WO2018193752A1

WO2018193752A1 - Blood purification through alkalifying agent

Info

Publication number: WO2018193752A1
Application number: PCT/JP2018/009679
Authority: WO
Inventors: 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: 2017-04-18
Filing date: 2018-03-13
Publication date: 2018-10-25
Also published as: WO2018193648A1; TW202345784A; JP2023022079A

Abstract

The present invention relates to a food composition containing an alkalifying agent, in particular an alkali metal salt of citric acid. Renal function is maintained through ingestion of this food composition.

Description

Blood purification with alkaline agent

The present invention relates to blood purification using an alkaline agent.
The present application was filed on April 18, 2017, Japanese Patent Application No. 2017-82423 filed in Japan, April 24, 2017, Japanese Patent Application No. 2017-85741 filed in Japan, May 25, 2017. No. 2017-103935, filed in Japan, and PCT / JP2017 / 032931 filed internationally on September 12, 2017, the contents of which are incorporated herein by reference.

The number of end-stage kidney disease (ESKD) patients requiring dialysis and transplantation is increasing worldwide. The number of dialysis patients at the end of 2014 is 320,000.
Recognized as a reserve for this ESKD is chronic kidney disease (CKD). 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 findings suggestive of kidney damage. It is a concept that includes all chronic (3 months or more) pathological conditions. Since CKD is not only a risk of progression to ESKD, but also a strong risk of developing cardiovascular disease (CVD), it is very important to detect CKD early and provide appropriate treatment. Many CKD treatments have been established so far, but it is still insufficient and further development of nephroprotective agents is required.

In CKD, various uremic substances accumulate in the body as kidney clearance decreases. In particular, indoxyl sulfate, a terminal metabolite of tryptophan, increases in blood concentration with the progress of CKD, and high concentration (100 μM to 1 mM) of indoxyl sulfate accumulates in the blood. Indoxyl sulfate is known to be deeply involved in the progression of kidney damage due to fibrosis of the kidney and CKD complications such as CVD due to vascular calcification. There is a report that it correlates with the rate and the incidence of cardiovascular events (Non-patent Document 1). And, it is considered that the progression to ESKD can be suppressed and the onset of CVD related to renal failure can be suppressed by reducing the blood indoxyl sulfate concentration in CKD patients. In fact, 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).

On the other hand, patients with advanced CKD experience low levels of bicarbonate (HCO ₃ ⁻ ) in the blood and develop metabolic acidosis. Therefore, alkaline agents such as sodium bicarbonate and citric acid are administered. And it has been reported that the progress of CKD is suppressed by administration of sodium hydrogen carbonate as an alkalizing agent (Non-patent Document 3). Moreover, 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).
However, 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 food for maintaining renal function (for example, for inhibiting tubular damage, for protecting tubular cells, or for maintaining tubular function). 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. As a result, 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.

In one aspect, the present invention provides a pharmaceutical composition for promoting the excretion of a uremic substance outside the body, which comprises an alkaline agent.

In one aspect, the present invention provides a pharmaceutical composition for reducing blood concentration of a uremic substance, comprising an alkalizing agent.

In one aspect, the present invention provides a pharmaceutical composition for promoting urinary excretion in chronic kidney disease, comprising an alkaline agent.

In one aspect, the present invention provides a pharmaceutical composition for improving uremia symptoms in chronic kidney disease, comprising an alkaline agent.

In one aspect, the present invention provides a pharmaceutical composition for delaying introduction of dialysis in chronic kidney disease, comprising an alkaline agent.

In one aspect, the present invention provides a pharmaceutical composition for treating or preventing a cardiovascular disease associated with chronic kidney disease, comprising an alkaline agent.

In one aspect, the present invention provides a pharmaceutical composition for suppressing progression from acute kidney disease to chronic kidney disease, which comprises an alkaline agent.

In one aspect, the present invention provides a food composition for promoting in vitro excretion of a uremic substance, comprising an alkaline agent.

In one aspect, the present invention provides a method for determining progression inhibition of chronic kidney disease.

In one aspect, 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.

That is, the present invention has the following aspects.
(1) A pharmaceutical composition for reducing blood concentration of a uremic substance, comprising an alkaline agent.
(2) A pharmaceutical composition for promoting urinary excretion of a uremic substance, comprising an alkaline agent.
(3) A pharmaceutical composition for promoting in vitro excretion of a uremic substance, comprising an alkaline agent.
(4) The pharmaceutical composition according to (2) or (3), wherein urinary excretion or extracorporeal excretion depends on the blood concentration of the uremic substance.
(5) The pharmaceutical composition according to any one of (1) to (4), which is administered to a patient with chronic kidney disease or acute kidney disease.
(6) 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.
(7) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid.
(8) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate, p-cresyl sulfate, and phenylacetyl L-glutamine.
(9) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate and phenylacetyl L-glutamine.
(10) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate and hippuric acid.
(11) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is phenylacetyl L-glutamine and p-cresyl sulfate.
(12) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate.
(13) A pharmaceutical composition for improving uremia symptoms in chronic kidney disease, comprising an alkaline agent.
(14) A pharmaceutical composition for delaying dialysis induction in chronic kidney disease, comprising an alkaline agent.
(15) A pharmaceutical composition for treating or preventing cardiovascular disease associated with chronic kidney disease, comprising an alkaline agent.
(16) The pharmaceutical composition according to (15), which improves arteriosclerosis.
(17) A pharmaceutical composition for inhibiting progression of chronic kidney disease, comprising an alkaline agent.
(18) A pharmaceutical composition for treating or preventing tubule injury, comprising an alkaline agent.
(19) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with early chronic kidney disease.
(20) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with chronic kidney disease of stage G3b or lower.
(21) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with chronic kidney disease at stage G2 or higher and G3b or lower.
(22) The pharmaceutical composition according to any one of (1) to (18), which is administered to patients with stage G2 and G3a chronic kidney disease.
(23) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with stage G2 chronic kidney disease.
(24) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient whose β2-microglobulin concentration in urine is 290 μg / L or less.
(25) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient whose β2-microglobulin concentration in urine is 50 to 150 μg / L or less.
(26) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient having a blood cystatin C concentration of 0.5 to 2.2 mg / L or less.
(27) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient having a blood cystatin C concentration of 1.0 to 1.3 mg / L or less.
(28) A pharmaceutical composition for inhibiting progression from acute kidney disease to chronic kidney disease, comprising an alkaline agent.
(29) The pharmaceutical composition according to any one of (1) to (28), wherein the alkalinizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.
(30) The pharmaceutical composition according to any one of (1) to (29), wherein the alkalinizing agent is sodium citrate, potassium citrate or a hydrate thereof, or a mixture thereof.
(31) 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.
(35) The medicament according to any one of (1) to (34), wherein an increase in the urine concentration of the uremic substance compared to before the start of the alkalizing agent administration is detected 12 weeks after the administration of the alkalizing agent. Composition.
(36) The pharmaceutical composition according to any one of (1) to (35), wherein an increase in in vitro excretion of the uremic substance compared to before the start of administration of the alkaline agent is detected 12 weeks after administration of the alkaline agent. object.
(37) The pharmaceutical composition according to any one of (1) to (36), wherein administration of the alkalizing agent suppresses an increase in β2-microglobulin concentration in urine.
(38) The pharmaceutical composition according to any one of (1) to (37), wherein the increase in the concentration of β2-microglobulin in urine is suppressed 12 weeks after administration by administration of the alkaline agent. .
(39) The pharmaceutical composition according to any one of (1) to (38), wherein administration of the alkaline agent does not substantially lower the urinary β2-microglobulin concentration compared to before administration. .
(40) The urinary β2-microglobulin concentration is not substantially reduced by administration of the alkaline agent after 12 weeks from the start of administration, any one of (1) to (39) A pharmaceutical composition according to 1.
(41) The pharmaceutical composition according to any one of (1) to (40), wherein administration of the alkaline agent does not substantially increase cystatin C in the blood as compared to before administration.
(42) 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.
(43) 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.
(44) After 12 weeks of administration of the alkalinizing agent, the improvement of the proximal tubule injury and / or the glomerular injury is not observed as a result of administration of the alkalinizing agent as compared with before the start of the administration. The pharmaceutical according to any one of (1) to (43), wherein a decrease in blood concentration of the uremic substance, promotion of urinary excretion of the uremic substance, and / or promotion of in vitro excretion of the uremic substance are observed in comparison. Composition.
(45) The pharmaceutical composition according to any one of (1) to (44), wherein the alkalinizing agent is administered at 1 to 3 g / day.
(46) The pharmaceutical composition according to any one of (1) to (45), wherein the alkalinizing agent is administered at 1 to 1.5 g / day.
(47) The pharmaceutical composition according to any one of (1) to (46), wherein the alkalinizing agent is administered so that the morning urine has a pH of 5.2 to 6.8.
(48) The pharmaceutical composition according to any one of (1) to (47), wherein the alkalinizing agent is administered so that the morning urine has a pH of 6.0 or more and less than 6.2.
(49) The pharmaceutical composition according to any one of (1) to (48), wherein the alkalinizing agent is administered for 12 weeks or more.
(50) The pharmaceutical composition according to any one of (1) to (49), wherein the alkalinizing agent is administered for 12 weeks.
(50-1) The pharmaceutical composition according to any one of (1) to (50), wherein the amount of the uremic substance in urine is increased by administration of the alkalinizing agent.
(50-2) The pharmaceutical composition according to any one of (1) to (50) and (50-1), wherein the concentration of the uremic substance in urine is increased by administration of the alkalinizing agent.
(50-3) The administration of the alkalinizing agent exerts a blood concentration lowering effect, a urinary excretion promoting effect, and / or an extracorporeal excretion promoting effect of the uremic substance, and the effect is observed with respect to placebo administration. The pharmaceutical composition according to any one of (1) to (50), (50-1) and (50-2).
(50-4) Administration of an alkaline agent exerts a blood concentration lowering effect, urinary excretion promoting effect, and / or extracorporeal excretion promoting effect of a uremic substance. The pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-3).
(50-5) The pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-4), wherein the pharmaceutical composition is a tablet.
(50-6) The pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-5), wherein the urine is early morning urine.
(51) A food composition for reducing blood concentration of a uremic substance, promoting urinary excretion, and / or promoting in vitro excretion, comprising an alkaline agent.
(52) The food composition according to (51), wherein the alkalinizing agent is an alkali metal citrate salt or a hydrate thereof, or a mixture thereof.
(52-1) The food composition according to (51) or (52), which maintains renal function (suppresses tubular damage, protects tubular cells, or maintains tubular function).
(52-2) The food composition according to any one of (51), (52), and (52-1), wherein the alkalinizing agent is taken at 1 to 3 g / day.
(52-3) The food composition according to any one of (51), (52), (52-1) and (52-2), wherein the alkalinizing agent is taken at 1 to 1.5 g / day. .
(52-4) The blood concentration of the uremic substance is reduced compared to before the start of ingesting the alkaline agent or compared to the placebo intake, (51), (52) and (52-1) to (52 -3) The food composition according to any one of the above.
(52-5) The urinary concentration of the uremic substance is increased compared to before the start of ingesting the alkaline agent or compared to the placebo intake, (51), (52) and (52-1) to (52 -4) The food composition according to any one of 4).
(52-6) The amount of uremia substance in the urine increases compared to before the start of ingesting the alkaline agent or compared to the placebo intake, (51), (52) and (52-1) to (52 The food composition according to any one of -5).
(52-7) In vitro excretion of uremic substances is increased compared to before the start of ingestion of an alkaline agent or compared to ingestion of a placebo, (51), (52) and (52-1) to (52- The food composition according to any one of 6).
(52-8) The increase in β2-microglobulin concentration in urine is suppressed by ingestion of an alkaline agent, any one of (51), (52) and (52-1) to (52-7) The food composition as described in 1.
(52-9) Concentration of β2-microglobulin in urine is not substantially decreased by ingestion of an alkaline agent before or after ingestion of placebo, (51), (52) and (52-1) ) To (52-8).
(52-10) The cystatin C in the blood is not substantially increased by ingestion of the alkaline agent, (51), (52) and any one of (52-1) to (52-9) Food composition.
(52-11) The food composition according to any one of (51), (52) and (52-1) to (52-10), wherein the alkalinizing agent is ingested for 12 weeks or more.
(52-12) The food composition according to any one of (51), (52) and (52-1) to (52-11), wherein the alkalinizing agent is ingested for 12 weeks.
(53) A method for determining inhibition of progression of chronic kidney disease, comprising measuring urine pH.
(54) A method for determining a decrease in the concentration of a uremic substance in the blood of a patient with chronic kidney disease, the method comprising measuring the pH of urine.
(55) 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.

