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WO2010112547A1 - Dialysis precursor composition - Google Patents

Dialysis precursor composition Download PDF

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Publication number
WO2010112547A1
WO2010112547A1 PCT/EP2010/054302 EP2010054302W WO2010112547A1 WO 2010112547 A1 WO2010112547 A1 WO 2010112547A1 EP 2010054302 W EP2010054302 W EP 2010054302W WO 2010112547 A1 WO2010112547 A1 WO 2010112547A1
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Prior art keywords
ready
dialysis solution
precursor composition
use dialysis
dry precursor
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PCT/EP2010/054302
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French (fr)
Inventor
Ola Carlsson
Hans-Rainer Drieschmanns
Gabriela Godaly
Anders Wieslander
Torbjörn LINDEN
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Gambro Lundia AB
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Gambro Lundia AB
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Publication of WO2010112547A1 publication Critical patent/WO2010112547A1/en
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    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • the present invention concerns a precursor composition for use during a method of forming a ready-for-use dialysis solution.
  • dialysis 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 semipermable membrane within the dialyzer has a blood side and a dialysate side.
  • Hemodialysis may be performed in three different treatment modes, hemodialysis, hemofiltration and hemodiafiltration. Common to all three treatment modes is 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 the 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.
  • toxins aqueous solution
  • 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 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.
  • 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 blood of a patient is effected by one of or a combination of the treatment modes hemodialysis, hemofiltration and hemodiafiltration.
  • the 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.
  • dialysis solutions dialysis solution concentrates, and dialysis concentrates are the components which occupy a considerable storage space.
  • One object of the present invention is to provide a precursor composition which is minimized in size of the consumables both for storage reasons and for environmental reasons, i.e. transportation.
  • Another object of the present invention is to provide a precursor composition which is stable for long term storage.
  • a further object of the present invention is to provide a precursor composition which comprises a stable antioxidant.
  • the present invention concerns a dry precursor composition for use during a method of forming a ready-for-use dialysis solution, wherein said dry precursor composition optionally comprises calcium, magnesium, potassium and glucose, wherein the different components are present in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0-1.75 mmol/L (mM) calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose.
  • said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine and 0.1 - 3.0 mM citric acid and having a pH of 6.5-7.8.
  • the dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, 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 N-acetyl cysteine and 0.5-2.0 mM citric acid.
  • the dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine and 0.5-1.5 mM citric acid.
  • the dry precursor composition further comprises sodium chloride in such a proportion and in such an amount that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready- for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 130- 150 mM sodium.
  • the dry precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid.
  • the dry precursor composition comprises N-acetyl cysteine, 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, other optional components, 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 N-acetyl cysteine, 0.5-2.0 mM citric acid, and 0.5-2.0 mM gluconic acid.
  • the dry precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine, 0.5-1.5 mM citric acid, and 0.5-1.5 mM gluconic acid.
  • the present invention further concerns a method of forming a ready-for- use dialysis solution comprising mixing a dry precursor composition with pure water, other optional components and a physiological buffer into a ready-for-use dialysis solution, said dry precursor composition comprising N-acetyl cysteine and citric acid, optionally calcium, magnesium, potassium, and glucose in such proportions and in such amounts that, the ready-for-use dialysis solution comprises 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, 0-1.75 mM calcium ions, 0-1.0 mM magnesium, 0- 4.0 mM potassium, 0-1 1.0 mM glucose and has a pH within the range of 6.5-7.8.
  • said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, 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 N-acetyl cysteine and 0.5-2.0 mM citric acid.
  • said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine and 0.5-1.5 mM citric acid.
  • said dry precursor composition further comprises sodium chloride in such a proportion and in such an amount, that when said dry precursor composition has been dissolved and mixed with pure water and other optional components into a ready-for-use dialysis solution, it provides a ready-for use dialysis solution comprising 130-150 mM sodium.
  • said dry precursor composition further comprises gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid.
  • said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, 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 N-acetyl cysteine, 0.5-2.0 mM citric acid, and 0.5-2.0 mM gluconic acid.
  • said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine, 0.5-1.5 mM citric acid, and 0.5-1.5 mM gluconic acid.
