Systems for dispensing liquids

Abstract

A system for preparing a ready-to-use peritoneal dialysis fluid is provided. [Solution] The system comprises: a) a distribution device; b) at least one water source; c) at least one first concentrate source adapted to connect with a) and b); d) at least one second concentrate source adapted to connect with a) and b); and optionally e) at least one further concentrate source adapted to connect with a) and b), wherein the first concentrate comprises glucose and has a pH between 1.5 and 4, and the second concentrate comprises a physiologically acceptable buffer and has a pH between 5.5 and 9.0.

Description

[Technical field]

[0001] The present invention relates to the field of compounding fluids for preparing fluids, in particular for the treatment of renal failure. In particular, the present invention relates to a system for the treatment of renal failure, configured for compounding a final fluid from one, two or more concentrates for use as a dialysis fluid. In particular, the present invention can be used for preparing fluids for peritoneal dialysis, in particular for preparing fluids on-site. [Background technology]

[0002] Patients with acute or chronic renal failure may require supportive therapy in the form of dialysis for the removal of waste products and excess fluid from the body. Dialysis is the process of removing fluid and waste products from the patient by the use of diffusive or convective transport. Different dialysis techniques can be distinguished, which relate to the dialysis fluid. The choice of which dialysis technique to use depends on the patient's needs, the treatment requirements, and the available resources.

[0003] Different dialysis treatments are available: hemodialysis (HD), hemofiltration (HF), hemodiafiltration (HDF), and peritoneal dialysis (PD). Ambulatory hemodialysis patients usually undergo dialysis therapy for 3 to 5 hours about three times a week. Dialysis therapy is usually performed in a dialysis center, but home dialysis is also possible. When home dialysis is performed, patients can perform dialysis more frequently and it is also a gentler treatment that is usually of longer duration, for example, 4 to 8 hours per treatment and 5 to 7 treatments per week. Dosage and duration of treatment can be adjusted according to the requirements and needs of each patient.

[0004] In the case of patients suffering from acute renal failure, they can be treated with either HD or PD, a special type of HD being continuous renal replacement therapy (CRRT), which is continuous treatment throughout the day and in some cases for several weeks. Alternatively, patients can also be treated with regular HD treatment (intermittent treatment) or a more time-consuming form of HD called long-term dialysis (SLED).

[0005] Peritoneal dialysis is one available dialysis technique for patients with renal failure. During this treatment, sterile peritoneal dialysis fluid is infused into the patient's peritoneal cavity via a catheter inserted through the abdominal wall. In peritoneal dialysis, the peritoneal membrane acts as the dialysis membrane. An osmotic gradient is applied to the dialysis fluid causing fluid removal from the blood by the addition of an osmotic agent. The amount of fluid removed during a dialysis treatment depends on the concentration of the selected osmotic agent in the fluid used; the higher the concentration, the greater the amount of fluid removed.

[0006] There are different methods of peritoneal dialysis treatment available, for example, continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD).

[0007] In automated peritoneal dialysis, an automated cycler is used to infuse and drain dialysis fluid. This form of treatment can be performed automatically at night while the patient sleeps. The cycler measures the amount of fluid infused and removed to calculate the net fluid removed. The treatment sequence usually begins with an initial drain cycle to empty the peritoneal cavity of dialysate (also called spent dialysis fluid). The cycler then performs a series of fill, dwell, and drain cycles, usually ending with a fill cycle.

[0008] Peritoneal dialysis generally requires large volumes of dialysis fluid. Typically, at each application, or exchange, a patient will have 0.5 to 3 liters of dialysis fluid infused into the peritoneal cavity. The fluid is allowed to dwell for approximately 3 to 4 hours, after which it is drained and replaced with new fluid. Typically, four such exchanges are performed each day. Approximately 8 to 20 liters of dialysis fluid are required per day for each patient, 7 days a week, 365 days a year.

[0009] Peritoneal dialysis fluid is traditionally provided in bags, often 1.5L, 2L, 3L, 5L, or 6L bags, and terminally sterilized. The transportation and storage of the vast quantities of fluid required is both extremely inconvenient and expensive. Furthermore, the repeated connection and disconnection of numerous fluid containers for the patient presents a substantial risk of microbial contamination at the connection points. Additionally, the sheer volume of waste, in the form of empty containers and packages, and their proper disposal, is becoming an increasing concern.