Furthermore, 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.
(59) 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.
(60) 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.
(63) The pharmaceutical composition according to any one of (56) to (62), wherein the alkalinizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.
(64) The pharmaceutical composition according to any one of (56) to (63), wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. .

Furthermore, the present invention has the following aspects.
(65) A food composition containing an alkaline agent and maintaining renal function.
(66) The food composition according to (65), wherein the maintenance of renal function is suppression of tubular damage, protection of tubular cells, or maintenance of tubular function.
(67) The food composition according to (66), wherein the tubule is a proximal tubule.
(68) The food composition according to any one of (65) to (67), wherein the alkalinizing agent is a food acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.
(69) The food composition according to any one of (65) to (68), wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. .
(70) The food composition according to any one of (65) to (69), wherein the alkalinizing agent is sodium citrate or a hydrate thereof.
(71) The food composition according to any one of (65) to (70), wherein the food composition is a tablet.
(72) The food composition according to any one of (65) to (71), wherein the effect of maintaining renal function is indicated on the package, container, or instructions of the food composition.
(73) Any one of (65) to (71), wherein the effect of inhibiting tubular damage, protecting tubular cells, or maintaining tubular function is displayed on the packaging, container or instruction of the food composition The food composition as described in 1.
(74) The food composition according to any one of (65) to (72), which is taken by a healthy person who is concerned about kidney health.
(75) The food composition according to any one of (65) to (71) and (73), which is taken by a healthy person concerned about the health of the tubule.
(76) The food composition according to any one of (65) to (75), which is taken by a subject having a urinary β2-microglobulin concentration of 290 μg / L or less.
(77) The food composition according to any one of (65) to (76), which is taken by a subject having a urinary β2-microglobulin concentration of 50 to 150 μg / L.
(78) The food composition according to any one of (65) to (77), which is taken by a subject having a blood cystatin C concentration of 0.5 to 2.2 mg / L.
(79) The food composition according to any one of (65) to (78), which is taken by a subject having a blood cystatin C concentration of 1.0 to 1.3 mg / L.
(80) The food composition according to any one of (65) to (79), wherein the intake of the food composition suppresses an increase in β2-microglobulin concentration in urine.
(81) The food composition according to any one of (65) to (80), wherein an increase in β2-microglobulin concentration in the urine is suppressed by ingestion of the food composition after 12 weeks of ingestion .
(82) The food according to any one of (65) to (81), wherein the concentration of β2-microglobulin in urine is not substantially decreased by ingestion of the food composition before the start of ingestion or compared with placebo. Composition.
(83) Any of (65) to (82), wherein the concentration of β2-microglobulin in urine is not substantially reduced after ingestion 12 weeks after ingestion or compared to placebo due to ingestion of the food composition The food composition according to one.
(84) The food composition according to any one of (65) to (83), wherein ingestion of the food composition does not substantially increase cystatin C in the blood as compared to before the start of ingestion.
(85) The food composition according to any one of (65) to (84), wherein ingestion of the food composition does not substantially increase cystatin C in blood compared to placebo.
(86) The intake of the food composition suppresses an increase in the amount of β2-microglobulin in early morning urine accompanying progression of the stage of chronic kidney disease, any one of (65) to (85) Food composition.
(87) Ingestion of the food composition does not affect the glomerular function of patients with chronic kidney disease, while suppressing proximal tubular cell damage associated with progression of the stage of chronic kidney disease, and proximal tubules The food composition according to any one of (65) to (86), which protects cells.

The uremic substance is excreted from the body of the mammal by the pharmaceutical composition provided by the present invention. By 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. With the food composition and the like provided by the present invention, it is possible to maintain renal function in mammals, more specifically, to suppress tubular damage, protect tubular cells, or maintain tubular function.

It is a figure which shows the correlation of the urinary indoxyl sulfate concentration and the plasma indoxyl sulfate concentration in the patient of the control group 6 weeks after the start of the test, 12 and 24 weeks. It is a figure which shows the correlation of the urinary indoxyl sulfate density | concentration and the plasma indoxyl sulfate density | concentration in the patient of the group administration administration group of potassium citrate and sodium citrate hydrate 6 weeks and 12 weeks after the start of the test. It is a figure which shows the correlation of the urinary indoxyl sulfate density | concentration and the plasma indoxyl sulfate density | concentration in the patient of the sodium hydrogencarbonate formulation administration group after the start of a test 6, 12 and 24 weeks. It is a figure which shows the correlation of the urinary indoxyl sulfate concentration and the plasma indoxyl sulfate concentration in all the patients 6th, 12th, and 24th week 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 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 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 | concentration and plasma hippuric acid density | concentration in the patient of a control group after the test start 6, 12 and 24 weeks. It is a figure which shows the correlation of the urinary hippuric acid density | concentration and the plasma hippuric acid density | concentration in the patient of the patient who is a combination dosage administration group of potassium citrate and sodium citrate hydrate 6 weeks and 12 weeks after the start of the test. It is a figure which shows the correlation of the urinary hippuric acid density | concentration and the plasma hippuric acid density | concentration in the patient of a sodium hydrogencarbonate formulation administration group 6 weeks, 12 weeks, and 24 weeks after a test start. It is a figure which shows the correlation of the urinary hippuric acid density | concentration and plasma hippuric acid density | concentration in all the patients 6th, 12th, and 24th week after a test start. It is a figure which shows the correlation of the urinary arginino succinic acid density | concentration and the plasma arginino succinic acid density | concentration in the patient of a control group 6, 12 and 24 weeks after the start of a test. It is a figure which shows the correlation of the urinary arginino succinic acid density | concentration and the plasma arginino succinic acid density | concentration in the patient of the patient who is the administration group of potassium citrate / sodium citrate hydrate combination preparation 6, 12 and 24 weeks after the start of the test. It is a figure which shows the correlation of the urinary arginino succinic acid concentration and the plasma arginino succinic acid density | concentration in the patient of a sodium hydrogencarbonate preparation group 6 weeks after the start of a test, 12 and 24 weeks. It is a figure which shows the correlation of the urinary arginino succinic acid density | concentration and plasma arginino succinic acid density | concentration in all the patients 6th, 12th, and 24 weeks after the start of a test. It is a figure which shows the correlation of the urinary phenylacetyl L glutamine density | concentration and the plasma phenylacetyl L glutamine density | concentration in the patient of a control group 6, 12 and 24 weeks after the start of a test. It is a figure which shows the correlation of the urinary phenyl acetyl L glutamine density | concentration and the plasma phenyl acetyl L glutamine density | concentration in the patient of the group administration administration group of potassium citrate and sodium citrate hydrate 6 weeks after the start of the test, 12 and 24 weeks. . It is a figure which shows the correlation of the urinary phenylacetyl L glutamine density | concentration and the plasma phenylacetyl L glutamine density | concentration in the patient of the sodium hydrogencarbonate formulation administration group 6 weeks after the start of a test, and 12 weeks. It is a figure which shows the correlation of the urinary phenylacetyl L glutamine density | concentration and the phenylacetyl L glutamine density | concentration in plasma in all the patients 6th, 12th, and 24 weeks after a test start.

1. Pharmaceutical Composition The pharmaceutical composition provided by the present invention 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. Examples of alkalinizing agents include pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, and sodium hydrogen carbonate (bicarbonate). Examples of pharmaceutically acceptable salts of citric acid include alkali metal citrate salts. Examples of 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.
Examples of 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.
Other examples of 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). There may be.
In one embodiment, 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.
In another embodiment, 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.
In the present specification, 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₎ When referring to the weight of O ₇ · 2H ₂ O)), the weight can be dry weight.

In this specification, 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. Examples of uremic substances include indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid.
Among these, indoxyl sulfate is produced by oxidation and sulfate conjugation in the liver of indole produced by enteric bacteria from tryptophan derived from dietary protein. 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. In one embodiment, the chronic kidney disease patient has progressive chronic kidney disease.
In the present specification, the expression [A, B and / or C] means that “at least one selected from the group consisting of A, B and C” is selected. Thus, for example, “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) and / or stroke, which is a cerebrovascular disease, is developed.
Therefore, by reducing the indoxyl sulfate concentration in the blood, it suppresses myocardial fibrosis, arteriosclerosis, vascular smooth muscle cell proliferation, vascular endothelial cell damage, arterial wall thickening, aortic calcification, etc. It becomes possible to treat and / or prevent cardiovascular diseases and / or cerebrovascular diseases, which are one of complications of kidney disease patients.

