WO2010112570A1 - Dialysis solution - Google Patents

Dialysis solution Download PDF

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Publication number
WO2010112570A1
WO2010112570A1 PCT/EP2010/054364 EP2010054364W WO2010112570A1 WO 2010112570 A1 WO2010112570 A1 WO 2010112570A1 EP 2010054364 W EP2010054364 W EP 2010054364W WO 2010112570 A1 WO2010112570 A1 WO 2010112570A1
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Prior art keywords
acid
precursor composition
ready
dialysis solution
dry
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PCT/EP2010/054364
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French (fr)
Inventor
Torbjörn LINDEN
Anders Wieslander
Ola Carlsson
Hans-Rainer Drieschmanns
Gabriela Godaly
Original Assignee
Gambro Lundia Ab
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Publication of WO2010112570A1 publication Critical patent/WO2010112570A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • 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
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides

Definitions

  • the present invention concerns a dialysis solution.
  • the present invention also concerns acid precursor compositions, dry precursor compositions, and methods of forming a ready-for-use dialysis solution.
  • dialysis artificially replaces the functions of the kidney.
  • dialysis There are two distinct types of dialysis, hemodialysis and peritoneal dialysis, and the present invention especially concerns hemodialysis.
  • Hemodialysis involves withdrawing blood from the body and cleaning it in an extracorporeal blood circuit and then returning the cleansed blood to the body.
  • the extracorporeal blood circuit includes a dialyzer which comprises a semipermeable membrane. Within this dialyzer waste substances and excess fluid is removed through the semipermeable membrane, and the semipermeable membrane within the dialyzer has a blood side and a dialysate side.
  • Hemodialysis could be performed in three different treatment modes, hemodialysis, hemofiltration and hemodiafiltration. Common to all three treatment modes are that the patient is connected by a blood line tube to a dialysis machine, which continuously withdraws blood from the patient. The blood is then brought in contact with the blood side of the semipermeable membrane within the dialyzer in a continuously flowing manner.
  • dialysis solution In hemodialysis, an aqueous solution called dialysis solution is brought in contact with an opposite side of said semipermeable membrane, the dialysate side of the semipermeable membrane, in a continuously flowing manner. Excess fluid and waste substances (toxins) diffuse from the blood, through the semipermeable membrane, and into the dialysis solution, thereby cleaning the blood. Solutes and nutrients may diffuse from the dialysis solution, through the semipermeable membrane and into the blood.
  • Hemodiafiltration is a combination of hemodialysis and hemofiltration, which treatment mode combines a transport of waste substances and excess fluids through the semipermeable membrane wall by both diffusion and convection.
  • a dialysis solution is brought in contact with the dialysate side of the semipermeable membrane in a continuously flowing manner, and a dialysis solution is used for infusion into the extracorporeal blood circuit in pre-infusion mode, post- infusion mode or both.
  • hemodialysis is performed for 3 to 5 hours, three times a week. It is usually performed at a dialysis centre, although home dialysis is also possible.
  • home dialysis patients are free to perform dialysis more frequently and also in more gentle treatments with longer treatment times, i.e. 4-8 hours per treatment and 5-7 treatments each week. The dose and treatment times may be adjusted due to different demands of the patients.
  • a continuous treatment throughout a major portion of the entire day for up to several weeks, a continuous renal replacement therapy (CRRT), or intermittent renal replacement therapy (IRRT) is the indicated treatment depending on the patients status.
  • CRRT continuous renal replacement therapy
  • IRRT intermittent renal replacement therapy
  • the removal of waste substances and excess fluid from the patient is effected by any of or a combination of the treatment modes hemodialysis, hemofiltration and hemodiafiltration.
  • heparin has to be used as an anticoagulant.
  • One object of the present invention is to provide a dialysis solution which decreases the use of anticoagulant or renders the use of anticoagulant redundant. Another object of the present invention is to provide a dialysis solution which decrease oxidative stress in dialysis patient.
  • the present invention relates to a dialysis solution, which, when ready for use, comprises a physiological buffer and optionally calcium, magnesium, potassium, and glucose. According to the invention said solution further comprises, when ready for use, a combination of citric acid and gluconic acid.
  • the present invention further concerns acid precursor compositions, dry precursor compositions, and a method of forming the ready-for-use dialysis solution.
  • the present invention concerns a dialysis solution, which, when ready for use, comprises 0-1.75 mmol/L (mM) calcium ions, 0-1.0 mM magnesium, 0- 4.0 mM potassium, 0-1 1 mM glucose and a physiological buffer, wherein said solution further comprises, when ready for use, 0.1 -3.0 mM citric acid and 0.1 -3.0 mM gluconic acid, and has a pH within the range of 6.5-7.8.
  • the dialysis solution comprises, when ready for use, 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid. In another embodiment of the present invention the dialysis solution comprises, when ready for use, 0.8 mM citric acid and 1.0 mM gluconic acid.
  • the physiological buffer may be bicarbonate in one embodiment.
  • said dialysis solution further comprises, when ready for use, 0.1 - 3.0 mM lactic acid. In another embodiment said dialysis solution further comprises, when ready for use, 0.1 - 3.0 mM N-acetyl cysteine.
  • the present invention further concerns an aqueous acid precursor composition for use during a method of forming a ready-for-use dialysis solution.
  • the aqueous acid precursor composition comprises 0-2.33 mol/L(M) calcium, 0-1.33 M magnesium, 0-2.29 M potassium, 0-6.28 M glucose, 20.0-600 mM citric acid and 20.0-600 mM gluconic acid.
  • the aqueous acid precursor composition may have a pH of 1 -2.
  • the aqueous acid precursor composition comprises 0-525 mM calcium, 0-300 mM magnesium, 0-1200 mM potassium, 0-3300 mM glucose, 3.5-900 mM citric acid and 3.5-900 mM gluconic acid.
  • the aqueous acid precursor composition may have a pH of 1 -2.
  • the aqueous acid precursor composition comprises 0-350 mM calcium, 0-200 mM magnesium, 0-800 mM potassium, 0-2200 mM glucose, 20-600 mM citric acid and 20-600 mM gluconic acid.
  • the aqueous acid precursor composition may have a pH of 1 -2.
  • the aqueous acid precursor composition comprises 0-62 mM calcium, 0-35 mM magnesium, 0-140 mM potassium, 0-385 mM glucose, 3.5-105 mM citric acid and 3.5-105 mM gluconic acid.
  • the aqueous acid precursor composition may have a pH of 1 -2.
  • the aqueous acid precursor composition comprises 0-79 mM calcium, 0-45 mM magnesium, 0-180 mM potassium, 0-495 mM glucose, 4.5-135 mM citric acid and 4.5-135 mM gluconic acid.
  • the aqueous acid precursor composition may have a pH of 1 -2.
  • the total amount of added acid, i.e. gluconic acid and citric acid, and optional lactic acid and/or optional N-acetyl cystein provides for a concentration of up to 3 mEq/L acid.
  • the aqueous acid precursor composition comprises 100-400 mM citric acid and 100-400 mM gluconic acid. In another embodiment of the present invention said aqueous acid precursor composition comprises 160 mM citric acid and 200 mM gluconic acid.
