Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics

Definitions

• the present invention relates to novel pharmaceutical compositions comprising citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof. More specifically, the present invention relates to a pharmaceutical composition for suppressing acidosis in patients with chronic kidney disease accompanied by anemia, for suppressing anemia, for suppressing a decrease in blood iron concentration, or for suppressing a decrease in blood ferritin concentration. ..
• the present application claims priority based on Japanese Patent Application No. 2019-86945 filed in Japan on April 28, 2019, and Japanese Patent Application No. 2019-119297 filed in Japan on June 27, 2019. , The contents are used here.
• CKD chronic kidney disease
• GFR glomerular filtration rate
• CVD cardiovascular disease
• Non-Patent Document 1 Advanced in CKD patients bicarbonate ions in blood (HCO 3 -) concentration is lowered, since the developing metabolic acidosis, alkaline agents such as sodium bicarbonate and citric acid formulation is administered. It has been reported that the progress of CKD is suppressed by administration of sodium hydrogen carbonate, which is an alkalizing agent (Non-Patent Document 1). Further, in a nephrotic animal model caused by protein overload, it has been reported that oral administration of sodium hydrogen carbonate suppresses tubular cell damage due to acidic urine (Non-Patent Document 2). It is also known that administration of an alkalizing agent to early-stage CKD patients suppresses the progression of renal damage and reduces the blood concentration of uremic substances (Patent Documents 1 and 2).
• One of the challenges of the present invention is the treatment or prevention of acidosis in patients with chronic kidney disease with anemia, which comprises citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof.
• anemia which comprises citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof.
• Another object of the present invention is to provide a medicine useful for suppressing anemia (for example, suppressing renal anemia, suppressing iron deficiency anemia).
• Another object of the present invention is to provide a drug useful for suppressing a decrease in blood iron concentration or suppressing a decrease in blood ferritin concentration.
• Another object of the present invention is for suppressing acidosis in patients with chronic kidney disease accompanied by anemia, for suppressing anemia (for example, for suppressing renal anemia, for suppressing iron deficiency anemia), and for suppressing a decrease in blood iron concentration. Or, to provide a food for suppressing a decrease in blood ferritin concentration.
• the present inventors have found that a composition containing ferritin, a pharmaceutically acceptable salt of ferritin, or a hydrate thereof or a mixture thereof is found.
• the drug suppresses acidosis or anemia in patients with chronic kidney disease with anemia or patients with acute kidney disease with anemia.
• it is useful for (for example, suppression of renal anemia and suppression of iron deficiency anemia), and completed the present invention.
• the present invention provides, in one aspect, a pharmaceutical composition for anemia control comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof.
• the present invention in one aspect, comprises a patient with chronic kidney disease with anemia or a patient with acute kidney disease with anemia, which comprises citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof.
• the present invention comprises citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, for suppressing a decrease in blood iron concentration as compared with sodium hydrogen carbonate.
• a pharmaceutical composition for suppressing a decrease in blood ferritin concentration as compared with sodium hydrogen carbonate comprises a patient with chronic kidney disease with anemia or a patient with acute kidney disease with anemia, which comprises citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof.
• a patient with chronic kidney disease with anemia or a patient with acute kidney disease with anemia which comprises citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof.
• the present invention contains citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, which suppresses a decrease in blood iron concentration as compared with sodium hydrogen carbonate, or Provided is a food material useful for suppressing a decrease in blood ferritin concentration as compared with sodium hydrogen carbonate.
• the pharmaceutical composition or food composition provided by the present invention it is possible to suppress a decrease in blood iron concentration as compared with sodium hydrogen carbonate or a decrease in blood ferritin concentration as compared with sodium hydrogen carbonate in mammals. is there.
• the pharmaceutical composition, food composition, or the like provided by the present invention can suppress acidosis in a chronic kidney disease patient with anemia or an acute kidney disease patient with anemia, or suppress anemia in mammals.
• the pharmaceutical composition provided by the present invention may contain citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof as an active ingredient.
• pharmaceutically acceptable salts of citric acid include alkali metal citrate salts.
• the alkali metal citrate salt include tripotassium citrate (hereinafter referred to as potassium citrate) and trisodium citrate (hereinafter referred to as sodium citrate), each of which is one of the stable potassium citrates. It may be a hydrate such as a hydrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) and a dihydrate of sodium citrate (C 6 H 5 Na 3 O 7 ⁇ 2 H 2 O). .
• Examples of citric acid include, but are not limited to, anhydrous citric acid.
• Examples of preferable active ingredients contained in the pharmaceutical composition provided by the present invention include sodium citrate, potassium citrate or a hydrate thereof, or a mixture thereof, and examples thereof include a monohydrate of potassium citrate. It may be a mixture of (C 6 H 5 K 3 O 7 ⁇ H 2 O) and sodium citrate dihydrate (C 6 H 5 Na 3 O 7 ⁇ 2 H 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 ⁇ 2 H 2 O) is A person skilled in the art can appropriately set the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate, for example, to dihydrate sodium citrate with respect to potassium citrate monohydrate 1.
