WO2018193648A1 - Procédé de purification du sang à l'aide d'un agent d'alcalinisation - Google Patents

Procédé de purification du sang à l'aide d'un agent d'alcalinisation Download PDF

Info

Publication number
WO2018193648A1
WO2018193648A1 PCT/JP2017/032931 JP2017032931W WO2018193648A1 WO 2018193648 A1 WO2018193648 A1 WO 2018193648A1 JP 2017032931 W JP2017032931 W JP 2017032931W WO 2018193648 A1 WO2018193648 A1 WO 2018193648A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
concentration
day
kidney disease
administration
Prior art date
Application number
PCT/JP2017/032931
Other languages
English (en)
Japanese (ja)
Inventor
倫明 阿部
生造 小柴
浩一郎 西岡
和彦 川口
里美 山崎
康行 寺中
Original Assignee
国立大学法人東北大学
日本ケミファ株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2017085741A external-priority patent/JP2018177752A/ja
Application filed by 国立大学法人東北大学, 日本ケミファ株式会社 filed Critical 国立大学法人東北大学
Priority to JP2019513213A priority Critical patent/JP7219898B2/ja
Priority to CA3060154A priority patent/CA3060154A1/fr
Priority to AU2018254884A priority patent/AU2018254884C1/en
Priority to PCT/JP2018/009679 priority patent/WO2018193752A1/fr
Priority to JP2019513265A priority patent/JPWO2018193752A1/ja
Priority to KR1020197033580A priority patent/KR20190137147A/ko
Priority to US16/605,885 priority patent/US20210121426A1/en
Priority to EP18787098.5A priority patent/EP3616721A4/fr
Priority to TW107108443A priority patent/TWI813560B/zh
Priority to CN201880025628.3A priority patent/CN110799214A/zh
Priority to TW112128862A priority patent/TW202345784A/zh
Publication of WO2018193648A1 publication Critical patent/WO2018193648A1/fr
Priority to JP2022180930A priority patent/JP2023022079A/ja
Priority to JP2023106201A priority patent/JP2023115271A/ja

