Renal protective agents

Abstract

To provide a pharmaceutical or food useful in mammals, particularly humans, for reducing random urinary albumin, early morning urinary albumin, random urinary protein, increasing pure acid excretion, protecting renal function, or reducing dietary acid load on the kidneys. [Solution] A pharmaceutical or food composition is provided that contains citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof. Ingestion of this composition can reduce urinary albumin levels as needed, reduce early morning urinary albumin levels, reduce urinary protein levels as needed, increase pure acid excretion, protect renal function, or reduce dietary acid load on the kidneys.

Description

[Technical Field]

[0001] The present invention relates to novel pharmaceutical compositions comprising citric acid, pharmaceutically acceptable salts of citric acid, hydrates thereof, or mixtures thereof. More specifically, the present invention relates to pharmaceutical compositions comprising citric acid, pharmaceutically acceptable salts of citric acid, hydrates thereof, or mixtures thereof, for the protection of renal function or for the reduction of dietary acid load on the kidneys. This application claims priority based on Japanese Patent Application No. 2020-056660, filed in Japan on March 26, 2020, and the contents of that application are incorporated herein by reference. [Background technology]

[0002] The number of patients with end-stage kidney disease (ESKD), requiring dialysis or transplantation, is increasing worldwide. This trend is also on the rise in Japan, with 320,000 dialysis patients at the end of 2014. Chronic kidney disease (CKD) is recognized as a precursor to ESKD. CKD is a comprehensive concept encompassing chronic kidney disease, regardless of the underlying disease, and includes all conditions in which there is a decline in renal function, expressed as glomerular filtration rate (GFR), or findings suggestive of kidney damage that persist chronically (for more than 3 months). CKD is not only a risk factor for progression to ESKD, but also a strong risk factor for cardiovascular disease (CVD), etc. Therefore, early detection and appropriate treatment of CKD are extremely important. While many CKD treatments have been established, they are still insufficient, and further development of renal protective agents is needed.

[0003] In patients with advanced CKD, the blood contains bicarbonate ions (HCO3) -As the concentration of uric acid decreases, metabolic acidosis develops, and alkalizing agents such as sodium bicarbonate and citrate preparations are administered. It has been reported that the administration of sodium bicarbonate, an alkalizing agent, suppresses the progression of CKD (Non-Patent Literature 1). In addition, in an animal model of nephrotic syndrome induced by protein overload, it has been reported that oral administration of sodium bicarbonate suppresses tubular cell damage caused by acidic urine (Non-Patent Literature 2). Furthermore, it is known that administering alkalizing agents to early-stage CKD patients suppresses the progression of renal damage and reduces the blood concentration of uremic substances (Patent Literature 1 and 2).

[0004] On the other hand, it is known that the higher the diet-dependent nonvolatile acid load, the faster the progression of chronic kidney disease. Net acid excretion (NAE) represents the net amount of acid excreted in the urine per unit time. By increasing net acid excretion, it is possible to reduce the dietary acid load on the kidneys, especially in chronic kidney disease, and it is expected that the progression of chronic kidney disease can be suppressed.

[0005] However, it is not known that administering alkalizing agents to patients with CKD can protect renal function or reduce dietary acid load on the kidneys. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2018 / 193648 [Patent Document 2] International Publication No. 2018 / 193752 [Non-patent literature]

[0007] [Non-Patent Document 1] Brito-Ashurst, ID, et al.: Bicarbonate supplementation slows progression of CKD and improves nutritional status. J. Am. Soc. Nephrol., 20: 2075-2084, 2009. [Non-Patent Document 2] Souma T., et al.: Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells. J. Am. Soc. Nephrol., 22: 635-648, 2011. [Overview of the project] [Problems that the invention aims to solve]

[0008] One objective of the present invention is to provide a pharmaceutical agent useful for protecting renal function. Another objective of the present invention is to provide a pharmaceutical agent useful for reducing dietary acid load on the kidneys. Yet another objective of the present invention is to provide a food product useful for reducing random urinary albumin, early morning urinary albumin, random urinary protein, increasing pure acid excretion, protecting renal function, or reducing dietary acid load on the kidneys. [Means for solving the problem]

[0009] The inventors of the present invention conducted diligent research to achieve the above objectives and discovered that citric acid, pharmaceutically acceptable salts of citric acid, or hydrates or mixtures thereof have the effect of reducing albumin in urinary samples, albumin in early morning samples, protein in urinary samples, and increased pure acid excretion, thereby being useful for protecting renal function or reducing dietary acid load on the kidneys, thus completing the present invention.

[0010] The present invention has the following aspects. (1) A pharmaceutical composition for the protection of renal function comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof. (2) A pharmaceutical composition for reducing dietary acid load on the kidneys, comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof. (3) The pharmaceutical composition described in (1) or (2) for administration to patients with early-stage chronic kidney disease. (4) A pharmaceutical composition according to any one of (1) to (3) that reduces the amount of protein in the urine (for example, by reducing the amount of protein in the urine compared to a placebo or control, or before administration of the pharmaceutical composition). (5) The pharmaceutical composition according to (4), wherein the urinary protein is urinary albumin (more specifically, random urinary albumin or early morning urinary albumin), or random urinary protein. (6) The pharmaceutical composition according to (4) or (5), wherein the urine is early morning urine. (7) A pharmaceutical composition according to any one of (1) to (3) that suppresses the increase in urinary protein levels associated with the progression of chronic kidney disease. (8) The pharmaceutical composition according to any one of (1) to (7), wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof is sodium citrate or its hydrate, potassium citrate or its hydrate, or a mixture thereof. (9) A pharmaceutical composition according to any one of (1) to (8), wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof comprises a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate. (10) A pharmaceutical composition according to any one of (1) to (9), wherein the pharmaceutical composition is a tablet. (11) A pharmaceutical composition according to any one of (1) to (10), wherein citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof is administered at a dose of 1 to 3 g / day. (12) A pharmaceutical composition according to any one of (1) to (11), wherein citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof is administered at a dose of 1 to 1.5 g / day. (13) The pharmaceutical composition according to any one of (1) to (12), wherein citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof is administered for 12 weeks or longer. (14) The pharmaceutical composition according to any one of (1) to (13), which contains anhydrous citric acid. (14-1) The pharmaceutical composition according to any one of (1) to (14), which reduces the dietary acid load on the kidney.

[0011] Moreover, the present invention has the following aspects. (15) A food composition containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof, for reducing albumin in random urine, reducing albumin in early morning urine, reducing protein in random urine, increasing net acid excretion, protecting kidney function, or reducing the dietary acid load on the kidney. (16) The food composition according to (15), wherein citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof contains a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate. (17) The food composition according to (15) or (16), wherein citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof is sodium citrate or its hydrate. (18) The food composition according to any one of (15) to (17), wherein the food composition is a tablet. (19) The food composition according to any one of (15) to (18), wherein the effect of reducing albumin in random urine, reducing albumin in early morning urine, reducing protein in random urine, increasing net acid excretion, protecting kidney function, or reducing the dietary acid load on the kidney is indicated on the package, container, or instruction manual of the food composition. (20) The food composition according to any one of (15) to (19), which is ingested by healthy individuals concerned about protein in urine or kidney health. (21) The food composition according to any one of (15) to (19), which is ingested by healthy individuals concerned about the dietary acid load on the kidney. (22) The food composition according to any one of (15) to (21), which contains anhydrous citric acid. [Effect of the Invention]

[0012] The pharmaceutical composition, food composition, etc. provided by the present invention can reduce albumin in urine at any time, reduce albumin in early morning urine, reduce protein in urine at any time, and increase pure acid excretion in mammals. The pharmaceutical composition, food composition, etc. provided by the present invention can protect renal function or reduce dietary acid load on the kidney in mammals. [Modes for Carrying Out the Invention]

[0013] 1. Pharmaceutical composition The pharmaceutical composition provided by the present invention can contain, as an active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof. Examples of pharmaceutically acceptable salts of citric acid include alkali metal salts of citric acid. Examples of alkali metal salts of citric acid include potassium citrate and sodium citrate, and may be hydrates such as stable monohydrate of potassium citrate (C6H5K3O7·H2O) and dihydrate of sodium citrate (C6H5Na3O7·2H2O), respectively. In one embodiment, the pharmaceutically acceptable salt of citric acid is other than iron citrate (for example, ferric citrate or a hydrate thereof).