In one aspect, 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. Examples of 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 sulfate; hippuric acid; and phenylacetyl L glutamine.
In the present specification, “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 the uremic substance in the blood is decreased, or the administration of the pharmaceutical composition provided by the present invention means that the concentration of the uremic substance in the blood is decreased as compared with the placebo administration.
In one embodiment, 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 and p-cresyl sulfate; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl L glutamine; p-cresyl sulfate and phenylacetyl L glutamine; hippuric acid and phenylacetyl L glutamine; indoxyl sulfate; Cresyl sulfate Hippuric acid; or phenylacetyl L-glutamine)), but the amount of decrease is 1 to 5%, 3 to 5%, 1 to 10%, 3% of the blood concentration of uremic substances before administration. -10%, 5-10%, 1-15%, 3-15%, 5-15%, 1-30%, 1-40%, 3-40%, 5-40%, 1-50%, 3 -50%, 5-50%, 30-50%, 1-60%, 5% or more, 10% or more, or 30% or more.
In one embodiment, the amount of decrease in the blood concentration of the uremic substance is calculated by the following calculation formula (1).
Decrease in blood concentration of 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 (1)
In one embodiment, 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 L-glutamine; indoxyl sulfate 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 phenylacetyl L glutamine; hippuric acid and phenylacetyl L Glutamine; Indoki P-cresylsulfuric acid; hippuric acid; or phenylacetyl L-glutamine)) is decreased, but the decreased amount is 1 to 5% of the blood concentration of uremic substance before administration, 3 to 5 %, 1-10%, 3-10%, 5-10%, 1-15%, 3-15%, 5-15%, 1-30%, 1-40%, 3-40%, 5-40 %, 1-50%, 3-50%, 5-50%, 30-50%, 1-60%, 5% or more, 10% or more, or 30% or more.
In one aspect, 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. Examples of 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 L-glutamine; Indoxyl sulfate and hippuric acid; Indoxyl sulfate and phenylacetyl L-glutamine; Hippuric acid and acetyl L-glutamine and argininosuccinic acid Indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and arginosuccinic acid Acids; phenylacetyl L-glutamine and arginosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; and phenylacetyl L-glutamine.
In this specification, “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 administration of a pharmaceutical composition provided by the present invention means that the concentration of uremic substances in the urine is increased compared to placebo administration, which means that the concentration of uremic substances in the urine is increased. Means that the amount of uremia substance in urine after administration is increased compared to the amount of uremia substance in urine before administration of the pharmaceutical composition provided by the invention or provided by the present invention Administration of the composition means an increase in the amount of uremic substances in the urine compared to placebo administration.
In this specification, “in urine” means, for example, “in early morning urine”.
In one embodiment, 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 sulfate, phenylacetyl L glutamine and argininosuccinic acid; indoxyl sulfate, hippuric acid and phenylacetyl Indoxyl sulfate and hippuric acid; Indoxyl sulfate and phenylacetyl L glutamine; Hippuric acid and phenylacetyl L glutamine; Indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl L-glutamine; p-cresyl sulfate Indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and arginosuccinic acid; phenylacetyl L-glutamine and arginosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenyl Acetyl L-Glutamine)) concentration is 1-100%, 1-50%, 3-50%, 5-50%, 10-50%, 15-50%, 1-40%, 5-40%, 10- 40%, 1-30%, 5-30%, 10-30%, 15-30%, more than 10%, more than 20%, more than 30% or more than 40% The
In one embodiment, the amount of increase in the urine concentration of the uremic substance is calculated by the following calculation formula (2).
Increase in urine concentration of uremic substance (%) = [(Urine concentration of uremic substance after administration of pharmaceutical composition (ng / mL)-Urinary concentration of uremic substance before administration of pharmaceutical composition (ng) / mL)) / Urine concentration of uremic substance before administration of pharmaceutical composition (ng / mL)] × 100 (2)
In one embodiment, 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, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine and Indoxyl 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 argininosuccinate; Indoxyl sulfate, Uric acid and phenylacetyl L glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl L glutamine; hippuric acid and phenylacetyl L glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl L glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and arginosuccinic acid; phenylacetyl L glutamine and arginosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; Acid; or phenylacetyl L-glutamine)) concentration is 1-100%, 1-50%, 3-50%, 5-50%, 10-50%, 15-50%, 1-40%, 5-40 %, 10-40%, 1-30%, 5-30%, 10-30%, 15-30%, 10% or more, 20% or more, 3 Increase by 0% or more or 40% or more.
In one aspect, 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. Examples of 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 L-glutamine; Indoxyl sulfate and hippuric acid; Indoxyl sulfate and phenylacetyl L-glutamine; Hippuric acid and acetyl L-glutamine and argininosuccinic acid Indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and arginosuccinic acid Acids; phenylacetyl L-glutamine and arginosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; and phenylacetyl L-glutamine.
In one embodiment, administration of the pharmaceutical composition provided by the present invention compares the ratio of the concentration of uremic substance in urine to the concentration of blood uremic substance prior to administration of the pharmaceutical composition provided by the present invention. Thus, the ratio of the urinary substance concentration in the urine to the blood uremic substance concentration after administration increases. In one embodiment, administration of a pharmaceutical composition provided by the present invention increases the ratio of urinary uremic substance concentration to blood uremic substance concentration relative to placebo administration.
In one embodiment, 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). 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; indoxyl sulfate and phenylacetyl L glutamine; hippuric acid and phenylacetyl L glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl L glutamine; p- Indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and arginosuccinic acid; phenylacetyl L-glutamine and arginosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; Or phenylacetyl L-glutamine)) (ratio in urine (ng / mL) / blood concentration (ng / mL)) 1-100%, 1-50%, 3-50%, 5-50% , 10-50%, 15-50%, 1-40%, 5-40%, 10-40%, 1-30%, 5-30%, 10-3 Increase by 0%, 15-30%, 10% or more, 20% or more, 30% or more or 40% or more.
In one embodiment, the increase in the ratio of the urine concentration to the blood concentration of the uremic substance (urine concentration (ng / mL) / blood concentration (ng / mL)) is calculated by the following formula (3): Is calculated by
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)
In one embodiment, 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, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenyl Acetyl 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, phenylacetyl L glutamine and argininosuccinic acid; I Doxyl sulfate, hippuric acid and phenylacetyl L glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl L glutamine; hippuric acid and phenylacetyl L glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenyl P-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and arginosuccinic acid; phenylacetyl L glutamine and arginosuccinic acid; indoxyl sulfate; p-cresyl sulfate; Ratio of hippuric acid; argininosuccinic acid; or phenylacetyl L-glutamine) (urinary concentration (ng / mL) / blood concentration (ng / mL)) is 1 to 100%, 1 to 50%, 3 to 50 %, 5-50%, 10-50%, 15-50%, 1-40%, 5-40%, 10-40 %, 1-30%, 5-30%, 10-30%, 15-30%, 10% or more, 20% or more, 30% or more, or 40% or more.
In one embodiment, 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.
In one embodiment, 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. Depending on the concentration, 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. When the blood concentration of the uremic substance is low, the excretion amount of the uremic substance into the urine is low. Such urinary excretion of uremic substances depending on blood concentration suggests that the pharmaceutical composition provided by the present invention has a low risk of side effects and excellent safety. Examples of 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.
In one embodiment, 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. Depending on the concentration, excretion of the uremic substance into the urine is facilitated, thereby reducing the blood concentration of the uremic substance. Examples of 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.
In one embodiment, 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 (urine concentration / blood concentration) can be 1 to 1000, preferably 1 to 200, more preferably 1 to 100, and even more preferably 10 to 100. In this embodiment, 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 μg / mL (eg, 0.1 to 30 μg / mL). Also good. Further, as a result of the administration, the blood concentration of indoxyl sulfate may be 0.01 to 10 μg / mL (for example, 0.03 to 10 μg / mL).
In one embodiment, 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 (urine concentration / blood concentration) can be 0.1 to 1000, preferably 1 to 300, more preferably 1 to 150, and even more preferably 1 to 100. In this embodiment, 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 μg / mL (eg, 0.01 to 30 μg / mL). May be. As a result of the administration, the blood concentration of p-cresyl sulfate may be 0.001 to 100 μg / mL (eg, 0.001 to 30 μg / mL).
In one embodiment, 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 (urinary concentration / blood concentration) can be 1-1500, preferably 1-1000, more preferably 10-800, and even more preferably 10-600. In this embodiment, 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 μg / mL (eg, 0.1 to 10 μg / mL). May be. Further, as a result of the administration, the blood concentration of phenylacetyl L-glutamine may be 0.01 to 10 μg / mL (for example, 0.03 to 10 μg / mL).
In one embodiment, 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. In this embodiment, 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 μg / mL (for example, 0.1 to 10 μg / mL), As a result of the administration, the blood concentration of indoxyl sulfate may be 0.01 to 10 μg / mL (for example, 0.1 to 10 μg / mL).
In one embodiment, 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. (Urine concentration / blood concentration) shows a high correlation. In this embodiment, 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 blood concentration of p-cresyl sulfate of 0.001 to 100 μg / mL (eg, 0.01 to 50 μg / mL). As a result of the administration, the blood concentration of p-cresyl sulfate may be 0.001 to 100 μg / mL (for example, 0.01 to 50 μg / mL).
In one embodiment, 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. In this embodiment, 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. In addition, 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 μg / mL (eg, 0.05 to 10 μg / mL). As a result, the blood concentration of phenylacetyl L-glutamine may be 0.01 to 10 μg / mL (for example, 0.05 to 10 μg / mL).
Due to such characteristics 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 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. It can be used either as a pharmaceutical composition for dialysis or as a pharmaceutical composition for delaying the introduction of dialysis in patients with chronic kidney disease.
As used herein, “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. Accordingly, in one embodiment, “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. In another embodiment, “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.
In the present specification, “healthy” represents a state in which there is no acute or chronic disease or disorder, and “normal” represents that a healthy subject is normally in a state of expression.
As used herein, “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. In one embodiment, “treatment” is to eliminate, cure, cure or ameliorate a “pathological” or “abnormal” symptom, condition or disease. In another embodiment, “treatment” is the elimination, complete cure, cure or amelioration of a “pathological” or “abnormal” symptom, condition or disease.
As used herein, “prevention” is a concept that includes the prevention and development of “pathological” or “abnormal” symptoms, conditions or diseases.
In the present specification, the term “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.
As used herein, “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. In one embodiment, “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.
Here, the symptom, condition or disease is compared before and after administration of the pharmaceutical composition provided by the present invention.
In addition, due to the characteristics of the pharmaceutical composition provided by the present invention as described above, 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.

In addition, when a drug that lowers the blood concentration of indoxyl sulfate was administered to patients with non-diabetic chronic kidney disease, the pulse wave velocity and carotid intima-media thickness were measured. Since it has been reported that it has improved significantly compared to before (Nakamura T., et al .: Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure. Kidney Blood Press s 27: 121-6, 2004.), 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.

In addition, drugs that reduce the blood concentration of indoxyl sulfate have been reported to suppress cisplatin-induced acute kidney injury (Morisaki T., et. Al.,: Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats. Pharm. Res., 25 (11): 2526-33, 2008). Therefore, 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.

In addition, p-cresyl sulfate, a uremic substance, has been reported to be a causative agent of vascular endothelial injury (Meijers BK, et. Al.,: The uremic retention solute p-cresyl sulfate and markers of endothelial damage). ., Am. J. Kidney Dis., 54: 891-901, 2009).
In one aspect, 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.
In addition, it is reported that phenylacetyl L-glutamine, which is a uremic substance, increases the risk of developing cardiovascular disease in patients with chronic kidney disease.
In one aspect, 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.
In one embodiment, 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.
In one embodiment, 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 (for example, a mixture of potassium citrate monohydrate and sodium citrate dihydrate) is a kidney disease patient (preferably a chronic kidney disease patient) To be administered.
In one embodiment, 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).
In one embodiment, 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. The
In one embodiment, sodium bicarbonate is administered to a kidney disease patient (preferably a chronic kidney disease patient) to increase the urinary arginosuccinic acid concentration.

In one aspect, 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.
In another aspect, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for maintaining renal function.
In one embodiment, the pharmaceutical composition provided by the present invention includes a pharmaceutical composition for inhibiting tubular cell damage, a pharmaceutical composition for protecting tubular cells, or a tubular cell function (for example, water, sodium ion, potassium ion, It is a pharmaceutical composition for maintaining (reabsorption of calcium ions, phosphate ions, bicarbonate ions, chlor ions, glucose, amino acids, vitamins, etc.).
In one embodiment, 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 the maintenance of reabsorption of amino acids and vitamins.
In one embodiment, the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) accompanying progression of the stage of chronic kidney disease. .
In one embodiment, 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.
In the present specification, “kidney function maintenance” means, for example, suppression of tubular damage, protection of tubular cells, or maintenance of tubular function. The tubules may be, for example, proximal tubules, and one aspect of maintaining tubule function or maintaining proximal tubule function is maintaining tubule cell function or maintaining proximal tubule cell function.
In the present specification, “protection of cells” means maintenance or maintenance of the state of cells or suppression of cell damage. Here, suppression has the above-mentioned meaning.
In the present specification, “maintenance of cell function” means maintenance of cell function or suppression of deterioration of cell function. Here, suppression has the above-mentioned meaning.
Here, the state or function of the cells is compared before and after the administration of the pharmaceutical composition provided by the present invention.
In this specification, “early morning urine” represents the first urine after getting up.
In one embodiment, the pharmaceutical composition provided by the present invention comprises β2-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.
In one embodiment, the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) accompanying progression of the stage of chronic kidney disease. However, compared to before administration of the pharmaceutical composition provided by the present invention, the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) is not substantially reduced. In this embodiment, for example, when the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) before the start of administration of the pharmaceutical composition provided by the present invention is 1, urine after administration (for example, The amount (concentration) of β2-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.
In one embodiment, the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) accompanying progression of the stage of chronic kidney disease. However, the amount of β2-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. In this embodiment, for example, when the amount (concentration) of β2-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 β2-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.
In one embodiment, 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. In this embodiment, for example, when 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, 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.
In one embodiment, 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. In this embodiment, for example, when 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 Alternatively, at 24 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. It can be ˜1.05, 0.9 to 1.2, 0.9 to 1.15, 0.9 to 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.
In one embodiment, 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.
In one embodiment, 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. Examples of 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. For example, for a tablet, the alkalinizing agent may be an excipient (eg lactose, D-mannitol, crystalline cellulose, glucose), 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.
The tablet according to the present invention will be described in more detail below.

In one embodiment, 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). In addition to a mixture; or sodium bicarbonate), 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.

Examples of excipients that can be used in the tablets provided by the present invention 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.

Examples of binders that can be used in the tablets provided by the present invention 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.

Examples of disintegrants that may be used in tablets provided by the present invention 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.

Examples of pH adjusters that can be used in tablets provided by the present invention 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.