  • the total amount of added acid i.e. N-acetyl cysteine and citric acid, and optional gluconic acid
  • 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 the salt form of N-acetyl cysteine, these amounts is not to be added to this total amount of up to 3 mEq/L acid (H + ).
  • the dry precursor composition may first be 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-to-use dialysis solution.
  • the dry precursor composition may be dissolved with pure water into a batch of a ready-for-use dialysis solution.
  • all components may be provided by dissolving powdered compositions in pure water.
  • the physiological buffer such as bicarbonate
  • the physiological buffer may be provided from a cartridge/container with dry powdered sodium bicarbonate. Pure water is introduced into the cartridge/container with the dry powdered sodium bicarbonate, and the sodium bicarbonate starts to dissolve and a saturated sodium bicarbonate solution is produced and withdrawn from the cartridge/container.
  • sodium chloride could also be provided as a separate dry powder within a cartridge/container. Also here pure water is introduced into the cartridge/container and a saturated sodium chloride solution is withdrawn from the cartridge/container. These two saturated solutions may then diluted and mixed with each other and the dissolved aqueous acid precursor compositioninto a ready-for-use dialysis solution.
  • sodium chloride and sodium bicarbonate is provided as a mixture of dry components in a cartridge/container. Also here pure water is introduced into the cartridge/container and a saturated solution of sodium chloride and sodium bicarbonate is drawn from the cartridge/container, diluted and mixed with the dissolved aqueous acid precursor compositioninto a ready-for-use dialysis solution.
  • sodium bicarbonate and sodium chloride may be provided as aqueous concentrates also, but due to stability (for bicarbonate) and storage space, it may be provided as dry powdered sodium bicarbonate and as dry powdered sodium chloride.
  • 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 and is to be diluted with additional components into the final ready-for-use dialysis solution.
  • Other synonyms are a powder concentrate or a powder composition, a particulate concentrate or a particulate composition, and a granulated concentrate or a granulated composition.
  • citric acid means that the component may be added as citric acid or as its sodium, calcium, magnesium, or potassium salt thereof, i.e. as 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 as citrate.
  • gluconic acid means that the component may be added as gluconic acid, glucono-delta-lactone or as its sodium, calcium, magnesium or potassium salt thereof, i.e. as gluconate, to the ready-for-use dialysis solution.
  • gluconic acid converts over to the salt form thereof, gluconate.
  • gluconic acid may be added as glucono-delta-lactone (C 6 H 10 O 6 ), which may be obtained in powdered form and in pure form, and which hydrolyses into gluconic acid when dissolved in water.
  • 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 it also means a ready-for-use solution which may be used for infusion into the extracorporeal blood circuit either pre or post the dialyzer.
  • the dry precursor composition may be dissolved in pure water and may be mixed with other components, which also may be prepared online from powder concentrates, and 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 or directly used as an infusion fluid for infusion into the extracorporeal blood circuit either pre or post the dialyzer.
  • the dry precursor composition may be dissolved in pure water and mixed with other components into a batch of a ready-for-use dialysis solution, that is, a batch-wise production of a ready-for-use dialysis solution.
  • the other components may be provided by dissolving powder concentrates in pure water.
  • 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. Where after this solution is mixed with the remaining components into a ready- for-use dialysis solution.
  • 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 i.e. after mixing and dilution
  • 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.O mM.
  • Mouse fibroblast cell line L929 was seeded in to 96 wells plates ( ⁇ 3000 cells/ well) in cell culture medium (MEM) supplemented with L-glutamin- NEA (10ml/500ml) and 10% Fetal Calf Serum clone III (FCS III).
  • MEM cell culture medium
  • FCS III Fetal Calf Serum clone III
  • the Asc-mix consisted of 5 mM Ascorbate, 1.5 mM (NH 4 ) 2 Fe(SO 4 ) 2 and 10 mM ADP in PBS.
  • the Asc-mix produces free radicals in order to injure the cells.
  • FIG. 1 illustrates inhibition of cell growth (ICG%) on cell line L929 preincubated with NAC in different concentrations for two days and then exposed to an Asc-mix described above.
  • the first sample demonstrates 10 mM NAC and Asc- mix and is to be compared with sample 2 and sample 7, which demonstrates the ICG% of cells exposed to only 10 mM NAC or only the Asc-mix.
  • sample 1 shows that the combination of NAC and Asc-mix (sample 1 ) has lower ICG% than the positive control (sample 7).