[0014] Examples of preferred active ingredients in the pharmaceutical composition provided by the present invention include sodium citrate, potassium citrate, or their hydrates, or mixtures thereof. For example, a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O) may be used. The mixing ratio of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O) can be appropriately set by those skilled in the art. For example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate can be 1 part potassium citrate monohydrate to 0.01 to 100 parts sodium citrate dihydrate. The molar ratio of potassium citrate (e.g., potassium citrate monohydrate) to sodium citrate (e.g., sodium citrate dihydrate) can be appropriately set by those skilled in the art. For example, it may be 0.85:1.15~1.15:0.85, 0.90:1.10~1.10:0.90, 0.95:1.05~1.05:0.95, or 0.99:1.01~1.01:0.99, with 1:1 being preferred. Other examples of active ingredients included in the pharmaceutical composition provided by the present invention include sodium citrate or its hydrate, which may be, for example, sodium citrate dihydrate (C6H5Na3O7·2H2O).

[0015] Furthermore, other examples of active ingredients contained in the pharmaceutical composition provided by the present invention include potassium citrate or its hydrate, which may be, for example, potassium citrate monohydrate (C6H5K3O7·H2O). In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may include a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate. In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may be a mixture of potassium citrate, sodium citrate, and citric acid (e.g., anhydrous citric acid). In this case, the mixing ratio of citric acid (e.g., anhydrous citric acid), potassium citrate, and sodium citrate can be appropriately set by those skilled in the art, for example, 1:1.7~2.3:1.7~2.3, 1:1.9~2.1:1.9~2.1, or 1:1.95~2.05:1.95~2.05, with 1:2:2 being preferred. In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may be a mixture of potassium citrate monohydrate (C6H5K3O7·H2O), sodium citrate dihydrate (C6H5Na3O7·2H2O), and anhydrous citric acid. In this case, the mixing ratio of anhydrous citric acid, potassium citrate monohydrate (C6H5K3O7·H2O), and sodium citrate dihydrate (C6H5Na3O7·2H2O) can be appropriately set by those skilled in the art. For example, it may be 1:1.7~2.3:1.7~2.3, 1:1.9~2.1:1.9~2.1, or 1:1.95~2.05:1.95~2.05, with 1:2:2 being preferred. In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may consist only of a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate. In this specification, when referring to the weight of citric acid, pharmaceutically acceptable salts of citric acid, or hydrates or mixtures thereof (e.g., potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O)), the weight may be the dry weight.

[0016] In this specification, the expression [A, B and / or C] means "at least one selected from the group consisting of A, B and C."

[0017] In one embodiment, administration of the pharmaceutical composition provided by the present invention reduces the dietary acid load on the kidneys. In one embodiment, administration of the pharmaceutical composition provided by the present invention is observed to protect renal function and increase pure acid excretion.

[0018] In this specification, “suppression” includes stopping or slowing down the worsening or progression of a symptom, condition, or disease, and the actions or means to do so, and also includes improving the symptom, condition, or disease, and the actions or means to do so. Here, “improvement” includes bringing a “pathological” or “abnormal” symptom, condition, or disease closer to a “healthy” or “normal” state, or the actions or means to do so, and bringing a “healthy” or “normal” state, or the actions or means to do so. Accordingly, in one embodiment, “improvement” includes a numerical indicator of a “pathological” or “abnormal” symptom or condition becoming smaller or larger in accordance with the “improvement” to approach or become a normal value. The “worsening or progression of a symptom, condition, or disease” includes the worsening or progression of a “pathological” or “abnormal” symptom, condition, or disease, and the worsening or progression from a “healthy” or “normal” state to a “pathological” or “abnormal” symptom, condition, or disease. In one embodiment, “suppression” means stopping or slowing down the worsening or progression of a symptom, condition, or disease, or an act or means for that purpose. In another embodiment, “suppression” means stopping or slowing down the worsening or progression of a symptom, condition, or disease.

[0019] In this specification, "healthy" means a state free from acute or chronic disease or disability, and "normal" means a state in which a healthy subject is in its usual condition. Here, the symptoms, conditions, or diseases are compared before and after administration of the pharmaceutical composition provided by the present invention, or when the pharmaceutical composition provided by the present invention is administered, compared with when a control or placebo is administered.

[0020] In this specification, “treatment” is a concept that includes causing “pathological” or “abnormal” symptoms, conditions, or diseases to disappear, be cured, be healed or go into remission, and the acts or means for that purpose; “suppression” of the worsening of “pathological” or “abnormal” symptoms, conditions, or diseases, and the acts or means for that purpose; and “improvement.” Here, “suppression” and “improvement” have the meanings set forth above. In one embodiment, “treatment” is the cause of “pathological” or “abnormal” symptoms, conditions, or diseases to disappear, be cured, be healed or go into remission, and the acts or means for that purpose. In another embodiment, “treatment” is the cause of “pathological” or “abnormal” symptoms, conditions, or diseases to disappear, be cured, be healed or go into remission.

[0021] In this specification, “prevention” is a concept that includes preventing the onset of “pathological” or “abnormal” symptoms, conditions, or diseases, and the actions or means taken for that purpose. In this specification, “protection of renal function” is a concept that includes stopping or slowing the deterioration of renal function, maintaining renal function, improving renal function, or any actions or means to achieve these purposes.

[0022] In one embodiment, "protection of renal function" means that, compared to renal function before administration of the pharmaceutical composition provided by the present invention, the deterioration of renal function after administration is stopped or slowed, renal function is maintained, or renal function is improved; or, compared to placebo administration or control, the deterioration of renal function is stopped or slowed, renal function is maintained, or renal function is improved by administration of the pharmaceutical composition provided by the present invention.

[0023] In one embodiment, "protection of renal function" can be evaluated by a decrease in the amount of random urinary albumin, early morning urinary albumin, or random urinary protein (mg / gCr) compared to placebo or control, upon administration of the pharmaceutical composition provided by the present invention. In one embodiment, "protection of renal function" can be evaluated by the amount of random urinary albumin (mg / gCr) 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention being 50% or more and less than 98%, preferably 70% or more and 95%, and more preferably 85% or more and 95%, compared to the amount of random urinary albumin 6 weeks, 12 weeks, and 24 weeks after administration of the control, respectively. In one embodiment, "protection of renal function" can be evaluated by the amount of albumin (mg / gCr) in the early morning urine 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention being 20% ​​or more and less than 95%, preferably 40% or more and 90%, and more preferably 60% or more and 90%, compared to the amount of albumin in the early morning urine 6 weeks, 12 weeks, and 24 weeks after administration of the control, respectively. In one embodiment, "protection of renal function" can be evaluated by the fact that the amount of random urinary protein (mg / gCr) 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention is 50% or more and less than 98%, preferably 60% or more and 95%, and more preferably 70% or more and 90%, compared to the amount of random urinary protein 6 weeks, 12 weeks, and 24 weeks after administration of the control, respectively.