Examples of surfactants that can be used in the tablets provided by the present invention 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.
Examples of stabilizers that can be used in the tablets provided by the present invention 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. In the coating layer, in addition to the coating base, 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. 6000 is preferred. 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.
Examples of 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.
Examples of 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. For example, in the case of tablets, 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. Moreover, before the tableting process, the process which mixes the mixture containing an alkalizing agent and an additive with a lubricant, a corrigent, and / or a fragrance | 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.
In one embodiment, 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. obtain. 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 μm) to 32 mesh sieve (aperture 500 μm), etc.
The tableting step can be performed by a tableting method known in the pharmaceutical field. Examples of the tableting method include a direct tableting method, a dry tableting method, a wet tableting method, and an external lubricant tableting method. For example, 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. When using a single tableting machine, a rotary tableting machine, etc., 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 | area. For example, 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.
In one embodiment, 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 plasticizer (eg triethyl citrate and / or Kurogoru 6000), colorants (e.g., ferric oxide and / or titanium oxide) and gloss agent (e.g., can be produced by forming a coating layer containing carnauba wax).
In one embodiment, the resulting tablets can have a hardness of 10-200N, preferably 30-150N.

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. Or 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 In case of 1 tablet: 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.
In one embodiment, 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.
In one embodiment, the pharmaceutical composition provided by the present invention is a tablet. In one 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.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, a tablet containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate may be a dosage unit.
In the present specification, “dosage unit” represents a unit of the preparation, and “1 dosage unit” represents the minimum unit of the preparation. Thus, for example, for tablets, the dosage unit is each tablet, and one dosage unit represents one tablet. In the case of an injection, 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.
When 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.
In one embodiment, when 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.
In one embodiment, when 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).
In one embodiment, when 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 dose may be increased up to the dose.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human as an alkaline agent, 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. It may be administered 1 to 5 times a day, preferably 3 times a day.
In one embodiment, when 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.
In one embodiment, when 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.

In one embodiment, 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 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.
In one embodiment, 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. Beneficial 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 β2-microglobulin concentration increasing inhibitory effect) Can be detected.

In one embodiment, the pharmaceutical composition provided by the present invention is administered to a human suffering from kidney disease. Kidney disease includes acute kidney disease and chronic kidney disease unless otherwise specified.
Examples of 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).

According to the CKD Medical Guide 2012 (Nichirenkai 2012), 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 )
G5: 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)
In addition, proteinuria (albuminuria: A) is classified into the following categories using the urine protein / creatinine (Cr) ratio when the primary disease is hypertension other than diabetes, nephritis, polycystic kidneys, transplanted kidneys, etc. Are classified as follows.
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)
According to CKD medical care guide 2012 (Nichirenkai 2012), the severity classification of chronic kidney disease (CKD) is expressed as, for example, diabetes G2A3, chronic nephritis G3bA1, etc. using the above C, G and A.
However, it is considered that 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. And G5 can also be described.

In one embodiment, the pharmaceutical composition provided by the present invention is administered to low-severity, early-stage chronic kidney disease patients.
In one embodiment, 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.
In one embodiment, 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
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, the pharmaceutical composition provided by the present invention has a concentration of β2-microglobulin in urine (eg, early morning urine) of 2000 μg / L or less, 1000 μg / L or less, 800 μg / L or less, 290 μg / L L or less, 200μg / L or less, 1 to 2000μg / L, 1 to 1000μg / L, 1 to 800μg / L, 1 to 290μg / L, 1 to 200μg / L, 10 to 2000μg / L, 10 to 1000μg / L, It is administered to patients with chronic kidney disease who are 10-800 μg / L, 10-290 μg / L, 10-200 μg / L or 80-200 μg / L.
In one embodiment, 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.
In one embodiment, 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 μg / mL (eg, 0.1 to 30 μg / 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 μg / mL (eg, 0.01 to 30 μg / mL). .
In one embodiment, 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 μg / mL (eg, 0.01 to 10 μg / 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 μg / mL (eg, 0.1 to 10 μg / mL).
In one embodiment, 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 μg / mL (eg, 0.1 to 10 μg / mL). .

In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient receiving treatment according to 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 α-glucosidase inhibitor, etc.), lipid management (statin, fibrate administration, etc.), anemia management (erythropoietin administration, etc.) and / or bone / mineral measures (bisphosphonate administration, etc.).
In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with an antihypertensive drug (eg, ARB, ACE inhibitor, diuretic, Ca antagonist).
In one embodiment, 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).

In one embodiment, 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. Reduce and promote excretion of uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid and / or phenylacetyl L-glutamine) out of the body (eg, into urine). In this embodiment, 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 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.
In one embodiment, 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 β2-microglobulin in the patient's urine. In this embodiment, 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.
In one embodiment, 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. Reduce the concentration of toxic substances (eg, indoxyl sulfate, hippuric acid and / or phenylacetyl L-glutamine) and reduce uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid and / or phenylacetyl) Promotes excretion of L-glutamine outside the body (eg, into urine). In this embodiment, 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.
In one embodiment, 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 β2 in the urine of the patient is administered. -Suppress the increase in microglobulin. In this embodiment, 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 agent to a subject in need of delaying dialysis introduction, wherein the subject suffers from chronic kidney disease. The method;
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 wherein the subject is suffering from kidney disease;
j) A method for inhibiting vascular endothelial cell injury in a mammalian subject (eg, human) comprising administering an effective amount of an alkaline agent to a subject in need of inhibiting vascular endothelial cell injury, wherein the subject is renal disease Suffering from a method;
k) A method for inhibiting arterial wall thickening in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of inhibiting arterial wall thickening, wherein the subject comprises a kidney Suffering from a disease, method;
l) A method for inhibiting aortic calcification in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of inhibiting aortic calcification, wherein the subject is a kidney Suffering from a disease, method;
m) A method of treating or preventing a cardiovascular disease 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 the cardiovascular disease, The subject is suffering from kidney disease;
n) A method of ameliorating arteriosclerosis in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of amelioration of arteriosclerosis, wherein the subject is suffering from kidney disease Is the method;
o) A method of improving arterial wall thickening in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of improving arterial wall thickening, wherein the subject is a kidney Suffering from a disease, method;
p) A method of treating acute kidney disease in a mammalian subject (eg, a human), comprising administering an effective amount of an alkaline agent to a subject in need of treatment of acute kidney disease;
q) A method for inhibiting the progression from acute kidney disease to chronic kidney disease in a mammalian subject (eg, human), wherein the subject needs to inhibit the progression from acute kidney disease to chronic kidney disease. 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 cell function in a mammalian subject (eg, a human) comprising administering an effective amount of an alkaline agent to a subject in need of maintaining proximal tubular cell function. ;
w) A method for promoting the excretion of a uremic substance outside a body in a mammalian subject (eg, a human), wherein 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;

aa) an alkaline agent for use in lowering blood levels of uremic substances;
bb) an alkaline agent for use in promoting the excretion of uremic substances into the urine;
cc) an alkalinizing agent for use in ameliorating uremia symptoms in patients with kidney disease;
dd) an alkaline agent for use in the treatment or prevention of uremia in patients with kidney disease;
ee) an alkaline agent for use in inhibiting the progression of chronic kidney disease;
ff) an alkaline agent for use in delaying dialysis induction in patients with chronic kidney disease;
gg) an alkaline agent for use in inhibiting myocardial fibrosis in patients with kidney disease;
hh) an alkalinizing agent for use in inhibiting arteriosclerosis in patients with kidney disease;
ii) an alkalinizing agent for use in inhibiting vascular smooth muscle cell proliferation in patients with kidney disease;
jj) an alkalinizing agent for use in inhibiting vascular endothelial cell injury in patients with kidney disease;
kk) an alkaline agent for use in inhibiting arterial wall thickening in patients with kidney disease;
ll) an alkaline agent for use in inhibiting aortic calcification in patients with kidney disease;
mm) an alkaline agent for use in the treatment or prevention of cardiovascular disease in patients with kidney disease;
nn) an alkaline agent for use in improving arteriosclerosis in patients with kidney disease;
oo) an alkaline agent for use in improving arterial wall thickening in patients with kidney disease;
pp) an alkaline agent for use in the treatment of acute kidney disease;
qq) an alkalinizing agent for use in inhibiting progression from acute kidney disease to chronic kidney disease;
rr) an alkaline agent for use in the treatment or prevention of tubular disorders;
ss) an alkalinizing agent for use in the suppression of tubular injury;
tt) an alkalinizing agent for use in inhibiting proximal tubular cell damage;
uu) an alkaline agent for use in protecting proximal tubular cells;
vv) an alkalinizing agent for use in maintaining proximal tubular cell function;
ww) an alkalinizing agent for use in promoting the excretion of uremic substances outside the body;
xx) an alkaline agent for use in urinary excretion depending on the blood concentration of the uremic substance;

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) a pharmaceutical composition comprising an alkaline agent for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease;
jjj) a pharmaceutical composition comprising an alkalinizing agent for use in inhibiting vascular endothelial cell injury in kidney disease patients;
kkk) a pharmaceutical composition comprising an alkaline agent for use in inhibiting thickening of the arterial wall in patients with kidney disease;
lll) a pharmaceutical composition comprising an alkaline agent for use in inhibiting aortic calcification in patients with kidney disease;
mmm) a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of cardiovascular disease in a patient with kidney disease;
nnn) a pharmaceutical composition comprising an alkaline agent for use in improving arteriosclerosis in patients with kidney disease;
oo) a pharmaceutical composition comprising an alkaline agent for use in improving arterial wall thickening in patients with kidney disease;
ppp) a pharmaceutical composition comprising an alkaline agent for use in the treatment of acute kidney disease;
qqq) a pharmaceutical composition comprising an alkalinizing agent for use in inhibiting progression from acute kidney disease to chronic kidney disease;
rrr) a pharmaceutical composition comprising an alkaline agent for use in the treatment or prevention of tubular disorders;
sss) a pharmaceutical composition comprising an alkalinizing agent for use in inhibiting tubular damage;
ttt) a pharmaceutical composition comprising an alkalinizing agent for use in inhibiting proximal tubular cell damage;
uu) a pharmaceutical composition comprising an alkalizing agent for use in protecting proximal tubular cells;
vvv) a pharmaceutical composition comprising an alkaline agent for use in maintaining proximal tubular cell function;
www) a pharmaceutical composition comprising an alkaline agent for use in promoting the excretion of a uremic substance outside the body;
xxx) a pharmaceutical composition comprising an alkaline agent for use in urinary excretion depending on the blood concentration of the uremic substance;

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 arteriosclerosis in patients with kidney disease;
iii) use of an alkaline agent for the manufacture of a pharmaceutical composition for inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease;
jjjj) Use of an alkalizing agent to produce a pharmaceutical composition for inhibiting vascular endothelial cell injury in patients with kidney disease;
kkkk) use of an alkalizing agent to produce a pharmaceutical composition for inhibiting thickening of the arterial wall in patients with kidney disease;
llll) use of an alkalinizing agent for the manufacture of a pharmaceutical composition for inhibiting aortic calcification in patients with kidney disease;
mmmm) use of an alkaline agent for the manufacture of a pharmaceutical composition for the treatment or prevention of cardiovascular disease in patients with kidney disease;
nnnn) use of an alkalinizing agent to produce a pharmaceutical composition for improving arteriosclerosis in patients with kidney disease;
oooo) use of an alkalizing agent to produce a pharmaceutical composition for improving arterial wall thickening in patients with kidney disease;
pppp) use of an alkalizing agent for the manufacture of a pharmaceutical composition for the treatment of acute kidney disease;
qqqq) Use of an alkaline agent for producing a pharmaceutical composition for inhibiting the progression from acute kidney disease to chronic kidney disease;
rrrr) use of an alkalinizing agent for the manufacture of a pharmaceutical composition for the treatment or prevention of tubular disorders;
ssss) use of an alkalinizing agent for producing a pharmaceutical composition for inhibiting tubule injury;
ttt) use of an alkalinizing agent for the manufacture of a pharmaceutical composition for inhibiting proximal tubular cell injury;
uuu) use of an alkalinizing agent to produce a pharmaceutical composition for protecting proximal tubular cells;
vvvv) use of an alkalinizing agent to produce a pharmaceutical composition for maintaining proximal tubular cell function;
www) use of an alkaline agent to produce a pharmaceutical composition for promoting the excretion of a uremic substance outside the body; and xxx) a pharmaceutical composition for excretion in the urine depending on the blood concentration of the uremic substance. Use of an alkalinizing agent for production.