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to blood purification using an alkaline agent.
  • This application includes Japanese Patent Application No. 2017-82423 filed in Japan on April 18, 2017, Japanese Patent Application No. 2017-85741 filed in Japan on April 24, 2017, and May 25, 2017. Furthermore, priority is claimed based on Japanese Patent Application No. 2017-103935 filed in Japan, the contents of which are incorporated herein.
  • ESKD end-stage kidney disease
  • GFR glomerular filtration rate
  • Non-Patent Document 2 a spherical adsorption charcoal preparation (Kremedin (registered trademark)) that adsorbs indole, a precursor of indoxyl sulfate in the intestinal tract, and lowers blood indoxyl sulfate concentration, delays the introduction of dialysis in CKD patients. Curing is improved (Non-Patent Document 2).
  • Non-patent Document 3 it has been reported that oral administration of sodium bicarbonate suppresses tubular cell damage caused by acidic urine in a nephrotic animal model caused by protein overload.
  • Non-patent Document 4 it has been reported that there has been no report on the suppression of the progression of renal damage by administering an alkaline agent to early CKD patients, and no decrease in blood levels of uremic substances.
  • One of the problems of the present invention is to provide a medicine useful for blood purification in kidney disease patients. Another object of the present invention is to provide a medicament useful for suppressing the progression of chronic kidney disease (severe chronic kidney disease), treating and preventing uremic symptoms, and delaying the introduction of dialysis. Another object of the present invention is to provide a medicament useful for suppressing the progression from acute kidney disease to chronic kidney disease. Another object of the present invention is to provide a food for promoting in vitro discharge of uremic substances. Another object of the present invention is to provide a method for determining the suppression of the progression of chronic kidney disease, a method for determining a decrease in the concentration of uremic substances in the blood, and / or a promotion of the discharge of uremic substances into the urine. That is.
  • the inventors of the present invention have made extensive studies to achieve the above-mentioned problems.
  • a drug that alkalizes a body fluid promotes excretion of a uremic substance from the body of a kidney disease patient (for example, urinary substance is released into the urine). It was found useful for the promotion of excretion) and the present invention was completed.
  • the present invention provides a pharmaceutical composition for promoting the excretion of a uremic substance outside the body, which comprises an alkaline agent.
  • the present invention provides a pharmaceutical composition for reducing blood concentration of a uremic substance, comprising an alkalizing agent.
  • the present invention provides a pharmaceutical composition for promoting urinary excretion in chronic kidney disease, comprising an alkaline agent.
  • the present invention provides a pharmaceutical composition for improving uremia symptoms in chronic kidney disease, comprising an alkaline agent.
  • the present invention provides a pharmaceutical composition for delaying introduction of dialysis in chronic kidney disease, comprising an alkaline agent.
  • the present invention provides a pharmaceutical composition for treating or preventing a cardiovascular disease associated with chronic kidney disease, comprising an alkaline agent.
  • the present invention provides a pharmaceutical composition for suppressing progression from acute kidney disease to chronic kidney disease, which comprises an alkaline agent.
  • the present invention provides a food composition for promoting in vitro excretion of a uremic substance, comprising an alkaline agent.
  • the present invention provides a method for determining progression inhibition of chronic kidney disease.
  • the present invention provides a method for determining a decrease in the concentration of uremic toxin in human blood and / or promotion of excretion of uremic toxin into urine.
  • the present invention has the following aspects.
  • any one of (1) to (5), wherein the uremic substance is selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid A pharmaceutical composition according to 1.
  • the pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is phenylacetyl L-glutamine and p-cresyl sulfate.
  • the pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate.
  • a pharmaceutical composition for improving uremia symptoms in chronic kidney disease comprising an alkaline agent.
  • a pharmaceutical composition for inhibiting progression of chronic kidney disease comprising an alkaline agent.
  • a pharmaceutical composition for treating or preventing tubule injury comprising an alkaline agent.
  • the alkalinizing agent is sodium citrate, potassium citrate or a hydrate thereof, or a mixture thereof.
  • composition The pharmaceutical composition according to any one of (1) to (30), wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. . (32) The pharmaceutical composition according to any one of (1) to (31), wherein the alkalinizing agent is sodium citrate or a hydrate thereof. (33) The pharmaceutical composition according to any one of (1) to (32), wherein the pharmaceutical composition is a tablet. (34) The medicament according to any one of (1) to (33), wherein a decrease in blood concentration of the uremic substance compared to before the start of the administration of the alkaline agent is detected 12 weeks after the administration of the alkaline agent. Composition.
  • the cystatin C in the blood is not substantially increased after 12 weeks of administration by administration of the alkalizing agent, according to any one of (1) to (41) Pharmaceutical composition.
  • Pharmaceutical composition By the administration of the alkalinizing agent, improvement in proximal tubular damage and / or glomerular damage is not observed as compared with before the start of the administration, and the blood concentration of the uremic substance as compared with before the start of the administration.
  • the pharmaceutical composition according to any one of (1) to (42), wherein reduction, promotion of urinary substance excretion in urine and / or promotion of in vitro excretion of uremic substance are observed.
  • a food composition for promoting in vitro excretion of a uremic substance comprising an alkaline agent.
  • a method for determining inhibition of progression of chronic kidney disease comprising measuring urine pH.
  • a method for determining promotion of excretion of a uremic substance into urine of a patient with chronic kidney disease the method comprising measuring pH of urine.
  • the present invention has the following aspects.
  • (56) A pharmaceutical composition for reducing blood concentration of a uremic substance, comprising an alkaline agent, wherein the pharmaceutical composition is a tablet.
  • (57) A pharmaceutical composition for promoting urinary excretion of a uremic substance, comprising an alkaline agent, wherein the pharmaceutical composition is a tablet.
  • (58) The pharmaceutical composition according to (56) or (57), which is administered to a patient with chronic kidney disease or acute kidney disease.
  • any one of (56) to (58), wherein the uremic substance is selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid
  • a pharmaceutical composition according to 1. The pharmaceutical composition according to any one of (56) to (59), wherein the uremic substance is indoxyl sulfate.
  • (61) A pharmaceutical composition for inhibiting progression of chronic kidney disease, comprising an alkaline agent, wherein the pharmaceutical composition is a tablet.
  • (62) A pharmaceutical composition for treating or preventing tubule injury, comprising an alkaline agent, wherein the pharmaceutical composition is a tablet.
  • the uremic substance is excreted from the body of the mammal by the pharmaceutical composition provided by the present invention.
  • the method provided by the present invention it is possible to make a preliminary determination as to whether or not the uremic substance is excreted from the body and / or whether or not the progression of chronic kidney disease can be suppressed.
  • FIG. 6 is a graph showing the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in control group patients at 6, 12, and 24 weeks after the start of the test.
  • FIG. 6 is a graph showing the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in patients in the group administered with a combination preparation of potassium citrate / sodium citrate hydrate after 6, 12 and 24 weeks from the start of the test. .
  • FIG. 6 is a graph showing the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in patients in the sodium bicarbonate preparation administration group at 6, 12, and 24 weeks after the start of the test.
  • FIG. 6 is a graph showing the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in patients in the sodium bicarbonate preparation administration group at 6, 12, and 24 weeks after the start of the test.
  • FIG. 6 is a graph showing the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in all patients 6, 12, and 24 weeks after the start of the test. It is a figure which shows the correlation of the urinary hippuric acid density
  • compositions can contain an alkalizing agent as an active ingredient.
  • An alkalinizing agent is a drug having the ability to increase the HCO 3 ⁇ concentration and pH of a body fluid of a mammal (particularly human), for example, blood or urine.
  • alkalinizing agents include pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, and sodium hydrogen carbonate (bicarbonate).
  • pharmaceutically acceptable salts of citric acid include alkali metal citrate salts.
  • alkali metal citrate salts include potassium citrate and sodium citrate, which are stable potassium citrate monohydrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) and sodium citrate, respectively.
  • a hydrate such as dihydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O) may be used.
  • preferred alkalizing agents include sodium citrate, potassium citrate or hydrates thereof or mixtures thereof, for example, potassium citrate monohydrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) and sodium citrate dihydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O).
  • the mixing ratio of potassium citrate monohydrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) and sodium citrate dihydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O) is A person skilled in the art can appropriately set, for example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate, the sodium citrate dihydrate to potassium citrate monohydrate 1
  • the product can be 0.01-100.
  • the mixing ratio may be about 1: 1 as a molar ratio.
  • Other examples of preferred alkalizing agents include sodium citrate or a hydrate thereof, such as sodium citrate dihydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O). There may be.
  • preferable alkalizing agents include potassium citrate or a hydrate thereof, such as potassium citrate monohydrate (C 6 H 5 K 3 O 7 .H 2 O).
  • the alkalinizing agent contained in the pharmaceutical composition of the present invention may comprise a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.
  • the alkalinizing agent contained in the pharmaceutical composition of the present invention may consist only of a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.
  • an alkalinizing agent for example, potassium citrate monohydrate (C 6 H 5 K 3 O 7 .H 2 O) and sodium citrate dihydrate (C 6 H 5 Na 3)
  • the weight can be dry weight.
  • a uremic substance is a substance excreted by normal kidneys (waste products, toxins, etc.), and increases in the blood when the excretory function decreases due to some cause such as decreased renal function ( Means a substance that accumulates) and causes symptoms or disease of uremia.
  • uremic substances include indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid.
  • indoxyl sulfate is produced by oxidation and sulfate conjugation in the liver of indole produced by enteric bacteria from tryptophan derived from dietary protein.
  • indoxyl sulfate Most of the indoxyl sulfate is bound to albumin in the blood and is not metabolized. In healthy people, it is excreted from the kidneys into the urine. It remains accumulated at high concentrations in the blood. Indoxyl sulfate, which is a uremic substance, not only causes uremia in kidney disease patients, but also causes chronic kidney disease patients to be introduced into dialysis. Therefore, by reducing the indoxyl sulfate concentration in the blood, the symptoms of uremia in patients with kidney disease are improved, and treatment and / or prevention of uremia becomes possible. Moreover, it is possible to delay the introduction of dialysis in patients with chronic kidney disease by lowering the indoxyl sulfate concentration in the blood.
  • the chronic kidney disease patient has progressive chronic kidney disease.
  • the expression [A, B and / or C] means that “at least one selected from the group consisting of A, B and C” is selected.
  • “indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid” means “indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid”. At least one selected from the group consisting of ".
  • Indoxyl sulfate a uremic substance, causes myocardial fibrosis, arteriosclerosis, vascular smooth muscle cell proliferation, vascular endothelial cell damage, arterial wall thickening, aortic calcification, etc.
  • Cardiovascular disease for example, heart failure, myocardial infarction
  • / or stroke which is a cerebrovascular disease
  • cardiovascular disease for example, heart failure, myocardial infarction
  • stroke which is a cerebrovascular disease
  • the pharmaceutical composition provided by the present invention has a concentration of a uremic substance (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) in the blood. It can be reduced.
  • a uremic substance eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof
  • indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof include indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate, p- Indoxyl sulfate and hippuric acid and phenylacetyl L glutamine; Indoxyl sulfate and p-cresyl sulfate; Indoxyl sulfate and hippuric acid; Indoxyl sulfate and phenylacetyl L glutamine; p-Cresyl sulfate and And phenylacetyl L glutamine; hippuric acid and phenylacetyl L glutamine; indoxyl sulfate; p-cresyl s
  • “reduction in the concentration of uremic substance in blood” means that the blood concentration after administration is lower than the concentration of uremic substance in blood before administration of the pharmaceutical composition provided by the present invention. This means that the concentration of uremic substances decreases.
  • administration of the pharmaceutical composition provided by the present invention results in comparison of uremic substances in blood (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, Argininosuccinic acid and combinations thereof (eg, indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl L-glutamine; indoxyl sulfate, hippuric acid and phenylacetyl L-glutamine Indoxyl sulfate
  • the amount of decrease in the blood concentration of the uremic substance is calculated by the following calculation formula (1).
  • uremic substance (%) [(Blood concentration of uremic substance before administration of pharmaceutical composition (ng / mL) ⁇ Blood concentration of uremic substance after administration of pharmaceutical composition (ng) / mL)) / Blood concentration of uremic substance before administration of pharmaceutical composition (ng / mL)] ⁇ 100
  • continuous administration of the pharmaceutical composition provided by the present invention for 6, 12, or 24 weeks results in uremic substances in blood (eg, indoxyl sulfate, p-cresyl sulfate, Phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof (eg, indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl
  • the pharmaceutical composition provided by the present invention provides excretion of uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) into the urine. Can be promoted.
  • uremic substances eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof
  • indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof include indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; P-cresyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl L-glutamine; indoxyl sulfate, phenyl Indoxyl sulfate, hippuric acid and phenylacetyl
  • promotion of excretion of uremic substance into urine means urine after administration as compared with the concentration of uremia substance in urine before administration of the pharmaceutical composition provided by the present invention. This means that the concentration of uremic substances in it increases.
  • in urine means, for example, “in early morning urine”.
  • administration of the pharmaceutical composition provided by the present invention results in urinary uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, Argininosuccinic acid and combinations thereof (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, p Cresyl sulfate, hippuric acid and phenylacetyl L glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl L glutamine; indoxyl s
  • the pharmaceutical composition provided by the present invention provides a uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) from blood to urine. It is possible to promote excretion outside the body and promote excretion outside the body.
  • a uremic substance for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof
  • indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof include indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; P-cresyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl L-glutamine; indoxyl sulfate, phenyl Indoxyl sulfate, hippuric acid and phenylacetyl
  • administration of a pharmaceutical composition provided by the present invention results in urinary uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine relative to blood levels compared to prior to administration).
  • urinary uremic substances eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine relative to blood levels compared to prior to administration.
  • Hippuric acid, argininosuccinic acid and combinations thereof eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; India Xyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl L glutamine; indoxyl sulfate, phenylacetyl L glutamine and argininosuccinic acid; indoxyl sulfate, hippuric acid and Indoxyl sulfate and hippuric acid; in
  • the amount of increase in the ratio of urine concentration to blood concentration of uremic substance (urine concentration (ng / mL) / blood concentration (ng / mL)) is calculated by the following calculation formula (3).
  • Increase in ratio of urine concentration to blood concentration of uremic substance (%) [(ratio of urine concentration to blood concentration of uremic substance after administration of pharmaceutical composition ⁇ uremia before administration of pharmaceutical composition Ratio of urine concentration to blood concentration of substance) / Ratio of urine concentration to blood concentration of uremic substance before administration of pharmaceutical composition] ⁇ 100 (3)
  • 6, 12, or 24 weeks of continuous administration of a pharmaceutical composition provided by the invention results in urinary uremic substances (eg, indoxyl sulfate, p -Cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof (eg indoxyl sulfate, p-cresyl sulfate
  • the administration of the pharmaceutical composition provided by the present invention promotes the excretion of the uremic substance outside the body depending on the blood concentration of the uremic substance.
  • administration of the pharmaceutical composition provided by the present invention causes blood of uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) into the blood.
  • uremic substances eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof
  • excretion of uremic substances into the urine is promoted. For example, when the blood concentration of the uremic substance is high, the amount of the uremic substance excreted in the urine becomes high accordingly.