  • the aqueous acid precursor composition further comprises 20.0-600 mM lactic acid.
  • said aqueous acid precursor composition is intended to be diluted in a ratio of from 1 :35 to 1 :300.
  • said aqueous acid precursor composition is diluted in a ratio of 1 :200.
  • the present invention further concerns a dry acid precursor composition for use during a method of forming a ready-for-use dialysis solution, which dry acid precursor composition optionally comprises calcium, magnesium, potassium and glucose.
  • said dry acid precursor composition further comprises citric acid and gluconic acid, wherein the different components are present in such proportions and in such amounts in said dry acid precursor composition that, the ready-for-use dialysis solution comprises 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 - 3.0 mM gluconic acid.
  • the dry acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid.
  • the dry acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
  • the dry acid precursor composition further comprises lactic acid in such a proportion and in such an amount that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM lactic acid.
  • the dry acid precursor composition further comprises N-acetyl cysteine in such a proportion and in such an amount that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine.
  • the present invention further concerns a method of forming a ready-for- use dialysis solution comprising mixing an acid precursor composition with pure water and a physiological buffer, said acid precursor composition comprising citric acid, gluconic acid, optionally calcium, magnesium, potassium and glucose in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.1 -3.0 mM citric acid, 0.1 -3.0 mM gluconic acid, 0-1.75 mM calcium ions, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1.0 mM glucose and having a pH within the range of 6.5-7.8.
  • said acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 gluconic acid.
  • said acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
  • said acid precursor composition further comprises lactic acid in such a proportion and in such an amount to provide a ready-for-use dialysis solution comprising 0.1 -3 mM lactic acid.
  • said acid precursor composition further comprises N-acetyl cysteine in such a proportion and in such an amount to provide a ready-for-use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine.
  • said acid precursor composition is a concentrated aqueous acid precursor composition.
  • said acid precursor composition is a dry acid precursor composition.
  • the dry composition is preferably first dissolved with pure water into an aqueous acid precursor composition before being mixed with the physiological buffer and other electrolyte components like sodium and chloride and additional pure water into the ready-for-use dialysis solution.
  • the dialysis solution When ready for use, the dialysis solution also includes a physiological buffer, such as bicarbonate, and electrolytes like sodium and chloride.
  • Bicarbonate containing concentrate may be produced from a cartridge with dry powdered sodium bicarbonate. Pure water is introduced into the cartridge with the dry powdered sodium bicarbonate, and the sodium bicarbonate starts to dissolve. A saturated solution of sodium bicarbonate is drawn from the cartridge and thereafter diluted and mixed with the acid concentrate into a final ready-for-use dialysis solution in such proportions that a ready-for-use dialysis solution with a pH of 6.5-7.8 is provided.
  • Sodium chloride may also be provided in the same way, thus as a dry powder within a cartridge. Also here pure water is introduced into the cartridge and a saturated sodium chloride solution is drawn from the cartridge, and this saturated sodium chloride solution is thereafter diluted and mixed with the sodium bicarbonate solution and the acid concentrate into the ready-for-use dialysis solution.
  • bicarbonate and sodium chloride could be provided as aqueous concentrates also, but due to stability (for bicarbonate) and storage space, dry powdered sodium bicarbonate and dry powdered sodium chloride may be provided in one embodiment of the present invention.
  • Sodium chloride and bicarbonate may also be provided as a mixed sodium chloride and sodium bicarbonate powdered concentration, or granulate concentrate, which may be dissolved in pure water into a mixed aqueous sodium chloride/sodium bicarbonate concentrate.
  • the present invention further concerns a dry precursor composition for use during a method of forming a ready-for-use dialysis solution.
  • said dry precursor composition comprises acid, physiological buffer and optionally calcium, magnesium, potassium and glucose, characterised in that said dry precursor composition comprises citric acid and gluconic acid.
  • the different components are present in such proportions and in such amounts in said dry precursor composition that, the ready-for-use dialysis solution comprises 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid and has a pH within the range of 6.5-7.8.
  • the dry precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid.
  • the dry precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
  • the dry precursor composition further comprises lactic acid in such a proportion and in such an amount that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for- use dialysis solution comprising 0.1 -3 mM lactic acid.
  • the dry precursor composition further comprises N-acetyl cysteine in such a proportion and in such an amount that, when said dry acid precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine.
  • the present invention also concerns a method of forming a ready-for-use dialysis solution comprising mixing a dry precursor composition comprising acid and physiological buffer and optionally calcium, magnesium, potassium and glucose, with pure water, wherein said dry precursor composition comprises citric acid and gluconic acid, and the different components within the dry precursor composition are present in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid and having a pH within the range of 6.5-7.8.
  • citric acid means that the component is added as citric acid or as its sodium, calcium, magnesium, or potassium salt thereof, i.e. citrate, to the ready-for-use dialysis solution. However, being mixed with a physiological buffer to end up at a pH within the range of 6.5-7.8, any citric acid converts into the salt form thereof, i.e. as citrate.
  • gluconic acid means that the component may be added as gluconic acid, glucono- ⁇ -lactone or as its sodium, calcium, magnesium or potassium salt thereof, i.e. gluconate, to the ready-for-use dialysis solution.
  • the salt form thereof will convert to its acid form.
  • all gluconic acid independently of being added as an acid or as a salt thereof to begin with has converted over to the salt form thereof, i.e. gluconate.
  • gluconic acid When added in the acid form thereof, gluconic acid may be added as glucono- ⁇ -lactone (C 6 Hi 0 O 6 ), which may be obtained in powder form and in pure form, and which hydrolyses into gluconic acid when dissolved in water.
  • glucono- ⁇ -lactone C 6 Hi 0 O 6
  • lactic acid means that the component may be added as lactic acid or as its sodium, calcium, magnesium or potassium salt thereof ,i.e. as lactate, to the ready-for-use dialysis solution.
  • the salt form thereof will converts to its acid form.
  • all lactic acid independently of being added as an acid or as a salt thereof to begin with has converted over to the salt form thereof, i.e. lactate.
  • the reason for adding gluconic acid and lactic acid as their sodium, calcium, magnesium or potassium salts into the acid precursor composition may be to obtain a slightly higher pH within the acid precursor composition to prevent formation of caramelized glucose and the thereby connected formation of yellow colour within the acid precursor composition. That is, if glucose is present within the acid precursor composition.
  • an aqueous acid precursor composition means a composition in liquid form, which forms a part of the final ready-for-use dialysis solution and which is concentrated and is to be diluted with pure water and additional components into the final ready-for-use dialysis solution.
  • Other synonyms are a liquid concentrate, an aqueous acid concentrate, or a liquid acid precursor composition.
  • a dry acid precursor composition means a composition in dry form, which forms a powder, particulates or granulates of the components within the composition, and which is dissolved in pure water and is to be diluted with additional components into the final ready-for-use dialysis solution.
  • Other synonyms are a powder acid concentrate or composition, a particulate acid concentrate or composition, and a granulated acid concentrate or composition.