• the thing can be 0.01-100.
• the molar ratio of potassium citrate (eg, potassium citrate monohydrate) to sodium citrate (eg, sodium citrate dihydrate) can be appropriately set by those skilled in the art, eg, 0.85: 1. 15 to 1.15: 0.85, 0.90: 1.10 to 1.10: 0.90, 0.95: 1.05 to 1.05: 0.95, or 0.99: 1.01 It may be ⁇ 1.01: 0.99, preferably 1: 1.
• other examples of the active ingredient contained in the pharmaceutical composition provided by the present invention include sodium citrate or a hydrate thereof, and examples thereof include a dihydrate of sodium citrate (C 6 H 5 Na). It may be 3 O 7 ⁇ 2H 2 O).
• the active ingredient contained in the pharmaceutical composition provided by the present invention include potassium citrate or a hydrate thereof, and examples thereof include a monohydrate of potassium citrate (C 6 H 5 K). It may be 3 O 7 ⁇ H 2 O).
• the active ingredient contained in the pharmaceutical composition of the present invention may include sodium citrate or a hydrate thereof and a mixture of potassium citrate or a hydrate thereof.
• the active ingredient contained in the pharmaceutical composition of the present invention may be a mixture of potassium citrate, sodium citrate and citric acid (eg, citric acid anhydride).
• the mixing ratio (molar ratio) of citric acid for example, anhydrous citric acid
• potassium citrate and sodium citrate can be appropriately set by those skilled in the art, for example, 1: 1.7 to 2.3: 1. It may be 7 to 2.3, 1: 1.9 to 2.1: 1.9 to 2.1, or 1: 1.95 to 2.05: 1.95 to 2.05, or 1: 2: 2. Is preferable.
• the active ingredient contained in the pharmaceutical composition of the present invention is a monohydrate of potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O), a dihydrate of sodium citrate. (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O) and may be a mixture of anhydrous citric acid.
• the mixing ratio (molar ratio) of O) can be appropriately set by those skilled in the art, for example, 1: 1.7 to 2.3: 1.7 to 2.3, 1: 1.9 to 2.1: 1. It may be 9 to 2.1 or 1: 1.95 to 2.05: 1.95 to 2.05, preferably 1: 2: 2.
• the active ingredient contained in the pharmaceutical composition of the present invention may be composed only of sodium citrate or a hydrate thereof and a mixture of potassium citrate or a hydrate thereof.
• citric acid a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof (for example, a monohydrate of potassium citrate (C 6 H 5 K 3 O 7 ⁇ ). H 2 O) and, when referring to the weight of the dihydrate of sodium citrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O)) , the weight may be a dry weight.
• compositions provided by the present invention can also be used for the treatment or prevention of chronic kidney disease or acute kidney disease.
• administration of the pharmaceutical composition provided by the present invention suppresses anemia (eg, renal anemia, iron deficiency anemia).
• anemia eg, renal anemia, iron deficiency anemia.
• administration of the pharmaceutical composition provided by the present invention suppresses a decrease in serum iron concentration and suppresses a decrease in serum ferritin concentration as compared with administration of sodium hydrogen carbonate.
• the pharmaceutical composition comprises treatment or prevention of acidosis in patients with chronic kidney disease in which anemia is suppressed, treatment or prevention of acidosis in patients with chronic kidney disease with anemia, treatment or prevention of acidosis in patients with acute kidney disease in which anemia is suppressed, or It is useful in the treatment or prevention of acidosis in patients with acute kidney disease with anemia.
• administration of the pharmaceutical composition provided by the present invention suppresses a decrease in blood iron concentration or a decrease in blood ferritin concentration.
• “suppression” includes stopping or slowing the exacerbation or progression of a symptom, condition or disease, and for that purpose, and ameliorating or ameliorating the symptom, condition or disease. It is a concept that includes.
• “improvement” means bringing "pathological” or “abnormal” symptoms, conditions or diseases closer to or for "healthy” or “normal” conditions, and “healthy” or It is a concept that includes making or for making a “normal” state. Therefore, in one embodiment, “improvement” means that a numerical value that is an index of a "pathological” or "abnormal” symptom or condition becomes smaller or larger according to the "improvement” and is normal. Includes approaching a normal value or becoming a normal value.
• exacerbation or progression of a symptom, condition or disease is defined as “pathological” or “abnormal” symptom, exacerbation or progression of the condition or disease, and “healthy” or “normal” condition. Includes exacerbation or progression to "na” or “abnormal” symptoms, conditions or illnesses.
• “suppression” is to stop or slow down or slow down the exacerbation or progression of a symptom, condition or disease.
• “suppression” is to stop or slow the exacerbation or progression of a symptom, condition or disease.
• health refers to a condition free of acute or chronic disease or disorder
• normal refers to a condition in which a healthy subject is normally expressed.
• 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, and control or placebo is used. The times of administration are compared.
• treatment includes the elimination, cure, cure or amelioration of "morbid” or “abnormal” symptoms, conditions or diseases, and for that purpose, “morbid”.