  • the pharmaceutical composition provided by the present invention has a low risk of side effects and excellent safety.
  • indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof include indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; , P-cresyl sulfate and phenylacetyl L glutamine; indoxyl sulfate and phenylacetyl L glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl L glutamine; indoxyl sulfate; p-cresyl sulfate; and phenyl Acetyl L-glutamine is mentioned.
  • administration of the pharmaceutical composition provided by the present invention causes blood of uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) into the blood.
  • uremic substances eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof
  • indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof include indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; , P-cresyl sulfate and phenylacetyl L glutamine; indoxyl sulfate and phenylacetyl L glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl L glutamine; indoxyl sulfate; p-cresyl sulfate; and phenyl Acetyl L-glutamine is mentioned.
  • administration of the pharmaceutical composition provided by the present invention results in excretion of indoxyl sulfate in the urine depending on the blood concentration of indoxyl sulfate, resulting in urine relative to the blood concentration of indoxyl sulfate.
  • the ratio of medium concentrations can be 1 to 1000, preferably 1 to 200, more preferably 1 to 100, and even more preferably 10 to 100.
  • the pharmaceutical composition provided by the present invention is administered to a human (eg, a patient with chronic kidney disease) having a blood concentration of indoxyl sulfate of 0.01 to 100 ⁇ g / mL (eg, 0.1 to 30 ⁇ g / mL). Also good.
  • the blood concentration of indoxyl sulfate may be 0.01 to 10 ⁇ g / mL (for example, 0.03 to 10 ⁇ g / mL).
  • administration of the pharmaceutical composition provided by the present invention results in excretion of p-cresyl sulfate in the urine depending on the blood concentration of p-cresyl sulfate.
  • the ratio of urine concentration to concentration can be 0.1 to 1000, preferably 1 to 300, more preferably 1 to 150, and even more preferably 1 to 100.
  • the pharmaceutical composition provided by the present invention is administered to a human (eg, a patient with chronic kidney disease) having a blood concentration of p-cresyl sulfate of 0.003 to 300 ⁇ g / mL (eg, 0.01 to 30 ⁇ g / mL). May be.
  • the blood concentration of p-cresyl sulfate may be 0.001 to 100 ⁇ g / mL (eg, 0.001 to 30 ⁇ g / mL).
  • administration of the pharmaceutical composition provided by the present invention results in the excretion of phenylacetyl L-glutamine in the urine depending on the blood concentration of phenylacetyl L-glutamine, resulting in the blood of phenylacetyl L-glutamine in the blood.
  • the ratio of urinary concentration to concentration can be 1-1500, preferably 1-1000, more preferably 10-800, and even more preferably 10-600.
  • the pharmaceutical composition provided by the present invention is administered to a human (eg, a patient with chronic kidney disease) having a blood concentration of phenylacetyl L-glutamine of 0.03 to 30 ⁇ g / mL (eg, 0.1 to 10 ⁇ g / mL). May be. Further, as a result of the administration, the blood concentration of phenylacetyl L-glutamine may be 0.01 to 10 ⁇ g / mL (for example, 0.03 to 10 ⁇ g / mL).
  • the pharmaceutical composition provided by the present invention is administered to a plurality of humans (for example, patients with chronic kidney disease), whereby the ratio of urinary concentration to indoxyl sulfate blood concentration in each individual ( (Urine concentration / blood concentration) shows a high correlation.
  • high correlation is indicated by a Pearson test having an r value of 0.4 or more and 1 or less, 0.5 or more and 1 or less, 0.6 or more and 1 or less, or 0.7 or more and 1 or less (preferably 0.7 or more and 1 or less). May be.
  • the pharmaceutical composition provided by the present invention may be administered to a human (for example, a patient with chronic kidney disease) having a blood concentration of indoxyl sulfate of 0.01 to 10 ⁇ g / mL (for example, 0.1 to 10 ⁇ g / mL), As a result of the administration, the blood concentration of indoxyl sulfate may be 0.01 to 10 ⁇ g / mL (for example, 0.1 to 10 ⁇ g / mL).
  • the pharmaceutical composition provided by the present invention is administered to a plurality of humans (for example, patients with chronic kidney disease), whereby the ratio of the urinary concentration to the blood concentration of p-cresyl sulfate in each individual.
  • the pharmaceutical composition provided by the present invention may be administered to a human (eg, a patient with chronic kidney disease) having a blood concentration of p-cresyl sulfate of 0.001 to 100 ⁇ g / mL (eg, 0.01 to 50 ⁇ g / mL).
  • the blood concentration of p-cresyl sulfate may be 0.001 to 100 ⁇ g / mL (for example, 0.01 to 50 ⁇ g / mL).
  • the pharmaceutical composition provided by the present invention is administered to a plurality of humans (eg, patients with chronic kidney disease), whereby the ratio of the urinary concentration to the blood concentration of phenylacetyl L-glutamine in each individual. (Urine concentration / blood concentration) shows a high correlation.
  • high correlation is indicated by a Pearson test having an r value of 0.4 or more and 1 or less, 0.5 or more and 1 or less, 0.6 or more and 1 or less, or 0.7 or more and 1 or less (preferably 0.7 or more and 1 or less). May be.
  • the pharmaceutical composition provided by the present invention may be administered to a human (eg, a patient with chronic kidney disease) having a phenylacetyl L-glutamine blood concentration of 0.01 to 10 ⁇ g / mL (eg, 0.05 to 10 ⁇ g / mL).
  • the blood concentration of phenylacetyl L-glutamine may be 0.01 to 10 ⁇ g / mL (for example, 0.05 to 10 ⁇ g / mL).
  • the pharmaceutical composition provided by the present invention is, in one aspect, a pharmaceutical composition for reducing blood concentration of a uremic substance and / or urine of a uremic substance. Not only can it be used as a pharmaceutical composition for promoting excretion, but also a pharmaceutical composition for improving uremia symptoms in patients with kidney disease, a pharmaceutical composition for the treatment and / or prevention of uremia in patients with kidney disease, and the progression inhibition of chronic kidney disease.
  • “amelioration” refers to bringing “pathological” or “abnormal” symptoms, conditions or diseases closer to “healthy” or “normal” conditions, and “healthy” ”Or“ normal ”state or a concept including the purpose.
  • “improvement” means that a numerical value indicative of a “pathological” or “abnormal” symptom or condition decreases or increases according to the “improvement”, and is normal. Approaching a normal value or becoming a normal value.
  • “improvement” includes a decrease in the concentration of the uremic substance in the blood according to the “improvement”, and an increase in the concentration of the uremic substance in the urine.
  • the concentration of the uremic substance in the blood may start to decrease when the concentration of the uremic substance in the blood becomes sufficiently small.
  • “treatment” includes “pathological” or “abnormal” symptoms, conditions, or diseases, including elimination, complete cure, cure or amelioration, and the purpose thereof. Or, it is a concept that includes the suppression of “abnormal” symptom, condition or disease, and the purpose thereof, and includes the above “improvement”. Here, the suppression has the meaning described later.
  • treatment is to eliminate, cure, cure or ameliorate a “pathological” or “abnormal” symptom, condition or disease.
  • treatment is the elimination, complete cure, cure or amelioration of a “pathological” or “abnormal” symptom, condition or disease.
  • prevention is a concept that includes the prevention and development of “pathological” or “abnormal” symptoms, conditions or diseases.
  • delay includes a concept that includes extending the time to a target event and extending the time so that the target event does not occur. It is.
  • “suppression” includes stopping or slowing down and slowing down or aggravating or progressing a symptom, condition or disease, and improving the symptom, condition or disease, or for that purpose. It is a concept that includes Here, the improvement has the above-mentioned meaning.
  • Said “aggravation or progression of a symptom, condition or disease” refers to a “pathological” or “abnormal” symptom, aggravation or progression of a condition or disease, and a “healthy” or “normal” state, Aggravation or progression to a “na” or “abnormal” symptom, condition or disease.
  • “suppression” is to stop or slow, or for the worsening or progression of a symptom, condition or disease. In another embodiment, “suppressing” is stopping or slowing the worsening or progression of a symptom, condition or disease.
  • the symptom, condition or disease is compared before and after administration of the pharmaceutical composition provided by the present invention.
  • the pharmaceutical composition provided by the present invention is, in one aspect, a pharmaceutical composition for suppressing myocardial fibrosis in a renal disease patient, a renal disease patient, Pharmaceutical composition for inhibiting arteriosclerosis in Japan, pharmaceutical composition for inhibiting proliferation of vascular smooth muscle cells in patients with kidney disease, pharmaceutical composition for inhibiting vascular endothelial cell injury in patients with kidney disease, pharmaceutical composition for inhibiting thickening of arterial wall in patients with kidney disease
  • the composition can be used as any one of a pharmaceutical composition for suppressing calcification of aorta in a patient with kidney disease and a pharmaceutical composition for treating and / or preventing cardiovascular disease associated with chronic kidney disease.
  • the pharmaceutical composition provided by the present invention that lowers the blood concentration of indoxyl sulfate is, in one aspect, a renal disease patient (preferably a chronic kidney disease patient, more preferably , Non-diabetic chronic kidney disease patients) can be used as a pharmaceutical composition for improving arteriosclerosis or an arterial (for example, carotid artery) wall thickening improving pharmaceutical composition.
  • a renal disease patient preferably a chronic kidney disease patient, more preferably , Non-diabetic chronic kidney disease patients
  • an arterial (for example, carotid artery) wall thickening improving pharmaceutical composition for improving arteriosclerosis or an arterial (for example, carotid artery) wall thickening improving pharmaceutical composition.
  • the pharmaceutical composition provided by the present invention that lowers the blood concentration of indoxyl sulfate is, in one aspect, a pharmaceutical composition for treating acute kidney disease, or for suppressing the progression from acute kidney disease to chronic kidney disease. It can be used as a pharmaceutical composition.
  • the pharmaceutical composition provided by the present invention that promotes urinary excretion of p-cresyl sulfate is used as a pharmaceutical composition for inhibiting vascular endothelial injury in a kidney disease patient (preferably a chronic kidney disease patient). it can.
  • the pharmaceutical composition provided by the present invention that promotes urinary excretion of phenylacetyl L-glutamine can be used as a pharmaceutical composition for the treatment and / or prevention of cardiovascular diseases in patients with chronic kidney disease.
  • the pharmaceutical composition provided by the present invention promotes urinary excretion of uremic substances such as indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, and phenylacetyl L-glutamine.
  • the pharmaceutical composition provided by the invention is for promoting urinary excretion of indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid and / or phenylacetyl L-glutamine in kidney disease patients (preferably chronic kidney disease patients). It can be used as a pharmaceutical composition.
  • the citric acid medicament is used to reduce blood indoxyl sulfate concentration, p-cresyl sulfate concentration in blood, hippuric acid concentration in blood and / or phenylacetyl L-glutamine concentration in blood.
  • An acceptable salt, or a hydrate thereof, or a mixture thereof is a kidney disease patient (preferably a chronic kidney disease patient) To be administered.
  • increasing urinary indoxyl sulfate concentration, urinary p-cresyl sulfate concentration, urinary hippuric acid concentration, urinary arginosuccinic acid concentration and / or urinary phenylacetyl L-glutamine concentration A pharmaceutically acceptable salt of citric acid, preferably (to increase urinary indoxyl sulfate concentration, urinary p-cresyl sulfate concentration and urinary phenylacetyl L-glutamine concentration), or The hydrate or a mixture thereof (eg, a mixture of potassium citrate monohydrate and sodium citrate dihydrate) is administered to a kidney disease patient (preferably a chronic kidney disease patient).
  • sodium bicarbonate is administered to a kidney disease patient (preferably a chronic kidney disease patient) to reduce blood p-cresyl sulfate concentration and / or blood phenylacetyl L-glutamine concentration.
  • a kidney disease patient preferably a chronic kidney disease patient
  • sodium bicarbonate is administered to a kidney disease patient (preferably a chronic kidney disease patient) to increase the urinary arginosuccinic acid concentration.
  • the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for treating tubular disorders, a pharmaceutical composition for preventing tubular disorders, or a pharmaceutical composition for inhibiting tubular disorders.
  • the tubule may be, for example, a proximal tubule.
  • the pharmaceutical composition provided by the present invention comprises a pharmaceutical composition for inhibiting proximal tubular cell damage, a pharmaceutical composition for protecting proximal tubular cells, or a proximal tubular cell function (for example, glucose, It is a pharmaceutical composition for maintaining reabsorption of amino acids and the like.
  • the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of ⁇ 2-microglobulin in urine (for example, early morning urine) accompanying progression of the stage of chronic kidney disease. .
  • the pharmaceutical composition provided by the present invention does not affect glomerular function in patients with chronic kidney disease, while suppressing proximal tubular cell damage associated with progression of the stage of chronic kidney disease. And protect the proximal tubule cells.
  • “protection of cells” means maintenance or maintenance of the state of cells or suppression of cell damage. Here, suppression has the above-mentioned meaning.
  • “maintenance of cell function” means maintenance of cell function or suppression of deterioration of cell function.
  • the state or function of the cells is compared before and after the administration of the pharmaceutical composition provided by the present invention.
  • “early morning urine” represents the first urine after getting up.
  • the pharmaceutical composition provided by the present invention comprises ⁇ 2-micro in urine (for example, early morning urine) 6 weeks, 12 weeks and / or 24 weeks after administration, compared to before administration. Suppresses the increase in the amount (concentration) of globulin.
  • the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of ⁇ 2-microglobulin in urine (for example, early morning urine) accompanying progression of the stage of chronic kidney disease.
  • the amount (concentration) of ⁇ 2-microglobulin in urine is not substantially reduced.
  • urine after administration for example, The amount (concentration) of ⁇ 2-microglobulin in early morning urine is 0.7 to 1.0 or 1.0 or more, 0.8 to 1.0 or 1.0 or more, 0.85 to 1.0 or 1.0 or more, 0.9 to 1.0 or 1.0 or more, 0.7 to 2.0, 0.8 to It can be 2.0, 0.85-2.0, 0.9-2.0, 0.7-1.6, 0.8-1.6, 0.85-1.6, or 0.9-1.6.
  • the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of ⁇ 2-microglobulin in urine (for example, early morning urine) accompanying progression of the stage of chronic kidney disease.
  • the amount of ⁇ 2-microglobulin in urine for example, early morning urine 6 weeks after administration, 12 weeks after administration and / or 24 weeks after administration, compared to before administration of the pharmaceutical composition provided by the present invention (Concentration) is not substantially reduced.
  • the amount (concentration) of ⁇ 2-microglobulin in urine (for example, early morning urine) before the start of administration of the pharmaceutical composition provided by the present invention is 1, 6 weeks after administration
  • the amount (concentration) of ⁇ 2-microglobulin in urine (for example, early morning urine) after week 24 or after administration is 0.7 to 1.0 or 1.0 or more, 0.8 to 1.0 or 1.0 or more, 0.85 to 1.0 or 1.0 or more, 0.9 It can be -1.0 or 1.0 or more, 0.7-2.0, 0.8-2.0, 0.85-2.0, 0.9-2.0, 0.7-1.6, 0.8-1.6, 0.85-1.6, or 0.9-1.6.
  • the pharmaceutical composition provided by the present invention does not substantially increase the amount (concentration) of cystatin C in the blood (eg, plasma) compared to before administration.
  • the blood (for example, plasma) after administration The amount (concentration) of cystatin C in (medium) is 1.0 or less, 1.0 to 1.2, 1.0 or less, or 1.0 to 1.15, 1.0 or less, or 1.0 to 1.1, 1.0 or less, or 1.0 to 1.05, 0.9 to 1.2, 0.9 to 1.15, 0.9 to It can be 1.1, 0.9 to 1.05, 0.95 to 1.2, 0.95 to 1.15, 0.95 to 1.1 or 0.95 to 1.05.
  • the pharmaceutical composition provided by the present invention is in blood (for example, in plasma) at 6 weeks after administration, 12 weeks after administration and / or 24 weeks after administration, as compared to before administration. Does not substantially increase the amount (concentration) of cystatin C.
  • the amount (concentration) of cystatin C in the blood (for example, plasma) before the start of administration of the pharmaceutical composition provided by the present invention is 1, 6 weeks after administration, 12 weeks after administration
  • the amount (concentration) of cystatin C in the blood (for example, plasma) is 1.0 or less, 1.0 to 1.2, 1.0 or less, or 1.0 to 1.15, 1.0 or less, or 1.0 to 1.1, 1.0 or less, or 1.0.
  • administration of the pharmaceutical composition provided by the present invention improves proximal tubule injury after 6 weeks of administration, 12 weeks of administration and / or 24 weeks of administration as compared to before administration. And / or a decrease in blood concentration of the uremic substance 6 weeks after administration, 12 weeks after administration and / or 24 weeks after administration, although no improvement in glomerular damage is observed. Promotion of urinary excretion of uremic substances and / or promotion of in vitro excretion of uremic substances is observed.
  • administration of the pharmaceutical composition provided by the present invention improves proximal tubule injury after 6 weeks of administration, 12 weeks of administration and / or 24 weeks of administration as compared to before administration. And / or a decrease in blood concentration of the uremic substance 6 weeks after administration, 12 weeks after administration and / or 24 weeks after administration, although no improvement in glomerular damage is observed. Promotion of urinary excretion of uremic substances and / or promotion of in vitro excretion of uremic substances is observed.
  • the pharmaceutical composition provided by the present invention is orally or parenterally administered to humans or other mammals.
  • parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, transmucosal Administration, transdermal administration, nasal administration, rectal administration, intrathecal administration, intraperitoneal administration, and local administration can be mentioned.