  • Sample 2 show that using 10 mM NAC itself also has an inhibition of cell growth. This inhibition disappear when the concentration is lowered (sample 4 and sample 6). Thus, the lower concentrations are more biocompatible, and are still giving a protective effect on the cells, which is shown in sample 3 (5 mM NAC) and 5 (1 mM NAC), which have a lower ICG% than the test with 10 mM NAC.
  • Trisodium citrate Na 3 C 6 H 5 O 7
  • Figure 2 illustrates inhibition of cell growth (ICG%) on cell line L929 preincubated with citrate (sodium citrate) in different concentrations for two days and then exposed to an Asc-mix described above.
  • the first sample demonstrate 10 mM citrate and Asc-mix and is to be compared with sample 2 and sample 7 which demonstrate the ICG% of cells exposed to only 10 mM citrate or only the Asc-mix.
  • sample 1 shows that the combination of citrate and Asc-mix (sample 1 ) has higher ICG than the positive control (sample 7). Indicating that using 10 mM citrate together with Asc-mix is more toxic to the cells than just using the Asc-mix. Additionally exposing the cells to only 10 mM citrate is not as harmful as the mix.
  • Sample 3 and sample 5 shows that using 5 and 1 mM citrate might reduce the ICG% values with as much as 20 % (delta values between sample 3 and 7 and between 5 and 7).
  • the lower concentrations of pure citrate does not show any intimidating harmful results on ICG%.
  • N-acetyl cysteine C 5 H 9 NO 3 S
  • Sodium gluconate C 6 HnO 7 Na
  • Trisodium citrate Na 3 C 6 H 5 O 7
  • NAC N-acetyl cystein
  • Figure 4 illustrates inhibition of cell growth (ICG%) on cell line L939 performed according to the method disclosed above.
  • the lighter, left hand column for each test shows the ICG% for the combination and the dark, right hand column for each test shows a positive control (a cell line only treated with Asc-mix).
  • Tests have been performed to analyse and determine particle formation when mixing a ready-for-use dialysis solution from dry acidic precursor compositions according to the invention together with dry basic concentrates.
  • Basic concentrates being, in this particular case, sodium bicarbonate and sodium chloride.
  • Aqueous acid precursor compositions were prepared with a volume 1 Litre by dissolving:
  • 200 ml of the aqueous acid 5X precursor concentrate was added to 600 ml Millipore water in a sealable glass vessel. Then 200 ml of the basic 5X buffer concentrate was added and particles and pH were measured during 24 hours. The procedure was repeated with 100 ml the aqueous acid 10X precursor concentrate, which were added to 800 ml of water, and then 100 ml of the basic 10X buffer concentrate was added. Also here pH and particles were measured with the particle counter and the pH meter disclosed above. The particle measurements were made in triplicate.
  • Example 1 -4 identify a variety of solutions made pursuant to embodiments of the present invention.
  • Example 1 -4 identify a variety of solutions made pursuant to embodiments of the present invention.
  • the dry precursor compositions 1 -4 above may be dissolved in pure water and mixed with a buffer and a sodium chloride concentrate into a ready-for-use dialysis solution. Below in table 6 you will find the ready-for-use dialysis solutions produced by the use of the above-identified dry precursor compositions.

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Abstract

The present invention 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 N-acetyl cysteine and citric acid. The present invention further concerns a method of forming a ready-for-use dialysis solution from the dry precursor composition.

Description

DIALYSIS PRECURSOR COMPOSITION
TECHNICAL FIELD
The present invention concerns a precursor composition for use during a method 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 semipermable membrane within the dialyzer has a blood side and a dialysate side.
Hemodialysis may be performed in three different treatment modes, hemodialysis, hemofiltration and hemodiafiltration. Common to all three treatment modes is 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 the 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 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 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 blood of a patient is effected by one 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 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.
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 a considerable 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 precursor composition which is minimized in size of the consumables both for storage reasons and for environmental reasons, i.e. transportation.
Another object of the present invention is to provide a precursor composition which is stable for long term storage.
A further object of the present invention is to provide a precursor composition which comprises a stable antioxidant. The present invention concerns a dry precursor composition for use during a method of forming a ready-for-use dialysis solution, wherein said dry precursor composition optionally comprises calcium, magnesium, potassium and glucose, wherein the different components are present in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0-1.75 mmol/L (mM) calcium, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose. According to the invention said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine and 0.1 - 3.0 mM citric acid and having a pH of 6.5-7.8.