[0010] It is desirable to reduce these concerns and to solve the problems associated with large volumes of dialysis fluid. The present invention provides a solution to the problem by providing a system in which small amounts of concentrated dialysis fluid are combined and diluted with purified water at the point of care, i.e., near the patient. Concentrates of ingredients for preparing ready-to-use peritoneal dialysis fluid are provided in approximately 1 L volumes each and would replace 8 to 55 L of peritoneal dialysis fluid commonly used today. Additionally, there is a need to provide on-site preparation of fluid for peritoneal dialysis fluid, as used in APD or CAPD, and to provide a treatment that is larger, safer, more sterile, and performs the requirements more accurately than currently available treatments.

[0011] WO 2013 / 1141896 describes systems, devices and methods for peritoneal dialysis. The system may include a control means configured to compare the conductivity of batches of liquid.

[0012] WO 2012 / 129501 describes systems, devices and methods for peritoneal dialysis, including prescription-driven dialysis fluid preparation.

[0013] An apparatus for distributing and dispensing concentrates in solutions for use as kidney dialysis solutions is known from US Pat. No. 5,344,392.

[0014] The concentrates used in this device are also described therein. Concentrate 1 contains: · 11.34g / 100ml NaCl - (Mw=58.44g / mol);1940mM 7.84g / 100ml Sodium lactate (Mw=112.06g / mol); 700mM 514mg / 100ml Calcium chloride (Mw(CaCl2·2H2O=147.01g / mol); 35.0mM 304mg / 100ml Magnesium chloride (Mw=203.31g / mol(hexahydrate)); 14.95mM

[0015] The concentrate has a pH of approximately 6.4.

[0016] Concentrate 1 is intended to be mixed with concentrate 2, which contains a solution of 50% dextrose. The resulting solution is a 1 to 20 (1+19) dilution, resulting in a peritoneal dialysis fluid ready for use.

[0017] However, because the pH of the glucose solution is not specified, the described solution is configured to produce unacceptable levels of glucose degradation products (GDPs). Sterilization of glucose containing fluids is challenging because some glucose degrades and forms cytotoxic GDPs during the sterilization process. A further need is to provide a system with a concentrate suitable for on-site preparation of peritoneal dialysis fluid that has sufficient storage stability and biocompatibility, and produces a ready-to-use pH close to physiological / neutral that reduces infusion pain, is clean of impurities including GDPs and sediments, is microbiologically safe, and provides an osmotic gradient that meets the patient's needs for dialysis and / or ultrafiltration. Summary of the Invention

[0018] It was an object of the present invention to provide a system for preparing a ready-to-use peritoneal dialysis fluid.

[0019] In one embodiment of the present invention, a system is provided, the system comprising: a) an allocation device; b) at least one water source adapted to connect with said distribution device; c) at least one first concentrate source adapted to connect with a) and b); d) at least one second concentrate source adapted to connect with a) and b); and Optionally, e) at least one further concentrate source adapted to connect with a) and b); and wherein the first concentrate comprises glucose and has a pH between 1.5 and 4, e.g., a pH between 2 and 3.5, or a pH between 2.2 and 3.2, and the second concentrate comprises a physiologically acceptable buffer and has a pH between 5.5 and 9.0.

[0020] The ready to use peritoneal fluid may also be prepared to have a pH between 5.5 and 8, for example between 6.5 and 7.5, or between 6.8 and 7.5.

[0021] In one embodiment of the invention, the system comprises a first concentrate comprising glucose having a pH between 1.5 and 4, or between 2 and 3.5, or between 2.2 and 3.2, and a second concentrate comprising a physiologically acceptable buffer having a pH between 6.0 and 8.5.

[0022] The prepared ready to use peritoneal dialysis fluid has the following contents: Sodium (Na + ) 100-140mM Potassium (K + ) 0-4mM Calcium (Ca 2+ ) 0-2mM Magnesium (Mg 2+ )0-0.75mM Lactate 0-40mM Bicarbonate 0-35mM Glucose 0-5%

[0023] In one embodiment of the invention, the physiologically acceptable buffer is selected from the group comprising acetate, lactate, citrate, pyruvate, carbonate, bicarbonate, and amino acid buffers, or mixtures thereof.