  • a dry precursor composition means a composition in dry form, which forms a powder, particulates or granulates of the components within the composition, and which is dissolved in pure water into the final ready-for-use dialysis solution.
  • Other synonyms are a powder concentrate or composition, a particulate concentrate or composition, and a granulated concentrate or composition.
  • dialysis solution means a ready-for-use solution which may be used as a dialysis solution to be brought in contact with the dialysate side of a semipermeable membrane within a dialyzer in a continuously flowing manner, but also means a ready-for-use solution which may be used for infusion into the extracorporeal blood circuit in either pre-dilution, post-dilution or both.
  • the ready-for-use dialysis solution is prepared from an aqueous acid precursor composition and is to be used during hemodialysis or hemodiafiltration.
  • the aqueous acid concentrate may then be provided in a single-compartment bag and may be mixed with a buffer concentrate (i.e. bicarbonate buffer concentrate), which may be prepared online from a powder concentrate, and then diluted with pure water for online preparation of a dialysis solution.
  • a buffer concentrate i.e. bicarbonate buffer concentrate
  • a separate third concentrate of sodium chloride may be combined with the two other mentioned concentrates.
  • the online preparation is done in a fluid preparation unit and then directly used as a dialysis solution continuously flowing on the dialysate side of the semipermeable membrane in the dialyzer in a hemodialysis treatment or hemodiafiltration treatment.
  • the aqueous acid precursor composition may be diluted in pure water and mixed with a buffer concentrate and a sodium chloride concentrate into a batch of ready-for-use dialysis solution, that is, a batch-wise production of a ready-for-use dialysis solution.
  • the buffer concentrate and the sodium chloride concentrate may be provided by dissolving powder concentrates in pure water.
  • the ready-for-use dialysis solution is prepared from a dry acid precursor composition.
  • the dry acid precursor composition is dissolved in pure water and may be mixed with a buffer concentrate (i.e. bicarbonate buffer concentrate) and a sodium chloride concentrate, which also may be prepared online from powder concentrates, and then diluted with pure water for online preparation of a dialysis solution.
  • the online preparation is done in a fluid preparation unit and then directly used as a dialysis solution continuously flowing on the dialysate side of the semipermeable membrane in the dialyzer in a hemodialysis treatment or a hemodiafiltration treatment.
  • the dry acid precursor composition may be dissolved in pure water and mixed with a buffer concentrate and a sodium chloride concentrate into a batch of ready-for-use dialysis solution, i.e., a batch-wise production of ready-for-use dialysis solution.
  • the buffer concentrate and the sodium chloride concentrate may be provided by dissolving powder concentrates in pure water.
  • sodium chloride may be provided in the acid precursor composition, both in the aqueous version of the acid precursor composition and the dry version of the acid precursor composition.
  • said buffer and sodium chloride may be provided in a mixed buffer/sodium chloride concentrate.
  • the mixed buffer/sodium chloride concentrate may be provided by dissolving a powder mix of the two components in pure water, or by dissolving a mixed granulate of buffer and sodium chloride in pure water.
  • a dry precursor composition is provided, which contains all the necessary components to prepare a ready-to-use dialysis solution in a dry form.
  • the dry precursor composition comprises acid, physiological buffer and optionally comprises calcium, magnesium, potassium and glucose, all dependent on which electrolyte and glucose concentrations that are best to meet the needs of a specific patient.
  • the dry precursor composition comprises citric acid and gluconic acid, wherein the different components are present in such proportions and in such amounts in said dry precursor composition that, when said dry precursor composition has been dissolved and mixed with pure water into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 - 3.0 mM gluconic acid and having a pH within the range of 6.5-7.8.
  • the potassium level within the ready-for-use dialysis solution i.e. after mixing and dilution
  • the magnesium level within the ready-for-use dialysis solution may be 0.25, 0.50, 0.60, 0.75 or 1.0O mM.
  • the calcium level within the ready-for-use dialysis solution may be 0, or between 1.00 and 1.75 mM.
  • the glucose level within the ready-for-use dialysis solution may be 0, 5.5 or 1 1.0 mM
  • the citric acid level and the gluconic acid level within the ready-for-use dialysis solution may be 0.8 mM citric acid and 1.0 mM gluconic acid.
  • the citric acid level and the gluconic acid level within the ready-for-use dialysis solution may be 1 mM citric acid and 0.5 mM gluconic acid.
  • the citric acid level and the gluconic acid level within the ready-for-use dialysis solution may be 1 mM citric acid and 1 mM gluconic acid.
  • the citric acid level, the gluconic acid level, and the lactic acid level within the ready-for-use dialysis solution may be 0.8 mM citric acid, 0.5 mM gluconic acid and 1 mM lactic acid.
  • the citric acid level, the gluconic acid level, and the lactic acid level within the ready-for-use dialysis solution may be 0.8 mM citric acid, 1 mM gluconic acid and 0.5 mM lactic acid.
  • the citric acid level, the gluconic acid level, and the N-acetyl cysteine level within the ready-for-use dialysis solution may be 0.8 mM citric acid, 0.5 mM gluconic acid and 1 mM N-acetyl cysteine.
  • the citric acid level, the gluconic acid level, and the N-acetyl cysteine level within the ready-for-use dialysis solution i.e. after mixing and dilution
  • the citric acid level, the gluconic acid level, the lactic acid level and the N-acetyl cysteine level within the ready-for-use dialysis solution may be 0.467 mM citric acid, 1 mM gluconic acid, 0.5 mM lactic acid and 1 mM N-acetyl cysteine.
  • TESTS A short-term clinical application study on safety and biocompatibility was performed for a hemodialysis solution (“solution”) comprising gluconic acid and citric acid.
  • solution hemodialysis solution
  • the safety and biocompatibility was measured as blood composition, cardiovascular state and general health, citrate and gluconate in plasma and urine, as well as coagulation markers as activated clotting time (ACT) and thrombin-anti- thrombin (TAT).
  • ACT activated clotting time
  • TAT thrombin-anti- thrombin
  • AGE oxidative stress suppression and advanced glycation end products
  • the clinical study design was an open label controlled two period cross over with 12 patients.
  • the 12 patients were dialysed 3 times during 1 week with normal dialysis fluid (like Control below) and thereafter 3 times with citrate/gluconate containing dialysis fluid according to "Solution” below. Samples were taken pre and post dialysis.
  • Glutathione exists in reduced (GSH) and oxidized (GSSG) states.
  • the thiol group is able to donate a reducing equivalent (H + and e " ) to other unstable molecules, such as reactive oxygen species.
  • glutathione In donating an electron, glutathione itself become reactive, but readily reacts with another reactive glutathione to form glutation disulfide (GSSG).
  • GSH reduced form
  • GSSG oxidized
  • the pre- and post dialytic levels of reduced GSH were significantly higher for treatments with the "Solution” compared to the control treatment (paired t- test p ⁇ 0.001 , p ⁇ 0.001 ).
  • the pre- and post dialytic levels of GSSG were significantly lower after treatment with the "Solution” compared to control treatment (paired t-test p ⁇ 0.001 , p ⁇ 0.001 ).