In one embodiment of the present invention the dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, 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 N-acetyl cysteine and 0.5-2.0 mM citric acid.
In another embodiment of the present invention the dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine and 0.5-1.5 mM citric acid.
In even another embodiment of the present invention the dry precursor composition further comprises sodium chloride in such a proportion and in such an amount that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready- for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 130- 150 mM sodium. According to another embodiment of the present invention the dry precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid.
In another embodiment of the present invention the dry precursor composition comprises N-acetyl cysteine, 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, other optional components, 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 N-acetyl cysteine, 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 precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine, 0.5-1.5 mM citric acid, and 0.5-1.5 mM gluconic acid.
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 bleeding. 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 a method of forming a ready-for- use dialysis solution comprising mixing a dry precursor composition with pure water, other optional components and a physiological buffer into a ready-for-use dialysis solution, said dry precursor composition comprising N-acetyl cysteine and citric acid, optionally calcium, magnesium, potassium, and glucose in such proportions and in such amounts that, the ready-for-use dialysis solution comprises 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, 0-1.75 mM calcium ions, 0-1.0 mM magnesium, 0- 4.0 mM potassium, 0-1 1.0 mM glucose and has a pH within the range of 6.5-7.8.
In another embodiment of the method of the present invention, said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, 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 N-acetyl cysteine and 0.5-2.0 mM citric acid.
In even another embodiment of the method of the present invention, said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine and 0.5-1.5 mM citric acid. In another embodiment of the method of the present invention, said dry precursor composition further comprises sodium chloride in such a proportion and in such an amount, that when said dry precursor composition has been dissolved and mixed with pure water and other optional components into a ready-for-use dialysis solution, it provides a ready-for use dialysis solution comprising 130-150 mM sodium. In another embodiment of the method, said dry precursor composition further comprises gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid.
In even another embodiment of the method, said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, 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 N-acetyl cysteine, 0.5-2.0 mM citric acid, and 0.5-2.0 mM gluconic acid. In another embodiment of the method, said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine, 0.5-1.5 mM citric acid, and 0.5-1.5 mM gluconic acid.
In one embodiment the total amount of added acid, i.e. N-acetyl cysteine and citric acid, and optional gluconic acid, provides for a concentration of up to 3 mEq/L acid. That is, when these components has been added to the 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 the salt form of N-acetyl cysteine, these amounts is not to be added to this total amount of up to 3 mEq/L acid (H+). When preparing the ready-for-use dialysis solution, the dry precursor composition may first be 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-to-use dialysis solution. In one embodiment the dry precursor composition may be dissolved with pure water into a batch of a ready-for-use dialysis solution. Here all components may be provided by dissolving powdered compositions in pure water.
In another embodiment the physiological buffer, such as bicarbonate, may be provided from a cartridge/container with dry powdered sodium bicarbonate. Pure water is introduced into the cartridge/container with the dry powdered sodium bicarbonate, and the sodium bicarbonate starts to dissolve and a saturated sodium bicarbonate solution is produced and withdrawn from the cartridge/container.
In another embodiment sodium chloride could also be provided as a separate dry powder within a cartridge/container. Also here pure water is introduced into the cartridge/container and a saturated sodium chloride solution is withdrawn from the cartridge/container. These two saturated solutions may then diluted and mixed with each other and the dissolved aqueous acid precursor compositioninto a ready-for-use dialysis solution.
In one further embodiment of the present invention sodium chloride and sodium bicarbonate is provided as a mixture of dry components in a cartridge/container. Also here pure water is introduced into the cartridge/container and a saturated solution of sodium chloride and sodium bicarbonate is drawn from the cartridge/container, diluted and mixed with the dissolved aqueous acid precursor compositioninto a ready-for-use dialysis solution. Of course, sodium bicarbonate and sodium chloride may be provided as aqueous concentrates also, but due to stability (for bicarbonate) and storage space, it may be provided as dry powdered sodium bicarbonate and as dry powdered sodium chloride.