[0024] In one embodiment of the invention, the physiologically acceptable buffer is lactate.

[0025] In one embodiment of the invention, the physiologically acceptable buffer is bicarbonate.

[0026] In another embodiment of the invention, the physiologically acceptable buffer is a mixture of lactate and bicarbonate.

[0027] In one embodiment of the invention, the first concentrate further comprises at least one electrolyte selected from the group comprising sodium, calcium, magnesium, and optionally potassium.

[0028] In one embodiment of the invention, the second concentrate further comprises at least one electrolyte selected from the group comprising sodium, calcium, magnesium, and optionally potassium.

[0029] In another embodiment of the invention, the further concentrate comprises at least one electrolyte selected from the group comprising sodium, calcium, magnesium, and optionally potassium.

[0030] Provided by the present invention is a system for preparing ready-to-use peritoneal fluid that has the flexibility and capability for profiling electrolytes, such as calcium.

[0031] In another embodiment of the invention, the further concentrate comprises a physiologically acceptable buffer selected from the group comprising acetate, lactate, citrate, pyruvate, carbonate, bicarbonate, and amino acid buffers, or mixtures thereof, which provides further flexibility for preparing the peritoneal dialysis fluid.

[0032] In another embodiment, the first concentrate and the second concentrate comprise calcium and at least one further electrolyte selected from the group comprising sodium, magnesium, and optionally potassium.

[0033] In another embodiment, the second concentrate and the further concentrate comprise calcium and at least one further electrolyte selected from the group comprising sodium, magnesium, and optionally potassium.

[0034] In another embodiment, the first concentrate and the second concentrate comprise calcium and at least one further electrolyte selected from the group comprising sodium, magnesium, and optionally potassium, and the optional further concentrate comprises at least one electrolyte selected from the group comprising sodium, calcium, magnesium, and optionally potassium.

[0035] A system containing calcium, and optionally magnesium, in the first concentrate as well as in the second concentrate provides a system in which calcium profiling can be achieved. The flexibility of calcium can vary within a wider range than in a system in which calcium is present only in one of the concentrates, be it the first, second or further concentrate. By reducing the concentration of calcium, and optionally magnesium, in the second concentrate, e.g., lactate containing concentrate, the stability of the second concentrate can be improved.

[0036] Another embodiment of the invention is a system in which the first concentrate, and / or the second concentrate, and / or the further concentrate are terminally sterilized.

[0037] In one embodiment of the present invention, a system is provided, the system comprising: a) an allocation device; b) at least one water source adapted to connect with said distribution device; c) at least one first concentrate source adapted for connection with a) and b) and terminally sterilized; d) at least one second concentrate source adapted for connection with a) and b) and terminally sterilized; Optionally, e) at least one further concentrate source adapted for connection with a) and b) and terminally sterilized; and wherein the first concentrate comprises glucose and has a pH between 1.5 and 4, e.g., a pH between 2 and 3.5, or a pH between 2.2 and 3.2, and the second concentrate comprises a physiologically acceptable buffer and has a pH between 5.5 and 9.0, e.g., a pH between 6.0 and 8.5.

[0038] The systems described herein include one or more water sources, preferably providing purified water. Terminal sterilization of the first concentrate, second concentrate, and / or further concentrates allows for the provision of very high quality peritoneal dialysis fluid.

[0039] In one embodiment of the invention, the second concentrate requires dilution with water and the first and optionally further concentrates. It is intended to be diluted between about 1:10 and 1:33, about 1:10 to about 1:40, and is also designated as 10x, 20x, 25x, 30x, 33x, 35x, and 40x.

[0040] In another embodiment, the first concentrate comprises glucose and has a pH between 1.5 and 4, e.g., a pH between 2 and 3.5, such as a pH between 2.2 and 3.0, or a pH between 2.2 and 2.8, and the second concentrate comprises sodium lactate, calcium chloride, and magnesium chloride and has a pH between 5.5 and 8.5, e.g., a pH between 6.5 and 8.5, or a pH between 6.8 and 8.5, and optionally at least one of the first concentrate and the second concentrate are terminally sterilized and mixed to form a ready-to-use peritoneal dialysis fluid as described herein.