  • the pre- and post dialytic ratio between reduced GSHred and GSSG was significantly higher for treatments with the "solution" (paired t-test p ⁇ 0.001 , p ⁇ 0.001 ) indicating less oxidative stress.
  • ACT activated clotting time
  • TAT thrombin-antithrombin
  • Post dialytic TAT concentration was significantly lower after treatments with the "Solution” compared to control devices (paired t-test p ⁇ 0.05). Generation rate during treatment was significantly (about 10%) lower during treatments with the "Solution” (paired t-test p ⁇ 0.05).
  • the aqueous acid precursor composition 7 above is diluted 1 :35 and the aqueous acid precursor compositions 8-10 are diluted 1 :200, with pure water, a sodium bicarbonate solution and a sodium chloride solution into ready-for-use dialysis solutions, corresponding to the ready-for-use dialysis solutions 1 , 3, 5 and 6 above.
  • dry acid precursor compositions 1 1 -16 above may be dissolved in pure water and mixed with bicarbonate and sodium chloride into the ready-for-use dialysis solutions in example 1 -6, respectively.
  • the dry precursor compositions 17-18 above may be dissolved in pure water into the ready-for-use dialysis solutions in examples 5-6, respectively.

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Abstract

The present invention concerns a dialysis solution, which, when ready for use, comprises a physiological buffer and optionally calcium ions, magnesium, potassium, and glucose. According to the invention said solution further comprises, when ready for use, citric acid and gluconic acid. The present invention further concerns acid precursor compositions, dry precursor compositions and a method of forming the ready-for-use dialysis solution.

Description

DIALYSIS SOLUTION
TECHNICAL FIELD
The present invention concerns a dialysis solution. The present invention also concerns acid precursor compositions, dry precursor compositions, and methods of forming a ready-for-use dialysis solution.
BACKGROUND When a person's kidneys do not function properly uremia is developed. A technique called dialysis has been developed and this is an established treatment for uremia. Essentially, dialysis artificially replaces the functions of the kidney. There are two distinct types of dialysis, hemodialysis and peritoneal dialysis, and the present invention especially concerns hemodialysis.
Hemodialysis involves withdrawing blood from the body and cleaning it in an extracorporeal blood circuit and then returning the cleansed blood to the body. The extracorporeal blood circuit includes a dialyzer which comprises a semipermeable membrane. Within this dialyzer waste substances and excess fluid is removed through the semipermeable membrane, and the semipermeable membrane within the dialyzer has a blood side and a dialysate side. Hemodialysis could be performed in three different treatment modes, hemodialysis, hemofiltration and hemodiafiltration. Common to all three treatment modes are that the patient is connected by a blood line tube to a dialysis machine, which continuously withdraws blood from the patient. The blood is then brought in contact with the blood side of the semipermeable membrane within the dialyzer in a continuously flowing manner.
In hemodialysis, an aqueous solution called dialysis solution is brought in contact with an opposite side of said semipermeable membrane, the dialysate side of the semipermeable membrane, in a continuously flowing manner. Excess fluid and waste substances (toxins) diffuse from the blood, through the semipermeable membrane, and into the dialysis solution, thereby cleaning the blood. Solutes and nutrients may diffuse from the dialysis solution, through the semipermeable membrane and into the blood.
In hemofiltration, no dialysis solution is brought in contact with the dialysate side of the semipermeable membrane. Instead the dialysis solution is used for infusion directly into the extracorporeal blood circuit, which infusion may be done either pre or post the dialyzer or both, also referred to as pre- and post-infusion mode. Further, a pump is withdrawing plasma liquid, comprising excess fluid and waste substances, from the blood through the semipermeable membrane wall and into the dialysate side thereof (convective flow) and this plasma liquid is then passed to drain. In this type of treatment a correctly electrolyte/buffer balanced dialysis solution is infused into the blood to replace the withdrawn plasma liquid.
Hemodiafiltration is a combination of hemodialysis and hemofiltration, which treatment mode combines a transport of waste substances and excess fluids through the semipermeable membrane wall by both diffusion and convection. Thus, here a dialysis solution is brought in contact with the dialysate side of the semipermeable membrane in a continuously flowing manner, and a dialysis solution is used for infusion into the extracorporeal blood circuit in pre-infusion mode, post- infusion mode or both. For many patients, hemodialysis is performed for 3 to 5 hours, three times a week. It is usually performed at a dialysis centre, although home dialysis is also possible. When home dialysis is performed patients are free to perform dialysis more frequently and also in more gentle treatments with longer treatment times, i.e. 4-8 hours per treatment and 5-7 treatments each week. The dose and treatment times may be adjusted due to different demands of the patients.
In the case of patients suffering from acute renal insufficiency, a continuous treatment, throughout a major portion of the entire day for up to several weeks, a continuous renal replacement therapy (CRRT), or intermittent renal replacement therapy (IRRT) is the indicated treatment depending on the patients status. Also here the removal of waste substances and excess fluid from the patient is effected by any of or a combination of the treatment modes hemodialysis, hemofiltration and hemodiafiltration.
However, even if the dialysis treatments have improved over the years, there is still room for additional improvements. Among other things, the majority of available hemodialysis concentrate fluids and hemodialysis solutions still contain acetic acid to balance the bicarbonate and to adjust pH values to pH 7.1 -7.3 in the final, ready-for-use dialysis solution. Acetic acid in the concentrations used in dialysis fluids is not physiological and it may also form esters when combined with glucose. The replacement of acetic acid with a more physiological alternative is regarded as an important step forward in the development of dialysis treatment.
Further, to be able to run a treatment without blood coagulation in the dialysis filter and tubing, heparin has to be used as an anticoagulant.
Another matter is the fact that the largest cause of mortality in hemodialysis patients is cardio-vascular problems in the form of arteriosclerosis. A main cause for this is that dialysis patients are in a chronic state of oxidative stress, which in turn is caused by the uremic state and lack of normal kidney functions. As of today there is no effective antioxidant suitable for use in dialysis fluids available. Most antioxidants described until now are either instable or has unwanted side effects.
Also looking into the home hemodialysis treatment situation, there are rooms for improvements. Today a large storage space is needed within the home of the care taker in order to be able to run hemodialysis treatments. Many different components are needed during the treatment, of course the dialysis machine, but also a lot of disposables like bloodlines, filters, needles, blood sampling equipment, priming solution for the dialysis machine, dialysis solutions, dialysis solution concentrates, and a proper water system to enable online dialysis solution preparation. Among all the disposables, dialysis solutions, dialysis solution concentrates, and dialysis concentrates are the components which occupy the most storage space. Thus, there may be a great advantage in using a totally dry concentrate to minimize storage space, weight, and transport of water and to also increase the stability and thereby also the shelf-life of the dialysis concentrates.
SUMMARY OF THE INVENTION
One object of the present invention is to provide a dialysis solution which decreases the use of anticoagulant or renders the use of anticoagulant redundant. Another object of the present invention is to provide a dialysis solution which decrease oxidative stress in dialysis patient. The present invention relates to a dialysis solution, which, when ready for use, comprises a physiological buffer and optionally calcium, magnesium, potassium, and glucose. According to the invention said solution further comprises, when ready for use, a combination of citric acid and gluconic acid. The present invention further concerns acid precursor compositions, dry precursor compositions, and a method of forming the ready-for-use dialysis solution.