DEFINITIONS
The term "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 and is to be diluted with additional components into the final ready-for-use dialysis solution. Other synonyms are a powder concentrate or a powder composition, a particulate concentrate or a particulate composition, and a granulated concentrate or a granulated composition. The term "citric acid" means that the component may be added as citric acid or as its sodium, calcium, magnesium, or potassium salt thereof, i.e. as 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 as citrate.
The term "gluconic acid" means that the component may be added as gluconic acid, glucono-delta-lactone or as its sodium, calcium, magnesium or potassium salt thereof, i.e. as gluconate, to the ready-for-use dialysis solution. However, when the dry precursor composition is being mixed with a physiological buffer to end up at a pH within the range of 6.5-7.8, gluconic acid converts over to the salt form thereof, gluconate. However, within the dry precursor composition, if to be added in its acid form, gluconic acid may be added as glucono-delta-lactone (C6H10O6), which may be obtained in powdered form and in pure form, and which hydrolyses into gluconic acid when dissolved in water.
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 it also means a ready-for-use solution which may be used for infusion into the extracorporeal blood circuit either pre or post the dialyzer.
DETAILED DESCRIPTION OF THE INVENTION In one embodiment of the present invention the dry precursor composition may be dissolved in pure water and may be mixed with other components, which also may be prepared online from powder concentrates, and 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 or directly used as an infusion fluid for infusion into the extracorporeal blood circuit either pre or post the dialyzer.
In another embodiment the dry precursor composition may be dissolved in pure water and mixed with other components into a batch of a ready-for-use dialysis solution, that is, a batch-wise production of a ready-for-use dialysis solution. Also here the other components may be provided by dissolving powder concentrates in pure water.
In 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. Where after this solution is mixed with the remaining components into a ready- for-use dialysis solution. 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.O mM.
TEST METHODS AND RESULTS
Investigation of antioxidative properties of N-acetyl cysteine, citrate and gluconate alone or in combinations Material and methods Day 1 Mouse fibroblast cell line L929 was seeded in to 96 wells plates (~ 3000 cells/ well) in cell culture medium (MEM) supplemented with L-glutamin- NEA (10ml/500ml) and 10% Fetal Calf Serum clone III (FCS III).
Day 2 Addition of antioxidants. The antioxidants were dissolved in MEM supplemented as before, sterilised by filtration and added to the cells.
Day 4 Addition of Asc-mix (1 hour) (200μl/well). The Asc-mix consisted of 5 mM Ascorbate, 1.5 mM (NH4)2Fe(SO4)2 and 10 mM ADP in PBS. The Asc-mix produces free radicals in order to injure the cells.
Day 5 The neutral red viability assay was performed and inhibition of cell growth (ICG) calculated.
N-acetyl cysteine (NAC) (C5H9NO3S) Figure 1 illustrates inhibition of cell growth (ICG%) on cell line L929 preincubated with NAC in different concentrations for two days and then exposed to an Asc-mix described above. The first sample demonstrates 10 mM NAC and Asc- mix and is to be compared with sample 2 and sample 7, which demonstrates the ICG% of cells exposed to only 10 mM NAC or only the Asc-mix. This shows that the combination of NAC and Asc-mix (sample 1 ) has lower ICG% than the positive control (sample 7). This indicates that using 10 mM NAC together with the Asc-mix has a slightly protective effect on the cells. Sample 2 show that using 10 mM NAC itself also has an inhibition of cell growth. This inhibition disappear when the concentration is lowered (sample 4 and sample 6). Thus, the lower concentrations are more biocompatible, and are still giving a protective effect on the cells, which is shown in sample 3 (5 mM NAC) and 5 (1 mM NAC), which have a lower ICG% than the test with 10 mM NAC.
Trisodium citrate (Na3C6H5O7)
Figure 2 illustrates inhibition of cell growth (ICG%) on cell line L929 preincubated with citrate (sodium citrate) in different concentrations for two days and then exposed to an Asc-mix described above. The first sample demonstrate 10 mM citrate and Asc-mix and is to be compared with sample 2 and sample 7 which demonstrate the ICG% of cells exposed to only 10 mM citrate or only the Asc-mix. This shows that the combination of citrate and Asc-mix (sample 1 ) has higher ICG than the positive control (sample 7). Indicating that using 10 mM citrate together with Asc-mix is more toxic to the cells than just using the Asc-mix. Additionally exposing the cells to only 10 mM citrate is not as harmful as the mix. Sample 3 and sample 5 shows that using 5 and 1 mM citrate might reduce the ICG% values with as much as 20 % (delta values between sample 3 and 7 and between 5 and 7). The lower concentrations of pure citrate (sample 4 and 6) does not show any intimidating harmful results on ICG%.