[0024] In one embodiment, "protection of renal function" can be evaluated by a decrease in the amount of random urinary albumin, early morning urinary albumin, or random urinary protein (mg / gCr) compared to before administration, following administration of the pharmaceutical composition provided by the present invention. In one embodiment, "protection of renal function" can be evaluated by the amount of random urinary albumin (mg / gCr) 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention being 60% or more and less than 98%, preferably 70% or more and 95%, and more preferably 85% or more and 95%, respectively, compared to the amount of random urinary albumin before administration. In one embodiment, "protection of renal function" can be evaluated by the amount of albumin (mg / gCr) in the early morning urine 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention being 40% or more and less than 95%, preferably 60% or more and 90%, and more preferably 70% or more and 90%, respectively, compared to the amount of albumin in the early morning urine before administration. In one embodiment, "protection of renal function" can be evaluated by the fact that the amount of random urinary protein (mg / gCr) 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention is 75% or more and less than 98%, preferably 80% or more and 98%, and more preferably 85% or more and 95%, respectively, compared to the amount of random urinary protein before administration.

[0025] In one embodiment, "protection of renal function" can be evaluated by the fact that the amount of random urinary albumin (mg / gCr) 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention is, as a change from the amount of random urinary albumin before administration, -60 mg / gCr or more and -3 mg / gCr or less, preferably -50 mg / gCr or more and -5 mg / gCr or less, more preferably -40 mg / gCr or more and -10 mg / gCr or less. In one embodiment, "protection of renal function" can be evaluated by the amount of albumin (mg / gCr) in the early morning urine 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention, being -60 mg / gCr or more and -5 mg / gCr or less, preferably -50 mg / gCr or more and -5 mg / gCr or less, and more preferably -40 mg / gCr or more and -10 mg / gCr or less, compared to the amount of albumin in the early morning urine before administration. In one embodiment, "protection of renal function" can be evaluated by the change in the amount of random urinary protein (mg / gCr) 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention, compared to the amount of random urinary protein before administration, being between -60 mg / gCr and -0.5 mg / gCr, preferably between -50 mg / gCr and -1 mg / gCr, and more preferably between -30 mg / gCr and -5 mg / gCr.

[0026] In one embodiment, "reduction of dietary acid load on the kidneys" means that the dietary acid load on the kidneys after administration of the pharmaceutical composition provided by the present invention is reduced compared to the dietary acid load on the kidneys before administration of the pharmaceutical composition provided by the present invention, or that the dietary acid load on the kidneys is reduced by administration of the pharmaceutical composition provided by the present invention compared to placebo administration or control.

[0027] In one embodiment, "reduction of dietary acid load on the kidneys" can be evaluated by an increase in the amount of pure acid excretion (mEq / gCr) compared to a control, upon administration of the pharmaceutical composition provided by the present invention. In one embodiment, "reduction of dietary acid load on the kidneys" can be evaluated by the fact that the amount of pure acid excretion (mEq / gCr) 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention is, respectively, 0.3 mEq / gCr to 30 mEq / gCr, preferably 0.3 mEq / gCr to 10 mEq / gCr, and more preferably 1 mEq / gCr to 10 mEq / gCr, compared to the amount of pure acid excretion of the control 6 weeks, 12 weeks, and 24 weeks after administration.

[0028] In one embodiment, "reduction of dietary acid load on the kidneys" can be evaluated by the change in the amount of pure acid excretion (mEq / gCr) 6 weeks, 12 weeks, and 24 weeks after administration of the pharmaceutical composition provided by the present invention, compared to the amount of pure acid excretion before administration, being 0.3 mEq / gCr or more and 10 mEq / gCr or less, preferably 0.3 mEq / gCr or more and 10 mEq / gCr or less, and more preferably 1 mEq / gCr or more and 5 mEq / gCr or less.

[0029] In this specification, "in urine" means, for example, "in early morning urine." In this specification, "early morning urine" refers to the first urine produced after waking up, and "random urine" refers to urine other than the aforementioned "early morning urine."

[0030] Due to the characteristics of the pharmaceutical composition provided by the present invention, in one respect, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for protecting renal function.

[0031] In another respect, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for reducing dietary acid load on the kidneys. Furthermore, in another respect, the pharmaceutical compositions provided by the present invention may be agents that reduce albumin in random urinary urine, agents that reduce albumin in early morning urinary urine, agents that reduce protein in random urinary urine, and agents that increase pure acid excretion. A decrease in random urinary albumin may be due to a decrease in the albumin concentration in the random urinary sample, or a decrease in the amount of albumin in the random urinary sample. A decrease in early morning urinary albumin may be due to a decrease in the concentration of early morning urinary albumin or a decrease in the amount of albumin in early morning urine. A decrease in random urinary protein may be due to a decrease in random urinary protein concentration or a decrease in random urinary protein volume. An increase in pure acid excretion can be due to an increase in the concentration of pure acid excreted or an increase in the amount of pure acid excreted.

[0032] The pharmaceutical compositions provided by the present invention are administered orally or parenterally to humans or other mammals. Examples of parenteral administration include intravenous, subcutaneous, intramuscular, intra-articular, transmucosal, transdermal, transnasal, rectal, intrathecal, intraperitoneal, and local administration.

[0033] The pharmaceutical compositions provided by the present invention may be prepared by mixing citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, either as is or with pharmaceutically acceptable carriers, such as excipients (e.g., lactose, D-mannitol, crystalline cellulose, glucose), binders (e.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate, talc), disintegrants (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), diluents (e.g., water for injection, physiological saline), and, if necessary, other additives (e.g., pH adjusters, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilizers), and may be in the form of tablets, capsules, suspensions, injections, suppositories, and other formulations. For example, to form tablets, citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof, or mixtures thereof may be mixed with excipients (e.g., lactose, D-mannitol, crystalline cellulose, glucose), disintegrants (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), binders (e.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate, talc), etc., to formulate the product. The tablets according to the present invention will be described in more detail below.

[0034] In one embodiment, the pharmaceutical composition provided by the present invention is a tablet. The tablet provided by the present invention may contain, in addition to the active ingredient (e.g., potassium citrate or its hydrate; sodium citrate or its hydrate; or a mixture of potassium citrate monohydrate and sodium citrate dihydrate), pharmaceutically acceptable additives commonly used in the pharmaceutical field. Examples of such additives include excipients, binders, disintegrants, fluidizers, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers, and fragrances. The content of the active ingredient in the tablets provided by the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight, relative to the tablet.

[0035] Examples of excipients that can be used in the tablets provided by the present invention include sugars such as lactose (e.g., lactose monohydrate, anhydrous lactose), glucose, sucrose, fructose, and maltose; sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, and D-mannitol; starch (e.g., corn starch, potato starch, rice starch, wheat starch); crystalline cellulose; magnesium aluminometasilicate; anhydrous calcium phosphate; precipitated calcium carbonate; calcium silicate; calcium lactate; and ethylcellulose, with crystalline cellulose being particularly preferred. The excipient content in the tablets 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, and even more preferably 3 to 20% by weight, relative to the tablet.

[0036] Examples of binders that can be used in tablets provided by the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, dextrin, methylcellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch (e.g., partially pregelatinized starch), agar, and gelatin, with hydroxypropylcellulose being particularly preferred. The binder content in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.1 to 10% by weight, and more preferably 0.3 to 3% by weight, relative to the tablet.

[0037] Examples of disintegrants that may be used in tablets provided by the present invention include croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, starch (e.g., wheat starch, corn starch, partially pregelatinized starch), and carmellose, with partially pregelatinized starch being particularly preferred. The content of the disintegrant in the tablets provided by the present invention may be 0.3 to 20% by weight, preferably 1 to 10% by weight, and more preferably 3 to 10% by weight, relative to the tablet.

[0038] Examples of fluidizing agents that can be used in the tablets provided by the present invention include light anhydrous silicic acid, talc, and magnesium aluminometasilicate. The content of the fluidizing agent in the tablets provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, and more preferably 0.3 to 3% by weight, relative to the tablet.