[0041] Specifically, the ready to use peritoneal dialysis fluid contains: Sodium (Na + ) 100-140mM, preferably 132mM Potassium (K + ) 0-4mM Calcium (Ca 2+ ) 0-2mM, preferably 0.5-2mM In particular, 1.25-1.75 mM Magnesium (Mg 2+ ) 0-0.75mM, preferably 0.25-0.50mM Lactate 0-45mM, preferably 0-40mM More preferably, 0, 30, 35, or 40 mM Glucose 0-5%, 1.5-5%

[0042] In another embodiment, the first concentrate comprises glucose and has a pH between 1.5 and 4, a pH between 2 and 3.5, a pH between 2.2 and 2.8, the second concentrate comprises sodium bicarbonate, sodium chloride, and optionally sodium lactate and has a pH between 6.0 and 8.5, and a further concentrate comprises calcium chloride, magnesium chloride, and optionally lactic acid, and optionally at least one of the first and second concentrates is terminally sterilized.

[0043] In another embodiment of the present invention, the first concentrate has a water activity (a w ), and has a pH < 3.2.

[0044] Another embodiment of the present invention is a method for preparing a corn starch having a water activity (a) of 0.89 or less, for example, less than 0.85, or less than 0.8. w ) is the second concentrate.

[0045] In another embodiment, the first concentrate comprises glucose and has a conductivity greater than 100 μS / cm and a pH between 1.5 and 3, specifically the first concentrate has a conductivity greater than 400 μS / cm and a pH between 2.3. Specifically the first concentrate comprises glucose and has a conductivity greater than 100 μS / cm and a pH between 1.5 and 3, and the second concentrate comprises a physiologically acceptable buffer and optionally at least one electrolyte selected from the group comprising sodium, calcium, magnesium, and optionally potassium, and has a pH between 6.5 and 8.5.

[0046] The first concentrate, containing glucose, having a conductivity of more than 100 μS / cm provides the possibility to distinguish the concentrate, thus making it possible to identify and distinguish the glucose containing concentrate from other concentrates contained in the system and the water source.

[0047] Another advantage of the present invention is that it can provide greater flexibility in the glucose concentrate in the fluid. Greater flexibility is provided when compared to the option where sodium ions are added to the glucose concentrate. The amount of sodium ions in a ready to use peritoneal dialysis fluid is limited by restrictions in the European Pharmacopoeia (±2.5%). Therefore, by avoiding sodium ions in the glucose concentrate, there is greater flexibility to modify and adjust the glucose concentrate.

[0048] In one embodiment, the first concentrate comprising glucose further comprises a strong acid, preferably selected from hydrochloric acid (HCl) and an organic acid, examples of which are citric acid, acetic acid, etc.

[0049] In another embodiment, the first concentrate further comprises one or more electrolytes selected from the group consisting of chloride and sodium.

[0050] In one embodiment, the first concentrate comprises glucose and has a conductivity greater than 100 μS / cm at a pH between 1.5 and 3, the second concentrate comprises sodium bicarbonate, sodium chloride, and optionally sodium lactate, and has a pH between 6.5 and 8.5, and the third concentrate comprises calcium chloride, magnesium chloride, and optionally lactic acid. Optionally, at least one of the concentrates included in this embodiment is sterilized, preferably terminally sterilized.

[0051] In one embodiment, the first concentrate comprises glucose and has a pH between 2 and 3.5, such as between 1.5 and 4, e.g., between 2.4 and 2.8, and the second concentrate comprises a physiologically acceptable buffer lactate, calcium as electrolytes and optionally one or more electrolytes selected from the group comprising sodium, magnesium and potassium, a stabilizing amount of citrate, and has a pH between 6.0 and 8.5.

