostatic agent.

6. 6. The preventive and / or therapeutic agent according to claim 1, which contains 500 mg or 1000 mg of ferric citrate as an effective daily amount.

7. 1. An agent for improving hemoglobin levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising ferric citrate as an active ingredient.

8. 1. An agent for improving serum iron levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising ferric citrate as an active ingredient.

9. An agent for improving serum ferritin levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

10. A total iron binding capacity (TIBC) improving agent for patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

11. An agent for improving transferrin saturation (TSAT) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

12. 1. An agent for improving mean corpuscular volume (MCV) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising ferric citrate as an active ingredient.

13. An agent for improving hepcidin concentration in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, comprising ferric citrate as an active ingredient.

14. An agent for improving serum soluble transferrin receptor (sTfR) levels in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

15. An agent for improving C-terminal FGF23 levels (cFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

16. An agent for improving full-length FGF23 levels (iFGF23) in patients with menorrhagia and / or patients with gynecological diseases accompanied by menorrhagia, which contains ferric citrate as an active ingredient.

17. The agent according to any one of claims 7 to 16, containing 500 mg or 1000 mg of ferric citrate as an effective daily amount.

18. A pharmaceutical composition for preventing and / or treating iron deficiency anemia in patients with menorrhagia and / or patients with gynecological disorders accompanied by menorrhagia, comprising ferric citrate and a pharmaceutically acceptable carrier.

19. The composition according to claim 18, wherein the iron(III) citrate is substantially free of β-iron hydroxide oxide and the molar ratio of iron(III) to citric acid is 1:0.80 to 1:0.

92.

20. 20. The composition of claim 18 or 19, wherein the pharmaceutically acceptable carrier comprises polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and polyvinyl alcohol-polyethylene glycol graft copolymer.

21. The composition according to any one of claims 18 to 20, wherein the patient with menorrhagia and / or a patient with a gynecological disease accompanied by menorrhagia is a woman receiving other medication that affects menstrual blood flow.

22. The composition according to any one of claims 18 to 21, containing 500 mg or 1000 mg of iron(III) citrate per day as an effective amount.

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