Sodium gluconate (C6HnO7Na)
Sodium gluconate has a small dose dependent antioxidative effect in this oxidative stress model, as may be seen in figure 3. Combination of N-acetyl cysteine (NAC) (C5H9NO3S) and Sodium gluconate (C6HnO7Na) and/or Trisodium citrate (Na3C6H5O7)
Tests were performed by combining N-acetyl cystein (NAC) with sodium gluconate, NAC with trisodium citrate and NAC with sodium gluconate and trisodium citrate. The following combinations and concentrations were used in the tests:
1. 1.5 mM NAC and 1.5 mM sodium gluconate
2. 1 mM NAC and 0.8 mM trisodium citrate
3. 0.8 mM citrate and 1 mM gluconate (by way of comparison)
4. 1 mM NAC and 0.467 mM trisodium citrate and 1 mM sodium gluconate
5. 1 mM citrate (by way of comparison)
6. 1 mM NAC
7. 1 mM gluconate (by way of comparison)
Figure 4 illustrates inhibition of cell growth (ICG%) on cell line L939 performed according to the method disclosed above. The lighter, left hand column for each test shows the ICG% for the combination and the dark, right hand column for each test shows a positive control (a cell line only treated with Asc-mix).
In table 1 below the differences between positive controls and the test mixtures for each test are shown.
Figure imgf000014_0001
All data are presented as mean ±SEM ***p<0.001 **p<0.01 * p<0.05.
Determination of particle formation and stability of pH
Tests have been performed to analyse and determine particle formation when mixing a ready-for-use dialysis solution from dry acidic precursor compositions according to the invention together with dry basic concentrates. Basic concentrates being, in this particular case, sodium bicarbonate and sodium chloride.
All the formulations in table 5 below were mixed into finish solutions according to table 6 and analyzed for particle formulation, all with similar results of very low particle values.
Below is shown the test results for the dry precursor composition according to example 7 in table 5 below.
Aqueous acid precursor compositions were prepared with a volume 1 Litre by dissolving:
Figure imgf000015_0001
Basic buffer concentrates were prepared with a volume of 1 Litre by dissolving:
Figure imgf000015_0002
200 ml of the aqueous acid 5X precursor concentrate was added to 600 ml Millipore water in a sealable glass vessel. Then 200 ml of the basic 5X buffer concentrate was added and particles and pH were measured during 24 hours. The procedure was repeated with 100 ml the aqueous acid 10X precursor concentrate, which were added to 800 ml of water, and then 100 ml of the basic 10X buffer concentrate was added. Also here pH and particles were measured with the particle counter and the pH meter disclosed above. The particle measurements were made in triplicate.
Results:
Figure imgf000016_0001
The results of the particle count shows very low values. Thus, there is negligible precipitation of calcium carbonate during 24 hours.
EXAMPLES
By way of example, and not limitation, the following examples identify a variety of solutions made pursuant to embodiments of the present invention. Example 1 -4
Below in table 5 you will find 4 dry precursor compositions according to embodiments of the present invention. The content is given in g/L in the ready-to-use dialysis solutions.
Figure imgf000016_0002
The dry precursor compositions 1 -4 above may be dissolved in pure water and mixed with a buffer and a sodium chloride concentrate into a ready-for-use dialysis solution. Below in table 6 you will find the ready-for-use dialysis solutions produced by the use of the above-identified dry precursor compositions.
Figure imgf000017_0001
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 dry precursor composition for use during a method of forming a ready-for-use dialysis solution, wherein said dry precursor composition optionally comprises calcium, magnesium, potassium and glucose, wherein the different components are present in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0-1.75 mmol/L (mM) calcium, 0- 1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1 mM glucose, characterised in that said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine and 0.1 - 3.0 mM citric acid and having a pH of 6.5-7.8.
2. A dry precursor composition according to claim 1 , wherein said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, 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 N-acetyl cysteine and 0.5-2.0 mM citric acid.