• it is a concept that includes “suppressing” the exacerbation of an "abnormal” symptom, condition or disease, and for that purpose, and also includes “improvement”.
• “suppression” and “improvement” have the above-mentioned meanings.
• “treatment” is to eliminate, cure, cure or ameliorate a "pathological” or “abnormal” symptom, condition or disease, and for that purpose.
• treatment is to eliminate, cure, cure or ameliorate a "pathological” or “abnormal” symptom, condition or disease.
• prevention is a concept including preventing the onset of "pathological” or “abnormal” symptoms, conditions or diseases, and for that purpose.
• anemia can be assessed by a lower blood iron concentration as compared to a "healthy” or “normal” state. Therefore, in one embodiment, “suppression of anemia” means the blood iron concentration or the blood ferritin concentration after administration as compared with the blood iron concentration or blood ferritin concentration before administration of the pharmaceutical composition provided by the present invention. It can be evaluated by suppressing the decrease in blood ferritin concentration, or by administration of the pharmaceutical composition provided by the present invention, the decrease in blood iron concentration or blood ferritin concentration is compared with the placebo administration or control. Can be evaluated by suppressing.
• "suppression of anemia” refers to the amount of iron (concentration; ⁇ g / dL) in serum 6 weeks, 12 weeks and 24 weeks after administration of the pharmaceutical composition provided by the present invention. , 100% or more and less than 120%, preferably 105% or more and 115% or less, more preferably 105% or more, respectively, with respect to the amount of iron in the serum 6 weeks after administration, 12 weeks after administration and 24 weeks after administration of the control, respectively. It can be evaluated by being 110% or less.
• "suppression of anemia” means that the amount of iron (concentration; ⁇ g / dL) in serum after 6 weeks, 12 weeks and 24 weeks after administration of the pharmaceutical composition provided by the present invention is determined. It can be evaluated that the amount of iron in the serum before administration is 100% or more and less than 120%, preferably 100% or more and 115% or less, and more preferably 100% or more and 110% or less, respectively. In one embodiment, “suppression of anemia” means that the amount of iron (concentration; ⁇ g / dL) in serum after 6 weeks, 12 weeks and 24 weeks after administration of the pharmaceutical composition provided by the present invention is determined.
• the amount of increase with respect to the amount of iron in serum before administration is 0 ⁇ g / dL or more and 20 ⁇ g / dL or less, preferably 0 ⁇ g / dL or more and 15 ⁇ g / dL or less, and more preferably 5 ⁇ g / dL or more and 10 ⁇ g / dL or less. Can be evaluated.
• anemia suppression means that the serum ferritin concentration (ng / mL) 24 weeks after administration of the pharmaceutical composition provided by the present invention is the ferritin concentration in serum 24 weeks after administration of the control. It can be evaluated by being 100% or more and less than 200%, preferably 100% or more and 150% or less, and more preferably 120% or more and 150% or less with respect to the concentration.
• anemia suppression means that the serum ferritin concentration (ng / mL) 24 weeks after administration of the pharmaceutical composition provided by the present invention is 80 relative to the serum ferritin concentration before administration. It can be evaluated by being% or more and less than 160%, preferably 80% or more and 120% or less, and more preferably 90% or more and 110% or less.
• "suppression of anemia” means that the ferritin concentration (ng / mL) in the serum 24 weeks after administration of the pharmaceutical composition provided by the present invention is increased as an increase in the ferritin concentration in the serum before administration.
• "suppression of decrease in blood iron concentration" or “inhibition of decrease in blood ferritin concentration” is compared with the concentration of each component of the pharmaceutical composition provided by the present invention before administration. Therefore, it can be evaluated by suppressing the increase or decrease in the concentration of each component after administration, or by administration of the pharmaceutical composition provided by the present invention, the concentration of each component is compared with that of placebo administration or control. It can be evaluated by suppressing the increase or decrease of.
• early morning urine means the first urine after waking up
• as needed urine means urine other than the above-mentioned "early morning urine”.
• the pharmaceutical composition provided by the present invention is orally or parenterally administered to humans or other mammals, and examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, and transmucosa. Examples include administration, transdermal administration, nasal administration, rectal administration, intrathecal administration, intraperitoneal administration, and local administration.
• the pharmaceutical composition provided by the present invention is an active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, as it is or pharmaceutically acceptable.
• Carriers such as excipients (eg lactose, D-mannitol, crystalline cellulose, glucose), binders (eg hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (eg stearer) Magnesium acid acid, talc), disintegrants (eg starch, carboxymethyl cellulose calcium (CMC-Ca)), diluents (eg water for injection, physiological saline), and other additives if necessary (eg pH adjustment).
• excipients eg lactose, D-mannitol, crystalline cellulose, glucose
• binders eg hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP
• Agents, surfactants, solubilizers, preservatives, emulsifiers, tonicity agents, stabilizers may be mixed and prepared, and preparations such as tablets, capsules, suspensions, injections, suppositories, etc. Can be.