[0052] In particular, the concentration of citrate is up to 10 mM. However, the concentration of citrate can be adjusted with the dilution ratio of the concentrate. An example is a dilution ratio of 1:40, a concentration of 10 mM citrate, and a concentration of 50 mM calcium in the second concentrate containing lactate. Another example is a dilution ratio of 1:20, a concentration of 10 mM citrate, and a concentration of 35 mM calcium in the second concentrate containing lactate.

[0053] A low amount of citrate is added to the further concentrate in order to stabilize the pH of the concentrate and the ready-to-use liquid. The addition of citrate to the calcium-containing liquid limits the risk of calcium lactate precipitation. The addition of citrate can reduce particle formation. Furthermore, the pH of the ready-to-use peritoneal dialysis fluid is closer to physiological pH, or neutral, with the addition of citrate. [Brief description of the drawings]

[0054] [Figure 1]1 provides a schematic diagram 100 illustrating a system for preparing ready-to-use peritoneal dialysis fluid. A container 10 containing a first concentrate and a container 12 containing a second concentrate are each connected by conduits to an allocation device 16 for mixing. A purified water source 14 is also connected by a conduit to the mixer 16. The allocation device 16 is controlled by a controller 18 based on input from a user interface 20. In response to such user input and control signals from the controller 18, the allocation device 16 receives the first and optionally the second concentrates, plus specified amounts of water from the sources 10, 12, 14, and generates a ready-to-use dialysis fluid that is delivered via an output / container 22.

[0055] [Diagram 2] FIG. 2 shows the known glucose degradation products and the degradation pathway starting from D-glucose.

[0056] [Diagram 3] Figure 3 shows the concentration of glucose degradation products in μmol / l determined according to Example 32 by UPLC / UV in reconstituted and sterilized peritoneal solutions of the first and second concentrates according to the invention, consisting of 4.25 g glucose, 538 mg sodium chloride, 448 mg sodium lactate, 18.3 mg calcium chloride dihydrate, 5.08 mg magnesium chloride hexahydrate and water (per 100 mL of solution) (exactly the same for samples 1 and 2). The abbreviations used can be found in Figure 2. Compared to the average GDP concentrations found in comparative conditions of conventional products, see Himmele et al. (2012), the GDP concentrations in solutions based on the system as invented herein are extremely low. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] (definition) The technical term "first concentrate" as used herein refers to a glucose source. The source may be provided in the form of a liquid concentrate or a dry powder concentrate.

[0058] The technical term "second concentrate" refers herein to a source of physiologically acceptable buffer. Examples of physiologically acceptable buffers, unless otherwise specified, are acetate, lactate, citrate, pyruvate, carbonate, bicarbonate, and amino acid buffers. Additionally, the buffer is intended to be in an alkaline form, e.g., alkaline lactates and alkaline bicarbonates, such as sodium lactate and sodium bicarbonate.

[0059] The technical term "citrate" means citric acid, or any salt thereof. The salt may be formed with sodium, magnesium, or potassium. Sodium citrate may exist as trisodium citrate ("Na-cit"), disodium hydrogen citrate, or sodium dihydrogen citrate.

[0060] The technical term "terminal sterilization" is intended herein to mean that the product is sterilized in its final packaging. Terminal sterilization may include heat sterilization and / or radiation sterilization, but is preferably heat sterilization accomplished in an autoclave at a temperature of at least 100°C, preferably at least 121°C.

[0061] As used herein, the technical term "dilution" refers to the mixing of a small measurement sample with a larger amount of, for example, sterile water, saline, or other suitable liquid, called a diluent or dilution blank. A single dilution is calculated as follows: Dilution = volume of sample / (total volume of sample + volume of diluent)

[0062] For example, diluting 1 mL to 9 mL is equal to 1 / 1+9, which is the same as 1 / 10, which is also h10. -1 This is then called a 1 to 10 dilution.

[0063] Detailed Description of the Invention According to the present invention, there is provided a system for preparing a ready-to-use peritoneal dialysis solution. The system comprises: a) an allocation device; b) at least one water source adapted to connect with said distribution device; c) at least one first concentrate source adapted to connect with a) and b); d) at least one second concentrate source adapted to connect with a) and b).