  • the pharmaceutical composition provided by the present invention comprises an alkalizing agent as it is or a pharmaceutically acceptable carrier such as an excipient (eg, lactose, D-mannitol, crystalline cellulose, glucose), a binder (eg, , Hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricant (eg, magnesium stearate, talc), disintegrant (eg, starch, carboxymethylcellulose calcium (CMC-Ca)), diluent ( For example, water for injection, physiological saline) and, if necessary, other additives (eg pH adjusters, surfactants, solubilizers, preservatives, emulsifiers, tonicity agents, stabilizers) It may be prepared in the form of tablets, capsules, suspensions, injections, suppositories and the like.
  • an excipient eg, lactose, D-mannitol, crystalline cellulose, glucose
  • the alkalinizing agent may be an excipient (eg lactose, D-mannitol, crystalline cellulose, glucose), a disintegrant (eg starch, carboxymethylcellulose calcium (CMC-Ca)), a binder.
  • a disintegrant eg starch, carboxymethylcellulose calcium (CMC-Ca)
  • a binder for example, hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (for example, magnesium stearate, talc) and the like may be mixed to prepare a formulation.
  • HPC hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • lubricants for example, magnesium stearate, talc
  • the pharmaceutical composition provided by the present invention is a tablet.
  • the tablet provided by the present invention comprises an alkalizing agent (eg potassium citrate or hydrate thereof; sodium citrate or hydrate thereof; potassium citrate monohydrate and sodium citrate dihydrate).
  • an alkalizing agent eg potassium citrate or hydrate thereof; sodium citrate or hydrate thereof; potassium citrate monohydrate and sodium citrate dihydrate.
  • pharmaceutically acceptable additives commonly used in the pharmaceutical field may be included. Examples of such additives include excipients, binders, disintegrants, fluidizers, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers and fragrances.
  • the content of the alkalinizing agent in the tablet provided by the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, more preferably 60 to 85% by weight based on the tablet.
  • excipients examples include lactose (eg, lactose hydrate, anhydrous lactose), sugars such as glucose, sucrose, fructose, maltose, erythritol, sorbitol, maltitol, Sugar alcohols such as xylitol and D-mannitol, starch (eg, corn starch, potato starch, rice starch, wheat starch), crystalline cellulose, magnesium aluminate metasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate And ethyl cellulose, and crystalline cellulose is particularly preferable.
  • the content of the excipient in the tablet provided by the present invention may be 1 to 95% by weight, preferably 1 to 80% by weight, more preferably 3 to 80% by weight, still more preferably 3 to It may be 20% by weight.
  • binders examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, dextrin, methylcellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch ( Examples thereof include partially pregelatinized starch), agar, and gelatin. Hydroxypropyl cellulose is particularly preferable.
  • the content of the binder in the tablet provided by the present invention may be 0.1 to 30% by weight, preferably 0.1 to 10% by weight, more preferably 0.3 to 3% by weight based on the tablet. There may be.
  • disintegrants examples include croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, low substituted hydroxypropylcellulose, crospovidone, starch (eg, wheat starch, corn starch , Partially pregelatinized starch) and carmellose, with partially pregelatinized starch being particularly preferred.
  • the content of the disintegrant in the tablet provided by the present invention may be 0.3 to 20% by weight, preferably 1 to 10% by weight, more preferably 3 to 10% by weight based on the tablet. .
  • Examples of superplasticizers that can be used in the tablets provided by the present invention include light anhydrous silicic acid, talc and magnesium aluminate metasilicate.
  • the content of the fluidizing agent in the tablet provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, more preferably 0.3 to 3% by weight, based on the tablet. It may be.
  • Examples of the corrigent that can be used in the tablets provided by the present invention include acidulants such as citric acid (for example, citric anhydride), malic acid, acetic acid, tartaric acid, fumaric acid, ascorbic acid (however, the corrigent is , Saccharin sodium, dipotassium glycyrrhizinate, aspartame (registered trademark), stevia, thaumatin, and sucralose.
  • the content of the flavoring agent in the tablet provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, more preferably 0.3 to 3% by weight, based on the tablet. There may be.
  • Examples of lubricants that can be used in the tablets provided by the present invention include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, sucrose fatty acid ester, carnauba wax, macrogol and sodium stearyl fumarate, In particular, magnesium stearate is preferable.
  • the content of the lubricant in the tablet provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, more preferably 1 to 3% by weight based on the tablet. May be.
  • pH adjusters examples include citric acid, phosphates (eg, sodium dihydrogen phosphate, potassium dihydrogen phosphate), carbonates (eg, magnesium carbonate, sodium carbonate) ), Tartrate, fumarate, acetate and amino acid salt (however, the pH adjusting agent does not include the alkalizing agent according to the present invention).
  • the content of the pH adjusting agent in the tablet provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, more preferably 1 to 5% by weight, based on the tablet. May be.
  • surfactants examples include sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, macrogol and poloxamer.
  • the content of the surfactant in the tablet provided by the present invention may be 0.01 to 3% by weight, preferably 0.03 to 1% by weight, more preferably 0.03 to 0.5%, based on the tablet. It may be weight percent.
  • stabilizers examples include citric acid (eg, anhydrous citric acid), malic acid, acetic acid, tartaric acid, maleic acid, ascorbic acid, sodium edetate, tocopherol (provided that the aforementioned Examples of the stabilizer include an alkalizing agent according to the present invention), and anhydrous citric acid is particularly preferable.
  • the content of the stabilizer in the tablet provided by the present invention may be 0.01 to 30% by weight, preferably 0.1 to 30% by weight, more preferably 1 to 20% by weight, based on the tablet. May be.
  • Examples of the flavors that can be used in the tablets provided by the present invention include citrus flavors such as lemon, orange, and grapefruit, peppermint, spearmint, and menthol. -1% by weight, more preferably 0.01-0.1% by weight)
  • the total content of the alkalinizing agent and the pharmaceutically acceptable additive in the tablet provided by the present invention is However, it does not exceed 100% by weight.
  • the tablet provided by the present invention can be an uncoated tablet containing the above components and not having a coating layer, or a film-coated tablet having a coating layer.
  • the content of the coating layer can be appropriately set by those skilled in the art. For example, it may be 0.1 to 10% by weight with respect to the uncoated tablet.
  • a plasticizer, a coloring agent, a brightening agent, and the like can be appropriately included.
  • Examples of coating bases that can be used in the tablets provided by the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer and polyvinylpyrrolidone, with hydroxypropylmethylcellulose being particularly preferred.
  • the content of the coating base in the tablet provided by the present invention may be 0.01 to 10% by weight, preferably 0.3 to 3% by weight, based on the tablet.
  • Examples of coating plasticizers that can be used in tablets provided by the present invention include triethyl citrate, medium chain fatty acid triglycerides, triacetin, glycerin, propylene glycol and polyethylene glycol (eg, macrogol 6000), particularly macrogol.
  • the content of the coating plasticizer in the tablet provided by the present invention may be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, based on the tablet.
  • coating colorants that can be used in the tablets provided by the present invention include titanium oxide, yellow iron sesquioxide, iron sesquioxide, black iron oxide, edible blue No. 2 and edible blue No. 2 aluminum lake.
  • the content of the coating colorant in the tablet provided by the present invention may be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, based on the tablet.
  • coating brighteners that can be used in the tablets provided by the present invention include carnauba wax.
  • the content of the coating brightener in the tablet provided by the present invention may be 0.0001 to 0.1% by weight, preferably 0.001 to 0.01% by weight, based on the tablet.
  • the pharmaceutical composition provided by the present invention can be produced by a method known in the pharmaceutical field.
  • the production method includes alkalinizing agents (eg, potassium citrate or hydrate thereof; sodium citrate or hydrate thereof; potassium citrate monohydrate and sodium citrate Hydrate mixture; or sodium bicarbonate) and additives may be mixed, granulated, tableted and / or coated.
  • the mixing step may include a step of mixing an alkalinizing agent and an additive such as an excipient, a stabilizer, a disintegrant and / or a binder.
  • flavor may be further included.
  • Mixing can be performed using a V-type mixer, a W-type mixer, a container mixer, a tumbler mixer, a stirring mixer, or the like.
  • the granulation step can be performed by a known granulation method in the pharmaceutical field. Examples of the granulation method include a dry granulation method, a wet granulation method, and a fluidized bed granulation method.
  • the mixture obtained in the mixing step and the granulated product obtained in the granulating step are appropriately pulverized and / or sieved to obtain a mixture or granulated product having a desired particle size.
  • the pulverization can be performed by a pulverizer known in the pharmaceutical field, such as a ball mill, a jet mill, or a hammer mill.
  • the sieving can be performed using a 16 mesh sieve (aperture 1000 ⁇ m) to 32 mesh sieve (aperture 500 ⁇ m), etc.
  • the tableting step can be performed by a tableting method known in the pharmaceutical field.
  • the tableting method examples include a direct tableting method, a dry tableting method, a wet tableting method, and an external lubricant tableting method.
  • the mixture or granulated product obtained in the above steps can be tableted using a tableting machine known in the pharmaceutical field such as a single-shot tableting machine or a rotary tableting machine.
  • a tableting pressure of 1 kN to 30 kN can be employed.
  • a coating process can be performed by a well-known method in the pharmaceutical field
  • the coating can be performed by spray coating a coating liquid containing a coating base and a plasticizer, a coloring agent, a brightening agent, and the like on the outside of the uncoated tablet.
  • the tablet provided by the present invention comprises an alkalizing agent, an excipient (eg, lactose, D-mannitol, crystalline cellulose and / or glucose), a binder (eg, hydroxypropylcellulose (HPC), Gelatin and / or polyvinylpyrrolidone (PVP)), stabilizers (eg, anhydrous citric acid), disintegrants (eg, starch (eg, partially pregelatinized starch) and / or carboxymethylcellulose calcium (CMC-Ca)) and Lubricant (for example, magnesium stearate) is mixed and tableted to obtain uncoated tablet; on the outside of uncoated tablet, coating base (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose and / or PVP) And a
  • the amount of the alkalizing agent in the pharmaceutical composition provided by the present invention can be appropriately set. In one embodiment, the amount of the alkalinizing agent in the pharmaceutical composition provided by the present invention is such that the dosage of the alkalinizing agent improves acid urine in gout or hyperuricemia when administered to a human.
  • a lower dose for example, a daily dose approved in Japan for the improvement of acidic urine in gout or hyperuricemia (for example, an alkaline agent is a citric acid formulation
  • an alkaline agent is a citric acid formulation
  • Potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) 231.5 mg and Sodium citrate hydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O) 195.0 mg 2 tablets at a time, orally administered 3 times a day, when the alkalinizing agent is sodium bicarbonate: 3 to 5 g per day orally)) is set to be 1 to 50%, or 10 to 20% May be.
  • the pharmaceutical composition provided by the present invention is a tablet, and in one tablet, potassium citrate monohydrate or sodium citrate dihydrate as an alkalizing agent is preferably 10 mg to 1 g, preferably May contain from 100 mg to 500 mg, more preferably from 400 mg to 500 mg.
  • the pharmaceutical composition provided by the present invention is a tablet.
  • potassium citrate monohydrate and sodium citrate dihydrate are each 10 mg to 300 mg, for a total of 20 mg to 600 mg may be included, preferably 150 to 250 mg each, and a total of 400 to 500 mg, more preferably each 190 to 240 mg, and a total of 400 to 450 mg.
  • the pharmaceutical composition provided by the present invention is a tablet, and 10 mg to 1 g, preferably 100 mg to 500 mg of sodium hydrogen carbonate as an alkalizing agent may be contained in one tablet.
  • the pharmaceutical composition provided by the present invention is a tablet, comprising 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate as an alkalizing agent, It may contain anhydrous citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol 6000, titanium oxide and carnauba wax.
  • a tablet containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate may be a dosage unit.
  • dosage unit represents a unit of the preparation
  • 1 dosage unit represents the minimum unit of the preparation.
  • the dosage unit is each tablet, and one dosage unit represents one tablet.
  • the dosage unit is an injection contained in a sealed container such as an ampoule or vial, and one dosage unit represents an injection contained in a sealed container such as one ampoule or vial.
  • the pharmaceutical composition provided by the present invention is administered to humans or other mammals, one or two or more of the above dosage units may be administered at one time, and the one dosage unit is divided and administered. May be.
  • the dose of the alkalinizing agent is appropriately determined according to the type of the alkalizing agent, the method of administration, the age, weight, sex, symptom, sensitivity to the drug, etc. of the subject of administration, but depending on the condition of symptom improvement Dosage may be adjusted.
  • an oral administration of a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate as an alkalizing agent to a human, gout and acid urine in hyperuricemia Daily dosage approved in Japan for improvement for example, when the alkalinizing agent is a citric acid preparation: 1 tablet with potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) 231.5 1 tablet containing 20 mg of sodium citrate hydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O), once orally, 3 times daily, when the alkaline agent is sodium bicarbonate: A daily dose of 3 to 5 g orally administered daily) may be used.
  • an oral administration of a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate as an alkalizing agent to a human, gout and acid urine in hyperuricemia Daily dosage approved in Japan for improvement for example, when the alkalinizing agent is a citric acid preparation: 1 tablet with potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) 231.5 1 tablet containing 20 mg of sodium citrate hydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O), once orally, 3 times daily, when the alkaline agent is sodium bicarbonate: The daily dose may be 3 to 5 g orally administered daily).
  • an oral administration of a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate as an alkalizing agent to a human, gout and acid urine in hyperuricemia Daily dosage approved in Japan for improvement (for example, when the alkalinizing agent is a citric acid preparation: 1 tablet with potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) 231.5 1 tablet containing 20 mg of sodium citrate hydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O), once orally, 3 times daily, when the alkaline agent is sodium bicarbonate: The daily dose of 3-5g per day) was started as a daily dose, and then the dose was approved in Japan for the improvement of acidic urine in gout and hyperuricemia.
  • the alkalinizing agent is a citric acid preparation: 1 tablet with potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) 231.5 1 tablet containing 20 mg of sodium citrate hydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O)
  • the dose may be increased up to the dose.
  • the dosage of the alkalinizing agent is such that when the alkalinizing agent is orally administered, the pH of human urine (for example, early morning urine) is pH 5.2 to pH 6.8, pH 5.5 to pH 6. 8, pH 5.8 to pH 6.8, pH 5.8 to pH 6.5, pH 5.8 to pH 6.2, pH 5.8 to less than pH 6.2, pH 6.0 to pH 6.5, pH 6.0 to pH 6.4 PH 6.0 to pH 6.3, pH 6.0 to pH 6.2, pH 6.0 to pH 6.2, pH 6.1 to pH 6.3, pH 6.2 to 6.8, pH 6.2 to pH 6.5 or pH 6.
  • the dose may be 5 to 6.8.
  • the dosage of the alkalinizing agent is such that the pH of the human urine (e.g., early morning urine) is adjusted to pH 5. after 6 weeks, 12 weeks or 24 weeks of administration by orally administering the alkalinizing agent. 2 to pH6.8, pH5.5 to pH6.8, pH5.8 to pH6.8, pH5.8 to pH6.5, pH5.8 to pH6.2, pH5.8 to less than pH6.2, pH6.0 ⁇ PH 6.5, pH 6.0 ⁇ pH 6.4, pH 6.0 ⁇ pH 6.3, pH 6.0 ⁇ pH 6.2, pH 6.0 or more, but less than pH 6.2, pH 6.1 ⁇ pH 6.3, pH 6.2 ⁇
  • the dose may be 6.8, pH 6.2 to pH 6.5, or pH 6.5 to 6.8.
  • potassium citrate monohydrate and sodium citrate dihydrate 0.1 to 5 g / day for a total of 0.2 to 10 g / day, 0.1 to 3 g / day for a total of 0.2 to 6 g / day, 0.5 to 3 g / day for a total of 1 to 6 g / day, preferably 0.5 A total dose of 1 to 3 g / day at 1 to 1.5 g / day, a total of 2 to 3 g / day at 1 to 1.5 g / day, or a total of 1 to 2 g / day at 0.5 to 1 g / day, respectively, may be administered.
  • potassium citrate monohydrate or sodium citrate dihydrate is orally administered to a human as an alkaline agent, 1-10 g / day, 1-6 g / day, 2-5.5 g / Day, 1 to 3 g / day, 2 to 3 g / day, or 1 to 1.5 g / day, or 1 to 5 times a day, preferably 3 times a day.
  • sodium bicarbonate is orally administered to a human as an alkalizing agent
  • 1 to 6 g / day preferably 1 to 3 g / day, or 3 to 5 g / day may be administered. It may be administered 1 to 5 times a day, preferably 3 times a day.
  • the alkalinizing agent may be administered for a long time, for example, 1 week, 2 weeks, 3 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 40 weeks, 60 weeks. 80 weeks, 100 weeks, 120 weeks, 1 week or more, 2 weeks or more, 3 weeks or more, 6 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 24 weeks or more, 40 weeks or more, 60 weeks or more, 80 weeks or more, 100 weeks or more, 120 weeks or more, 6 weeks or more and 24 weeks or less, 12 weeks or more and 24 weeks or less, 6 weeks or more and 30 weeks or less, 12 weeks or more and 30 weeks or less, 6 weeks or more and 30 weeks or less, 6 weeks or more and 40 weeks or less, 12 weeks or more 40 weeks or less, 12 weeks or more 40 weeks or less, 6 to 60 weeks, 12 to 60 weeks, 6 to 80 weeks, 12 to 80 weeks, 6 to 100 weeks, 12 to 10 weeks Week hereinafter is administered below 120 weeks or less or more than 12 weeks 120 weeks or 6 weeks.
  • the pharmaceutical composition provided by the present invention can be administered to patients with kidney disease (eg, chronic kidney disease) by continuous administration for 6 weeks, continuous administration for 12 weeks, and / or continuous administration for 24 weeks.
  • kidney disease eg, chronic kidney disease
  • beneficialal effects eg, uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid) blood concentration lowering effects, uremic substances (eg, indoxyl sulfate) , P-cresylsulfuric acid, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid) urinary concentration increasing effect (urine excretion promoting effect) and / or urinary ⁇ 2-microglobulin concentration increasing inhibitory effect) Can be detected.