• the active ingredient citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof is used as an excipient (for example, lactose, D-mannitol).
• Crystalline cellulose glucose
• disintegrants eg starch, carboxymethyl cellulose calcium (CMC-Ca)
• binders eg hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)
• lubricants eg , Magnesium stearate, talc, etc.
• disintegrants eg starch, carboxymethyl cellulose calcium (CMC-Ca)
• binders eg hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)
• lubricants eg , Magnesium stearate, talc
• the pharmaceutical composition provided by the present invention is a tablet.
• the tablets provided by the present invention are citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof (for example, potassium citrate or a hydrate thereof; citric acid; Sodium acid or its hydrate; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium hydrogen carbonate), as well as commonly used, pharmaceutically acceptable additives in the pharmaceutical field. May include. Examples of such additives include excipients, binders, disintegrants, fluidizers, flavoring agents, lubricants, pH regulators, surfactants, stabilizers and fragrances.
• the content of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, which are the active ingredients in the tablets provided by the present invention is preferably 10 to 95% by weight based on the tablets. May be 30 to 90% by weight, more preferably 60 to 85% by weight.
• the pharmaceutical composition provided by the present invention can be produced by a method known in the pharmaceutical field.
• the hardness of the resulting tablet can be 10-200 N, preferably 30-150 N.
• the amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, which are the active ingredients in the pharmaceutical composition provided by the present invention can be appropriately set. In one embodiment, the amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, which are the active ingredients in the pharmaceutical composition provided by the present invention, is effective.
• Administration of a dose of the component citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof to humans improves acidic urine in gout or hyperuricemia.
• the daily dose approved in Japan for the improvement of acidic urine in gout or hyperuric acidemia may be set to be an amount or less.
• tablets containing potassium citrate in 1 tablet (C 6 H 5 K 3 O 7 ⁇ H 2 O) 231.5mg and sodium citrate hydrate (C 6 H 5 Na 3 O 7 ⁇ 2H 2 O) 195.0mg 2 tablets at a time, orally administered 3 times a day) may be set to 1 to 50%, or 10 to 20%.
• the pharmaceutical composition provided by the present invention is a tablet, containing 10 mg to 1 g, preferably 100 mg to 500 mg of potassium citrate monohydrate or sodium citrate dihydrate in one tablet. , More preferably, 400 mg to 500 mg may be contained.
• the pharmaceutical composition provided by the present invention is a tablet, in which potassium citrate monohydrate and sodium citrate dihydrate, respectively, at 10 mg to 300 mg as active ingredients. , 20 mg to 600 mg in total, preferably 150 to 250 mg in total, 400 to 500 mg in total, and more preferably 190 to 240 mg in total, 400 to 450 mg in total.
• the pharmaceutical composition provided by the present invention is a tablet, which contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate as active ingredients, and is anhydrous as an additive. It may contain citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol 6000, titanium oxide and carnauba wax. In this embodiment, the content of citric acid anhydride may be 72.5 mg.
• a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate may be used as a unit of administration.
• the "administration unit” represents a unit of a preparation
• the "1 administration unit” represents the minimum unit of a preparation. Therefore, for example, in the case of tablets, the administration unit is each tablet, and one administration unit represents one tablet. If it is an injection, the administration unit is an injection placed in a sealed container such as an ampoule or vial, and one administration unit represents an injection placed in a sealed container such as an ampoule or vial.
• one or more of the above-mentioned administration units may be administered at a time, and the one-of-a-kind administration unit may be administered in divided doses. May be done.
• the dose of the active ingredient citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof is pharmaceutically acceptable of the active ingredient citric acid, citric acid. It is appropriately determined according to the type of citric acid, its hydrate or a mixture thereof, the administration method, the age, weight, sex, symptom, sensitivity to the drug, etc. of the administration target, but it depends on the situation of improvement of the symptom. The dose may be adjusted accordingly. In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate as an active ingredient is orally administered to humans, Japan for the improvement of acidic urine in gout and hyperuricemia.
• Daily doses approved by eg, for citric acid preparations: 231.5 mg of potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) and sodium citrate hydrate (for example, 1 tablet) C 6 H 5 Na 3 O 7 ⁇ 2H 2 O)
• Half the dose of 2 tablets containing 195.0 mg at a time, orally administered 3 times a day may be used as the daily dose.
• a mixture of potassium citrate monohydrate and sodium citrate dihydrate as an active ingredient is orally administered to humans, Japan for the improvement of acidic urine in gout and hyperuricemia.
• Daily doses approved by eg, for citric acid preparations: 231.5 mg of potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) and sodium citrate hydrate (for example, 1 tablet) C 6 H 5 Na 3 O 7 ⁇ 2H 2 O) 2 tablets containing 195.0 mg at a time, orally administered 3 times a day) may be used as the daily dose.
• Japan for the improvement of acidic urine in gout and hyperuricemia.