[0064] The system also optionally comprises at least one further concentrate source adapted to connect with a) and b). The first concentrate comprises glucose and has a pH between 1.5 and 4. For example, the pH is between 2 and 3.5, particularly the pH is between 2.2 and 3.0. The second concentrate comprises a physiologically acceptable buffer and has a pH between 5.5 and 9.0, for example, 6.5 and 9, 6.0 and 8.5, or 6.5 and 8.5.

[0065] The systems described herein are suitable for preparing a ready-to-use peritoneal dialysis fluid, which may be prepared from a first concentrate together with a second concentrate, and optionally one or more additional concentrates.

[0066] The systems described herein include a dispensing device, where the concentrates are mixed, e.g., dispensed and compounded, to form a ready-to-use peritoneal dialysis fluid. The systems specified herein provide a simple method of preparing dialysis fluid for peritoneal dialysis treatment. Small amounts and volumes of concentrates are to be handled for patient treatment.

[0067] As mentioned above, systems for peritoneal dialysis are described in WO 2013 / 1141896 and WO 2012 / 129501. Also, distribution devices are described herein. Additionally, there are commercially available distribution devices, such as AMIA (Baxter International, Inc.).

[0068] Additionally, the systems described herein include at least one water source. The water added to the concentrate contained in the product will have specific chemical or microbiological properties (e.g., as defined in the European Pharmacopoeia) appropriate for its intended use.

[0069] The water to be contained in the water source should be within safe limits from a microbiological and chemical standpoint, and may be, for example, "purified water", "highly purified water", "ultrapure water", "water for injection" (WFI), "sterile WFI", "water for hemodialysis", "distilled water", "sterile purified water", and "water for medical use".

[0070] The first concentrate, the second concentrate and the further concentrates specified herein can be terminally sterilized before they are included in the system. By having the concentrates sterilized, for example by terminal sterilization, included in the system, they can be mixed with water having the properties as specified above, and a high quality ready-to-use peritoneal dialysis liquid is provided. There is no need for sterilization of the ready-to-use peritoneal dialysis liquid. The present invention can provide a ready-to-use peritoneal dialysis liquid at the point of care.

[0071] FIG. 1 provides a schematic diagram 100 illustrating a system for preparing a ready-to-use peritoneal dialysis fluid. A container 10 containing a first concentrate and a container 12 containing a second concentrate are each connected by conduits to a distribution device 16 for mixing. In one embodiment (not shown in the drawing), a container containing an additional concentrate is also included in the system. A source of purified water 14 is also connected by conduits to the mixer 16. The distribution device 16 is controlled by a controller 18 based on input from a user interface 20. In response to such user input and control signals from the controller 18, the distribution device 16 receives the first and optionally the second concentrates, plus a specified amount of water from the sources 10, 12, 14, and generates a ready-to-use dialysis fluid that is delivered via an output / container 22.

[0072] In accordance with the systems specified herein, a ready to use peritoneal dialysis solution may include the following contents: Sodium (Na + ) 100-140mM Potassium (K + ) 0-4mM Calcium (Ca 2+ ) 0-2mM Magnesium (Mg 2+ )0-0.75mM Lactate 0-40mM Bicarbonate 0-35mM Glucose 0-5% The pH of the ready to use peritoneal dialysis solution is between 5.5-8, for example, between 6.5-7.5, or between 6.8-7.5.

[0073] Further preferably, the ready to use peritoneal dialysis fluid comprises: Sodium (Na + ) 120-140 mM, more preferably 132 mM, Potassium (K + ) 0-4mM, e.g., 0, 1, 2, 3, 4mM, Calcium (Ca 2+ ) 0-2 mM, preferably 0.5-2 mM, In particular, 1.25, 1.5 mM, or 1.75 mM, Magnesium (Mg 2+ ) 0-0.75 mM, preferably 0.25-0.5 mM, For example, 0.25, 0.3, 0.35, 0.4, 0.45, and 0.5, Lactate 0-40 mM, preferably 0, 30, 35, or 40 mM; Bicarbonate 0-35 mM, preferably 0, 30, 35 mM; Contains 0-5% glucose.