2. Food Composition In one embodiment, 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.
In one embodiment, the food composition provided by the present invention contains an alkalinizing agent and exhibits an effect of lowering the blood concentration of a uremic substance.
In one embodiment, the food composition provided by the present invention includes an alkalizing agent and exhibits an effect of promoting urinary excretion of a uremic substance.
In one embodiment, the food composition provided by the present invention contains an alkalinizing agent and exhibits a renal function maintenance effect.
In one embodiment, the food composition provided by the present invention contains an alkalinizing agent, and has an effect of suppressing tubule injury. Here, examples of the tubule include a proximal tubule.
In one embodiment, the food composition provided by the present invention contains an alkalinizing agent and exhibits an effect of suppressing proximal tubular cell damage.
In one embodiment, the food composition provided by the present invention includes an alkalinizing agent and exhibits a protective effect on proximal tubular cells.
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent, and has a tubule function (eg, water, sodium ion, potassium ion, calcium ion, phosphate ion, bicarbonate ion, chlorion ion, Resorbs and maintains glucose, amino acids, vitamins, etc. Here, examples of the tubule include a proximal tubule, and examples of the proximal tubule function include reabsorption of glucose, amino acids, vitamins, and the like.
In the above embodiment, the food composition provided by the present invention has an effect of suppressing an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) accompanying the progression of the stage of chronic kidney disease. Play.
In the above embodiment, the food composition provided by the present invention does not affect the glomerular function of chronic kidney disease patients, while suppressing proximal tubular cell damage associated with progression of the stage of chronic kidney disease. It has the effect of protecting the proximal tubular cells.
For the alkalinizing agent, the alkalizing agent described in “1. Pharmaceutical composition” can be applied. Examples of alkalinizing agents include pharmaceutically acceptable salts of citric acid as a food acceptable salt of citric acid (eg, alkali metal citrate salts or hydrates thereof or mixtures thereof), sodium bicarbonate Preferably, 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) or sodium citrate dihydrate.
The uremic substance is also as described in “1. Pharmaceutical composition” above. Examples of 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. Examples of food compositions include foods for specified health use, dietary supplements, functional foods, hospital patient foods, and supplements. The form of these food compositions is not particularly limited as long as it contains an effective amount of an alkalizing agent for exerting the above-mentioned effects and can be taken orally, and is in the form of a normal food or drink. Of the preparations that can be applied to the pharmaceutical composition, the preparation may be provided as a preparation suitable for oral administration, for example, a preparation such as a tablet, a capsule, or a suspension. Regarding the constitution and production method of these preparations, in this specification, the constitution and production method of the pharmaceutical preparation described in the above “1. Pharmaceutical composition” can be applied as it is, and also in the field of pharmaceutical preparation technology itself. Known formulation techniques can be applied.
For example, in the case of foods for specified health use, dietary supplements, functional foods, or foods for hospital patients, potassium citrate monohydrate and sodium citrate dihydrate as the alkalinizing agent are combined in total for each serving of food. 1 to 3 g of 1/3 amount may be contained, or 1 to 6 g of 1/3 amount of sodium hydrogen carbonate as an alkalizing agent may be contained. When specified health foods, dietary supplements, functional foods, hospital patient foods, or supplements are provided as tablets, for example, a tablet of 300 mg to 600 mg per tablet with an alkalinizing agent of 70 to 80% by weight. May be included.
When the food composition provided by the present invention is not formulated and is provided in the form of a normal food or drink, a person skilled in the art can appropriately manufacture the food depending on the type of the food. For example, an alkaline agent (for example, Potassium citrate and / or sodium citrate).
As the form of the food and drink, liquid or milky or pasty foods such as beverages, soy sauce, milk, yogurt and miso; semisolid foods such as jelly and gummy; solid foods such as salmon, gum, tofu and supplements; Or a powdery food etc. are mentioned.
Beverages include fruit juice and fruit drinks, coffee drinks, oolong tea drinks, green tea drinks, tea drinks, barley tea drinks, vegetable drinks, soft drinks carbonated drinks, fruit extract drinks, vegetable extract juices, near water, sports drinks, A diet drink etc. are mentioned.
For beverages, antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, seasonings, sweeteners, acidulants, fruit juice extracts , Vegetable extracts, nectar extracts, pH adjusters, quality stabilizers and other additives can be added alone or in combination.
The food composition provided by the present invention can be used in the same manner as the method of using the pharmaceutical composition described in “1. Pharmaceutical composition” above, and also used in a range not intended to treat or prevent diseases. can do. That is, when the alkalinizing agent contained in the food composition according to the present invention is used as a reference, the amount of the alkalinizing agent used in the food composition is the same as the alkalinizing agent contained in the pharmaceutical composition. Furthermore, it can be applied to the application target of the pharmaceutical composition. Also, in one embodiment, a “food composition” according to the present invention is a subject that does not have a “pathological” or “abnormal” symptom, condition or disease (eg, a human or other mammal), Applies to maintain or enhance a “healthy” or “normal” state for a subject in “healthy” or “normal” state (eg, a human or other mammal) be able to. Furthermore, in order to maintain or promote a “healthy” or “normal” state with respect to “a healthy person concerned about kidney health” or “healthy person concerned about tubule health” Can be applied to. In this case, even if the alkaline agent is a component of a pharmaceutical composition or a component of a food composition, the pharmacological effect of the alkaline agent itself is basically the same. The application amount and application method of the composition can be appropriately adjusted based on the alkalinizing agent according to the expected effect.
A subject who does not have a “pathological” or “abnormal” symptom, condition or disease (eg, a human or other mammal), ie, a subject who is in a “healthy” or “normal” state (eg, a human or A food composition applied to maintain or promote a “healthy” or “normal” state with respect to (other mammals) may be particularly referred to as a “functional food”.
The term “administration” described in the above “1. Pharmaceutical composition” can also be applied to the “food composition” according to the present invention. Furthermore, for the “food composition” according to the present invention, The term “administration” can be read as “intake”. Therefore, for example, the terms “administer”, “administered”, and the like can be read as “ingested”, “ingested”, “ingested”, etc., with different word forms depending on the context.
Therefore, the following is mentioned as embodiment of the food composition which concerns on this invention.
<1> a food composition for reducing blood concentration of a uremic substance, comprising an alkaline agent;
<2> a food composition for promoting urinary excretion of uremic substances, comprising an alkaline agent;
<3> a food composition for maintaining renal function, comprising an alkaline agent;
<4> a food composition for inhibiting tubule injury, comprising an alkaline agent;
<5> A food composition for inhibiting tubular cell damage, preferably for inhibiting proximal tubular cell damage, comprising an alkaline agent;
<6> Food composition for protecting tubular cells, preferably protecting proximal tubular cells, comprising an alkaline agent;
<7> For maintaining tubule function (for example, reabsorption of water, sodium ion, potassium ion, calcium ion, phosphate ion, bicarbonate ion, chlor ion, glucose, amino acid, vitamin, etc.), including an alkaline agent, Preferably a food composition for maintaining proximal tubular function (eg reabsorption of glucose, amino acids, vitamins, etc.);
<11> A method for reducing the blood concentration of a uremic substance, wherein a subject requiring a reduction in the blood concentration of a uremic substance is ingested with a food composition containing an effective amount of an alkaline agent;
<22> A method for promoting urinary excretion of a uremic substance, wherein a subject requiring promotion of urinary excretion of a uremic substance is ingested with a food composition containing an effective amount of an alkaline agent;
<33> A method for maintaining renal function, wherein a subject requiring maintenance of renal function is ingested with a food composition containing an effective amount of an alkaline agent;
<44> A method for suppressing tubule injury, wherein a subject requiring suppression of tubule injury is ingested with a food composition containing an effective amount of an alkaline agent;
<55> A method for inhibiting damage of tubular cells, preferably proximal tubular cells, wherein an effective amount of alkalinized is applied to a subject in need of inhibition of tubular cells, preferably proximal tubular cells. A method of ingesting a food composition containing an agent;
<66> A method for protecting tubular cells, preferably proximal tubular cells, which contains an effective amount of an alkaline agent for a subject in need of protection of tubular cells, preferably proximal tubular cells A method of ingesting the composition;
<77> Tubular function (for example, reabsorption of water, sodium ion, potassium ion, calcium ion, phosphate ion, bicarbonate ion, chlor ion, glucose, amino acid, vitamin, etc.), preferably proximal tubular function ( For example, a method for maintaining reabsorption of glucose, amino acids, vitamins, etc.) and a food composition comprising an effective amount of an alkaline agent for a subject that needs to maintain tubular function, preferably proximal tubular function To ingest;
<111> a food composition containing an alkaline agent for reducing the blood concentration of a uremic substance;
<222> a food composition containing an alkaline agent for promoting urinary excretion of a uremic substance;
<333> a food composition containing an alkaline agent for maintaining renal function;
<444> a food composition containing an alkaline agent for inhibiting tubular damage;
<555> Food composition comprising an alkaline agent for inhibiting tubular cells, preferably proximal tubular cell damage;
<666> a food composition comprising an alkaline agent for protecting tubular cells, preferably proximal tubular cells;
<777> tubular function (for example, reabsorption of water, sodium ion, potassium ion, calcium ion, phosphate ion, bicarbonate ion, chlor ion, glucose, amino acid, vitamin, etc.), preferably proximal tubular function ( For example, a food composition containing an alkalizing agent for maintaining (reabsorption of glucose, amino acids, vitamins, etc.);
Use of an alkalizing agent for producing a food composition for lowering blood concentration of <1111> uremic substances;
<2222> Use of an alkalizing agent for producing a food composition for promoting urinary excretion of a uremic substance;
<3333> Use of an alkalizing agent for producing a food composition for maintaining renal function;
<4444> Use of an alkalizing agent for producing a food composition for inhibiting tubule injury;
<5555> Use of an alkaline agent for producing a food composition for inhibiting tubular cells, preferably proximal tubular cell damage;
<6666> the use of an alkaline agent to produce a food composition for protecting tubular cells, preferably proximal tubular cells; and <7777> tubular function (e.g., water, sodium ion, potassium ion, Food composition for maintaining calcium ion, phosphate ion, bicarbonate ion, chlor ion, glucose, amino acids, vitamins, etc.), preferably proximal tubule function (eg, glucose, amino acids, vitamins, etc.) Use of an alkalizing agent to produce a product.
The food composition according to the present invention includes a package, a container, or an instruction sheet for reducing blood concentration of a uremic substance, promoting urinary excretion of a uremic substance, maintaining renal function, suppressing tubular damage, tubular cell damage Inhibition, proximal tubular cell injury inhibition, tubular cell protection, proximal tubular cell protection, tubular function (eg, water, sodium ion, potassium ion, calcium ion, phosphate ion, bicarbonate ion, chlorion ion, It is preferable that an effect such as maintenance of reabsorption of glucose, amino acid, vitamin, etc.) or maintenance of proximal tubular function (for example, reabsorption of glucose, amino acid, vitamin, etc.) is displayed.
In one embodiment, the “food composition” according to the present invention is a subject (for example, a human or other mammal) whose β2-microglobulin concentration in urine is 290 μg / L or less, preferably 50 to 150 μg / L. ).
In one embodiment, the “food composition” according to the present invention is a subject having a blood cystatin C concentration of 0.5 to 2.2 mg / L, preferably 1.0 to 1.3 mg / L (eg, human or other mammals). ).
In one embodiment, the intake of the “food composition” according to the present invention suppresses an increase in β2-microglobulin concentration in urine.
In one embodiment, the intake of the “food composition” according to the present invention suppresses the increase in β2-microglobulin concentration in urine 12 weeks after administration.
In one embodiment, the intake of the “food composition” according to the present invention does not substantially reduce the β2-microglobulin concentration in urine compared to before administration.
In one embodiment, the intake of the “food composition” according to the present invention does not substantially lower the β2-microglobulin concentration in urine 12 weeks after administration compared to before administration.
In one embodiment, the intake of the “food composition” according to the present invention does not substantially increase cystatin C in the blood as compared to before administration.
In one embodiment, the intake of the “food composition” according to the present invention does not substantially increase cystatin C in the blood as compared to before administration.
In one embodiment, the intake of the “food composition” according to the present invention suppresses an increase in the amount of β2-microglobulin in early morning urine accompanying progression of the stage of chronic kidney disease.
In one embodiment, the intake of the “food composition” according to the present invention does not affect the glomerular function of patients with chronic kidney disease, while the proximal tubular cells are associated with the progression of the stage of chronic kidney disease. Inhibits injury and protects proximal tubule cells.