• Daily doses approved by eg, for citric acid preparations: 231.5 mg of potassium citrate (C 6 H 5 K 3 O 7 ⁇ H 2 O) and sodium citrate hydrate (for example, 1 tablet) C 6 H 5 Na 3 O 7 ⁇ 2H 2 O) 2 tablets containing 195.0 mg at a time, orally administered 3 times a day
• the dose was increased to the daily dose approved in Japan for the improvement of acidic urine in gout and hyperuric acidemia.
• the dosage of the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof is the active ingredient, citric acid, citric acid.
• the pH of human urine for example, early morning urine
• the pH of human urine is pH 5.2 to pH 6.8, pH 5.5 to pH6.8, pH5.8-pH6.8, pH5.8-pH6.5, pH5.8-pH6.2, pH5.8 or more and less than pH6.2, pH6.0-pH6.5, pH6.0-pH6 .4, pH6.0 to pH6.3, pH6.0 to pH6.2, pH6.0 to less than pH6.2, pH6.1 to pH6.3, pH6.2 to 6.8, pH6.2 to pH6.5 or
• the dose may be such that the pH is 6.5 to 6.8.
• the dosage of the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof is the active ingredient, citric acid, citric acid.
• the pH of human urine (eg, early morning urine) by oral administration of a pharmaceutically acceptable salt thereof, or a hydrate thereof or a mixture thereof, is 6 weeks, 12 weeks or 24 weeks after administration.
• the dose may be 2 to 6.8, pH 6.2 to pH 6.5 or pH 6.5 to 6.8.
• potassium citrate monohydrate and sodium citrate dihydrate when a mixture of potassium citrate monohydrate and sodium citrate dihydrate as an active ingredient is orally administered to humans, 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 to each.
• a total of 1 to 3 g / day at 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 may be administered per day. It may be administered 1 to 5 times, preferably 3 times a day.
• potassium citrate monohydrate or sodium citrate dihydrate as an active ingredient when potassium citrate monohydrate or sodium citrate dihydrate as an active ingredient is orally administered to humans, 1 to 10 g / day, 1 to 6 g / day, 2 to 5.5 g / day. It may be administered daily, 1 to 3 g / day, 2 to 3 g / day or 1 to 1.5 g / day, or may be administered 1 to 5 times a day, preferably divided into 3 times a day.
• the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof may be administered for a long period of time, eg, for one 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 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 below, 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 or more and 80 weeks or less, 6 weeks or more and 100 weeks or less, 12 weeks or more and 100 weeks or less, 12 weeks or more and 100 weeks or less, 6 weeks or more and
• the pharmaceutical compositions provided by the present invention are administered by 6 weeks of continuous administration, 12 weeks of continuous administration, and / or 24 weeks of continuous administration to kidney disease (eg, acute kidney disease or chronic kidney disease).
• kidney disease eg, acute kidney disease or chronic kidney disease.
• Beneficial effects eg, anemia-suppressing effects
• Kidney disease includes acute kidney disease and chronic kidney disease unless otherwise noted.
• acute kidney disease include drugs (eg, non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, aminoglycoside antibiotics, new quinolone antibacterial agents, iodo contrast agents, platinum such as cisplatin).
• drugs eg, non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, aminoglycoside antibiotics, new quinolone antibacterial agents, iodo contrast agents, platinum such as cisplatin.
• examples thereof include acute kidney disease caused by (preparation) and acute kidney disease caused by renal ischemia.
• Chronic kidney disease (CKD) is a concept that includes chronic kidney disease regardless of the underlying disease, and there is a decrease in renal function represented by glomerular filtration rate (GFR), or renal damage. It is a concept that includes all pathological conditions in which the findings suggesting
• GFR renal function
• albuminuria albuminuria
• G1 GFR is normal or high ( ⁇ 90 mL / min / 1.73 m 2 )
• G2 GFR is normal or slightly decreased (60-89 mL / min / 1.73 m 2 )
• G3a Mild to moderate decrease in GFR (45-59 mL / min / 1.73 m 2 )
• G3b Moderate to severely reduced GFR (30-44 mL / min / 1.73 m 2 )
• G4 GFR is highly reduced (15-29 mL / min / 1.73 m 2 )
• EKD End-stage renal disease
• the classification by proteinuria is classified as follows using the urinary albumin / creatinine (Cr) ratio when the underlying disease is diabetes.
• the classification by proteinuria is as follows using the urinary protein / creatinine (Cr) ratio. It is classified as.
• A2 Mild proteinuria (0.15-0.49 g / gCr)
• CKD chronic kidney disease
• the pharmaceutical compositions provided by the present invention are administered to patients with less severe, early-stage chronic kidney disease.
• the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G3b or lower, preferably stage G2 or lower.
• the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient who is stage G2 or higher and stage G3b or lower (eg, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b).
• stage G2 or higher and stage G3b or lower eg, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b.
• the pharmaceutical composition provided by the present invention is a chronic kidney disease patient with stage G3b or lower and microalbuminuria, preferably stage G2 with microalbuminuria. Administered to the patient.