Thus, the present invention concerns a dialysis solution, which, when ready for use, comprises 0-1.75 mmol/L (mM) calcium ions, 0-1.0 mM magnesium, 0- 4.0 mM potassium, 0-1 1 mM glucose and a physiological buffer, wherein said solution further comprises, when ready for use, 0.1 -3.0 mM citric acid and 0.1 -3.0 mM gluconic acid, and has a pH within the range of 6.5-7.8.
In one embodiment of the present invention the dialysis solution comprises, when ready for use, 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid. In another embodiment of the present invention the dialysis solution comprises, when ready for use, 0.8 mM citric acid and 1.0 mM gluconic acid.
The physiological buffer may be bicarbonate in one embodiment.
In a further embodiment said dialysis solution further comprises, when ready for use, 0.1 - 3.0 mM lactic acid. In another embodiment said dialysis solution further comprises, when ready for use, 0.1 - 3.0 mM N-acetyl cysteine.
The use of the different acids are limited by physiological limitations, i.e. metabolism and toxicity. For example, too high citric acid concentrations will bind calcium in blood leading to dramatic disturbances in organ functions. Too high citric acid may also affect clotting of blood leading to bleedings. Too high gluconic acid concentrations are not metabolised properly leading to unphysiological levels in blood. Too high N-acetyl cysteine concentrations are also unphysiological. However, low concentration of N-acetyl cysteine has beneficial properties for dialysis patients.
Thus, it is of most importance to get a correctly balanced mix and combination of acids within a dialysis solution ready for use.
The present invention further concerns an aqueous acid precursor composition for use during a method of forming a ready-for-use dialysis solution. According to the invention, the aqueous acid precursor composition comprises 0-2.33 mol/L(M) calcium, 0-1.33 M magnesium, 0-2.29 M potassium, 0-6.28 M glucose, 20.0-600 mM citric acid and 20.0-600 mM gluconic acid. The aqueous acid precursor composition may have a pH of 1 -2.
In one embodiment of the present invention the aqueous acid precursor composition comprises 0-525 mM calcium, 0-300 mM magnesium, 0-1200 mM potassium, 0-3300 mM glucose, 3.5-900 mM citric acid and 3.5-900 mM gluconic acid. The aqueous acid precursor composition may have a pH of 1 -2.
In one embodiment of the present invention the aqueous acid precursor composition comprises 0-350 mM calcium, 0-200 mM magnesium, 0-800 mM potassium, 0-2200 mM glucose, 20-600 mM citric acid and 20-600 mM gluconic acid. The aqueous acid precursor composition may have a pH of 1 -2.
In one embodiment of the present invention the aqueous acid precursor composition comprises 0-62 mM calcium, 0-35 mM magnesium, 0-140 mM potassium, 0-385 mM glucose, 3.5-105 mM citric acid and 3.5-105 mM gluconic acid. The aqueous acid precursor composition may have a pH of 1 -2.
In one embodiment of the present invention the aqueous acid precursor composition comprises 0-79 mM calcium, 0-45 mM magnesium, 0-180 mM potassium, 0-495 mM glucose, 4.5-135 mM citric acid and 4.5-135 mM gluconic acid. The aqueous acid precursor composition may have a pH of 1 -2. In one embodiment the total amount of added acid, i.e. gluconic acid and citric acid, and optional lactic acid and/or optional N-acetyl cystein, provides for a concentration of up to 3 mEq/L acid. That is, when these components has been added to the solution, aquoues acid concentrate or dry acid concentrate in its acid form, the total amount should be up to 3 mEq/L acid (H+). If any of these components have been added in its salt form, thus as citrate, as gluconate, or as lactate or as the salt form of N-acetyl cystein, these amounts is not to be added to this total amount of up to 3 mEq/L acid (H+).
In one embodiment of the present invention the aqueous acid precursor composition comprises 100-400 mM citric acid and 100-400 mM gluconic acid. In another embodiment of the present invention said aqueous acid precursor composition comprises 160 mM citric acid and 200 mM gluconic acid.
In even another embodiment of the present invention the aqueous acid precursor composition further comprises 20.0-600 mM lactic acid.
In one embodiment of the present invention, said aqueous acid precursor composition is intended to be diluted in a ratio of from 1 :35 to 1 :300.
In another embodiment of the present invention, said aqueous acid precursor composition is diluted in a ratio of 1 :200. The present invention further concerns a dry acid precursor composition for use during a method of forming a ready-for-use dialysis solution, which dry acid precursor composition optionally comprises calcium, magnesium, potassium and glucose. According to the invention said dry acid precursor composition further comprises citric acid and gluconic acid, wherein the different components are present in such proportions and in such amounts in said dry acid precursor composition that, the ready-for-use dialysis solution comprises 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 - 3.0 mM gluconic acid. In another embodiment of the present invention the dry acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid.
In even another embodiment of the present invention the dry acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
In a further embodiment of the present invention the dry acid precursor composition further comprises lactic acid in such a proportion and in such an amount that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM lactic acid.
In another embodiment of the present invention the dry acid precursor composition further comprises N-acetyl cysteine in such a proportion and in such an amount that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine. The present invention further concerns a method of forming a ready-for- use dialysis solution comprising mixing an acid precursor composition with pure water and a physiological buffer, said acid precursor composition comprising citric acid, gluconic acid, optionally calcium, magnesium, potassium and glucose in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.1 -3.0 mM citric acid, 0.1 -3.0 mM gluconic acid, 0-1.75 mM calcium ions, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1.0 mM glucose and having a pH within the range of 6.5-7.8.
In one embodiment of the method according to the present invention said acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 gluconic acid.
In another embodiment of the method according to the present invention said acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
In even another embodiment of the method according to the present invention said acid precursor composition further comprises lactic acid in such a proportion and in such an amount to provide a ready-for-use dialysis solution comprising 0.1 -3 mM lactic acid.
In another embodiment of the method according to the present invention said acid precursor composition further comprises N-acetyl cysteine in such a proportion and in such an amount to provide a ready-for-use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine. In a further embodiment of the method according to the present invention said acid precursor composition is a concentrated aqueous acid precursor composition.
In another embodiment of the method according to the present invention said acid precursor composition is a dry acid precursor composition. When said acid precursor composition is provided as a dry acid precursor composition, the dry composition is preferably first dissolved with pure water into an aqueous acid precursor composition before being mixed with the physiological buffer and other electrolyte components like sodium and chloride and additional pure water into the ready-for-use dialysis solution.
When ready for use, the dialysis solution also includes a physiological buffer, such as bicarbonate, and electrolytes like sodium and chloride. Bicarbonate containing concentrate may be produced from a cartridge with dry powdered sodium bicarbonate. Pure water is introduced into the cartridge with the dry powdered sodium bicarbonate, and the sodium bicarbonate starts to dissolve. A saturated solution of sodium bicarbonate is drawn from the cartridge and thereafter diluted and mixed with the acid concentrate into a final ready-for-use dialysis solution in such proportions that a ready-for-use dialysis solution with a pH of 6.5-7.8 is provided.