3. Method for Determining Decreased Concentration of Uremic Substances in Blood, etc. In one embodiment, the present invention relates to uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L) in blood of patients with chronic kidney disease. 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 is provided comprising measuring urine pH.
Further, in one embodiment, 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 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.
As described herein, by administering an alkaline agent, uremic substances in the blood (eg, indoxyl sulfate concentration, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid) 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. (E.g., indoxyl sulfate concentration, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid) and / or uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, The promotion of excretion of phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid) can be determined. For the measurement of pH, a well-known technique may be used. For example, a pH test paper, a pH test solution, or a simple pH measuring device can be used.
In one embodiment, 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). Measure the pH of early morning urine (wake up and first urine) over time from the start, and if the urine pH rises, 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, phenylacetyl L group) Tamine, hippuric acid and / or argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate, hippuric acid and / or phenylacetyl L-glutamine, more preferably indoxyl sulfate and phenylacetyl L-glutamine, even more preferably indoxyl sulfate ) Excretion can be easily determined.
Also, in one embodiment, 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). PH 6.8, pH 5.8 to pH 6.5, pH 5.8 to pH 6.2, pH 5.8 to 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 or more and less than 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 6.5 to 6.8 ) Uremic substances in blood (eg indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid, preferably India Reduced concentrations of sylsulfate, hippuric acid and / or phenylacetyl L-glutamine, more preferably indoxyl sulfate and phenylacetyl L-glutamine, even more preferably indoxyl sulfate) and / or uremic substances in the urine (e.g. 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.
Reduction of the concentration of uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid) obtained in this way and / or into the urine Determining whether or not the promotion of excretion of uremic substances (eg, indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid) has been achieved suppresses progression of chronic kidney disease It can be an aid to diagnosis of whether or not it is done.
Thus, in one embodiment, 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 There is provided 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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. .
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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) In addition, 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.

In one embodiment, 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. .
In one embodiment, 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.

In one embodiment, 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. .
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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. .

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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. .
In one embodiment, 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.

In one embodiment, 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. .
In one embodiment, 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.

In one embodiment, 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. .
In one embodiment, 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.

In one embodiment, 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. Is.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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. .

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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). In addition, 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.

In one embodiment, 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.
In one embodiment, 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. .

In one embodiment, 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. .
In one embodiment, 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.

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 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.
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) containing 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, 3 to 6 doses a day, 3 times a day Separately orally administered.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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) In addition, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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 Is one tablet) containing 500 mg of sodium bicarbonate, and orally administering 3 to 6 dosage units a day in three divided doses per day.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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). In addition, 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.

In one embodiment, 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.
In one embodiment, 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.

In one embodiment, 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.
In one embodiment, 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.

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 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.

Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited thereto.

Conducted human clinical trial to examine whether oral administration of potassium citrate / sodium citrate hydrate combination preparation and sodium bicarbonate preparation, which are oral alkalinizing agents, promotes urinary excretion of uremic substances did.

1. Methods 47 patients with chronic kidney disease at stage G2 to G3b (eGFR: 30 to 89 ml / min / 1.73m ² ) group administered with potassium citrate / sodium citrate hydrate (A group: 16), sodium bicarbonate (Sodium hydrogen carbonate) preparation group (B group: 16 people) and control group (C group: 15 people) were randomly divided. Patients were assigned to each group so that age, sex, presence of diabetes, and eGFR were not biased. Each group was treated according to the “CKD medical care guide-summary of treatment” (hereinafter referred to as standard treatment).
No alkaline agent was administered to the control group. 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. In addition, 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. In group 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. In addition, 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. Al., Metabolic alteration by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease., Sci Rep. 2016 Nov 10; 6: 36618. doi: 10.1038 / srep36618. etc.) and the following liquid chromatography triple quadrupole mass spectrometer Quantitative analysis was performed using (LC-MS / MS).
For LC, NANOSPACE SI-2 (manufactured by Shiseido) was used, and CAPCELLPAK MGIII was selected as the analytical column.
For MS, TSQ Quantiva (manufactured by Thermo Fisher Scientific Co., Ltd.) was used, and 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 β2-microglobulin in urine was determined by latex agglutination immunization using LZ test 'Eiken' β2-M and LZ-β2-M standard U'Eiken '(Eiken Chemical, Tokyo, Japan). It was measured. Furthermore, the amount of cystatin C in the serum was measured by a colloidal gold agglutination method using Nescoat GC cystatin C (Nm) (Alfresa Pharma, Osaka, Japan).
For statistical analysis, 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.

2. Results From the measurement results using LC-MS / MS, it was confirmed that group A (potassium citrate / sodium citrate hydrate combination preparation administration group), group B (sodium bicarbonate preparation administration group) and group C (control group) For each patient, the following was calculated:
(I) Concentration of each uremic substance in plasma before starting administration (ii) Concentration of each uremic substance in early morning urine before starting administration (iii) Concentration and plasma of uremic substances in early morning urine before starting administration Of the concentration of uremic substances in the urine (amount of uremic substances in the urine / amount of uremic substances in the plasma)
(Iv) The concentration of each uremic substance in plasma at 6 weeks, 12 weeks and 24 weeks after the start of administration (v) The concentration of each uremic substance in early morning urine at 6 weeks, 12 weeks and 24 weeks after the start of administration ( vi) Ratio of urinary substance concentration in early morning urine and uremia substance concentration in plasma at 6 weeks, 12 weeks, and 24 weeks after the start of administration (amount of uremia substance in urine / amount of uremic substance in plasma)
(Vii) The amount of change in the concentration of each uremic substance in plasma at 6 weeks, 12 weeks, and 24 weeks after the start of administration (viii) Early morning urine at 6, 12, and 24 weeks after the start of administration Change in concentration of each uremic substance from before start of administration (ix) Ratio of uremia substance concentration in early morning urine and plasma uremic substance concentration in 6 weeks, 12 weeks, and 24 weeks after start of administration (urine The amount of change from the start of administration of the amount of uremic substance in plasma / the amount of uremic substance in plasma) The average value and SD of each group were calculated for the above (i) to (ix). For each of the above (iv) to (ix), the average value and SD of each group were calculated for all data of 6 weeks, 12 weeks and 24 weeks after the start of administration in each group.
The results are shown in the following table. In the tables and figures, the group A: potassium citrate / sodium citrate hydrate preparation administration group was described as “Citrate”, and the group B: sodium bicarbonate preparation administration group was described as “Bicarbonate”. Moreover, the numerical value in the parenthesis in the table indicates the number of cases.
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),
Table 2-2-1: Amount of p-cresyl sulfate in early morning urine (ng / mL),
Table 2-2-2: Change (ng / mL) from the start of administration of p-cresyl sulfate in early morning urine,
Table 2-3-1: Ratio of p-cresyl sulfate in urine to p-cresyl sulfate in plasma
Table 2-3-2: Changes in the ratio of the amount of p-cresyl sulfate in urine to the amount of p-cresyl sulfate in plasma from the start of administration,
Table 3-1-1: Hippuric acid level in plasma (ng / mL),
Table 3-1-2: Change in plasma hippuric acid before start of administration (ng / mL),
Table 3-2-1: Amount of hippuric acid in early morning urine (ng / mL),
Table 3-2-2: Change in hippuric acid in early morning urine from the start of administration (ng / mL),
Table 3-3-1: Ratio of hippuric acid in urine to hippuric acid in plasma,
Table 3-3-2: Change from the start of administration of the ratio of hippuric acid in urine to hippuric acid in plasma,
Table 4-1-1: Arginosuccinic acid amount in plasma (ng / mL),
Table 4-1-2: Amount of change of arginosuccinic acid in plasma from the start of administration (ng / mL),
Table 4-2-1: Arginosuccinic acid amount (ng / mL) in early morning urine,
Table 4-2-2: Change in arginosuccinic acid in the early morning urine from before the start of administration (ng / mL),
Table 4-3-1: The ratio of the amount of arginosuccinic acid in urine to the amount of arginosuccinic acid in plasma,
Table 4-3-2: Changes in the ratio of the amount of arginosuccinic acid in urine and the amount of arginosuccinic acid in plasma from before administration,
Table 5-1-1: Amount of phenylacetyl L-glutamine (PAG) in plasma (ng / mL),
Table 5-1-2: Change amount (ng / mL) of phenylacetyl L-glutamine (PAG) in plasma from before the start of administration,
Table 5-2-1: Amount of phenylacetyl L-glutamine (PAG) in early morning urine (ng / mL),
Table 5-2-2: Change amount (ng / mL) of phenylacetyl L-glutamine (PAG) in the early morning urine from the start of administration,
Table 5-3-1: Ratio of the amount of phenylacetyl L-glutamine (PAG) in urine to the amount of phenylacetyl L-glutamine (PAG) in plasma,
Table 5-3-2: Amount of change in the ratio between the amount of phenylacetyl L-glutamine (PAG) in urine and the amount of phenylacetyl L-glutamine (PAG) in plasma from before administration.

In group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation administration group), compared to group B (Bicarbonate: sodium bicarbonate preparation administration group) and group C (Control: control group), administration 6, 12 And after 24 weeks, plasma indoxyl sulfate concentration was low (see Table 1-1-1). In group A, indoxyl sulfate (IS) concentration was higher in early morning urine 12 and 24 weeks after administration than in group C (see Table 1-2-1). 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).
In addition, 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. Compared with 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.
Based on the ratio of indoxyl sulfate concentration in urine to indoxyl sulfate concentration in plasma, 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).

As for p-cresyl sulfate (PCS), 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).
In addition, by administering a combination preparation of potassium citrate / sodium citrate hydrate to chronic kidney disease patients, the urinary concentration of p-cresyl sulfate, a uremic substance, increased compared to that before administration (Table 2). See 2-1 and 2-2-2). Even with the same alkalinizing agent, such an effect is not observed in the sodium hydrogencarbonate preparation, and the potassium citrate / sodium citrate hydrate combination preparation is stronger in urine than the sodium hydrogencarbonate preparation. -Demonstrated the effect of increasing cresyl sulfate concentration. The effect of increasing the urinary p-cresyl sulfate concentration by the combined preparation of potassium citrate / sodium citrate hydrate was observed 12 weeks after administration.
On the other hand, administration of the sodium bicarbonate preparation decreased the plasma concentration of p-cresyl sulfate, which is a uremic substance, compared to before administration (see Table 2-1-2). Such a plasma concentration lowering effect of p-cresyl sulfate was strongly observed in group B as compared to group A and group C (see Table 2-1-2).
From the value of the ratio of p-cresyl sulfate concentration in urine to p-cresyl sulfate concentration in plasma, excretion of p-cresyl sulfate from blood into urine by administration of a combination preparation of potassium citrate / sodium citrate hydrate It is suggested that excretion outside the body is promoted. The excretion effect of p-cresyl sulfate from blood into urine was shown to be stronger when administered with a combination of potassium citrate / sodium citrate hydrate than when administered with a sodium bicarbonate formulation (Table 2). See 3-1 and 2-3-2).