[0039] Examples of flavoring agents that may be used in the tablets provided by the present invention include acidulants such as citric acid (e.g., anhydrous citric acid), malic acid, acetic acid, tartaric acid, fumaric acid, and ascorbic acid (however, the aforementioned flavoring agents are not included in the active ingredients of the present invention), and sweeteners such as sodium saccharin, dipotassium glycyrrhizinate, aspartame®, stevia, thaumatin, and sucralose. The content of the flavoring agent in the tablets provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, and more preferably 0.3 to 3% by weight, relative to the tablet.

[0040] 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, with magnesium stearate being particularly preferred. The lubricant content in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 3% by weight, relative to the tablet.

[0041] Examples of pH adjusters that may be used in tablets provided by the present invention include citric acid, phosphates (e.g., sodium dihydrogen phosphate, potassium dihydrogen phosphate), carbonates (e.g., magnesium carbonate, sodium carbonate), tartrates, fumarates, acetates, and amino acid salts (however, the above pH adjusters are not included in the active ingredients of the present invention). The pH adjusting agent content in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 5% by weight, relative to the tablet.

[0042] 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 surfactant content in the tablets provided by the present invention may be 0.01 to 3% by weight, preferably 0.03 to 1% by weight, and more preferably 0.03 to 0.5% by weight, relative to the tablet. Examples of stabilizers that may be used in the tablets provided by the present invention include citric acid (e.g., anhydrous citric acid), malic acid, acetic acid, tartaric acid, maleic acid, ascorbic acid, sodium edetate, and tocopherol (however, the aforementioned stabilizers are not included in the active ingredients of the present invention), with anhydrous citric acid being particularly preferred. The content of the stabilizer in the tablets provided by the present invention may be 0.01 to 30% by weight, preferably 0.1 to 30% by weight, and more preferably 1 to 20% by weight, relative to the tablet.

[0043] Examples of flavorings that can be used in the tablets provided by the present invention include citrus flavorings such as lemon, orange, and grapefruit, peppermint, spearmint, and menthol, which can be contained in appropriate amounts in the tablets (for example, 0.01 to 1% by weight, more preferably 0.01 to 0.1% by weight relative to the tablet). The total content of the active ingredient and pharmaceutically acceptable additives in the tablets provided by the present invention does not exceed 100% by weight of the tablet.

[0044] The tablets provided by the present invention may contain the above-mentioned components and may be uncoated tablets without a coating layer, or film-coated tablets with a coating layer. The content of the coating layer can be appropriately determined by those skilled in the art, but for example, it may be 0.1 to 10% by weight relative to the uncoated tablet. In addition to the coating base, the coating layer may appropriately contain plasticizers, colorants, glossing agents, etc. Examples of coating bases that can be used in the tablets provided by the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, and polyvinylpyrrolidone, with hydroxypropyl methylcellulose being particularly preferred. The content of the coating base in the tablets provided by the present invention may be 0.01 to 10% by weight, preferably 0.3 to 3% by weight, relative to the tablet. Examples of coating plasticizers that can be used in the tablets provided by the present invention include triethyl citrate, medium-chain triglyceride, triacetin, glycerin, propylene glycol, and polyethylene glycol (e.g., macrogol 6000), with macrogol 6000 being particularly preferred. The content of the coating plasticizer in the tablets provided by the present invention may be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, relative to the tablet.

[0045] Examples of coating colorants that can be used in the tablets provided by the present invention include titanium dioxide, yellow ferric oxide, ferric oxide, black iron oxide, Food Blue No. 2, and Food Blue No. 2 aluminum lake. The content of the coating colorant in the tablets provided by the present invention may be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, relative to the tablet. An example of a coating glossing agent that can be used in the tablets provided by the present invention is carnauba wax. The content of the coating glossing agent in the tablets provided by the present invention may be 0.0001 to 0.1% by weight, preferably 0.001 to 0.01% by weight, relative to the tablet.

[0046] The pharmaceutical compositions provided by the present invention can be manufactured by methods known in the pharmaceutical field. For example, in the case of tablets, the manufacturing method may include a mixing step of mixing the active ingredient (e.g., potassium citrate or its hydrate; sodium citrate or its hydrate; or a mixture of potassium citrate monohydrate and sodium citrate dihydrate) with additives, a granulation step, a tableting step, and / or a coating step.

[0047] The mixing step may include mixing the active ingredient with additives such as excipients, stabilizers, disintegrants, and / or binders. Furthermore, prior to the tableting step, the mixture containing the active ingredient and additives may be further mixed with lubricants, flavoring agents, and / or fragrances. Mixing can be carried out using a V-type mixer, W-type mixer, container mixer, tumbler mixer, agitator mixer, or the like.

[0048] The granulation process can be carried out using granulation methods known in the pharmaceutical field. Examples of granulation methods include dry granulation, wet granulation, and fluidized bed granulation. In one embodiment, the mixture obtained in the mixing step or the granules obtained in the granulation step can be appropriately ground and / or sieved to obtain a mixture or granules having a desired particle size. Grinding can be performed using grinders known in the pharmaceutical field, such as ball mills, jet mills, and hammer mills. Sieving can be performed using sieves such as 16-mesh sieves (mesh opening 1000 μm) to 32-mesh sieves (mesh opening 500 μm).

[0049] The tableting process can be carried out using tableting methods known in the pharmaceutical field. Examples of tableting methods include direct tableting, dry tableting, wet tableting, and external lubrication tableting. For example, the mixture or granules obtained in the above process can be tableted using tablet presses known in the pharmaceutical field, such as single-pull tablet presses or rotary tablet presses. When using single-pull tablet presses, rotary tablet presses, etc., a tableting pressure of 1kN to 30kN can be used.

[0050] The coating process can be carried out by methods known in the pharmaceutical field. For example, it can be done by spray coating the outside of the uncoated tablet with a coating solution containing a coating base and appropriate amounts of plasticizer, colorant, glossing agent, etc.

[0051] In one embodiment, the tablets provided by the present invention can be manufactured by mixing an active ingredient, an excipient (e.g., lactose, D-mannitol, crystalline cellulose and / or glucose), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin and / or polyvinylpyrrolidone (PVP)), a stabilizer (e.g., anhydrous citric acid), a disintegrant (e.g., starch (e.g., partially pregelatinized starch) and / or carboxymethylcellulose calcium (CMC-Ca)) and a lubricant (e.g., magnesium stearate), and compressing them to obtain a tablet; and then forming a coating layer on the outside of the tablet containing a coating base (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose and / or PVP), a plasticizer (e.g., triethyl citrate and / or macrogol 6000), a colorant (e.g., ferric oxide and / or titanium dioxide), and a brightening agent (e.g., carnauba wax). In one embodiment, the hardness of the resulting tablets may be 10 to 200 N, preferably 30 to 150 N.

[0052] The amount of active ingredient in the pharmaceutical composition provided by the present invention can be set as appropriate. In one embodiment, the amount of the active ingredient in the pharmaceutical composition provided by the present invention may be set to an amount that, when administered to a human, improves acidic urine in gout or hyperuricemia, or a smaller amount. For example, it may be set to 1-50% or 10-20% of the daily dose approved in Japan for the improvement of acidic urine in gout or hyperuricemia (for example, if the active ingredient is a citrate preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) per tablet, administered orally three times a day).

[0053] In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and each tablet may contain 10 mg to 1 g, preferably 100 mg to 500 mg, and more preferably 400 mg to 500 mg, of potassium citrate monohydrate or sodium citrate dihydrate as an active ingredient. In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, which may contain 10 mg to 300 mg each of potassium citrate monohydrate and sodium citrate dihydrate, totaling 20 mg to 600 mg per tablet, preferably 150 to 250 mg each, totaling 400 to 500 mg, and more preferably 190 to 240 mg each, totaling 400 to 450 mg.