[0074] In another embodiment of the invention, a ready to use peritoneal dialysis fluid is provided that includes lactate and bicarbonate buffer. For example, the fluid has the following contents: Sodium (Na+ ) 100-140 mM, preferably 120-140 mM, More preferably 132 mM, Potassium (K + ) 0-4mM, e.g., 0, 1, 2, 3, 4mM, Calcium (Ca 2+ ) 0-2 mM, preferably 0.5-2 mM, In particular, 1.25, 1.5 mM, or 1.75 mM, Magnesium (Mg 2+ ) 0-0.75 mM, preferably 0.25-0.5 mM, For example, 0.25, 0.3, 0.35, 0.4, 0.45, and 0.5, Lactate 10mM Bicarbonate 25mM Glucose 0-5%

[0075] For example, the liquid has the following contents: Sodium (Na + ) 100-140 mM, preferably 120-140 mM, More preferably 132 mM, Potassium (K + ) 0-4mM, e.g., 0, 1, 2, 3, 4mM, Calcium (Ca 2+ ) 0-2 mM, preferably 0.5-2 mM, In particular, 1.25, 1.5 mM, or 1.75 mM, Magnesium (Mg 2+ ) 0-0.75 mM, preferably 0.25-0.5 mM, For example, 0.25, 0.3, 0.35, 0.4, 0.45, and 0.5, Lactate 15mM Bicarbonate 25mM Glucose 0-5%

[0076] In another example, the liquid is Sodium (Na + ) 100-140 mM, preferably 120-140 mM, More preferably 132 mM, Potassium (K + ) 0-4mM, e.g., 0, 1, 2, 3, 4mM, Calcium (Ca 2+ ) 0-2 mM, preferably 0.5-2 mM, In particular, 1.25, 1.5 mM, or 1.75 mM, Magnesium (Mg 2+ ) 0-0.75 mM, preferably 0.25-0.5 mM, For example, 0.25, 0.3, 0.35, 0.4, 0.45, and 0.5, Lactate 15mM Bicarbonate 15mM Contains 0-5% glucose.

[0077] This list of examples of ready-to-use peritoneal dialysis fluids is not intended to be exhaustive or to limit the invention.

[0078] The first concentrate described herein contains glucose and is adjusted to a pH of 1.5-4. The concentrate is acidified, for example, by the addition of hydrochloric acid (HCl). The concentrate contains 1.5-4M glucose, for example, between 1.5-3.9M, or between 1.6-3.9M. The first concentrate contains 0-0.05M calcium (Ca 2+ ), 0-0.01M Magnesium (Mg 2+ ), and 0-0.05M sodium (Na + ) may optionally be included.

[0079] The second concentrate described herein comprises a physiologically acceptable buffer and, optionally, one or more electrolytes. The second concentrate comprises 1.0-5.5M sodium (Na + ), 0-0.12M calcium (Ca 2+ 0-0.15M calcium (Ca 2+ ), 0-0.03M Magnesium (Mg 2+), 0-1.60M lactate, and 0-1.60M bicarbonate. Optionally, the second concentrate may contain 0-0.1M potassium (K + Optionally, the second concentrate contains 0-15 mM citrate, for example 0-10 mM citrate.

[0080] Additional concentrates may be included in the systems described herein, such as, for example, 0-2M sodium (Na + ), 0-0.06M calcium (Ca 2+ ), and 0-0.15M magnesium (Mg 2+ ).

[0081] The system further comprises at least one second concentrate source comprising a physiologically acceptable buffer. The buffer may be selected from the group comprising acetate, lactate, citrate, pyruvate, carbonate, bicarbonate, or mixtures thereof. The physiologically acceptable buffer may also comprise one or more amino acids, such as histidine, its isomers, polymers, and derivatives thereof. An example of histidine is L-histidine.

[0082] The concentrates contained herein have a specified water activity. w is the vapor pressure of pure H2O at the same temperature (P O ) is the ratio of the vapor pressure of HO in the product to the water activity of the concentrate. By specifying and modifying the water activity of the concentrate, high resistance to microbial growth can be obtained. A common limit for bacterial growth and proliferation is a water activity of 0.91, below which bacterial / microbial growth slows down. Therefore, the objective is to provide a concentrate with a water activity that limits bacterial growth.