As for hippuric acid (HA), 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).
In addition, administration of a combination preparation of potassium citrate / sodium citrate hydrate to chronic kidney disease patients resulted in a decrease in plasma concentration of hippuric acid, a uremic substance, compared to before administration 24 weeks after administration. (See Tables 3-1-1 and 3-2-2), the urinary concentration of hippuric acid increased compared to that before administration (see Tables 3-2-1 and 3-2-2). An increase in hippuric acid concentration in the early morning urine from 6 to 24 weeks was observed only in the group A (see Table 2-2-2). Even with the same alkalinizing agent, the citrate / sodium citrate hydrate combination preparation exhibited a higher effect of increasing the urinary hippuric acid concentration than the sodium bicarbonate preparation. The effect of increasing the urinary hippuric acid concentration by the combined preparation of potassium citrate / sodium citrate hydrate was observed 6 weeks after administration.
From the value of the ratio of hippuric acid concentration in urine and hippuric acid concentration in plasma, administration of potassium citrate / sodium citrate hydrate combination formulation promotes excretion of hippuric acid from blood into urine and goes out of the body It is suggested that the excretion of is promoted. In addition, the effect of hippuric acid excretion from blood into urine at 6 to 24 weeks was shown to be stronger when administered with a combination of potassium citrate / sodium citrate hydrate than when administered with a sodium bicarbonate preparation. (See Tables 3-3-1 and 3-3-2).

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).
In addition, by administering a combination preparation of potassium citrate / sodium citrate hydrate to chronic kidney disease patients, the urinary concentration of argininosuccinic acid, which is a uremic substance, increased compared to before administration (Table 4-2). -1, 4-2-2). 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 increase in argininosuccinic acid concentration in early morning urine from 6 to 24 weeks was more increased in group B than in group A (see Table 4-2-2).
Based on the ratio between the urinary argininosuccinic acid concentration and the plasma argininosuccinic acid concentration, 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. In addition, the effect of excretion of argininosuccinic acid from blood into urine at 6 to 24 weeks was shown to be stronger when administered with sodium bicarbonate than when administered with potassium citrate / sodium citrate hydrate. (See Table 4-3-1, 4-3-3).

As for phenylacetyl L-glutamine (PAG), 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). In 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).
In addition, by administering a combined preparation of potassium citrate / sodium citrate hydrate to patients with chronic kidney disease, the urinary concentration of phenylacetyl L-glutamine, a uremic substance 12 and 24 weeks after administration, was compared before administration. (See Tables 5-2-1 and 5-2-2). Even with the same alkalinizing agent, such an effect was not observed in the sodium bicarbonate preparation. The effect of increasing the urinary phenylacetyl L-glutamine concentration by the combined preparation of potassium citrate / sodium citrate hydrate was observed 12 weeks after administration. By administering a combination preparation of potassium citrate / sodium citrate hydrate to patients with chronic kidney disease, the plasma concentration of phenylacetyl L-glutamine, which is a uremic substance, decreased compared to that before administration (Table 5-1). 1, 5-2-2). 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. In addition, the effect of phenylacetyl L-glutamine excretion from the blood into the urine was shown to be stronger when the potassium citrate / sodium citrate hydrate combination preparation was administered than when the sodium bicarbonate preparation was administered (Table 5). 3-1 and 5-3-2).

Concentrations of potassium citrate / sodium citrate hydrate (Citrate) and sodium bicarbonate (Bicarbonate) for plasma concentration of each uremic substance, concentration in early morning urine, and ratio of concentration in early morning urine to plasma concentration The following table summarizes the effects. In the table below, the reference drugs are sodium bicarbonate preparation (Bicarbonate) for potassium citrate / sodium citrate hydrate combination preparation (Citrate) and potassium citrate for sodium bicarbonate preparation (Bicarbonate). -Sodium citrate hydrate formulation (Citrate). When the effect is significantly superior to the control group or the control drug group, ○ is described, when the effect is significantly inferior to the control group or the control drug group, × is described, and when there is no significant difference, -Is described. 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.
From the table below, the effect of reducing the concentration of uremic substances in blood (plasma) by the alkalizing agent was clearly observed with indoxyl sulfate (IS) and phenylacetyl L-glutamine (PAG). Among them, administration of potassium citrate / sodium citrate hydrate combination preparation (Citrate) with indoxyl sulfate (IS) was significantly lower than administration of sodium bicarbonate preparation (Bicarbonate).
Moreover, the urinary uremic substance concentration increasing effect by alkalizing agent (urine uremic substance excretion effect) is indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid. Clearly observed with acid (ASA) and phenylacetyl L-glutamine (PAG). Of these, 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 ) Significantly increased the concentration of urinary uremic substances (excretion in the urine).
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. Of these, indoxyl sulfate (IS), potassium citrate / sodium citrate hydrate combination preparation (Citrate) is significantly more urinary than uremia from blood to urine than sodium bicarbonate preparation (Bicarbonate) Excretion (extracorporeal) increased.

From the above table, it can be generally understood that a combination preparation of potassium citrate / sodium citrate hydrate exhibits a higher in vitro excretion effect of uremic substances than a sodium bicarbonate preparation. In addition, administration of an alkaline agent to patients with stage G3 chronic kidney disease as well as stage G3b can suppress the progression of chronic kidney disease, and potassium citrate / sodium citrate compared to sodium bicarbonate preparations It was suggested that the hydrate combination preparation suppresses the progression of chronic kidney disease more.

The results of measuring the amount of β2-microglobulin in urine and the amount of cystatin C in serum are shown below.

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).
On the other hand, regarding β2-microglobulin concentration in urine, group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) compared to group C (Control: control group), β2 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 β2-microglobulin concentration was low. Group B (Bicarbonate: sodium bicarbonate preparation administration group) had a higher β2-microglobulin concentration in urine than Group C (Control: control group). Administration of a combination of potassium citrate / sodium citrate hydrate suppresses the increase in β2-microglobulin concentration in the urine accompanying the progression of the stage, and there is no change in β2-microglobulin concentration in the urine compared to before administration Was recognized.
From these results, it was shown that administration of a combination preparation of potassium citrate / sodium citrate hydrate suppresses tubular damage (proximal tubular damage) associated with progression of the stage. In addition, it was shown that administration of a sodium bicarbonate preparation did not suppress tubule injury (proximal tubule injury) associated with progression of the stage, but rather worsened it. These effects were observed from 6 weeks after administration.
In addition, 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 There was no correlation with the effect of suppressing the increase in urinary β2-microglobulin concentration. It was suggested that the 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.

Correlation between indoxyl sulfate (IS) concentration in early morning urine and plasma indoxyl sulfate (IS) concentration at 6th, 12th and 24th week (6W, 12W and 24W) after the start of the study Group), A group (Citrate: potassium citrate / sodium citrate hydrate combination preparation administration group), B group (Bicarbonate: sodium bicarbonate preparation administration group) and all patients (all of A group, B group and C group) Each patient) was analyzed using the Pearson test. The results are shown in FIGS.
As for indoxyl sulfate, 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. Excretion of indoxyl sulfate in the urine depending on the blood indoxyl sulfate concentration suppressed the increase in the blood concentration of indoxyl sulfate, and the ratio of the blood indoxyl sulfate concentration to the urinary indoxyl sulfate concentration Was suggested to be within a certain range.

Correlation between early morning urine p-cresyl sulfate (PCS) concentration and plasma p-cresyl sulfate (PCS) concentration at 6, 12, and 24 weeks after the start of the study (6 W, 12 W and 24 W) : Control group), group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation administration group), group B (Bicarbonate: sodium bicarbonate preparation administration group) and all patients (groups A, B and C) All patients were analyzed using the Pearson test. The results are shown in FIGS.
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. Excretion of p-cresyl sulfate in the urine depending on the p-cresyl sulfate concentration in the blood suppresses an increase in the blood concentration of p-cresyl sulfate. It was suggested that the ratio of cresyl sulfate concentration was within a certain range.

Correlation between the hippuric acid (HA) concentration in early morning urine and the hippuric acid (HA) concentration in plasma at 6, 12, and 24 weeks after the start of the test (6 W, 12 W and 24 W) , Group A (Citrate: potassium citrate / sodium citrate hydrate formulation administration group), Group B (Bicarbonate: Sodium bicarbonate formulation administration group) and all patients (Group A, Group B and Group C all patients) Each of these was analyzed using the Pearson test. The results are shown in FIGS.
Regarding hippuric acid, no high correlation was observed between plasma concentration and urinary concentration in the control group, the potassium citrate / sodium citrate hydrate combination preparation administration group and the sodium bicarbonate preparation administration group.

Correlation between argininosuccinic acid (ASA) concentration in early morning urine and plasma argininosuccinic acid (ASA) concentration at 6, 12, and 24 weeks after the start of the test (6W, 12W and 24W) , Group A (Citrate: potassium citrate / sodium citrate hydrate formulation administration group), Group B (Bicarbonate: Sodium bicarbonate formulation administration group) and all patients (Group A, Group B and Group C all patients) Each of these was analyzed using the Pearson test. The results are shown in FIGS.
With regard to argininosuccinic acid, a high correlation was not observed between the plasma concentration and the urine concentration in the control group, the potassium citrate / sodium citrate hydrate combination preparation administration group and the sodium bicarbonate preparation administration group.

Correlation between early morning urine phenylacetyl L-glutamine (PAG) concentration and plasma phenylacetyl L-glutamine (PAG) concentration at 6, 12, and 24 weeks after the start of the study (6W, 12W and 24W) : Control group), group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation administration group), group B (Bicarbonate: sodium bicarbonate preparation administration group) and all patients (groups A, B and C) All patients were analyzed using the Pearson test. The results are shown in FIGS.
Regarding phenylacetyl L-glutamine, there was a correlation between plasma concentration and urinary concentration in the control group, the potassium citrate / sodium citrate hydrate combination drug administration group and the sodium bicarbonate preparation administration group, and potassium citrate A higher correlation was observed in the sodium bicarbonate preparation-administered group compared to the sodium citrate hydrate combination preparation-administered group (see r values in FIGS. 17 to 19). From FIGS. 17 to 20, the administration of a sodium bicarbonate preparation or a combination preparation of potassium citrate / sodium citrate hydrate causes phenylacetyl L-glutamine to be excreted in urine depending on the phenylacetyl L-glutamine concentration in blood. Was suggested. Excretion of phenylacetyl L-glutamine in the urine depending on the phenylacetyl L-glutamine concentration in blood suppresses the increase in the blood concentration of phenylacetyl L-glutamine, and the blood phenylacetyl L-glutamine concentration and urinary phenylacetyl It was suggested that the ratio of L glutamine concentration was within a certain range.

Indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid (ASA) and phenylacetyl L-glutamine at 6, 12, and 24 weeks after the start of the study (6W, 12W and 24W) Correlation of early morning urine concentration of (PAG) was determined by group C (Control: control group), Group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) and Group B (Bicarbonate: sodium bicarbonate). Each of the preparation administration groups) was analyzed using the Pearson test. The results are shown in Table 9. In the table, “Contro” indicates a control group, “Citrate” indicates a potassium citrate / sodium citrate hydrate combination preparation administration group, and “Bicarb” indicates a sodium bicarbonate preparation administration group.
As a result, in the group administered with citrate potassium / sodium citrate hydrate, indoxyl sulfate and phenylacetyl L-glutamine, p-cresyl sulfate and phenylacetyl L-glutamine, argininosuccinic acid and phenylacetyl L-glutamine are highly correlated. Admitted. 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. It was suggested that the combined preparation of 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. In addition, it was suggested that the sodium bicarbonate preparation may increase the urinary concentration of indoxyl sulfate, phenylacetyl L-glutamine, p-cresyl sulfate and argininosuccinic acid by the same mechanism.

Indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid (ASA) and phenylacetyl L-glutamine at 6, 12, and 24 weeks after the start of the study (6W, 12W and 24W) (PAG) plasma concentration correlation, group C (Control: control group), group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) and group B (Bicarbonate: sodium bicarbonate preparation) Each of the (administration group) was analyzed using the Pearson test. The results are shown in Table 10. In the table, “Contro” indicates a control group, “Citrate” indicates a potassium citrate / sodium citrate hydrate combination preparation administration group, and “Bicarb” indicates a sodium bicarbonate preparation administration group.
As a result, in the group administered with potassium citrate / sodium citrate hydrate, highly correlated with indoxyl sulfate and p-cresyl sulfate, indoxyl sulfate and phenylacetyl L-glutamine, p-cresyl sulfate and phenylacetyl L-glutamine Was recognized. In the sodium bicarbonate preparation administration group, a high correlation was observed between indoxyl sulfate and p-cresyl sulfate. It was suggested that the combined preparation of potassium citrate / sodium citrate hydrate may reduce the blood concentration of indoxyl sulfate, phenylacetyl L-glutamine and p-cresyl sulfate by the same mechanism. In addition, it was suggested that sodium bicarbonate preparation may reduce the blood concentration of p-cresyl sulfate and phenylacetyl L-glutamine by the same mechanism. It was suggested that potassium citrate / sodium citrate hydrate combination preparations and sodium bicarbonate preparations have different mechanisms for reducing the blood concentration of uremic substances.