[0054] In one embodiment, the pharmaceutical composition provided by the present invention is a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate as active ingredients, and may also contain anhydrous citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol 6000, titanium dioxide, and carnauba wax as additives.

[0055] In one embodiment, one dose unit may be a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate. In this specification, "dosage unit" refers to a unit of the preparation, and "1 dose unit" refers to the smallest unit of the preparation. Therefore, for example, in the case of tablets, the dose unit is each tablet, and 1 dose unit represents one tablet. In the case of injectable preparations, the dose unit is the injectable preparation contained in a sealed container such as an ampoule or vial, and 1 dose unit represents the injectable preparation contained in a sealed container such as an ampoule or vial. When the pharmaceutical composition provided by the present invention is administered to a human or other mammal, one or more of the aforementioned administration units may be administered at a time, or one of the aforementioned administration units may be divided and administered in parts.

[0056] The dosage of the active ingredient is determined appropriately according to the type of active ingredient, method of administration, age, weight, sex, symptoms, and drug sensitivity of the recipient, but the dosage may be adjusted according to the improvement of symptoms.

[0057] In one embodiment, the dosage of the active ingredient may be such that, upon oral administration of the active ingredient, the pH of human urine (e.g., early morning urine) becomes pH 5.2-7.4, pH 5.2-6.8, pH 5.5-6.8, pH 5.8-6.8, pH 5.8-6.5, pH 5.8-6.2, pH 5.8 or higher but less than pH 6.2, pH 6.0-6.5, pH 6.0-6.4, pH 6.0-6.3, pH 6.0-6.2, pH 6.0 or higher but less than pH 6.2, pH 6.1-6.3, pH 6.2-6.8, pH 6.2-6.5, or pH 6.5-6.8.

[0058] In one embodiment, the dosage of the active ingredient may be such that, after oral administration of the active ingredient, the pH of human urine (e.g., early morning urine) after 6, 12, or 24 weeks of administration is pH 5.2-pH 7.4, pH 5.2-pH 6.8, pH 5.5-pH 6.8, pH 5.8-pH 6.8, pH 5.8-pH 6.5, pH 5.8-pH 6.2, pH 5.8 or higher but less than pH 6.2, pH 6.0-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 higher but less than pH 6.2, pH 6.1-pH 6.3, pH 6.2-6.8, pH 6.2-pH 6.5, or pH 6.5-6.8.

[0059] In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human as an active ingredient, potassium citrate monohydrate and sodium citrate dihydrate may be administered in doses of 0.1 to 5 g / day each, totaling 0.2 to 10 g / day; 0.1 to 3 g / day each, totaling 0.2 to 6 g / day; 0.5 to 3 g / day each, totaling 1 to 6 g / day; preferably, 0.5 to 1.5 g / day each, totaling 1 to 3 g / day; 1 to 1.5 g / day each, totaling 2 to 3 g / day; or 0.5 to 1 g / day each, totaling 1 to 2 g / day, and may be administered 1 to 5 times a day, preferably divided into 3 doses per day.

[0060] In one embodiment, when potassium citrate monohydrate or sodium citrate dihydrate is orally administered to humans as an active ingredient, the dosage may be 1-10 g / day, 1-6 g / day, 2-5.5 g / day, 1-3 g / day, 2-3 g / day, or 1-1.5 g / day, and may be administered 1-5 times a day, preferably divided into 3 doses per day.

[0061] In one embodiment, citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof may be administered for a long period of 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. The above medications are administered for periods of 100 weeks or more, 120 weeks or more, 6 weeks to 24 weeks, 12 weeks to 24 weeks, 6 weeks to 30 weeks, 12 weeks to 30 weeks, 6 weeks to 40 weeks, 12 weeks to 40 weeks, 6 weeks to 60 weeks, 12 weeks to 60 weeks, 6 weeks to 80 weeks, 12 weeks to 80 weeks, 6 weeks to 100 weeks, 12 weeks to 100 weeks, 6 weeks to 120 weeks, or 12 weeks to 120 weeks.

[0062] In one embodiment, the pharmaceutical composition provided by the present invention may exhibit beneficial effects in patients with kidney disease (e.g., a reduction in random urinary albumin, a reduction in early morning urinary albumin, a reduction in random urinary protein, an increase in pure acid excretion, a protective effect on renal function, or a reduction in dietary acid load on the kidneys) after continuous administration for 6 weeks, 12 weeks, and / or 24 weeks.

[0063] In one embodiment, the pharmaceutical composition provided by the present invention is administered to a person suffering from kidney disease. Unless otherwise specified, kidney disease includes acute kidney disease and chronic kidney disease. Examples of acute kidney disease include acute kidney disease caused by medications (e.g., nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, aminoglycoside antibiotics, fluoroquinolone antibacterial agents, iodine contrast agents, platinum-based drugs such as cisplatin), and acute kidney disease caused by renal ischemia. Chronic kidney disease (CKD) is a comprehensive concept encompassing all kidney diseases that progress chronically, regardless of the underlying disease. It includes all conditions in which there is a decline in renal function, expressed as glomerular filtration rate (GFR), or where findings suggestive of kidney damage persist chronically (for three months or more).

[0064] According to the CKD Treatment Guidelines 2012 (Japanese Journal of Nephrology 2012), the severity of chronic kidney disease is evaluated by classification based on the cause (C), renal function (GFR: G), and proteinuria (albuminuria: A). The GFR classifications are as follows: G1: GFR is normal or elevated (≧90 mL / min / 1.73 m) 2 ) G2: GFR is normal or slightly decreased (60-89 mL / min / 1.73 m²) 2 ) G3a: Mild to moderate decrease in GFR (45-59 mL / min / 1.73 m²) 2 ) G3b: Moderate to severe decrease in GFR (30-44 mL / min / 1.73 m) 2 ) G4: Severely decreased GFR (15-29 mL / min / 1.73 m)2 ) G5: End-stage renal disease (ESKD) (<15 mL / min / 1.73 m 2 )

[0065] When the underlying disease is diabetes, the classification of proteinuria (albuminuria: A) is determined using the urinary albumin / creatinine (Cr) ratio as follows: A1: Normal (less than 30 mg / gCr) A2: Microalbuminuria (30-299 mg / gCr) A3: Overt albuminuria (≥300 mg / gCr) Furthermore, when the underlying disease is hypertension other than diabetes, nephritis, polycystic kidney disease, transplanted kidney, or other conditions, the classification based on proteinuria (albuminuria: A) is made using the urinary protein / creatinine (Cr) ratio as follows. A1: Normal (less than 0.15 g / gCr) A2: Mild proteinuria (0.15~0.49 g / gCr) A3: Severe proteinuria (0.50 g / gCr or more)

[0066] According to the CKD Treatment Guidelines 2012 (Japanese Journal of Nephrology 2012), the severity classification of chronic kidney disease (CKD) is expressed using the above C, G, and A, for example, diabetes G2A3, chronic nephritis G3bA1, etc. However, considering that the severity of chronic kidney disease has traditionally been expressed only in terms of stages classified by GFR, it is also possible to express the severity of chronic kidney disease in the traditional way, using stages G1, G2, G3a, G3b, G4, and G5.

[0067] In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with mild, early-stage chronic kidney disease. 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 in stage G2 or higher and stage G3b or lower (for example, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b).

[0068] In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease in stage G3b or lower with mild proteinuria, preferably in stage G2 with mild proteinuria. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease who are in stage G2 or higher and stage G3b or lower (for example, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) and have mild proteinuria.