• the pharmaceutical composition provided by the present invention is stage G2 or higher and stage G3b or lower (eg, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) and is microalbuminuria. It is administered to patients with chronic kidney disease.
• the pharmaceutical composition provided by the present invention is a chronic kidney disease patient, preferably stage G2, with stage G3b or lower and urinary protein excretion of less than 3.5 g / gCr. It is administered to patients with chronic kidney disease whose urinary protein excretion is less than 3.5 g / gCr.
• the pharmaceutical composition provided by the present invention is stage G2 or higher and stage G3b or lower (eg, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) and urinary protein excretion. Is administered to patients with chronic kidney disease who have less than 3.5 g / g Cr.
• the pharmaceutical composition provided by the present invention is administered to a patient with progressive chronic kidney disease.
• the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease with anemia.
• the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease with hypertension.
• the pharmaceutical composition provided by the present invention is administered to a patient who is treated according to the CKD clinical guide.
• blood pressure control 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 treatment guide. It is administered to patients undergoing (administration of ⁇ -glucosidase inhibitors, etc.), lipid management (administration of statins, fibrates, etc.), anemia management (administration of erythropoetin, etc.) and / or measures against bone and minerals (administration of bisphosphonates, etc.).
• the pharmaceutical compositions provided by the present invention are used in combination with antihypertensive agents (eg, ARBs, ACE inhibitors, diuretics, Ca antagonists).
• the pharmaceutical composition provided by the present invention is a spherical adsorbed carbon obtained by oxidizing and reducing spherical fine porous carbon derived from a petroleum hydrocarbon at a high temperature (as Kremezin (registered trademark) in Japan). (Sold at) is used in combination.
• the pharmaceutical compositions provided by the present invention are less severe, early chronic kidney disease patients (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 patient with stage G2 chronic kidney disease), which can suppress anemia in that patient.
• the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for suppressing acidosis for a patient with chronic kidney disease accompanied by anemia, or a pharmaceutical composition for suppressing anemia.
• the pharmaceutical compositions provided by the present invention are less severe, early chronic kidney disease patients (eg, stage G3b or lower, preferably stage G2 or higher, stage G3b or lower, more preferably stage G2). And, more preferably, patients with chronic kidney disease in stage G2), who have a lower blood iron concentration or a lower blood ferritin concentration as compared to the case of sodium bicarbonate administration. Suppress.
• the pharmaceutical composition provided by the present invention may be an acidosis inhibitor for patients with chronic kidney disease associated with anemia, an inhibitor of a decrease in blood iron concentration, or an agent for suppressing a decrease in blood ferritin concentration.
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing a decrease in blood iron concentration or suppressing a decrease in blood ferritin concentration, and potassium citrate as an active ingredient.
• the monohydrate and sodium citrate dihydrate are orally administered at 0.5 to 1.5 g / day, for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. is there.
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing a decrease in blood iron concentration or suppressing a decrease in blood ferritin concentration, and is one administration unit (preferably).
• One tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosing units per day (eg, 3 dosing units or 6 dosing units per day).
• the administration unit) is orally administered in 3 divided doses a day.
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing a decrease in blood iron concentration or suppressing a decrease in blood ferritin concentration, and is one administration unit (preferably).
• (1 tablet) contains 72.5 mg of anhydrous citric acid, 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dose units per day (for example, 1 day). 3 administration units or 6 administration units) are orally administered in 3 divided doses a day.
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing a decrease in blood iron concentration or suppressing a decrease in blood ferritin concentration in a patient with chronic kidney disease.
• Potassium citrate monohydrate and sodium citrate dihydrate as active ingredients are divided into 0.5 to 1.5 g / day for a total of 1 to 3 g / day, preferably 1 to 5 times a day, preferably 3 times a day. It is to be administered orally.
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing a decrease in blood iron concentration or suppressing a decrease in blood ferritin concentration in a patient with chronic kidney disease.
• One dosing unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosing units per day (eg, per day). 3 administration units or 6 administration units) are orally administered in 3 divided doses a day.
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing a decrease in blood iron concentration or suppressing a decrease in blood ferritin concentration in a patient with chronic kidney disease.
• One dosing unit (preferably one tablet) contains 72.5 mg of anhydrous citric acid, 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosing units daily. The unit (for example, 3 or 6 administration units per day) is orally administered in 3 divided doses per day.
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in acidosis suppression or anemia suppression for patients with chronic kidney disease associated with anemia, and potassium citrate as an active ingredient.
• the hydrate 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. ..
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in acidosis suppression or anemia suppression for patients with chronic kidney disease associated with anemia, and is 1 administration unit (preferably 1).
• Tablets contain 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, 3 to 6 doses per day (eg, 3 or 6 doses per day). Unit) is orally administered in 3 divided doses a day.
• the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in acidosis suppression or anemia suppression for patients with chronic kidney disease associated with anemia, and is 1 administration unit (preferably 1).
• Tablets contain 72.5 mg of anhydrous citric acid, 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosing units per day (eg, per day). 3 administration units or 6 administration units) are orally administered in 3 divided doses a day.