Sodium chloride may also be provided in the same way, thus as a dry powder within a cartridge. Also here pure water is introduced into the cartridge and a saturated sodium chloride solution is drawn from the cartridge, and this saturated sodium chloride solution is thereafter diluted and mixed with the sodium bicarbonate solution and the acid concentrate into the ready-for-use dialysis solution. Of course bicarbonate and sodium chloride could be provided as aqueous concentrates also, but due to stability (for bicarbonate) and storage space, dry powdered sodium bicarbonate and dry powdered sodium chloride may be provided in one embodiment of the present invention. Sodium chloride and bicarbonate may also be provided as a mixed sodium chloride and sodium bicarbonate powdered concentration, or granulate concentrate, which may be dissolved in pure water into a mixed aqueous sodium chloride/sodium bicarbonate concentrate.
The present invention further concerns a dry precursor composition for use during a method of forming a ready-for-use dialysis solution. According to the invention said dry precursor composition comprises acid, physiological buffer and optionally calcium, magnesium, potassium and glucose, characterised in that said dry precursor composition comprises citric acid and gluconic acid. The different components are present in such proportions and in such amounts in said dry precursor composition that, the ready-for-use dialysis solution comprises 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid and has a pH within the range of 6.5-7.8. In one embodiment the dry precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid.
In another embodiment the dry precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
In another embodiment the dry precursor composition further comprises lactic acid in such a proportion and in such an amount that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for- use dialysis solution comprising 0.1 -3 mM lactic acid. In even another embodiment the dry precursor composition further comprises N-acetyl cysteine in such a proportion and in such an amount that, when said dry acid precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine.
The present invention also concerns a method of forming a ready-for-use dialysis solution comprising mixing a dry precursor composition comprising acid and physiological buffer and optionally calcium, magnesium, potassium and glucose, with pure water, wherein said dry precursor composition comprises citric acid and gluconic acid, and the different components within the dry precursor composition are present in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid and having a pH within the range of 6.5-7.8.
DEFINITIONS The term "citric acid" means that the component is added as citric acid or as its sodium, calcium, magnesium, or potassium salt thereof, i.e. citrate, to the ready-for-use dialysis solution. However, being mixed with a physiological buffer to end up at a pH within the range of 6.5-7.8, any citric acid converts into the salt form thereof, i.e. as citrate.
The term "gluconic acid" means that the component may be added as gluconic acid, glucono-δ-lactone or as its sodium, calcium, magnesium or potassium salt thereof, i.e. gluconate, to the ready-for-use dialysis solution. However, being added to an acid precursor composition with a pH of 1 -2, the salt form thereof, will convert to its acid form. Then again, when mixed with a physiological buffer to end up at a pH within the range of 6.5-7.8, all gluconic acid (independently of being added as an acid or as a salt thereof to begin with) has converted over to the salt form thereof, i.e. gluconate. When added in the acid form thereof, gluconic acid may be added as glucono-δ-lactone (C6Hi0O6), which may be obtained in powder form and in pure form, and which hydrolyses into gluconic acid when dissolved in water.
The term "lactic acid" means that the component may be added as lactic acid or as its sodium, calcium, magnesium or potassium salt thereof ,i.e. as lactate, to the ready-for-use dialysis solution. However, being added to an acid precursor composition with a pH of 1 -2, the salt form thereof, will converts to its acid form. Then again, when mixed with a physiological buffer to end up at a pH within the range of 6.5-7.8, all lactic acid (independently of being added as an acid or as a salt thereof to begin with) has converted over to the salt form thereof, i.e. lactate. The reason for adding gluconic acid and lactic acid as their sodium, calcium, magnesium or potassium salts into the acid precursor composition may be to obtain a slightly higher pH within the acid precursor composition to prevent formation of caramelized glucose and the thereby connected formation of yellow colour within the acid precursor composition. That is, if glucose is present within the acid precursor composition.
The term "an aqueous acid precursor composition" means a composition in liquid form, which forms a part of the final ready-for-use dialysis solution and which is concentrated and is to be diluted with pure water and additional components into the final ready-for-use dialysis solution. Other synonyms are a liquid concentrate, an aqueous acid concentrate, or a liquid acid precursor composition.
The term "a dry acid precursor composition" means a composition in dry form, which forms a powder, particulates or granulates of the components within the composition, and which is dissolved in pure water and is to be diluted with additional components into the final ready-for-use dialysis solution. Other synonyms are a powder acid concentrate or composition, a particulate acid concentrate or composition, and a granulated acid concentrate or composition.
The term "a dry precursor composition" means a composition in dry form, which forms a powder, particulates or granulates of the components within the composition, and which is dissolved in pure water into the final ready-for-use dialysis solution. Other synonyms are a powder concentrate or composition, a particulate concentrate or composition, and a granulated concentrate or composition.
The term "dialysis solution" means a ready-for-use solution which may be used as a dialysis solution to be brought in contact with the dialysate side of a semipermeable membrane within a dialyzer in a continuously flowing manner, but also means a ready-for-use solution which may be used for infusion into the extracorporeal blood circuit in either pre-dilution, post-dilution or both.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention the ready-for-use dialysis solution is prepared from an aqueous acid precursor composition and is to be used during hemodialysis or hemodiafiltration. The aqueous acid concentrate may then be provided in a single-compartment bag and may be mixed with a buffer concentrate (i.e. bicarbonate buffer concentrate), which may be prepared online from a powder concentrate, and then diluted with pure water for online preparation of a dialysis solution. Also a separate third concentrate of sodium chloride may be combined with the two other mentioned concentrates.
The online preparation is done in a fluid preparation unit and then directly used as a dialysis solution continuously flowing on the dialysate side of the semipermeable membrane in the dialyzer in a hemodialysis treatment or hemodiafiltration treatment.
In another embodiment the aqueous acid precursor composition may be diluted in pure water and mixed with a buffer concentrate and a sodium chloride concentrate into a batch of ready-for-use dialysis solution, that is, a batch-wise production of a ready-for-use dialysis solution. Also here the buffer concentrate and the sodium chloride concentrate may be provided by dissolving powder concentrates in pure water. In another embodiment of the present invention the ready-for-use dialysis solution is prepared from a dry acid precursor composition. The dry acid precursor composition is dissolved in pure water and may be mixed with a buffer concentrate (i.e. bicarbonate buffer concentrate) and a sodium chloride concentrate, which also may be prepared online from powder concentrates, and then diluted with pure water for online preparation of a dialysis solution.
Also here the online preparation is done in a fluid preparation unit and then directly used as a dialysis solution continuously flowing on the dialysate side of the semipermeable membrane in the dialyzer in a hemodialysis treatment or a hemodiafiltration treatment.
In another embodiment the dry acid precursor composition may be dissolved in pure water and mixed with a buffer concentrate and a sodium chloride concentrate into a batch of ready-for-use dialysis solution, i.e., a batch-wise production of ready-for-use dialysis solution. Also here the buffer concentrate and the sodium chloride concentrate may be provided by dissolving powder concentrates in pure water.