  • uremic substances eg, indoxyl sulf
  • Kidney disease includes acute kidney disease and chronic kidney disease unless otherwise specified.
  • acute kidney disease include drugs (eg, non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, aminoglycoside antibiotics, new quinolone antibacterials, iodinated contrast agents, cisplatin and other platinum Acute kidney disease caused by the formulation) and acute kidney disease caused by renal ischemia.
  • Chronic kidney disease (CKD) is a concept encompassing chronic kidney disease regardless of the underlying disease, and there is a decrease in renal function expressed by glomerular filtration rate (GFR), or kidney damage. Is a concept that encompasses all pathological conditions that persist chronically (more than 3 months).
  • the severity of chronic kidney disease is evaluated by classification according to cause (Cause: C), renal function (GFR: G), and proteinuria (albuminuria: A). .
  • the classification of GFR is as follows.
  • G1 GFR is normal or high ( ⁇ 90 mL / min / 1.73 m 2 )
  • G2 Normal or mild decrease in GFR (60-89 mL / min / 1.73 m 2 )
  • G3a Mild to moderate decrease in GFR (45 to 59 mL / min / 1.73 m 2 )
  • G3b Moderate to high decrease in GFR (30 to 44 mL / min / 1.73 m 2 )
  • G4 GFR is highly reduced (15-29 mL / min / 1.73 m 2 )
  • EKD End stage renal failure (ESKD) ( ⁇ 15 mL / min / 1.73 m 2 )
  • the classification by proteinuria albuminuria: A) is classified as follows using the urine albumin / creatinine (Cr) ratio when the primary disease is diabetes.
  • A1 Normal (less than 30 mg / gCr)
  • A2 Microalbuminuria (30-299 mg / gCr)
  • A3 Overt albuminuria (300 mg / gCr or more)
  • proteinuria albuminuria: A
  • A1 Normal (less than 0.15 g / gCr)
  • A2 Mild proteinuria (0.15-0.49 g / gCr)
  • A3 High proteinuria (0.50 g / gCr or more)
  • CKD medical care guide 2012 Nechirenkai 2012
  • the severity classification of chronic kidney disease is expressed as, for example, diabetes G2A3, chronic nephritis G3bA1, etc. using the above C, G and A.
  • the severity of chronic kidney disease has conventionally been described only in the stages classified by GFR, and the severity of chronic kidney disease is conventionally changed to G1, G2, G3a, G3b, G4.
  • G5 can also be described.
  • the pharmaceutical composition provided by the present invention is administered to low-severity, early-stage chronic kidney disease patients.
  • the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease of stage G3b or lower, preferably stage G2 or lower.
  • the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease who are stage G2 or more and stage G3b or less (eg, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b).
  • the pharmaceutical composition provided by the present invention is a chronic kidney disease patient having stage G3b or lower and having microalbuminuria, preferably stage G2, chronic kidney disease having microalbuminuria. Administered to patients.
  • the pharmaceutical composition provided by the present invention is from stage G2 to stage G3b (eg, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b), and is microalbuminuria. It is administered to patients with chronic kidney disease.
  • the pharmaceutical composition provided by the present invention is stage G3b or less and a chronic kidney disease patient whose urinary protein excretion is less than 3.5 g / gCr, preferably stage G2, Administered to patients with chronic kidney disease whose urinary protein excretion is less than 3.5 g / gCr.
  • the pharmaceutical composition provided by the present invention is from stage G2 to stage G3b (for example, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b), and the amount of protein excreted in urine Is administered to patients with chronic kidney disease who are less than 3.5 g / gCr. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with progressive chronic kidney disease.
  • the pharmaceutical composition provided by the present invention has a concentration of ⁇ 2-microglobulin in urine (eg, early morning urine) of 2000 ⁇ g / L or less, 1000 ⁇ g / L or less, 800 ⁇ g / L or less, 290 ⁇ g / L L or less, 200 ⁇ g / L or less, 1 to 2000 ⁇ g / L, 1 to 1000 ⁇ g / L, 1 to 800 ⁇ g / L, 1 to 290 ⁇ g / L, 1 to 200 ⁇ g / L, 10 to 2000 ⁇ g / L, 10 to 1000 ⁇ g / L, It is administered to patients with chronic kidney disease who are 10-800 ⁇ g / L, 10-290 ⁇ g / L, 10-200 ⁇ g / L or 80-200 ⁇ g / L.
  • ⁇ 2-microglobulin in urine eg, early morning urine
  • the pharmaceutical composition provided by the present invention has a cystatin C blood concentration (for example, plasma or serum) of 0.1 to 3.0 mg / L, 0.1 to 2.0 mg / L, 0.1 to 1.6.
  • Chronic kidneys that are mg / L, 0.1-1.3 mg / L, 0.5-3.0 mg / L, 0.5-2.0 mg / L, 0.5-1.6 mg / L, 0.5-1.3 mg / L or 0.9-1.3 mg / mL It is administered to sick patients.
  • the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient having a blood concentration of indoxyl sulfate of 0.001 to 100 ⁇ g / mL (eg, 0.1 to 30 ⁇ g / mL). In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease, wherein the blood concentration of p-cresyl sulfate is 0.003 to 300 ⁇ g / mL (eg, 0.01 to 30 ⁇ g / mL). .
  • the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient having a hippuric acid blood concentration of 0.01 to 100 ⁇ g / mL (eg, 0.01 to 10 ⁇ g / mL). In one embodiment, the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient having a blood concentration of arginosuccinic acid of 0.01 to 100 ⁇ g / mL (eg, 0.1 to 10 ⁇ g / mL).
  • the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient having a phenylacetyl L-glutamine blood concentration of 0.03 to 30 ⁇ g / mL (eg, 0.1 to 10 ⁇ g / mL). .
  • the pharmaceutical composition provided by the present invention is administered to a patient receiving treatment according to a CKD medical guide.
  • a CKD medical guide For example, blood pressure management (administration of RA inhibitors such as ARB and ACE inhibitors, diuretics, Ca antagonists, etc.), proteinuria measures (administration of RA inhibitors, etc.), blood glucose level management according to the CKD medical guide (Administered ⁇ -glucosidase inhibitor, etc.), lipid management (statin, fibrate administration, etc.), anemia management (erythropoietin administration, etc.) and / or bone / mineral measures (bisphosphonate administration, etc.).
  • the pharmaceutical composition provided by the present invention is used in combination with an antihypertensive drug (eg, ARB, ACE inhibitor, diuretic, Ca antagonist).
  • an antihypertensive drug eg, ARB, ACE inhibitor, diuretic, Ca antagonist
  • the pharmaceutical composition provided by the present invention is a spherical adsorbed carbon (Kremedin (registered trademark) as Japan) obtained by oxidizing and reducing a spherical fine porous carbon derived from petroleum hydrocarbon at a high temperature. And sold together).
  • the pharmaceutical composition provided by the present invention comprises a low-severity, early-stage chronic kidney disease patient (eg, stage G3b or lower, preferably stage G2 or higher, stage G3b or lower, more preferably stage G2 And stage G3a, and even more preferably, a stage G2 chronic kidney disease patient) and the concentration of uremic substances (eg, indoxyl sulfate, hippuric acid and / or phenylacetyl L-glutamine) in the blood of the patient.
  • uremic substances eg, indoxyl sulfate, hippuric acid and / or phenylacetyl L-glutamine
  • the pharmaceutical composition provided by the present invention includes a pharmaceutical composition for improving uremia symptoms, a pharmaceutical composition for treating or preventing uremia, a pharmaceutical composition for inhibiting progression of chronic kidney disease, and dialysis-introduced pharmaceutical composition.
  • uremic substances eg, indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid and / or phenylacetyl L-glutamine
  • the pharmaceutical composition provided by the present invention includes a pharmaceutical composition for improving uremia symptoms, a pharmaceutical composition for treating or preventing uremia, a pharmaceutical composition for inhibiting progression of chronic kidney disease, and dialysis-introduced pharmaceutical composition.
  • Delayed pharmaceutical composition pharmaceutical composition, pharmaceutical composition for inhibiting myocardial fibrosis, pharmaceutical composition for inhibiting arteriosclerosis, pharmaceutical composition for improving arteriosclerosis, pharmaceutical composition for inhibiting proliferation of vascular smooth muscle cells, and inhibiting vascular endothelial cell injury
  • a pharmaceutical composition a pharmaceutical composition for suppressing arterial wall thickening, a pharmaceutical composition for improving arterial wall thickening, a pharmaceutical composition for suppressing aortic calcification, or a cardiovascular disease that is a complication (eg, heart failure, myocardial infarction, stroke) Etc.) and the pharmaceutical composition for treatment or prevention.
  • the pharmaceutical composition provided by the present invention comprises a low-severity, early-stage chronic kidney disease patient (eg, stage G3b or lower, preferably stage G2 or higher, stage G3b or lower, more preferably stage G2 And stage G3a, and even more preferably, stage G2 chronic kidney disease patients) to suppress an increase in ⁇ 2-microglobulin in the patient's urine.
  • a low-severity, early-stage chronic kidney disease patient eg, stage G3b or lower, preferably stage G2 or higher, stage G3b or lower, more preferably stage G2 And stage G3a, and even more preferably, stage G2 chronic kidney disease patients
  • the pharmaceutical composition provided by the present invention comprises a composition for inhibiting tubule (eg, proximal tubule) injury, a composition for inhibiting tubule (eg, proximal tubule) cell injury, It can be a tubule (eg, proximal tubule) cell protecting composition or a tubule (eg, proximal tubule) cell function (eg, reabsorption of glucose, amino acids, etc.) maintenance pharmaceutical composition.
  • the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient of moderate severity or higher (eg, a chronic kidney disease patient of stage G3b or higher), and uremia in the blood of the patient.
  • the pharmaceutical composition provided by the present invention includes a pharmaceutical composition for improving uremia symptoms, a pharmaceutical composition for treating or preventing uremia, a pharmaceutical composition for inhibiting progression of chronic kidney disease, and dialysis-introduced pharmaceutical composition.
  • Delayed pharmaceutical composition pharmaceutical composition for inhibiting myocardial fibrosis, pharmaceutical composition for inhibiting arteriosclerosis, pharmaceutical composition for improving arteriosclerosis, pharmaceutical composition for inhibiting proliferation of vascular smooth muscle cells, and inhibiting vascular endothelial cell injury
  • Pharmaceutical composition pharmaceutical composition for inhibiting arterial wall thickening, pharmaceutical composition for improving arterial wall thickening, pharmaceutical composition for inhibiting calcification of aorta, pharmaceutical composition for inhibiting reduction of energy production in muscle cells, muscle mass and It can be a pharmaceutical composition for inhibiting muscle strength reduction, or a pharmaceutical composition for treating or preventing cardiovascular diseases (for example, heart failure, myocardial infarction, stroke, etc.) which are complications.
  • the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient of moderate severity or higher (eg, a chronic kidney disease patient of stage G3b or higher), and ⁇ 2 in the urine of the patient is administered. -Suppress the increase in microglobulin.
  • the pharmaceutical composition provided by the present invention comprises a composition for inhibiting tubule (eg, proximal tubule) injury, a composition for inhibiting tubule (eg, proximal tubule) cell injury, It can be a tubule (eg, proximal tubule) cell protecting composition or a tubule (eg, proximal tubule) cell function (eg, reabsorption of glucose, amino acids, etc.) maintenance pharmaceutical composition.
  • Examples of other embodiments of the present invention include the following. a) A method for reducing the blood concentration of a uremic substance in a mammalian subject (eg, a human), wherein an effective amount of an alkaline agent is administered to the subject in need of reducing the blood concentration of the uremic substance A method comprising: b) A method of promoting urinary excretion of a uremic substance in a mammalian subject (eg, a human), wherein the subject is required to promote the excretion of the uremic substance into the urine in an effective amount.
  • a method comprising administering an agent; c) A method for ameliorating uremia symptoms in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of amelioration of the uremic symptoms, wherein the subject has kidney disease Suffering from a method; d) A method of treating or preventing uremia in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of treatment or prevention of uremic disease, wherein the subject has kidney disease Suffering from a method; e) A method of inhibiting the progression of chronic kidney disease in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of inhibiting the progression of chronic kidney disease; f) A method of delaying dialysis induction in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline
  • the method comprising: g) A method of inhibiting myocardial fibrosis in a mammalian subject (eg, human), comprising administering an effective amount of an alkaline agent to a subject in need of inhibiting myocardial fibrosis, wherein the subject is a kidney Suffering from a disease, method; h) A method for inhibiting arteriosclerosis in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of inhibiting arteriosclerosis, wherein the subject suffers from kidney disease.
  • the method i) A method of inhibiting the proliferation of vascular smooth muscle cells in a mammalian subject (eg, human), comprising administering an effective amount of an alkaline agent to a subject in need of inhibiting the proliferation of vascular smooth muscle cells.
  • a method comprising: r) A method of treating or preventing tubular damage in a mammalian subject (eg, a human) comprising administering an effective amount of an alkaline agent to a subject in need of treating or preventing the tubular damage; s) a method for inhibiting tubular damage in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of inhibiting tubular damage; t) A method of inhibiting proximal tubular cell damage in a mammalian subject (eg, a human) comprising administering an effective amount of an alkalizing agent to a subject in need of inhibiting proximal tubular cell damage ; u) A method of protecting proximal tubular cells in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of protecting the proximal tubular cells; v) A method of maintaining proximal tubular
  • a method for promoting the excretion of a uremic substance outside a body in a mammalian subject eg, a human
  • an effective amount of an alkaline agent is administered to the subject that needs to promote the excretion of the uremic substance outside the body.
  • a method comprising: x) A method of excreting uremic substances into urine depending on the blood concentration of uremic substances in a mammalian subject (eg, human), the subject requiring excretion of uremic substances into urine Administering an effective amount of an alkalinizing agent;
  • aaa a pharmaceutical composition comprising an alkaline agent for use in lowering blood levels of uremic substances; bbb) a pharmaceutical composition comprising an alkalinizing agent for use in promoting urinary excretion of uremic substances; ccc) a pharmaceutical composition comprising an alkaline agent for use in ameliorating uremia symptoms in patients with kidney disease; ddd) a pharmaceutical composition comprising an alkalinizing agent for use in the treatment or prevention of uremia in patients with kidney disease; eeee) a pharmaceutical composition comprising an alkaline agent for use in inhibiting progression of chronic kidney disease; fff) a pharmaceutical composition comprising an alkaline agent for use in delaying dialysis induction in patients with chronic kidney disease; ggg) a pharmaceutical composition comprising an alkaline agent for use in inhibiting myocardial fibrosis in patients with kidney disease; hhh) a pharmaceutical composition comprising an alkaline agent for use in inhibiting arteriosclerosis in kidney disease patients; iii)
  • aaa Use of an alkalizing agent for producing a pharmaceutical composition for lowering blood concentration of a uremic substance; bbbb) use of an alkalinizing agent to produce a pharmaceutical composition for promoting the excretion of uremic substances in urine; cccc) use of an alkalizing agent to produce a pharmaceutical composition for ameliorating uremic symptoms in patients with kidney disease; dddd) use of an alkaline agent for the manufacture of a pharmaceutical composition for the treatment or prevention of uremia in patients with kidney disease; eeee) use of an alkalizing agent to produce a pharmaceutical composition for inhibiting the progression of chronic kidney disease; ffff) use of an alkalizing agent to produce a pharmaceutical composition for delaying dialysis induction in patients with chronic kidney disease; gggg) use of an alkalinizing agent to produce a pharmaceutical composition for inhibiting myocardial fibrosis in patients with kidney disease; hhhh) use of an alkalizing agent to produce a pharmaceutical composition for inhibiting arterios
  • the food composition provided by the present invention comprises an alkalinizing agent and contains a uremic substance (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or Argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate and phenylacetyl L-glutamine, more preferably indoxyl sulfate and phenylacetyl L-glutamine, and even more preferably indoxyl sulfate are exerted in vitro excretion promoting effect.
  • a uremic substance eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or Argininosuccinic acid, preferably indoxyl sulfate, p-
  • the alkalinizing agent is as described in “1.
  • Pharmaceutical composition examples include pharmaceutically acceptable salts of citric acid (for example, alkali metal citrate salts or hydrates thereof or mixtures thereof), preferably sodium bicarbonate, preferably potassium citrate. Of monohydrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) and sodium citrate dihydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O), or sodium citrate It is a dihydrate.
  • the uremic substance is also as described in “1. Pharmaceutical composition” above.
  • uremic substances include indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid.
  • the content of the alkalizing agent in the food composition provided by the present invention can be appropriately determined depending on the type of food.
  • food compositions include foods for specified health use, dietary supplements, functional foods, hospital patient foods, and supplements.
  • potassium citrate monohydrate and sodium citrate dihydrate as the alkalinizing agent are combined in total for each serving of food.
  • the food composition provided by the present invention can be appropriately produced by those skilled in the art depending on the type of food.
  • the food composition is produced by blending a food material with an alkaline agent (for example, potassium citrate and / or sodium citrate). obtain.
  • an alkaline agent for example, potassium citrate and / or sodium citrate.
  • the present invention relates to uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L) in blood of patients with chronic kidney disease.
  • uremic substances eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L
  • Glutamine, hippuric acid and / or argininosuccinic acid preferably indoxyl sulfate, hippuric acid and / or phenylacetyl L-glutamine, more preferably indoxyl sulfate and phenylacetyl L-glutamine, and even more preferably indoxyl sulfate.
  • a method of determining comprising measuring urine pH.
  • the present invention relates to a uremic substance (indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid, preferably Indian, in the urine of a chronic kidney disease patient.