• Examples of other embodiments of the present invention include: a) A method for suppressing acidosis in chronic kidney disease or acute kidney disease associated with anemia in mammalian subjects (for example, humans), which is effective for subjects requiring suppression of acidosis in chronic kidney disease or acute kidney disease associated with anemia. Methods comprising administering an amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof; b) A method for suppressing renal anemia or iron deficiency anemia in mammalian subjects (for example, humans), which is an effective amount of citric acid or citric acid drug for subjects who need to suppress renal anemia or iron deficiency anemia.
• Methods comprising administering a pharmaceutically acceptable salt, or a hydrate thereof or a mixture thereof; c) A method of treating or preventing renal anemia or iron deficiency anemia in a mammalian subject (eg, human), wherein an effective amount of citric acid is used in the subject requiring treatment or prevention of renal anemia or iron deficiency anemia. Methods comprising administering a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof;
• Citric acid pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof for use in the control of acidosis in chronic kidney disease or acute kidney disease with anemia
• Citric acid pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof for use in the control of renal or iron deficiency anemia
• Citric acid a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for use in the treatment or prevention of renal anemia or iron deficiency anemia
• aaa A pharmaceutical composition comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for use in the control of acidosis in chronic kidney disease or acute kidney disease with anemia. Stuff; bbb) A pharmaceutical composition comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for use in the control of renal anemia or iron deficiency anemia; ccc) A pharmaceutical composition comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for use in the treatment or prevention of renal or iron deficiency anemia;
• Citric acid a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for producing a pharmaceutical composition for suppressing acidosis in chronic kidney disease or acute kidney disease with anemia.
• Use of; bbbb) Use of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for producing a pharmaceutical composition for suppressing renal anemia or iron deficiency anemia; cccc) Use of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for producing a pharmaceutical composition for the treatment or prevention of renal anemia or iron deficiency anemia. ..
• the food composition provided by the present invention suppresses acidosis in patients with chronic kidney disease or patients with acute kidney disease with anemia, or suppresses anemia (eg, suppresses renal anemia, iron deficiency). It has the effect of suppressing anemia.
• the active ingredient the active ingredient described in "1. Pharmaceutical composition" above can be applied.
• the active ingredient include pharmaceutically acceptable salts of citric acid (for example, alkali metal citrate salts or hydrates thereof or mixtures thereof) as food-acceptable salts of citric acid, and preferable thereof.
• the content of citric acid, a food-acceptable salt of citric acid, or a hydrate thereof or a mixture thereof in the food composition provided by the present invention can be appropriately determined depending on the type of food.
• food compositions include foods for specified health uses, foods with functional claims, foods for hospital patients, and supplements. These food compositions include an effective amount of citric acid for exerting the above effects, a food-acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, and can be orally ingested.
• the form is not particularly limited, and may be in the form of ordinary foods and drinks, and among the preparations applicable to the pharmaceutical composition, preparations suitable for oral administration, for example, tablets and capsules. It may be provided as a preparation such as an agent or a suspending agent.
• Pharmaceutical composition can be applied as they are, and in the field of pharmaceutical preparation technology itself. Known formulation techniques can be applied.
• foods for hospital patients or supplements for example, in the case of foods for specified health use, foods with functional claims, foods for hospital patients or supplements, a total of 1 to 1 to potassium citrate monohydrate and sodium citrate dihydrate as active ingredients per serving of food. It may contain 1/3 amount of 3 g.
• foods for hospital patients or supplements are provided as tablets, for example, foods containing 70 to 80% by weight of citric acid and citric acid in 300 mg to 600 mg tablets per tablet. May contain acceptable salts, or hydrates thereof or mixtures thereof.
• 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 produce it depending on the type of the food, for example, citric acid or citric acid as a food material. It can be produced by blending a food-acceptable salt, or a hydrate thereof or a mixture thereof (for example, potassium citrate and / or sodium citrate).
• the forms of the food and drink include liquid or 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; Alternatively, powdered foods and the like can be mentioned.
• Beverages include fruit juice / fruit beverages, coffee beverages, Karyu tea beverages, green tea beverages, tea beverages, barley tea beverages, vegetable beverages, soft drinks such as carbonated beverages, fruit extract beverages, vegetable extract juices, near water, sports beverages, Examples include diet beverages.
• Beverages include antioxidants, flavors, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, seasonings, sweeteners, acidulants, fruit juice extracts.
• Additives such as esters, vegetable extracts, flower honey extracts, pH adjusters, quality stabilizers and the like can be blended 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 can also be used in a range not intended for the treatment or prevention of diseases. can do.
• citric acid, citric acid in the food composition based on the citric acid contained in the food composition according to the present invention, a food-acceptable salt of citric acid, or a hydrate thereof or a mixture thereof.
• the amount of citric acid used as a food-acceptable salt, or a hydrate thereof, or a mixture thereof is the citric acid contained in the pharmaceutical composition, a pharmaceutically acceptable salt of citric acid, or hydration thereof. It can be applied to the subject of the pharmaceutical composition so that the amount is the same as that of the product or a mixture thereof.