In another embodiment sodium chloride may be provided in the acid precursor composition, both in the aqueous version of the acid precursor composition and the dry version of the acid precursor composition. In even another embodiment said buffer and sodium chloride may be provided in a mixed buffer/sodium chloride concentrate. The mixed buffer/sodium chloride concentrate may be provided by dissolving a powder mix of the two components in pure water, or by dissolving a mixed granulate of buffer and sodium chloride in pure water. In another embodiment of the present invention a dry precursor composition is provided, which contains all the necessary components to prepare a ready-to-use dialysis solution in a dry form. Thus, the dry precursor composition comprises acid, physiological buffer and optionally comprises calcium, magnesium, potassium and glucose, all dependent on which electrolyte and glucose concentrations that are best to meet the needs of a specific patient. According to the invention the dry precursor composition comprises citric acid and gluconic acid, wherein the different components are present in such proportions and in such amounts in said dry precursor composition that, when said dry precursor composition has been dissolved and mixed with pure water into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 - 3.0 mM gluconic acid and having a pH within the range of 6.5-7.8. In one embodiment of the present invention the potassium level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0, 1 , 2, 3 or 4 mM.
In another embodiment of the present invention the magnesium level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0.25, 0.50, 0.60, 0.75 or 1.0O mM.
In another embodiment of the present invention the calcium level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0, or between 1.00 and 1.75 mM.
In another embodiment of the present invention the glucose level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0, 5.5 or 1 1.0 mM
In another embodiment of the present invention the citric acid level and the gluconic acid level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0.8 mM citric acid and 1.0 mM gluconic acid. In another embodiment of the present invention the citric acid level and the gluconic acid level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 1 mM citric acid and 0.5 mM gluconic acid.
In another embodiment of the present invention the citric acid level and the gluconic acid level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 1 mM citric acid and 1 mM gluconic acid.
In another embodiment of the present invention the citric acid level, the gluconic acid level, and the lactic acid level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0.8 mM citric acid, 0.5 mM gluconic acid and 1 mM lactic acid. In another embodiment of the present invention the citric acid level, the gluconic acid level, and the lactic acid level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0.8 mM citric acid, 1 mM gluconic acid and 0.5 mM lactic acid. In another embodiment of the present invention the citric acid level, the gluconic acid level, and the N-acetyl cysteine level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0.8 mM citric acid, 0.5 mM gluconic acid and 1 mM N-acetyl cysteine. In another embodiment of the present invention the citric acid level, the gluconic acid level, and the N-acetyl cysteine level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0.467 mM citric acid, 1 mM gluconic acid and 1 mM N-acetyl cysteine.
In another embodiment of the present invention the citric acid level, the gluconic acid level, the lactic acid level and the N-acetyl cysteine level within the ready-for-use dialysis solution (i.e. after mixing and dilution) may be 0.467 mM citric acid, 1 mM gluconic acid, 0.5 mM lactic acid and 1 mM N-acetyl cysteine.
TESTS A short-term clinical application study on safety and biocompatibility was performed for a hemodialysis solution ("solution") comprising gluconic acid and citric acid. The safety and biocompatibility was measured as blood composition, cardiovascular state and general health, citrate and gluconate in plasma and urine, as well as coagulation markers as activated clotting time (ACT) and thrombin-anti- thrombin (TAT). As secondary objectives of this study, also oxidative stress suppression and advanced glycation end products (AGE) was measured.
The clinical study design was an open label controlled two period cross over with 12 patients. The 12 patients were dialysed 3 times during 1 week with normal dialysis fluid (like Control below) and thereafter 3 times with citrate/gluconate containing dialysis fluid according to "Solution" below. Samples were taken pre and post dialysis.
Figure imgf000016_0001
In order to measure the oxidative stress suppression concentrations of oxidative stress markers in blood were measured after each treatment (post) and before the next treatment (pre). Glutathione exists in reduced (GSH) and oxidized (GSSG) states. In the reduced state, the thiol group is able to donate a reducing equivalent (H+ and e") to other unstable molecules, such as reactive oxygen species. In donating an electron, glutathione itself become reactive, but readily reacts with another reactive glutathione to form glutation disulfide (GSSG). In healthy cells and tissue, more than 90 % of the total glutathione pool is in the reduced form (GSH) and less than 10 % exists in the disulfide form (GSSG).
The pre- and post dialytic levels of reduced GSH were significantly higher for treatments with the "Solution" compared to the control treatment (paired t- test p<0.001 , p<0.001 ). The pre- and post dialytic levels of GSSG were significantly lower after treatment with the "Solution" compared to control treatment (paired t-test p<0.001 , p<0.001 ). The pre- and post dialytic ratio between reduced GSHred and GSSG was significantly higher for treatments with the "solution" (paired t-test p<0.001 , p<0.001 ) indicating less oxidative stress. In table 1 it is evident that the reduced glutathione (GSH) was increased and oxidized glutathione (GSSG) was reduced in the group treated with the "Solution" in comparison with the control group. Table 1 : Concentration of Oxidative stress markers in blood (n=33 treatments) after (post) the respective treatment and before the next treatment (pre)
CONTROL "Solution"
Mean Std Dev Min Max Mean Std Dev Min Max
GSHred post [μM] 297 61 203 454 371 71 253 560
GSHred pre [μM] 331 75 109 481 415 74 273 576
GSSG post [μM] 620 198 324 1223 324 140 293 836
GSSG pre [μM] 657 213 247 1226 448 152 137 755
Ratio GSHred/GSSG post 0.53 0.16 0.27 0.82 0.74 0.22 0.35 1 .36
Ratio GSHred/GSSG pre 0.54 0.16 0.20 0.79 1.12 0.70 0.55 3.47
Concerning coagulation activation, activated clotting time (ACT) and thrombin-antithrombin (TAT) was measured, see table 2 below.
There was a significant increase in ACT from pre treatment to post treatment measurement for treatments with the "Solution" compared to treatments of control. However, there were no significant differences comparing the actual ACT values.
Post dialytic TAT concentration was significantly lower after treatments with the "Solution" compared to control devices (paired t-test p<0.05). Generation rate during treatment was significantly (about 10%) lower during treatments with the "Solution" (paired t-test p<0.05).
Table 2. Coagulation parameters during treatments 1 to 6 (n=33 treatments)
CONTROL "Solution"
Mean Std Dev Min Max Mean Std Dev Min Max
ACT pre (s) 110 24 81 178 101 17 61 144
ACT 30 min before end (s) 122 30 80 240 119 16 93 154
ACT post (s) 116 25 86 195 124 31 96 251
TAT post [μg/L] 11.8 7.6 3.1 27.8 8.5 5.7 2.2 26.1
TAT pre [μg/L] 3.9 1 .7 2.1 8.9 4.2 4.3 1 .9 29.8 Below you find examples of ready-for-use dialysis solutions, aqueous acid precursor compositions and dry acid precursor compositions according to embodiments of the present invention.
EXAMPLES
By way of example, and not limitation, the following examples identify a variety of solutions made pursuant to an embodiment of the present invention.
Example 1 -6
Below in table 1 you will find 6 ready-for-use dialysis solutions according to embodiments of the present invention. The concentrations are given in mM (mmol/L).