[0069] In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease in stage G3b or lower, with urinary protein excretion less than 3.5 g / gCr, preferably in stage G2, with urinary protein excretion less than 3.5 g / gCr. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease who are in stage G2 or higher and stage G3b or lower (for example, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) and whose urinary protein excretion is less than 3.5 g / gCr. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with progressive chronic kidney disease. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease (for example, patients with chronic kidney disease in stage G2 or higher and stage G3b or lower) whose albumin levels in random urine are 0.1 to 1000 mg / gCr, preferably 1 to 500 mg / gCr, and more preferably 1 to 300 mg / gCr. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease (for example, patients with chronic kidney disease in stage G2 or higher and stage G3b or lower) whose random urine protein levels are 0.1 to 1500 mg / gCr, preferably 1 to 1000 mg / gCr, and more preferably 1 to 500 mg / gCr. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease (for example, patients with chronic kidney disease in stage G2 or higher and stage G3b or lower) whose albumin levels in early morning urine are 0.1 to 1000 mg / gCr, preferably 1 to 500 mg / gCr, more preferably 1 to 200 mg / gCr.

[0070] In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient receiving treatment in accordance with the CKD treatment guidelines. For example, it is administered to a patient receiving blood pressure management (administration of RA system inhibitors such as ARBs and ACE inhibitors, diuretics, calcium channel blockers, etc.), proteinuria management (administration of RA system inhibitors, etc.), blood glucose management (administration of α-glucosidase inhibitors, etc.), lipid management (administration of statins, fibrates, etc.), anemia management (administration of erythropoietin, etc.), and / or bone and mineral management (administration of bisphosphonates, etc.) in accordance with the CKD treatment guidelines. In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with antihypertensive drugs (e.g., ARBs, ACE inhibitors, diuretics, calcium channel blockers). In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with spherical adsorbent carbon (sold in Japan as Kremezin®) obtained by oxidizing and reducing spherical fine porous carbon derived from petroleum hydrocarbons at high temperatures.

[0071] In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with mild, early-stage chronic kidney disease (for example, stage G3b or lower, preferably stage G2 to stage G3b, more preferably stage G2 and stage G3a, and even more preferably stage G2 chronic kidney disease), and exhibits the following effects in such patients: a reduction in random urinary albumin, a reduction in early morning urinary albumin, a reduction in random urinary protein, an increase in pure acid excretion, a protective effect on renal function, or a reduction in dietary acid load on the kidneys. In this embodiment, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for protecting renal function or a pharmaceutical composition for reducing dietary acid load on the kidneys.

[0072] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in protecting renal function, comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally in doses of 0.5 to 1.5 g / day each, totaling 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in protecting renal function, comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into three doses per day.

[0073] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in reducing dietary acid load on the kidneys, comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient, administered orally in doses of 0.5 to 1.5 g / day each of potassium citrate monohydrate and sodium citrate dihydrate, 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 for use in reducing dietary acid load on the kidneys, comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0074] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient for use in reducing random urinary albumin, early morning urinary albumin, random urinary protein, or increasing pure acid excretion, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally in doses of 0.5 to 1.5 g / day each, totaling 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses.

[0075] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient for use in reducing random urinary albumin, early morning urinary albumin, random urinary protein, or increasing pure acid excretion, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and three to six dose units are administered orally in three divided doses per day.

[0076] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient for use in patients with early chronic kidney disease in reducing random urinary albumin, early morning urinary albumin, random urinary protein, or increasing pure acid excretion, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally in doses of 0.5 to 1.5 g / day each, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day.

[0077] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient for use in patients with early chronic kidney disease in reducing random urinary albumin, early morning urinary albumin, random urinary protein, or increasing pure acid excretion, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and three to six dose units are administered orally in three divided doses per day.

[0078] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient for use in reducing urinary protein levels or suppressing the increase in urinary protein levels associated with the progression of chronic kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally in doses of 0.5 to 1.5 g / day each, totaling 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. Here, the term "urine" may refer to "early morning urine." The term "urinary protein" may refer to "urinary albumin."

[0079] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof as an active ingredient for use in reducing urinary protein levels or suppressing the increase in urinary protein levels associated with the progression of chronic kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dose units are administered orally in three divided doses per day. Here, the term "urine" may refer to "early morning urine." The term "urinary protein" may refer to "urinary albumin."

[0080] Other examples of embodiments of the present invention include the following. <1-1> A method for protecting renal function in a mammal (e.g., a human), comprising administering an effective amount of citrate, a pharmaceutically acceptable salt of citrate, or a hydrate or mixture thereof to a subject in need of protection of renal function; <1-2> A method for reducing dietary acid load on the kidneys in mammals (e.g., humans), comprising administering an effective amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof to a subject in need of reduction of dietary acid load on the kidneys; <1-3> A method for reducing random urinary albumin, early morning urinary albumin, random urinary protein, or increasing pure acid excretion in mammalian subjects (e.g., humans), comprising administering an effective amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof to a subject for which a reduction in random urinary albumin, an early morning urinary albumin, a reduction in random urinary protein, or an increase in pure acid excretion is required;

[0081] <2-1> Citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, for use in protecting renal function; <2-2> Citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, for use in reducing dietary acid load on the kidneys; <2-3> Citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, for use in reducing random urinary albumin, early morning urinary albumin, random urinary protein, or increasing pure acid excretion; <2-4> Furthermore, citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof, or mixtures thereof, for use in the protection of renal function, as described in <2-1>;

[0082] <3-1> Pharmaceutical compositions comprising citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, for use in protecting renal function; <3-2> Pharmaceutical compositions comprising citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, for use in reducing dietary acid load on the kidneys; <3-3> Pharmaceutical compositions comprising citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, for use in reducing random urinary albumin, early morning urinary albumin, random urinary protein, or increasing pure acid excretion; <3-4> Furthermore, pharmaceutical compositions for use in the protection of renal function as described in <3-1>;

[0083] <4-1> Use of citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof for the manufacture of pharmaceutical compositions for the protection of renal function; <4-2> Use of citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof for the manufacture of pharmaceutical compositions for reducing dietary acid load on the kidneys; and <4-3> Use of citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof for the manufacture of pharmaceutical compositions for reducing random urinary albumin, early morning urinary albumin, random urinary protein, or increasing pure acid excretion.

[0084] 2. Food composition In one embodiment, the food composition provided by the present invention comprises citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, and exerts the effects of reducing urinary albumin as needed, reducing early morning urinary albumin, reducing urinary protein as needed, increasing pure acid excretion, protecting renal function, or reducing dietary acid load on the kidneys.

[0085] For citric acid, pharmaceutically acceptable salts of citric acid, or hydrates or mixtures thereof, the citric acid, pharmaceutically acceptable salts of citric acid, or hydrates or mixtures thereof described in "1. Pharmaceutical Compositions" above can be used. Examples of citric acid, pharmaceutically acceptable salts of citric acid, or hydrates or mixtures thereof include pharmaceutically acceptable salts of citric acid as food-grade salts (e.g., alkali metal citrate salts or hydrates thereof or mixtures thereof), preferably a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O), or sodium citrate dihydrate.

[0086] The content of citric acid, pharmaceutically acceptable salts of citric acid, or hydrates or mixtures thereof 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 uses, foods with functional claims, foods for hospital patients, and supplements. The form of these food compositions is not particularly limited as long as they contain an effective amount of citric acid, pharmaceutically acceptable salts of citric acid, or hydrates or mixtures thereof to produce the above-mentioned effects and are in a form that can be taken orally. They may be in the form of ordinary food and beverages, or they may be provided as formulations suitable for oral administration from among the formulations that can be applied to the pharmaceutical composition, such as tablets, capsules, or suspensions. Regarding the composition and manufacturing method of these formulations, the composition and manufacturing method of pharmaceutical formulations described in "1. Pharmaceutical Compositions" above can be applied as is, and pharmaceutical formulation technologies that are known in the field of pharmaceutical formulation technology can also be applied.