3. A dry precursor composition according to claim 1 , wherein said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine and 0.5-1.5 mM citric acid.
4. A dry precursor composition according to claim 1 , wherein said dry precursor composition further comprises sodium chloride in such a proportion and in such an amount that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 130-150 mM sodium.
5. A dry precursor composition according to claim 1 , wherein said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid.
6. A dry precursor composition according to claim 5, wherein said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, 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 N-acetyl cysteine, 0.5-2.0 mM citric acid, and 0.5-2.0 mM gluconic acid.
7. A dry precursor composition according to claim 5, wherein said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine, 0.5-1.5 mM citric acid, and 0.5-1.5 mM gluconic acid.
8. A method of forming a ready-for-use dialysis solution comprising mixing a dry precursor composition with pure water and other optional components and a physiological buffer into a ready-for-use dialysis solution, said dry precursor composition comprising N-acetyl cysteine and citric acid, optionally calcium, magnesium, potassium, and glucose in such proportions and in such amounts that, the ready-for-use dialysis solution comprises 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, 0-1.75 mM calcium ions, 0-1.0 mM magnesium, 0-4.0 mM potassium, 0-1 1.0 mM glucose and has a pH within the range of 6.5-7.8.
9. A method of forming a ready-for-use dialysis solution according to claim 8, wherein said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, 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 N-acetyl cysteine and 0.5-2.0 mM citric acid.
10. A method of forming a ready-for-use dialysis solution according to claim 8, wherein said dry precursor composition comprises N-acetyl cysteine and citric acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine and 0.5-1.5 mM citric acid.
1 1. A method of forming a ready-for-use dialysis solution according to claim 8 or 10, wherein said dry precursor composition further comprises sodium chloride in such a proportion and in such an amount, that when said dry precursor composition has been dissolved and mixed with pure water and other optional components into a ready-for-use dialysis solution, it provides a ready-for use dialysis solution comprising 130-150 mM sodium.
12. A method of forming a ready-for-use dialysis solution according to claim 8, wherein said dry precursor composition further comprises gluconic acid in such proportions and in such amounts that, when said dry precursor composition has been dissolved and mixed with pure water, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.1 -3.0 mM N-acetyl cysteine, 0.1 -3.0 mM citric acid, and 0.1 -3.0 mM gluconic acid.
13. A method of forming a ready-for-use dialysis solution according to claim 12, wherein said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, 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 N-acetyl cysteine, 0.5-2.0 mM citric acid, and 0.5-2.0 mM gluconic acid.
14. A method of forming a ready-for-use dialysis solution according to claim 12, wherein said dry precursor composition comprises N-acetyl cysteine, 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, other optional components, and a physiological buffer into a ready-for-use dialysis solution, it provides a ready-for-use dialysis solution comprising 0.5-1.5 mM N-acetyl cysteine, 0.5-1.5 mM citric acid, and 0.5-1.5 mM gluconic acid.
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TWI561256B (en) * 2011-12-21 2016-12-11 Gambro Lundia Ab Dialysis precursor composition
AU2012363594B2 (en) * 2011-12-21 2014-08-14 Gambro Lundia Ab Dialysis precursor composition
WO2013092284A1 (en) * 2011-12-21 2013-06-27 Gambro Lundia Ab Dialysis precursor composition
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CN104159579B (en) * 2012-03-08 2017-06-30 甘布罗伦迪亚股份公司 Dialysis composition comprising citrate, calcium and magnesium
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WO2013131906A1 (en) * 2012-03-08 2013-09-12 Gambro Lundia Ab Dialysis composition comprising citrate, calcium and magnesium
CN104159579A (en) * 2012-03-08 2014-11-19 甘布罗伦迪亚股份公司 Dialysis composition comprising citrate, calcium and magnesium
US9452149B2 (en) 2012-03-08 2016-09-27 Gambro Lundia Ab Dialysis composition comprising citrate, calcium and magnesium
AU2013201615B2 (en) * 2012-03-08 2015-02-19 Gambro Lundia Ab Dialysis composition
EP4223290A1 (en) * 2012-03-08 2023-08-09 Gambro Lundia AB Dialysis composition comprising citrate, calcium and magnesium
US9925155B2 (en) 2012-12-18 2018-03-27 Gambro Lundia Ab Dialysis composition

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