Figure imgf000018_0001
Example 7-10
Below in table 2 you will find 4 aqueous acid precursor compositions according to embodiments of the present invention. The concentrations are given in mM (mmol/L).
Figure imgf000019_0001
The aqueous acid precursor composition 7 above is diluted 1 :35 and the aqueous acid precursor compositions 8-10 are diluted 1 :200, with pure water, a sodium bicarbonate solution and a sodium chloride solution into ready-for-use dialysis solutions, corresponding to the ready-for-use dialysis solutions 1 , 3, 5 and 6 above.
Example 1 1 -16
Below in table 3 you will find 6 dry acid precursor compositions according to embodiments of the present invention. The content is given in g/L in the ready-for- use dialysis solution.
Figure imgf000020_0001
The dry acid precursor compositions 1 1 -16 above may be dissolved in pure water and mixed with bicarbonate and sodium chloride into the ready-for-use dialysis solutions in example 1 -6, respectively.
Example 17-18
Below in table 4 you will find 2 dry precursor compositions according to embodiments of the present invention. The content is given in g/L in the ready-for-use dialysis solution.
Figure imgf000021_0001
The dry precursor compositions 17-18 above may be dissolved in pure water into the ready-for-use dialysis solutions in examples 5-6, respectively.
It should be understood that various changes and modifications to the embodiments described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

Claims

1. A dialysis solution, which, when ready for use, comprises 0-1.75 mmol/L (mM) calcium ions, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose and a physiological buffer, characterised in that said solution further comprises, when ready for use, 0.1 -3.0 mM citric acid and 0.1 -3.0 mM gluconic acid, and has a pH within the range of 6.5-7.8.
2. A dialysis solution according to claim 1 , wherein said solution comprises, when ready for use, 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid.
3. A dialysis solution according to claim 1 , wherein said solution comprises, when ready for use, 0.8 mM citric acid and 1.0 mM gluconic acid.
4. A dialysis solution according to anyone of claims 1 -3, wherein said solution further comprises, when ready for use, 0.1 - 3.0 mM lactic acid.
5. A dialysis solution according to anyone of claims 1 to 4, wherein said solution further comprises, when ready for use, 0.1 - 3.0 mM N-acetyl cysteine.
6. An aqueous acid precursor composition for use during a method of forming a ready-for-use dialysis solution, which aqueous acid precursor composition comprises 0-2.33 mol/L(M) calcium, 0-1.33 M magnesium, 0-2.29 M potassium, and 0-6.28 M glucose, characterised in that said aqueous acid precursor composition further comprises 20.0-600 mM citric acid and 20.0-600 mM gluconic acid.
7. An aqueous acid precursor composition for use during a method of forming a ready-for-use dialysis solution, which aqueous acid precursor composition comprises 0-525 mM calcium, 0-300 mM magnesium, 0-1200 mM potassium, and 0- 3300 mM glucose, characterised in that said aqueous acid precursor composition further comprises 3.5-900 mM citric acid and 3.5-900 mM gluconic acid.
8. An aqueous acid precursor composition according to claim 6 or 7, wherein said aqueous acid precursor composition comprises 100-400 mM citric acid and 100-400 mM gluconic acid.
9. An aqueous acid precursor composition according to claim 6 or 7, wherein said aqueous acid precursor composition comprises 160 mM citric acid and 200 mM gluconic acid.
10. An aqueous acid precursor composition according to anyone of claims 6-10, wherein said aqueous acid precursor composition further comprises 20.0-600 mM lactic acid.
1 1. A dry acid precursor composition for use during a method of forming a ready-for-use dialysis solution, which dry acid precursor composition optionally comprises calcium, magnesium, potassium and glucose, characterised in that said dry acid precursor composition further comprises citric acid and gluconic acid, wherein the different components are present in such proportions and in such amounts in said dry acid precursor composition that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid.
12. A dry acid precursor composition according to claim 1 1 , wherein said dry acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for- use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid.
13. A dry acid precursor composition according to claim 1 1 , wherein said dry acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for- use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
14. A dry acid precursor composition according to anyone of claims 1 1 -
13, wherein said dry acid precursor composition further comprises lactic acid in such a proportion and in such an amount that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM lactic acid.
15. A dry acid precursor composition according to anyone of claims 1 1 -
14, wherein said dry acid precursor composition further comprises N-acetyl cysteine in such a proportion and in such an amount that, when said dry acid precursor composition has been dissolved and mixed with pure water and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine.
16. A method of forming a ready-for-use dialysis solution comprising mixing an acid precursor composition with pure water and a physiological buffer, said acid precursor composition comprising citric acid, gluconic acid, optionally calcium, magnesium, potassium and glucose in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.1 -3.0 mM citric acid, 0.1 -3.0 mM gluconic acid, 0-1.75 mM calcium ions, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1.0 mM glucose and having a pH within the range of 6.5-7.8.
17. A method of forming a ready-for-use dialysis solution according to claim 16, wherein said acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 gluconic acid.
18. A method of forming a ready-for-use dialysis solution according to claim 16, wherein said acid precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts to provide a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
19. A method of forming a ready-for-use dialysis solution according to anyone of claims 16-18, wherein said acid precursor composition further comprises lactic acid in such a proportion and in such an amount to provide a ready-for-use dialysis solution comprising 0.1 -3 mM lactic acid.
20. A method of forming a ready-for-use dialysis solution according to anyone of claims 16-18, wherein said acid precursor composition further comprises
N-acetyl cysteine in such a proportion and in such an amount to provide a ready-for- use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine.
21. A method of forming a ready-for-use dialysis solution according to anyone of claims 16-19, wherein said acid precursor composition is a concentrated aqueous acid precursor composition.
22. A method of forming a ready-for-use dialysis solution according to anyone of claims 16-20, wherein said acid precursor composition is a dry acid precursor composition.
23. A dry precursor composition for use during a method of forming a ready-for-use dialysis solution, which dry precursor composition comprises acid, physiological buffer and optionally calcium, magnesium, potassium and glucose, characterised in that said dry precursor composition comprises citric acid and gluconic acid, wherein the different components are present in such proportions and in such amounts in said dry precursor composition that, when said dry precursor composition has been dissolved and mixed with pure water into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0-1.75 mM calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid and having a pH within the range of 6.5-7.8.
24. A dry precursor composition according to claim 23, wherein said dry precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.5-2.0 mM citric acid and 0.5-2.0 mM gluconic acid.
25. A dry precursor composition according to claim 23, wherein said dry precursor composition comprises citric acid and gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.8 mM citric acid and 1.0 mM gluconic acid.
26. A dry precursor composition according to anyone of claims 23-25, wherein said dry precursor composition further comprises lactic acid in such a proportion and in such an amount that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM lactic acid.
27. A dry precursor composition according to anyone of claims 23-26, wherein said dry precursor composition further comprises N-acetyl cysteine in such a proportion and in such an amount that, when said dry precursor composition has been dissolved and mixed with pure water, it provides a ready-for-use dialysis solution comprising 0.1 -3 mM N-acetyl cysteine.
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