[0087] For example, in the case of Foods for Specified Health Uses, Foods with Function Claims, Foods for Hospital Patients, or Supplements, one serving of food may contain 1 / 3 of a total of 1 to 3 g of potassium citrate monohydrate and sodium citrate dihydrate as active ingredients. When Foods for Specified Health Uses, Foods with Function Claims, Foods for Hospital Patients, or Supplements are provided in tablet form, for example, each 300 mg to 600 mg tablet may contain 70 to 80% by weight of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof.

[0088] If the food composition provided by the present invention is not formulated but provided in the form of ordinary food or beverage, it can be manufactured appropriately by a person skilled in the art depending on the type of food. For example, it can be manufactured by blending citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof (e.g., potassium citrate and / or sodium citrate) with a food ingredient. Examples of such food or beverage forms include liquid, milky, or paste-like foods such as beverages, soy sauce, milk, yogurt, and miso; semi-solid foods such as jelly and gummies; solid foods such as candy, gum, tofu, and supplements; or powdered foods. Examples of beverages include fruit juices, coffee drinks, oolong tea drinks, green tea drinks, black tea drinks, barley tea drinks, vegetable drinks, soft drinks such as carbonated beverages, fruit extract drinks, vegetable extract juices, near-water, sports drinks, and diet drinks.

[0089] Beverages may contain additives such as antioxidants, flavorings, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, colorants, emulsifiers, preservatives, seasonings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, and quality stabilizers, either individually or in combination. The food composition provided by the present invention can be used in the same manner as the pharmaceutical composition described in "1. Pharmaceutical Composition" above, and can also be used in areas not intended for the treatment or prevention of disease. That is, when using the citric acid, pharmaceutically acceptable salt of citric acid, or hydrate or mixture thereof contained in the food composition according to the present invention as a reference, the amount of citric acid, pharmaceutically acceptable salt of citric acid, or hydrate or mixture thereof contained in the food composition can be applied to the target of the pharmaceutical composition in the same amount as the amount of citric acid, pharmaceutically acceptable salt of citric acid, or hydrate or mixture thereof contained in the pharmaceutical composition. Furthermore, in one embodiment, the "food composition" according to the present invention can be applied to a subject (e.g., a human or other mammal) that does not have "pathological" or "abnormal" symptoms, conditions, or diseases, i.e., a subject (e.g., a human or other mammal) that is in a "healthy" or "normal" state, in order to maintain or improve that "healthy" or "normal" state. Furthermore, it can be applied to "healthy individuals concerned about urinary protein or kidney health" or "healthy individuals concerned about dietary acid load on the kidneys" in order to maintain or improve a "healthy" or "normal" state. In this case, whether the citric acid, pharmaceutically acceptable salt of citric acid, or hydrate or mixture thereof is an ingredient in a pharmaceutical composition or an ingredient in a food composition, the pharmacological effects of the citric acid, pharmaceutically acceptable salt of citric acid, or hydrate or mixture thereof itself are basically the same. Therefore, the amount and method of application of the food composition can be appropriately adjusted based on the citric acid, pharmaceutically acceptable salt of citric acid, or hydrate or mixture thereof, according to the expected effect.

[0090] Food compositions applied to subjects (e.g., humans or other mammals) that do not have "pathological" or "abnormal" symptoms, conditions, or diseases, that is, subjects (e.g., humans or other mammals) that are in a "healthy" or "normal" state, in order to maintain or enhance that "healthy" or "normal" state, may be specifically referred to as "foods with functional claims."

[0091] The term "administration" as described in "1. Pharmaceutical Compositions" above can also be applied to the "food composition" according to the present invention, and furthermore, in the case of the "food composition" according to the present invention, the term "administration" can be read as "ingestion". Therefore, for example, terms such as "administer," "be administered," etc. can be changed in form and read as "cause to ingestion," "ingestion," "be ingestion," etc., depending on the context. Therefore, the following are examples of embodiments of the food composition according to the present invention.

[0092] (1-1) Food compositions comprising citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, for the purpose of reducing random urinary albumin, reducing early morning urinary albumin, reducing random urinary protein, increasing pure acid excretion, protecting renal function, or reducing dietary acid load on the kidneys; (2-1) A method for reducing random urinary albumin, early morning urinary albumin, random urinary protein, or protecting renal function, comprising administering a food composition containing an effective amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof to a subject who requires reduction of random urinary albumin, reduction of early morning urinary albumin, reduction of random urinary protein, or protection of renal function; (2-2) If the subject requiring a decrease in random urinary albumin, a decrease in early morning urinary albumin, a decrease in random urinary protein, or protection of renal function is a healthy person concerned about urinary protein or kidney health, the method described in (2-1); (2-3) A method for increasing pure acid excretion, comprising administering to a subject in need of increased pure acid excretion a food composition containing an effective amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate or mixture thereof; (2-4) The subjects who need increased pure acid excretion are healthy individuals who are concerned about dietary acid load on the kidneys, as described in (2-3); (3-1) Food compositions containing citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof, for use in reducing random urinary albumin, early morning urinary albumin, random urinary protein, increasing pure acid excretion, protecting renal function, or reducing dietary acid load on the kidneys; and (4-1) Use of citric acid, pharmaceutically acceptable salts of citric acid, hydrates thereof, or mixtures thereof for the manufacture of food compositions for reducing random urinary albumin, early morning urinary albumin, random urinary protein, increasing pure acid excretion, protecting renal function, or reducing dietary acid load on the kidneys. Preferably, the packaging, container, or instructions for the food composition according to the present invention indicate the effects of reducing urinary albumin levels at any given time, reducing early morning urinary albumin levels, reducing urinary protein levels at any given time, increasing pure acid excretion, protecting renal function, or reducing dietary acid load on the kidneys.

[0093] The present invention will be further described below with reference to examples, but the present invention is not limited thereto. [Examples]

[0094] Human clinical trials were conducted to investigate whether oral administration of potassium citrate / sodium citrate hydrate formulations and sodium bicarbonate formulations, which are oral alkalizing agents, lowers random urinary albumin levels, lowers early morning urinary albumin levels, lowers random urinary protein levels, and increases pure acid excretion.

[0095] 1. Method Chronic kidney disease patients with stages G2-G3b (eGFR: 30-89 ml / min / 1.73m²) 2 93 patients were randomly divided into three groups: a potassium citrate / sodium citrate hydrate combination therapy group (Group A: 31 patients), a sodium bicarbonate (baking soda) preparation therapy group (Group B: 31 patients), and a control group (Group C: 31 patients). Patients were assigned to each group in a manner that avoids bias in age, sex, presence or absence of diabetes, and eGFR. Each group received treatment based on the "CKD Treatment Guidelines - Summary of Treatment" (hereinafter referred to as standard treatment).

[0096] No alkalinizing agent was administered to the control group. In group A, tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) were orally administered three tablets a day, three times a day (in the morning, at noon, and in the evening) for 24 weeks. In addition, the pH of early morning urine was monitored over time, and in cases where the early morning urine had a pH of less than 6.5, the dosage could be increased up to six tablets a day, three times a day (in the morning, at noon, and in the evening) at the discretion of the physician. In group B, tablets containing 500 mg of sodium bicarbonate were orally administered three tablets a day, three times a day (in the morning, at noon, and in the evening) for 24 weeks. In addition, the pH of early morning urine was monitored over time, and in cases where the early morning urine had a pH of less than 6.5, the dosage could be increased up to six tablets a day, three times a day (in the morning, at noon, and in the evening) at the discretion of the physician.