  • a uremic substance indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid, preferably Indian, in the urine of a chronic kidney disease patient.
  • a method for determining the promotion of excretion of xyl sulfate, p-cresyl sulfate, hippuric acid and / or phenylacetyl L-glutamine, more preferably indoxyl sulfate and phenylacetyl L-glutamine, and even more preferably indoxyl sulfate) A method comprising measuring the pH of the solution.
  • the content of the uremic substance (for example, indoxyl sulfate) in the body fluid can be measured by an HPLC method or an enzymatic method. However, these measurement methods require specialized and expensive reagents.
  • Urinary substances in the blood can be measured very easily and inexpensively by measuring the pH of their urine by patients with chronic kidney disease.
  • indoxyl sulfate concentration p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid
  • / or uremic substances e.g., indoxyl sulfate, p-cresyl sulfate, The promotion of excretion of phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid
  • pH a well-known technique may be used.
  • a pH test paper, a pH test solution, or a simple pH measuring device can be used.
  • the patient with chronic kidney disease takes an alkaline agent (eg, a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate).
  • an alkaline agent eg, a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate.
  • blood uremic substances eg indoxyl sulfate, p-cresyl sulfate, phenylacetyl
  • L-glutamine hippuric acid and / or argininosuccinic acid, preferably indoxyl sulfate, hippuric acid and / or phenylacetyl L-glutamine, more preferably indoxyl sulfate and phenylacetyl L-glutamine, even more preferably indoxyl sulfate
  • Reduced and / or urinary uremic substances eg indoxyl sulfate, p-cresyl sulfate, phenylace
  • the chronic kidney disease patient is an alkaline agent (eg, a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate).
  • the urine pH is measured in the range of 5.2 to 6.8 (for example, urine pH is pH 5.5 to pH 6.8, pH 5.8).
  • Indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid preferably indoxyl sulfate, p-cresyl sulfate, hippuric acid and / or phenylacetyl L-glutamine, more preferably indoxyl sulfate and It can be easily determined that promotion of excretion of phenylacetyl L-glutamine, and even more preferably indoxyl sulfate is achieved.
  • uremic substances eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid
  • uremic substances eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid
  • the present invention provides a method of determining progression inhibition of chronic kidney disease comprising an alkaline agent (eg, potassium citrate monohydrate and sodium citrate dihydrate).
  • an alkaline agent eg, potassium citrate monohydrate and sodium citrate dihydrate
  • a method comprising measuring the pH of urine (eg, early morning urine) of a patient to whom a mixture, or sodium citrate dihydrate) has been administered. If it is observed that the urine pH increases over time or the urine pH is in the range of 5.8 to 6.8 (eg, the urine pH is in the range of 6.0 to 6.2), then chronic kidney It can aid in the diagnosis that progression of the disease stage is suppressed.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in lowering blood levels of uremic substances, wherein potassium citrate monohydrate is used as the alkaline agent.
  • the Japanese and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day, in total 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in lowering blood levels of uremic substances, comprising one dosage unit (preferably one tablet). Tablet) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate and orally administrating 3 to 6 dosage units a day, divided into 3 times a day is there.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in promoting urinary substance excretion into the urine, wherein potassium citrate is used as the alkaline agent.
  • Monohydrate and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. is there.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in promoting urinary substance excretion into the urine, comprising one dosage unit (preferably 1 Tablets) containing potassium citrate monohydrate (231.5 mg) and sodium citrate dihydrate (195.0 mg). Orally administer 3 to 6 dosage units a day, divided into 3 times a day. Is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in ameliorating uremia symptoms in patients with kidney disease, wherein potassium citrate is used as the alkaline agent. Hydrate and sodium citrate dihydrate are each orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in ameliorating uremia symptoms in kidney disease patients, comprising one dosage unit (preferably one tablet). Tablets) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and orally administrating 3 to 6 dosage units a day, divided into 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of uremia in patients with kidney disease, wherein potassium citrate as the alkaline agent Monohydrate and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. is there.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of uremia in patients with kidney disease, comprising one dosage unit (preferably 1 Tablets) containing potassium citrate monohydrate (231.5 mg) and sodium citrate dihydrate (195.0 mg). Is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting progression of chronic kidney disease, wherein potassium citrate monohydrate as the alkaline agent And sodium citrate dihydrate is orally administered at 0.5 to 1.5 g / day, in total 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting progression of chronic kidney disease, wherein one dosage unit (preferably one tablet)
  • 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate are orally administered from 3 to 6 dosage units per day divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in delaying dialysis induction in patients with chronic kidney disease, wherein potassium citrate is used as the alkaline agent. Hydrate and sodium citrate dihydrate are each orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in delaying dialysis induction in patients with chronic kidney disease, comprising one dosage unit (preferably one tablet). Tablets) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and orally administrating 3 to 6 dosage units a day, divided into 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting myocardial fibrosis in a kidney disease patient, wherein potassium citrate is used as the alkaline agent. Hydrate and sodium citrate dihydrate are each orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting myocardial fibrosis in a renal disease patient, comprising one dosage unit (preferably one tablet). Tablets) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and orally administrating 3 to 6 dosage units a day, divided into 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting arteriosclerosis in renal disease patients, wherein potassium citrate monohydrate as the alkaline agent And sodium citrate dihydrate at 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting arteriosclerosis in kidney disease patients, comprising one dosage unit (preferably one tablet). ) Contains potassium citrate monohydrate 231.5 mg and sodium citrate dihydrate 195.0 mg, and is orally administered in 3 to 6 dose units a day, divided into 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease, wherein citric acid is used as the alkaline agent.
  • Potassium monohydrate and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting vascular smooth muscle cell proliferation in a renal disease patient, 1 tablet) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, orally administered in 3 to 6 dose units divided into 3 times a day To do.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting vascular endothelial cell injury in a kidney disease patient, wherein potassium citrate is used as the alkaline agent. Hydrate and sodium citrate dihydrate are each orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting vascular endothelial cell damage in a renal disease patient, comprising one dosage unit (preferably one tablet). Tablets) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and orally administrating 3 to 6 dosage units a day, divided into 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in inhibiting arterial wall thickening in patients with kidney disease, wherein potassium citrate is used as the alkalinizing agent. Hydrate and sodium citrate dihydrate are each orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting arterial wall thickening in patients with kidney disease, comprising one dosage unit (preferably one tablet). Tablets) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and orally administrating 3 to 6 dosage units a day, divided into 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting aortic calcification in kidney disease patients, wherein potassium citrate is used as the alkaline agent. Hydrate and sodium citrate dihydrate are each orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting aortic calcification in patients with kidney disease, comprising one dosage unit (preferably one tablet). Tablets) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and orally administrating 3 to 6 dosage units a day, divided into 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in the treatment or prevention of cardiovascular disease in a patient with kidney disease, wherein Potassium acid monohydrate and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times daily, preferably 3 times daily.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment or prevention of cardiovascular disease in a patient with kidney disease, comprising one dosage unit (preferably 1 tablet) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate orally in 3 to 6 dose units a day, divided into 3 times a day To be administered.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in improving arteriosclerosis in kidney disease patients, wherein potassium monocitrate monohydrate as the alkaline agent.
  • the Japanese and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day, in total 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in improving arteriosclerosis in kidney disease patients, comprising one dosage unit (preferably one tablet). Tablet) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate and orally administrating 3 to 6 dosage units a day, divided into 3 times a day is there.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in improving arterial wall thickening in patients with kidney disease, wherein potassium citrate as the alkaline agent Monohydrate and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. is there.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in improving arterial wall thickening in patients with kidney disease, comprising one dosage unit (preferably 1 Tablets) containing potassium citrate monohydrate (231.5 mg) and sodium citrate dihydrate (195.0 mg). Orally administer 3 to 6 dosage units a day, divided into 3 times a day. Is.
  • the pharmaceutical composition provided by the invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment of acute kidney disease, wherein potassium citrate monohydrate and Sodium citrate dihydrate is orally administered at 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment of acute kidney disease, in one dosage unit (preferably one tablet). , Potassium citrate monohydrate 231.5 mg and sodium citrate dihydrate 195.0 mg, 3 to 6 dosage units per day are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting the progression from acute kidney disease to chronic kidney disease, wherein citric acid is used as the alkaline agent.
  • Potassium monohydrate and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting progression from acute kidney disease to chronic kidney disease, comprising one dosage unit (preferably 1 tablet) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, orally administered in 3 to 6 dose units divided into 3 times a day To do.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of tubular disorders, wherein potassium citrate monohydrate is used as the alkaline agent. And sodium citrate dihydrate at 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of tubule disorders, comprising one dosage unit (preferably one tablet). ) Contains potassium citrate monohydrate 231.5 mg and sodium citrate dihydrate 195.0 mg, and is orally administered in 3 to 6 dose units a day, divided into 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in the suppression of tubular damage, wherein potassium citrate monohydrate and Sodium citrate dihydrate is orally administered at 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in the suppression of tubule injury, and comprises one dosage unit (preferably one tablet).
  • Potassium citrate monohydrate 231.5 mg and sodium citrate dihydrate 195.0 mg, 3 to 6 dosage units per day are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the suppression of proximal tubular cell damage, wherein potassium citrate monohydrate is used as the alkaline agent.
  • the Japanese and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day, in total 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the suppression of proximal tubule cell injury, comprising one dosage unit (preferably one tablet). Tablet) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate and orally administrating 3 to 6 dosage units a day, divided into 3 times a day is there.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in protecting proximal tubular cells, wherein potassium citrate monohydrate as the alkaline agent And sodium citrate dihydrate is orally administered at 0.5 to 1.5 g / day, in total 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in protecting proximal tubule cells, comprising one dosage unit (preferably one tablet).
  • 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate are orally administered from 3 to 6 dosage units per day divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in maintaining proximal tubular cell function, wherein potassium citrate monohydrate is used as the alkaline agent. And sodium citrate dihydrate at 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in maintaining proximal tubular cell function, comprising one dosage unit (preferably one tablet). ) Contains potassium citrate monohydrate 231.5 mg and sodium citrate dihydrate 195.0 mg, and is orally administered in 3 to 6 dose units a day, divided into 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in promoting the excretion of a uremic substance outside the body, wherein potassium citrate is used as the alkaline agent. Hydrate and sodium citrate dihydrate are each orally administered at 0.5 to 1.5 g / day, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. .
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in promoting the excretion of a uremic substance outside the body, and comprises one dosage unit (preferably one tablet). Tablets) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and orally administrating 3 to 6 dosage units a day, divided into 3 times a day It is.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in urinary excretion depending on blood concentration of uremic substances, Potassium citrate monohydrate and sodium citrate dihydrate as agents are divided into 0.5 to 1.5 g / day for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. Oral administration.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in urinary excretion depending on the blood concentration of a uremic substance.
  • a unit preferably one tablet
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in lowering blood levels of uremic substances, wherein sodium bicarbonate is used as the alkaline agent, Orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in lowering blood levels of uremic substances, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in promoting urinary excretion of uremic substances, wherein sodium bicarbonate is used as the alkaline agent. Is orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in promoting urinary substance excretion into the urine, comprising one dosage unit (preferably 1 Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in ameliorating uremia symptoms in patients with kidney disease, wherein sodium bicarbonate is used as the alkaline agent. 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day, orally.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in ameliorating uremia symptoms in kidney disease patients, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of uremia in patients with kidney disease, wherein sodium bicarbonate is used as the alkaline agent. Is orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of uremia in patients with kidney disease, comprising one dosage unit (preferably 1 Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting the progression of chronic kidney disease, wherein sodium bicarbonate is used as the alkaline agent, 3 g / day, 1 to 5 times a day, preferably 3 times a day for oral administration.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting progression of chronic kidney disease, wherein one dosage unit (preferably one tablet)
  • 500 mg of sodium hydrogen carbonate is included, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in delaying dialysis induction in patients with chronic kidney disease, wherein sodium bicarbonate is used as the alkaline agent. 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day for oral administration.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in delaying dialysis induction in patients with chronic kidney disease, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting myocardial fibrosis in a kidney disease patient, wherein sodium bicarbonate is used as the alkaline agent. 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day, orally.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting myocardial fibrosis in a renal disease patient, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting arteriosclerosis in a renal disease patient, wherein sodium bicarbonate is used as the alkalinizing agent, -3 g / day, 1 to 5 times a day, preferably 3 times a day for oral administration.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting arteriosclerosis in kidney disease patients, comprising one dosage unit (preferably one tablet). ) Containing 500 mg of sodium bicarbonate, 3 to 6 dosage units per day are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease, wherein hydrogen carbonate is used as the alkaline agent.
  • Sodium is orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting vascular smooth muscle cell proliferation in a renal disease patient, 1 tablet) contains 500 mg of sodium bicarbonate and is orally administered in 3 to 6 dose units a day, divided into 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting vascular endothelial cell injury in a kidney disease patient, wherein sodium bicarbonate is used as the alkaline agent. 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day, orally.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting vascular endothelial cell damage in a renal disease patient, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in inhibiting arterial wall thickening in a kidney disease patient, wherein sodium bicarbonate is used as the alkalinizing agent. 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day, orally.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting arterial wall thickening in patients with kidney disease, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in inhibiting aortic calcification in kidney disease patients, wherein sodium bicarbonate is used as the alkalinizing agent. 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day, orally.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting aortic calcification in patients with kidney disease, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in the treatment or prevention of cardiovascular disease in a patient with kidney disease, wherein carbonic acid is used as the alkalinizing agent.