The urine specific gravity of early morning urine before the start of the test (0 W) and at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was measured as C group (Control: control group) and A group (Citrate: citric acid). Each of the potassium / sodium citrate hydrate combination preparation administration group) and B group (Bicarbonate: sodium bicarbonate preparation administration group) was analyzed. The results are shown in Table 11-0-1. In addition, the amount of change in each urine specific gravity 6 weeks, 12 and 24 weeks after the start of the test from the start of the test is expressed as a% relative value with respect to the urine specific gravity before the start of the test and a difference from the urine specific gravity before the start of the test. -0-2 and Table 11-0-3, respectively. The urine specific gravity was measured using a urine hydrometer (PAL-09S, Atago Co., Ltd., Tokyo, Japan).

As a result of the above, compared with group C (Control: control group), in group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) and group B (Bicarbonate: sodium bicarbonate preparation administration group) There was a tendency to maintain or increase the value of urine specific gravity over 6, 12, and 24 weeks after the start of the test. In addition, the urine specific gravity is more maintained in group A (Citrate: potassium citrate / sodium citrate hydrate preparation) compared to group B (Bicarbonate: sodium bicarbonate preparation administration group). A tendency to increase or increase was observed.
It can be understood that maintaining or increasing urine specific gravity is based on maintaining or improving renal function. Therefore, from the above, it is possible to suppress the progression of chronic kidney disease by administering an alkaline agent to patients with stage G3 chronic kidney disease as well as stage G3b, and citric acid compared to sodium bicarbonate preparations. It was suggested that the combined preparation of potassium and sodium citrate hydrate suppresses the progression of chronic kidney disease.

Urinary substances in early morning urine, ie indoxyl sulfate (IS), p-cresyl sulfate (PCS) before the start of the test (0W) and at 6, 12, and 24 weeks after the start of the test (6W, 12W and 24W) , Phenylacetyl L-glutamine (PAG), hippuric acid (HA) and argininosuccinic acid (ASA) concentrations before the start of the test (0 W) and after 6, 12 and 24 weeks of the test (6 W, 12 W and 24 W), respectively. The values corrected with the following formula using the urine specific gravity of early morning urine in group C (Control: control group), group A (Citrate: potassium citrate / sodium citrate hydrate combination drug administration group) and group B Each (Bicarbonate: sodium bicarbonate preparation administration group) was analyzed. See Tetsuo Aoki et al., Medical Examination, Vol. 44, No. 1, 1995, pages 79-83. The urine specific gravity of 1.022 was converted to a reference value.
Specific gravity correction value (Unit / 1.022 · UG) = Actual measurement value × (1.022-1.000) / (Specific gravity value-1.000)
The results are shown in Table 11-1-1, Table 11-2-1, Table 11-3-1, Table 11-4-1 and Table 11-5-1. Further, the amount of change in the value obtained by correcting the concentration of the uremic substance in the early morning urine by the urine specific gravity after 6 weeks, 12 and 24 weeks after the start of the test, with respect to the correction value before the start of the test. Table 11-1-2, Table 11-1-3, Table 11-2-2, Table 11-2-3, Table 11-3 as differences from the% relative value and the correction value before the start of the test -2, Table 11-3-3, Table 11-4-2, Table 11-4-3, Table 11-5-2, and Table 11-5-3.

As a result, a group in which potassium citrate / sodium citrate hydrate combination preparation (Citrate) was administered with indoxyl sulfate (IS), p-cresyl sulfate (PCS) and phenylacetyl L-glutamine (PAG) The urinary substance concentration in the urine (excretion in the urine) increased significantly from the group and the group administered with the sodium bicarbonate preparation (Bicarbonate). As for hippuric acid (HA) and argininosuccinic acid (ASA), the group administered with potassium citrate / sodium citrate hydrate combination preparation (Citrate) was more controlled than the control group and the group administered with sodium bicarbonate preparation (Bicarbonate). Urinary uremic substance concentration (excretion in urine) increased. In addition, administration of potassium citrate / sodium citrate hydrate combination preparation (Citrate), indoxyl sulfate (IS), p-cresyl sulfate (PCS), The concentration of acetyl L-glutamine (PAG) (excretion in urine) increased.

The osmotic pressure of early morning urine before the start of the test (0 W) and at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was measured for group C (Control: control group) and group A (Citrate: citric acid). Each of the potassium / sodium citrate hydrate combination preparation administration group) and B group (Bicarbonate: sodium bicarbonate preparation administration group) was analyzed. The results are shown in Table 12-0-1. In addition, the amount of change in the osmotic pressure of each early morning urine after 6, 12, and 24 weeks after the start of the test, the% relative value to the osmotic pressure of the early morning urine before the start of the test, and the early morning urine before the start of the test. The differences from the osmotic pressure are shown in Tables 12-0-2 and 12-0-3 below. The osmotic pressure was measured using the freezing point depression method.

As a result of the above, compared with group C (Control: control group), in group A (Citrate: potassium citrate / sodium citrate hydrated preparation administration group) and group B (Bicarbonate: sodium bicarbonate preparation administration group) The osmotic pressure value of early morning urine was maintained or increased over the 6th, 12th and 24th week after the start of the test. In addition, compared to group B (Bicarbonate: sodium bicarbonate preparation administration group), group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation administration group) has an early urine osmotic pressure, A tendency to be more sustained or increased was observed.
It can be understood that maintaining or increasing the osmotic pressure of early morning urine is based on maintaining or improving renal function. Therefore, from the above, it is possible to suppress the progression of chronic kidney disease by administering an alkaline agent to patients with stage G3 chronic kidney disease as well as stage G3b, and citric acid compared to sodium bicarbonate preparations. It was suggested that the combined preparation of potassium and sodium citrate hydrate suppresses the progression of chronic kidney disease.

Urinary substances in early morning urine, ie indoxyl sulfate (IS), p-cresyl sulfate (PCS) before the start of the test (0W) and at 6, 12, and 24 weeks after the start of the test (6W, 12W and 24W) , Phenylacetyl L-glutamine (PAG), hippuric acid (HA) and argininosuccinic acid (ASA) concentrations before the start of the test (0 W) and after 6, 12 and 24 weeks of the test (6 W, 12 W and 24 W), respectively. The values corrected by the following formula using the osmotic pressure of early morning urine in group C (Control: control group), group A (Citrate: potassium citrate / sodium citrate hydrate combination drug administration group) and group B Each (Bicarbonate: sodium bicarbonate preparation administration group) was analyzed. See Tetsuo Aoki et al., Medical Examination, Vol. 44, No. 1, 1995, pages 79-83. In addition, urine osmotic pressure 770 mOsm / kg was converted into a reference value.
Osmotic pressure correction value (unit / 500 mOsm · P) = actual value × 500 / osmotic pressure value The results are shown in Table 12-1-1, Table 12-2-1, Table 12-3-1, Table 12-4-1. And Table 12-5-1. In addition, the change amount of the value obtained by correcting the concentration of the uremic substance in the early morning urine with the osmotic pressure of the early morning urine after 6 weeks, 12 and 24 weeks after the start of the test is calculated before the start of the test. Table 12-1-2, Table 12-1-3, Table 12-2-2, Table 12-2-3, Table below as the% relative value to the correction value and the difference from the correction value before the start of the test 12-3-2, Table 12-3-3, Table 12-4-2, Table 12-4-3, Table 12-5-2, and Table 12-5-3, respectively.

As a result, the group administered with potassium citrate / sodium citrate hydrate combination preparation (Citrate) with p-cresyl sulfate (PCS) and phenylacetyl L-glutamine (PAG) was divided into the Control group and the sodium bicarbonate preparation ( Urinary uremic substance concentrations (excretion into the urine) were significantly higher than those in the group receiving bicarbonate. As for indoxyl sulfate (IS), hippuric acid (HA), and argininosuccinic acid (ASA), the group administered with potassium citrate / sodium citrate hydrate combination preparation (Citrate) was divided into the Control group and sodium bicarbonate preparation ( Urinary uremic substance concentrations (excretion into the urine) increased from the group receiving bicarbonate. In addition, administration of potassium citrate / sodium citrate hydrate combination preparation (Citrate) resulted in urinary indoxyl sulfate (IS), p-cresyl sulfate (PCS) and phenyl compared to before the start of the test (0 W). The concentration of acetyl L-glutamine (PAG) (excretion in urine) increased.

The uremic substance is excreted from the body of the mammal by the pharmaceutical composition provided by the present invention. By 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.

Claims

Food composition containing an alkalinizing agent and maintaining renal function.
2. The food composition according to claim 1, wherein the maintenance of renal function is suppression of tubular injury, protection of tubular cells, or maintenance of tubular function.
The food composition according to claim 2, wherein the tubule is a proximal tubule.
The food composition according to any one of claims 1 to 3, wherein the alkalinizing agent is a citric acid-acceptable salt, a hydrate thereof, or a mixture thereof.
The food composition according to any one of claims 1 to 4, wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.
The food composition according to any one of claims 1 to 5, wherein the alkalinizing agent is sodium citrate or a hydrate thereof.
The food composition according to any one of claims 1 to 6, wherein the food composition is a tablet.
The food composition according to any one of claims 1 to 7, wherein the effect of maintaining renal function is indicated on the packaging, container or instructions of the food composition.
The food according to any one of claims 1 to 7, wherein the effect of inhibiting tubular damage, protecting tubular cells, or maintaining tubular function is indicated on the packaging, container or instruction of the food composition. Composition.
The food composition according to any one of claims 1 to 8, which is taken by a healthy person who is concerned about kidney health.
The food composition according to any one of claims 1 to 7 and 9, which is taken by a healthy person who is concerned about the health of tubules.
The food composition according to any one of claims 1 to 11, which is ingested by a subject whose β2-microglobulin concentration in urine is 290 µg / L or less.
The food composition according to any one of claims 1 to 12, which is ingested by a subject having a β2-microglobulin concentration in urine of 50 to 150 µg / L.
The food composition according to any one of claims 1 to 13, which is taken by a subject having a blood cystatin C concentration of 0.5 to 2.2 mg / L.
15. The food composition according to any one of claims 1 to 14, which is taken by a subject having a blood cystatin C concentration of 1.0 to 1.3 mg / L.
The food composition according to any one of claims 1 to 15, wherein an increase in β2-microglobulin concentration in urine is suppressed by ingestion of the food composition.
The food composition according to any one of claims 1 to 16, wherein an increase in β2-microglobulin concentration in urine is suppressed by ingestion of the food composition after 12 weeks of ingestion.
The food composition according to any one of claims 1 to 17, wherein the ingestion of the food composition does not substantially lower the urinary β2-microglobulin concentration compared to before the start of ingestion.
The food composition according to any one of claims 1 to 18, wherein the concentration of β2-microglobulin in urine is not substantially reduced by ingestion of the food composition after 12 weeks of ingestion compared to before the start of administration. object.
The food composition according to any one of claims 1 to 19, wherein the intake of the food composition does not substantially increase cystatin C in the blood compared to before the start of the intake.
The food composition according to any one of claims 1 to 20, wherein the intake of the food composition does not substantially increase cystatin C in the blood compared to before the start of the intake.
The food composition according to any one of claims 1 to 21, which suppresses an increase in the amount of β2-microglobulin in early morning urine accompanying the progression of the stage of chronic kidney disease by ingesting the food composition.
Ingestion of food composition does not affect glomerular function in patients with chronic kidney disease, but suppresses proximal tubular cell damage and protects proximal tubular cells as the stage of chronic kidney disease progresses The food composition according to any one of claims 1 to 22, wherein