• the "food composition” according to the invention is a subject (eg, a human or other mammal) having no "morbid” or "abnormal” symptoms, conditions or diseases, ie. , Applies to subjects in a "healthy” or “normal” state (eg, humans or other mammals) to maintain or promote a “healthy” or “normal” state be able to. Furthermore, it can be applied to "healthy people who are concerned about anemia" in order to maintain or promote a "healthy” or "normal” state.
• the citric acid, a food-acceptable salt of citric acid, or a hydrate thereof or a mixture thereof is a component of a pharmaceutical composition, or a component of a food composition, the above. Since the pharmacological effects of citric acid, a food-acceptable salt of citric acid, or a hydrate thereof or a mixture thereof themselves are basically the same, the applied amount and method of applying the food composition are: Depending on the expected effect, it can be appropriately adjusted based on the citric acid, a food-acceptable salt of citric acid, or a hydrate thereof or a mixture thereof.
• Subjects without “morbid” or “abnormal” symptoms, conditions or diseases eg, humans or other mammals
• subjects in a "healthy” or “normal” condition eg, humans or
• Food compositions applied to maintain or enhance a "healthy” or “normal” state with respect to (other mammals) may be particularly referred to as "functionally labeled foods”.
• administration described in "1.
• Pharmaceutical composition above can also be applied to the "food composition” according to the present invention, and further, the "food composition” according to the present invention can be referred to.
• the term “administration” can be read as "ingestion.” Therefore, for example, the terms “administer”, “administer”, etc. can be read by changing the word form according to the context, such as “ingest”, “intake”, and “ingest”. Therefore, embodiments of the food composition according to the present invention include the following.
• a food composition for controlling anemia which comprises citric acid, a food-acceptable salt of citric acid, or a hydrate thereof or a mixture thereof;
• the food composition according to the present invention has an effect of suppressing anemia displayed on its packaging, container, or instruction manual.
• a human clinical trial was conducted to examine the effects of oral administration of potassium citrate / sodium citrate hydrate combination preparation and baking soda preparation, which are oral alkalizing agents.
• No alkalizing 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 times a day, 3 times a day (morning, noon, evening) for 24 weeks.
• the pH of early morning urine should be controlled over time, and in cases where early morning urine has a pH of less than 6.5, the dose can be increased up to 6 tablets a day, 3 times a day (morning, noon, evening) at the discretion of the doctor. And said.
• Group B was orally administered 3 tablets containing 500 mg of sodium hydrogen carbonate 3 times a day (morning, noon, evening) for 24 weeks.
• the pH of early morning urine should be controlled over time, and in cases where early morning urine has a pH of less than 6.5, the dose can be increased up to 6 tablets a day, 3 times a day (morning, noon, evening) at the discretion of the doctor. And said.
• Table 1 Amount of iron in serum ( ⁇ g / dL)
• Table 2 Serum ferritin concentration before and 24 weeks after the start of administration (ng / mL); Ratio of serum ferritin concentration at 24 weeks after the start of administration to the ferritin concentration in serum before the start of administration ( %); And the amount of change in serum ferritin concentration from before the start of administration (ng / mL),
• Group B (Bicarbonate: sodium hydrogen carbonate preparation administration group) has significantly higher serum iron concentration at 6 to 24 weeks than group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation administration group). It has decreased. In group A (Citrate: potassium citrate / sodium citrate hydrate combination administration group) and group C (Control: control group), no decrease in serum iron concentration was observed at 6 to 24 weeks (Table). 1). Therefore, it was suggested that the administration of the potassium citrate / sodium citrate hydrate combination preparation suppressed anemia as compared with the administration of the sodium hydrogen carbonate preparation. Both potassium citrate / sodium citrate hydrate combination preparation and sodium hydrogen carbonate preparation are used for the treatment of acidosis in chronic kidney disease. Based on the above results, potassium citrate / sodium citrate water was compared with the sodium hydrogen carbonate preparation. It was suggested that the Japanese combination preparation can be used for the treatment of acidosis without causing anemia.
• group A (Citrate: potassium citrate / sodium citrate hydrate combination administration group) and group C (Control: control group)
• group B (Bicarbonate: sodium hydrogen carbonate preparation administration group)
• group B (Bicarbonate: sodium hydrogen carbonate preparation)
• the administration group) was significantly larger (see Table 2).
• potassium citrate / sodium citrate hydrate combination preparation suppressed anemia as compared with the administration of the sodium hydrogen carbonate preparation.
• Both potassium citrate / sodium citrate hydrate combination preparation and sodium hydrogen carbonate preparation are used for the treatment of acidosis in chronic kidney disease. Based on the above results, potassium citrate / sodium citrate water was compared with the sodium hydrogen carbonate preparation. It was suggested that the Japanese combination preparation can be used for the treatment of acidosis without causing anemia.
• the pharmaceutical composition provided by the present invention it is possible to suppress acidosis or anemia in patients with chronic kidney disease accompanied by anemia in mammals.

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• 2020
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