  • Sodium hydride is orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention comprises renal disease A pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of cardiovascular disease in a patient, comprising 500 mg sodium bicarbonate in one dosage unit (preferably one tablet) per day Three to six dosage units are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in improving arteriosclerosis in kidney disease patients, wherein sodium bicarbonate is used as the alkalizing agent, Orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in improving arteriosclerosis in kidney disease patients, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dose units a day, divided into 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in improving arterial wall thickening in patients with kidney disease, wherein sodium bicarbonate is used as the alkaline agent. Is orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in improving arterial wall thickening in patients with kidney disease, comprising one dosage unit (preferably 1 Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in the treatment of acute kidney disease, wherein 1 to 3 g of sodium bicarbonate is used as the alkalinizing agent. / Day, 1 to 5 times a day, preferably 3 times a day, orally.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment of acute kidney disease, in one dosage unit (preferably one tablet). Including sodium bicarbonate 500 mg, 3 to 6 dosage units per day are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting progression from acute kidney disease to chronic kidney disease, wherein hydrogen carbonate is used as the alkalizing agent.
  • Sodium is orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in inhibiting progression from acute kidney disease to chronic kidney disease, comprising one dosage unit (preferably 1 tablet) contains 500 mg of sodium bicarbonate and is orally administered in 3 to 6 dose units a day, divided into 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of tubule disorders, wherein sodium bicarbonate is used as the alkaline agent, -3 g / day, 1 to 5 times a day, preferably 3 times a day for oral administration.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of tubule disorders, comprising one dosage unit (preferably one tablet). ) Containing 500 mg of sodium bicarbonate, 3 to 6 dosage units per day are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in inhibiting tubule injury, wherein 1 to 3 g of sodium bicarbonate is used as the alkalinizing agent. / Day, 1 to 5 times a day, preferably 3 times a day, orally.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in the suppression of tubule injury, and comprises one dosage unit (preferably one tablet). Including sodium bicarbonate 500 mg, 3 to 6 dosage units per day are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the suppression of proximal tubular cell damage, wherein sodium bicarbonate is used as an alkalizing agent, Orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in the suppression of proximal tubule cell injury, comprising one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dose units a day, divided into 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in protecting proximal tubular cells, wherein sodium bicarbonate is used as the alkaline agent, 3 g / day, 1 to 5 times a day, preferably 3 times a day for oral administration.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in protecting proximal tubule cells, comprising one dosage unit (preferably one tablet).
  • 500 mg of sodium hydrogen carbonate is included, and 3 to 6 dosage units per day are orally administered divided into 3 times a day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in maintaining proximal tubular cell function, wherein sodium bicarbonate is used as the alkalinizing agent, -3 g / day, 1 to 5 times a day, preferably 3 times a day for oral administration.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in maintaining proximal tubular cell function, comprising one dosage unit (preferably one tablet). ) Containing 500 mg of sodium bicarbonate, 3 to 6 dosage units per day are orally administered in three divided doses per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in promoting the excretion of a uremic substance outside the body, wherein sodium bicarbonate is used as the alkaline agent. 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day for oral administration.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkaline agent for use in promoting the excretion of a uremic substance outside the body, and comprises one dosage unit (preferably one tablet). Tablets) containing 500 mg of sodium bicarbonate and orally administered in 3 to 6 dosage units per day, divided into 3 times per day.
  • the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in urinary excretion depending on blood concentration of uremic substances, As an agent, sodium bicarbonate is orally administered in 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in urinary excretion depending on the blood concentration of a uremic substance.
  • a unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and is orally administered in 3 to 6 dose units per day divided into 3 times a day.
  • the group A containing potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) 231.5 mg and sodium citrate hydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O) 195.0 mg
  • the tablets were orally administered 3 tablets a day, 3 times a day (morning, noon, evening) for 24 weeks.
  • the morning urine pH should be controlled over time, and in cases where the early morning urine is less than pH 6.5, the dosage can be increased up to 6 tablets a day, 3 times a day (morning, noon, evening) as needed. It was.
  • groups B tablets containing 500 mg of sodium bicarbonate were orally administered 3 tablets a day, 3 times a day (morning, noon, evening) for 24 weeks.
  • the morning urine pH should be controlled over time, and in cases where the early morning urine is less than pH 6.5, the dosage can be increased up to 6 tablets a day, 3 times a day (morning, noon, evening) as needed. It was. Early morning urine and blood samples were collected before administration and 6 weeks, 12 weeks and 24 weeks after administration, and each sample was stored at -80 ° C. Methods used in the art for urinary and plasma indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid (Sato, E., et.
  • TSQ Quantiva manufactured by Thermo Fisher Scientific Co., Ltd.
  • five types of compounds were ionized in the negative in mode and detected using the selected reaction monitoring method.
  • the quantitative value was calculated using a calibration curve prepared with a standard solution of each compound.
  • the amount of ⁇ 2-microglobulin in urine was determined by latex agglutination immunization using LZ test 'Eiken' ⁇ 2-M and LZ- ⁇ 2-M standard U'Eiken '(Eiken Chemical, Tokyo, Japan). It was measured.
  • cystatin C in the serum was measured by a colloidal gold agglutination method using Nescoat GC cystatin C (Nm) (Alfresa Pharma, Osaka, Japan).
  • Nm Nescoat GC cystatin C
  • Mann-Whitney test was used for comparison between groups, and Wilcoxon test was used for comparison with time.
  • the Pearson test was used for correlation.
  • Table 1-1-1 Indoxyl sulfate in plasma (ng / mL)
  • Table 1-1-2 Change amount (ng / mL) of indoxyl sulfate in plasma from before the start of administration
  • Table 1-2-1 Indoxyl sulfate amount (ng / mL) in early morning urine
  • Table 1-2-2 Change in indoxyl sulfate in early morning urine from the start of administration (ng / mL)
  • Table 1-3-1 Ratio of indoxyl sulfate in urine to indoxyl sulfate in plasma
  • Table 1-3-2 Changes in the ratio of indoxyl sulfate in urine to indoxyl sulfate in plasma from the start of administration
  • Table 2-1-1 Amount of p-cresyl sulfate in plasma (ng / mL)
  • Table 2-1-2 Change amount of p-cresyl sulfate in plasma from the start of administration (ng / mL)
  • the plasma indoxyl sulfate concentration at 6 to 24 weeks is significantly lower in group A than in groups B and C (see Table 1-1-1), and India in early morning urine at 6 to 24 weeks
  • the increase in xylsulfate concentration was significantly greater in group A than in groups B and C (see Table 1-2-2).
  • administration of potassium citrate / sodium citrate hydrate preparations to patients with chronic kidney disease increased the urinary concentration of indoxyl sulfate, a uremic substance, compared to before administration.
  • the blood concentration of was decreased compared to before administration. Even with the same alkalinizing agent, such an effect was not observed in the sodium bicarbonate preparation.
  • the potassium citrate / sodium citrate hydrate combination preparation exhibited higher blood indoxyl sulfate concentration lowering effect and urinary indoxyl sulfate concentration increasing effect.
  • the effect of decreasing the blood indoxyl sulfate concentration and the effect of increasing the urinary indoxyl sulfate concentration by the combined preparation of potassium citrate / sodium citrate hydrate were observed 12 weeks after administration.
  • administration of potassium citrate / sodium citrate hydrate formulation promotes excretion of indoxyl sulfate from blood into urine. It was shown that excretion outside the body is promoted.
  • the effect of excretion of indoxyl sulfate from blood into urine was observed by administration of a combination preparation of potassium citrate / sodium citrate hydrate, but not by administration of a sodium bicarbonate preparation (Table 1-3-1). 1-3-3).
  • group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) was compared with group C (Control: control group) at 12 and 24 weeks after administration.
  • P-cresyl sulfate concentration in early morning urine is high, and even compared to group B (bicarbonate: sodium bicarbonate preparation administration group), group A (potassium citrate / sodium citrate hydrate preparation administration group) P-cresyl sulfate concentration in the early morning urine at 6, 12, and 24 weeks after administration was high (see Table 2-2-1).
  • An increase in p-cresyl sulfate concentration in early morning urine at 6 to 24 weeks was observed only in group A (see Table 2-2-2).
  • Group A (Citrate: potassium citrate / sodium citrate hydrate formulation administration group) is Group B (Bicarbonate: Sodium bicarbonate formulation administration group) and Group C (Control: control group) Compared with, the hippuric acid concentration in plasma 24 weeks after administration was low (see Table 3-1-1). Such an effect was not seen in the administration of the sodium bicarbonate preparation. In addition, in group A, the hippuric acid concentration in the early morning urine 12 and 24 weeks after administration was higher than in group C (see Table 3-2-1).
  • argininosuccinic acid As for argininosuccinic acid (ASA), the group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) has a higher concentration of argininosuccinic acid in the early morning urine than the group C (Control: control group). On the other hand, the value was lower than that of Group B (Bicarbonate: sodium bicarbonate preparation administration group) (see Table 4-2-1).
  • Group B Bicarbonate: sodium bicarbonate preparation administration group
  • the effect of increasing the urinary argininosuccinic acid concentration by the combined preparation of potassium citrate / sodium citrate hydrate was observed 12 weeks after administration.
  • the administration of potassium citrate / sodium citrate hydrate promotes the excretion of argininosuccinic acid from the blood into the urine and goes outside the body. It is suggested that the excretion of is promoted.
  • group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) is compared with group C (Control: control group), and phenylacetyl L-glutamine in plasma The concentration was low (see Table 5-1-1).
  • group A the phenylacetyl L-glutamine concentration was higher in the early morning urine 12 and 24 weeks after administration than in group C (see Table 5-2-1).
  • group C the urinary concentration of phenylacetyl L-glutamine, a uremic substance 12 and 24 weeks after administration, was compared before administration.
  • the plasma concentration-lowering effect of phenylacetyl L-glutamine was strongly observed in the sodium bicarbonate preparation as compared with the preparation containing potassium citrate / sodium citrate hydrate (see Table 5-1-2). From the value of the ratio between the phenylacetyl L-glutamine concentration in urine and the phenylacetyl L-glutamine concentration in plasma, the administration of a combination preparation of potassium citrate / sodium citrate hydrate causes phenylacetyl L-glutamine to be excreted from blood into urine was promoted, and it was shown that excretion outside the body was promoted.
  • the effect of the sodium bicarbonate preparation (Bicarbonate) administration group on the control group for the indoxyl sulfate concentration in the early morning urine is indicated as ( ⁇ ) in the table below. This is because the sodium bicarbonate preparation (Bicarbonate) administration group significantly increased the indoxyl sulfate concentration in the early morning urine compared to the control group, but after the administration of sodium bicarbonate preparation (Bicarbonate) compared to before the start of administration. This is because, since the indoxyl sulfate concentration in the early morning urine is lowered, it cannot be determined whether or not there is an effect of promoting excretion of indoxyl sulfate into the urine.
  • the effect of increasing the concentration of uremic substances in the urine is indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid.
  • IS indoxyl sulfate
  • PCS p-cresyl sulfate
  • HA hippuric acid
  • argininosuccinic acid is Clearly observed with acid (ASA) and phenylacetyl L-glutamine (PAG).
  • indoxyl sulfate (IS), p-cresyl sulfate (PCS) and phenylacetyl L-glutamine (PAG), potassium citrate / sodium citrate hydrate combination preparation (Citrate) was administered as a sodium bicarbonate preparation (Bicarbonate )
  • Idoxyl sulfate (IS), p-cresyl sulfate (PCS) and phenylacetyl L-glutamine (PAG) potassium citrate / sodium citrate hydrate combination preparation
  • the uremic substance excretion effect (extracorporeal effect) from blood to urine by alkalinizing agent is clearly observed in indoxyl sulfate (IS), p-cresyl sulfate (PCS) and phenylacetyl L-glutamine (PAG). It was.
  • indoxyl sulfate IS
  • potassium citrate / sodium citrate hydrate combination preparation Cacarbonate
  • excretion extracorporeal
  • the combined preparation of potassium citrate / sodium citrate hydrate exhibits a higher in vitro excretion effect of the uremic substance compared to the sodium bicarbonate preparation. Also, It is possible to suppress the progression of chronic kidney disease by administering an alkalinizing agent not only to stage G3b but also to stage G2 chronic kidney disease patients, and potassium citrate / sodium citrate hydration compared to sodium bicarbonate preparations It was suggested that the combined preparations inhibit the progression of chronic kidney disease.
  • the concentration of cystatin C in the plasma was determined by group A (Citrate: potassium citrate / sodium citrate hydrate preparation administration group), group B (Bicarbonate: sodium bicarbonate preparation administration group) and group C (Control: control group). ), And there was no effect on the function of the glomeruli by administration of the potassium citrate / sodium citrate hydrate combination preparation or sodium bicarbonate preparation (Table 8).
  • group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) compared to group C (Control: control group), ⁇ 2 in urine -The microglobulin concentration is low, and even in comparison with group B (Bicarbonate: sodium bicarbonate preparation administration group), group A (potassium citrate / sodium citrate combination preparation administration group) The ⁇ 2-microglobulin concentration was low.
  • Group B (Bicarbonate: sodium bicarbonate preparation administration group) had a higher ⁇ 2-microglobulin concentration in urine than Group C (Control: control group).
  • urinary uremic substance concentration increase effect and blood uremia substance concentration decrease effect by administration of potassium citrate / sodium citrate hydrate combination preparation is administered with potassium citrate / sodium citrate hydrate combination preparation
  • urinary substance excretion promoting effect in the urine by administration of the combined preparation of potassium citrate / sodium citrate hydrate was not caused only by inhibition of glomerular and proximal tubule injury.
  • the potassium citrate / sodium citrate hydrate combination drug administration group showed a higher correlation between plasma concentration and urine concentration compared to the control group, compared with the sodium bicarbonate preparation administration group Even so, a high correlation was observed (see r values in FIGS. 1 to 3). 1 to 4, it was suggested that administration of a combined preparation of potassium citrate / sodium citrate hydrate causes excretion of indoxyl sulfate into urine depending on the indoxyl sulfate concentration in blood.
  • p-cresyl sulfate As for p-cresyl sulfate, there was a correlation between plasma concentration and urine concentration in the control group, the potassium citrate / sodium citrate hydrate combination drug administration group, and the sodium bicarbonate preparation administration group. A higher correlation was observed in the sodium bicarbonate preparation administration group compared to the sodium citrate hydrate combination preparation administration group (see r values in FIGS. 5 to 7). 5-8, p-cresyl sulfate is excreted in the urine depending on the blood p-cresyl sulfate concentration by administration of a sodium bicarbonate preparation or a combination preparation of potassium citrate / sodium citrate hydrate. Was suggested.
  • indoxyl sulfate and argininosuccinic acid In the sodium bicarbonate preparation administration group, indoxyl sulfate and argininosuccinic acid, indoxyl sulfate and phenylacetyl L-glutamine, p-cresyl sulfate and argininosuccinic acid, p-cresyl sulfate and phenylacetyl L-glutamine, argininosuccinic acid and phenylacetyl L-glutamine A high correlation was observed.
  • potassium citrate / sodium citrate hydrate may increase urinary concentrations of indoxyl sulfate, phenylacetyl L-glutamine, p-cresyl sulfate and argininosuccinic acid by the same mechanism.
  • sodium bicarbonate preparation may increase the urinary concentration of indoxyl sulfate, phenylacetyl L-glutamine, p-cresyl sulfate and argininosuccinic acid by the same mechanism.
  • the uremic substance is excreted from the body of the mammal by the pharmaceutical composition provided by the present invention.
  • the method provided by the present invention it is possible to make a preliminary determination as to whether or not the uremic substance is excreted from the body and / or whether or not the progression of chronic kidney disease can be suppressed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne une composition pharmaceutique qui consiste en un comprimé ayant pour principe actif un agent d'alcalinisation, plus particulièrement un sel de métal alcalin d'acide citrique. Selon l'invention, la concentration dans le sang en substances urémiques est réduite par administration de cette composition pharmaceutique, et ces substances urémiques sont évacuées à l'extérieur du corps par l'urine.
PCT/JP2017/032931 2017-04-18 2017-09-12 Procédé de purification du sang à l'aide d'un agent d'alcalinisation WO2018193648A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
JP2019513213A JP7219898B2 (ja) 2017-04-18 2017-09-12 アルカリ性化剤による血液浄化
TW112128862A TW202345784A (zh) 2017-04-18 2018-03-13 利用鹼性化劑的血液淨化
US16/605,885 US20210121426A1 (en) 2017-04-18 2018-03-13 Blood purification by alkalinizing agent
AU2018254884A AU2018254884C1 (en) 2017-04-18 2018-03-13 Blood purification through alkalifying agent
PCT/JP2018/009679 WO2018193752A1 (fr) 2017-04-18 2018-03-13 Procédé de purification du sang à l'aide d'un agent d'alcalinisation
JP2019513265A JPWO2018193752A1 (ja) 2017-04-18 2018-03-13 アルカリ性化剤による血液浄化
KR1020197033580A KR20190137147A (ko) 2017-04-18 2018-03-13 알칼리성화제에 의한 혈액 정화
CA3060154A CA3060154A1 (fr) 2017-04-18 2018-03-13 Procede de purification du sang a l'aide d'un agent d'alcalinisation
EP18787098.5A EP3616721A4 (fr) 2017-04-18 2018-03-13 Procédé de purification du sang à l'aide d'un agent d'alcalinisation
TW107108443A TWI813560B (zh) 2017-04-18 2018-03-13 利用鹼性化劑的血液淨化
CN201880025628.3A CN110799214A (zh) 2017-04-18 2018-03-13 利用碱化剂的血液净化
JP2022180930A JP2023022079A (ja) 2017-04-18 2022-11-11 アルカリ性化剤による血液浄化
JP2023106201A JP2023115271A (ja) 2017-04-18 2023-06-28 アルカリ性化剤による血液浄化