[0097] Early morning urine and blood were collected before the start of administration, 6 weeks, 12 weeks, and 24 weeks after the start of administration, and each sample was stored at -80°C. The concentration of albumin in random urine, the concentration of albumin in early morning urine, and the concentration of protein in random urine were measured using immunoturbidimetry and colorimetry. The urinary anion gap (U-Anion gap), urinary titratable acid concentration (U-Titratable acid), and urinary ammonia concentration (U-NH4) were determined using the following formula, and the net acid excretion (U-NAE) was calculated. U-NAE = U-NH4 + U-Titratable Acid - U-HCO3 - U-NH4 = (Osmotic pressure - 2×(Urinary Na concentration + Urinary K concentration) + Urinary urea nitrogen concentration / 2.8 + Urinary glucose concentration / 18) / 2 The units of urinary Na concentration and urinary K concentration are [mEq / L], and the units of urinary urea nitrogen concentration and urinary glucose concentration are [mg / dL]. U-Titratable acid = U-NH4 + Anion gap U-Anion gap = Urinary Na concentration + Urinary K concentration - Urinary Cl concentration The creatinine concentration in urine was measured by the enzyme method. For statistical analysis, the Mann-Whitney test was used for group comparisons, and the Wilcoxon test was used for comparing changes over time.

[0098] 2.Results Based on the measurement results, the following was calculated for each patient in Group A (potassium citrate / sodium citrate hydrate preparation), Group B (sodium bicarbonate preparation preparation), and Group C (control group): (i) The values ​​obtained by dividing the concentrations of random urinary albumin, early morning urinary albumin, random urinary protein, urinary pure acid excretion, and urinary bicarbonate ions before the start of administration by the urinary creatinine concentration. (ii) The values ​​obtained by dividing the concentrations of random urinary albumin, early morning urinary albumin, random urinary protein, urinary pure acid excretion, and urinary bicarbonate ions at 6, 12, and 24 weeks after the start of administration by the urinary creatinine concentration. (iii) The ratio of the values ​​obtained by dividing the concentrations of random urinary albumin, early morning urinary albumin, and random urinary protein at 6, 12, and 24 weeks after the start of administration by the urinary creatinine concentration, to the values ​​obtained by dividing the concentrations of random urinary albumin, early morning urinary albumin, and random urinary protein before the start of administration by the urinary creatinine concentration (value obtained by dividing the concentrations of random urinary albumin, early morning urinary albumin, and random urinary protein at 6, 12, and 24 weeks after the start of administration by the urinary creatinine concentration / value obtained by dividing the concentrations of random urinary albumin, early morning urinary albumin, and random urinary protein before the start of administration) (iv) Changes from baseline in the values ​​obtained by dividing the concentrations of random urinary albumin, early morning urinary albumin, random urinary protein, urinary pure acid excretion, and urinary bicarbonate ions by urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration.

[0099] Then, for each of the above (i) to (iv), the mean and standard deviation were calculated for each group. The results are shown in the table below. Group A, the group administered a potassium citrate / sodium citrate hydrate preparation, is labeled "Citrate," and Group B, the group administered a sodium bicarbonate preparation, is labeled "Bicarbonate."

[0100] Table 1-1-1-1: Value obtained by dividing random urinary albumin concentration by urinary creatinine concentration (mg / gCr), Table 1-1-1-2: Ratio (%) of random urinary albumin concentration divided by urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration to the ratio (%) of random urinary albumin concentration before the start of administration divided by urinary creatinine concentration. Table 1-1-1-3: Change from baseline (mg / gCr) of random urinary albumin concentration divided by urinary creatinine concentration.

[0101] Table 1-2-1-1: Value obtained by dividing random urinary protein concentration by urinary creatinine concentration (mg / gCr), Table 1-2-1-2: Ratio (%) of random urinary protein concentration divided by urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration to the random urinary protein concentration before the start of administration divided by urinary creatinine concentration. Table 1-2-1-3: Change in random urinary protein concentration divided by urinary creatinine concentration from baseline (mg / gCr),

[0102] Table 2-1-1-1: Value obtained by dividing the early morning urinary albumin concentration by the urinary creatinine concentration (mg / gCr), Table 2-1-1-2: Ratio (%) of the early morning urinary albumin concentration divided by the urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration, to the early morning urinary albumin concentration divided by the urinary creatinine concentration before the start of administration. Table 2-1-1-3: Change from baseline (mg / gCr) of the value obtained by dividing the early morning urinary albumin concentration by the urinary creatinine concentration.

[0103] Table 1-3: Change in urinary pure acid excretion concentration divided by urinary creatinine concentration (mEq / gCr) from baseline at 6, 12, and 24 weeks after the start of administration (start of administration).

[0104] [Table 1-1-1-1]

[0105] [Table 1-1-1-2]

[0106] [Table 1-1-1-3]

[0107] In Group A (Citrate: potassium citrate / sodium citrate hydrate combination therapy group), random urinary albumin levels at 6, 12, and 24 weeks after administration were lower compared to Group B (Bicarbonate: sodium bicarbonate combination therapy group) and Group C (Control group) (see Table 1-1-1-1). Random urinary albumin levels at 6-24 weeks were lower in Group A compared to Groups B and C (see Table 1-1-1-1). The change in random urinary albumin levels from baseline at 6, 12, and 24 weeks after administration, and from 6-24 weeks, increased in Groups B and C, while decreased in Group A (see Table 1-1-1-3). Therefore, administration of the potassium citrate / sodium citrate hydrate combination therapy was shown to be useful in protecting renal function compared to administration of sodium bicarbonate or the control group.

[0108] [Table 1-2-1-1]

[0109] [Table 1-2-1-2]

[0110] [Table 1-2-1-3]

[0111] In Group A (Citrate: potassium citrate / sodium citrate hydrate combination therapy group), random urinary protein levels at 6, 12, and 24 weeks after administration were lower compared to Group B (Bicarbonate: sodium bicarbonate combination therapy group) and Group C (Control group) (see Table 1-2-1-1). Random urinary protein levels at 6-24 weeks were lower in Group A compared to Groups B and C (see Table 1-2-1-1). The change in random urinary protein levels from baseline at 6, 12, and 24 weeks after administration, as well as from 6-24 weeks after administration, increased in Groups B and C, while decreased in Group A (see Table 1-2-1-3). Therefore, administration of the potassium citrate / sodium citrate hydrate combination therapy was shown to be useful in protecting renal function compared to administration of sodium bicarbonate or the control group.

[0112] [Table 2-1-1-1]

[0113] [Table 2-1-1-2]

[0114] [Table 2-1-1-3]

[0115] In Group A (Citrate: potassium citrate / sodium citrate hydrate combination therapy group), early morning urinary albumin levels at 6, 12, and 24 weeks after administration were lower compared to Group B (Bicarbonate: sodium bicarbonate combination therapy group) and Group C (Control group) (see Table 2-1-1-1). Early morning urinary albumin levels from 6 to 24 weeks were lower in Group A compared to Groups B and C (see Table 2-1-1-1). The change in early morning urinary albumin levels from baseline at 6, 12, and 24 weeks after administration, and from 6 to 24 weeks, increased in Groups B and C, while decreased in Group A (see Table 2-1-1-3). Therefore, administration of the potassium citrate / sodium citrate hydrate combination therapy was shown to be useful in protecting renal function compared to administration of sodium bicarbonate or the control group.

[0116] [Table 1-3]

[0117] In Group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation), compared to Group B (Bicarbonate: sodium bicarbonate preparation preparation preparation group) and Group C (Control: control group), the change in pure acid excretion from baseline at 6, 12, and 24 weeks after administration, as well as from 6 to 24 weeks after administration, showed an increase in Group A, or a smaller decrease compared to Groups B and C, while Groups B and C showed a decrease. The change in the amount of pure acid excretion from baseline was high in Group A (see Table 1-3). Therefore, administration of the potassium citrate / sodium citrate hydrate combination preparation was shown to be useful in reducing dietary acid load on the kidneys compared to administration of sodium bicarbonate preparation or the control group. [Industrial applicability]

[0118] The pharmaceutical composition or food composition provided by the present invention makes it possible to protect renal function or reduce dietary acid load on the kidneys in mammals.

Claims

[Claim 1] A pharmaceutical or food composition for the protection of renal function comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

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