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2017082423 2017-04-18
JP2017-082423 2017-04-18
JP2017-085741 2017-04-24
JP2017085741A JP2018177752A (ja) 2017-04-18 2017-04-24 アルカリ性化剤による血液浄化
JP2017103935 2017-05-25
JP2017-103935 2017-05-25

Publications (1)

Publication Number Publication Date
WO2018193648A1 true WO2018193648A1 (fr) 2018-10-25

Family

ID=63855742

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/JP2017/032931 WO2018193648A1 (fr) 2017-04-18 2017-09-12 Procédé de purification du sang à l'aide d'un agent d'alcalinisation
PCT/JP2018/009679 WO2018193752A1 (fr) 2017-04-18 2018-03-13 Procédé de purification du sang à l'aide d'un agent d'alcalinisation

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/JP2018/009679 WO2018193752A1 (fr) 2017-04-18 2018-03-13 Procédé de purification du sang à l'aide d'un agent d'alcalinisation

Country Status (3)

Country Link
JP (1) JP2023022079A (fr)
TW (1) TW202345784A (fr)
WO (2) WO2018193648A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020080499A1 (fr) 2018-10-17 2020-04-23 国立大学法人東北大学 Nouvelle composition pharmaceutique
WO2020080451A1 (fr) * 2018-10-17 2020-04-23 京都府公立大学法人 Inhibiteur de fibrose rénale dans une néphropathie diabétique
WO2020222302A1 (fr) 2019-04-28 2020-11-05 国立大学法人東北大学 Nouvelle composition pharmaceutique
WO2021193856A1 (fr) 2020-03-26 2021-09-30 国立大学法人東北大学 Agent protecteur de la fonction rénale

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112839678A (zh) * 2019-07-18 2021-05-25 德尔塔菲制药股份有限公司 抗癌剂的效果增强剂
TW202308604A (zh) * 2021-05-10 2023-03-01 國立大學法人東北大學 肌肉量增加用組成物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1171287A (ja) * 1997-08-27 1999-03-16 Nisshin Flour Milling Co Ltd 猫慢性腎不全治療用組成物及びその治療方法
JP2007217366A (ja) * 2006-02-17 2007-08-30 Kirin Brewery Co Ltd 尿酸値降下用組成物
JP2009525276A (ja) * 2006-01-30 2009-07-09 グロボアジア エルエルシー 慢性腎疾患の治療法
WO2011052765A1 (fr) * 2009-10-27 2011-05-05 味の素株式会社 Atténuateur de troubles rénaux provoqués par l'administration d'un médicament contenant du platine
WO2012005240A1 (fr) * 2010-07-05 2012-01-12 株式会社明治 Bifidobactérium possédant une activité de réduction de la quantité de substance putréfiée intestinale

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60105619A (ja) * 1983-11-15 1985-06-11 Nippon Chemiphar Co Ltd 尿アルカリ化性食品組成物
JPS60197624A (ja) * 1984-03-21 1985-10-07 Nippon Chemiphar Co Ltd 尿アルカリ化性食品組成物
MX357998B (es) * 2015-03-20 2018-07-11 Antonio Hernandez Miramontes Jorge Una mezcla de acidos carboxilicos, especificamente acido citrico, acido succinico, acido fumarico y acido malico para el tratamiento de pacientes con insuficiencia renal cronica, insuficiencia renal aguda, hepatopatias agudas o cronicas que cursen con hiperamonemia, enfermedades congenitas con alteraciones enzimaticas en el ciclo de la urea, asi como condiciones clínicas que cursen con balance nitrogenado negativo.
JP2017082423A (ja) 2015-10-23 2017-05-18 信越ポリマー株式会社 トリム部材、及び該トリム部材を用いた施工方法
JP2017085741A (ja) 2015-10-27 2017-05-18 住友電装株式会社 ワイヤハーネスの外装材
JP2017103935A (ja) 2015-12-02 2017-06-08 田淵電機株式会社 分散型電源のシステム制御装置、及びパワーコンディショナ

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1171287A (ja) * 1997-08-27 1999-03-16 Nisshin Flour Milling Co Ltd 猫慢性腎不全治療用組成物及びその治療方法
JP2009525276A (ja) * 2006-01-30 2009-07-09 グロボアジア エルエルシー 慢性腎疾患の治療法
JP2007217366A (ja) * 2006-02-17 2007-08-30 Kirin Brewery Co Ltd 尿酸値降下用組成物
WO2011052765A1 (fr) * 2009-10-27 2011-05-05 味の素株式会社 Atténuateur de troubles rénaux provoqués par l'administration d'un médicament contenant du platine
WO2012005240A1 (fr) * 2010-07-05 2012-01-12 株式会社明治 Bifidobactérium possédant une activité de réduction de la quantité de substance putréfiée intestinale

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ABE, MICHIAKI ET AL.: "Discussion of Uremic Substance Subjected to Medicinal Blood Purification Using Oral Alkalinizers", JAPANESE JOURNAL OF NEPHROLOGY, vol. 59, no. 3, 25 April 2017 (2017-04-25), pages 324, ISSN: 0385-2385 *
ABE, MICHIAKI ET AL.: "Discussion of Uremic Substance Subjected to Medicinal Blood Purification Using Oral Alkalinizers", THE 60TH ANNUAL MEETING OF THE JAPANESE SOCIETY OF NEPHROLOGY, LECTURE, 13 March 2017 (2017-03-13), Retrieved from the Internet <URL:https://endai.umin.ac.jp/cgi-open-bin/hanyou/lookup/detail.cgi?cond=%27AO0018-00058-20341%27&&&parm=a00018-00058> [retrieved on 20171207] *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020080499A1 (fr) 2018-10-17 2020-04-23 国立大学法人東北大学 Nouvelle composition pharmaceutique
WO2020080451A1 (fr) * 2018-10-17 2020-04-23 京都府公立大学法人 Inhibiteur de fibrose rénale dans une néphropathie diabétique
KR20210078499A (ko) 2018-10-17 2021-06-28 고쿠리츠다이가쿠호진 도호쿠다이가쿠 신규 의약 조성물
WO2020222302A1 (fr) 2019-04-28 2020-11-05 国立大学法人東北大学 Nouvelle composition pharmaceutique
KR20220004643A (ko) 2019-04-28 2022-01-11 고쿠리츠다이가쿠호진 도호쿠다이가쿠 신규 의약 조성물
WO2021193856A1 (fr) 2020-03-26 2021-09-30 国立大学法人東北大学 Agent protecteur de la fonction rénale
KR20220164517A (ko) 2020-03-26 2022-12-13 고쿠리츠다이가쿠호진 도호쿠다이가쿠 신장 기능 보호제

Also Published As

Publication number Publication date
WO2018193752A1 (fr) 2018-10-25
JP2023022079A (ja) 2023-02-14
TW202345784A (zh) 2023-12-01

Similar Documents

Publication Publication Date Title
WO2018193648A1 (fr) Procédé de purification du sang à l&#39;aide d&#39;un agent d&#39;alcalinisation
JP2023115271A (ja) アルカリ性化剤による血液浄化
JP2018177752A (ja) アルカリ性化剤による血液浄化
WO2020072645A1 (fr) Dérivé benzimidazole destiné à être utilisé dans le traitement de troubles inflammatoires
WO2020080499A1 (fr) Nouvelle composition pharmaceutique
JP6509729B2 (ja) 慢性腎臓病の進行抑制又は改善剤
JP7482033B2 (ja) 夜間多尿の治療又は予防剤
AU2011339150B2 (en) Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof
WO2006105726A1 (fr) Composition pour le traitement de l’hypertension
WO2020222302A1 (fr) Nouvelle composition pharmaceutique
JP2023001352A (ja) アルカリ性化剤による血液浄化
JP2010013364A (ja) 高尿酸血症の予防または改善剤
JP2016514125A (ja) バルサルタン及びロスバスタチンカルシウムを含む複合製剤及びその製造方法
WO2021193856A1 (fr) Agent protecteur de la fonction rénale
WO2019004465A1 (fr) Composition pharmaceutique contenant du pémafibrate
JP5982715B2 (ja) 抗高血圧薬組成物
US20240115572A1 (en) Methods for treating glioblastomas with sepiapterin
UA146879U (uk) Фармацевтична композиція
KR20230119303A (ko) 높은 혈중 요산 농도를 갖는 대상체의 만성 신장 질환의 예방 또는 치료를 위한 알로푸리놀, 페북소스타트 또는 이들의 약학적으로 허용 가능한 염을 포함하는 약제학적 조성물
UA146315U (uk) Фармацевтична композиція
JP2021024803A (ja) クエン酸第二鉄水和物を含む固形製剤
UA146758U (uk) Фармацевтична композиція
CN105106962A (zh) 一种复方降压制剂及其应用
JP2008133271A (ja) 生活習慣病の予防および／または治療用組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17906001

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019513213

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17906001

Country of ref document: EP

Kind code of ref document: A1