[0083] A concentrate having a specified water activity may be capable of being used for an extended period of time ("extended use") compared to a concentrate that does not have a specified water activity.

[0084] The first concentrate described herein has a water activity (a) of less than 0.95 when used for an extended period of time. w ), and have a pH below 3.3.

[0085] The second concentrate described herein has a water activity (a) of less than 0.9, preferably less than 0.89, for example less than 0.85, or less than 0.8. w )

[0086] As mentioned above, it is necessary to provide a system containing a concentrate suitable for on-site preparation of peritoneal dialysis fluid that removes impurities including GDPs. According to the invention described herein, a system is provided that provides a ready-to-use peritoneal dialysis fluid having a concentration of glucose degradation products of <20 μmol / L of 3,4-DGE, e.g., <15 μmol / L of 3,4-DGE, <10 μmol / L of 3,4-DGE, or <5 μmol / L of 3,4-DGE. In another embodiment of the invention, the ready-to-use peritoneal dialysis fluid has a concentration of glucose degradation products of <8 μmol / L of glucosone, e.g., <5 μmol / L of glucosone, or <3 μmol / L of glucosone. In another embodiment of the invention, the ready to use peritoneal dialysis fluid has a concentration of glucose degradation products of <17 μmol / L of 5-HMF, e.g., <14 μmol / L of 5-HMF, or <10 μmol / L of 5-HMF, or <8 μmol / L of 5-HMF. In another embodiment of the invention, the ready to use peritoneal dialysis fluid has a concentration of glucose degradation products of <25 μmol / L of 3-DG, e.g., <20 μmol / L of 3-DG, or <15 μmol / L of 3-DG, or <10 μmol / L of 3-DG.

[0087] Another embodiment of the present invention is a system comprising the second concentrate described herein, a physiologically acceptable buffer, and optionally at least one electrolyte selected from the group comprising sodium, calcium, magnesium, and potassium, with the proviso that the second concentrate does not comprise the following compositions having a pH of approximately 6.4: ·11.34g / 100ml NaCl (Mw=58.44g / mol);1940mM 7.84g / 100ml Sodium lactate (Mw=112.06g / mol); 700mM 514mg / 100ml Calcium chloride (Mw(CaCl2·2H2O=147.01g / mol); 35.0mM 304mg / 100ml Magnesium chloride (Mw=203.31g / mol(hexahydrate)); 14.95mM

[0088] In one embodiment of the present invention, a system is provided, the system comprising: a) an allocation device; b) at least one water source adapted to connect with said distribution device; c) at least one first concentrate source adapted to connect with a) and b); d) at least one second concentrate source adapted to connect with a) and b); and optionally, e) at least one further concentrate source adapted to connect with a) and b); and further specified by the first concentrate optionally containing glucose and having a pH between 1.5 and 4, e.g., a pH between 2 and 3.5, or a pH between 2.2 and 3.2, and the second concentrate containing a physiologically acceptable buffer and having a pH between 5.5 and 9.0.

[0089] The ready to use peritoneal fluid may also be prepared to have a pH between 5.5-8.0, for example between 6.5-7.5, or between 6.8-7.5, or between 6.0-8.5. EXAMPLES

[0090] By way of example, and not by way of limitation, the following examples demonstrate various concentrate candidates and their use in a system to provide a final peritoneal dialysis fluid. These are shown in Examples 1-18. The water activity of the concentrates was tested and is shown in Examples 19-20. The stability of the fluids was tested and is shown in Examples 21-22. The pH of the ready-to-use dialysis fluid was measured and is shown in Examples 23-29. Testing of the pH of the first concentrate before and after sterilization was performed and is shown in Example 30. Testing of the pH of the second concentrate before and after sterilization was performed and is shown in Example 31. Example 32 provides data on the production of glucose degradation products and their concentrations in the ready-to-use solution.

[0091] Example 1 Concentrate A1 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0092] Concentrate B1 Sodium chloride 3.68M Calcium chloride 0.07M Magnesium chloride 0.01M Sodium lactate 1.60M Sodium hydroxide ad. pH 6.5-9.0

[0093] [Table 1]

[0094] Example 2 Concentrate A2 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0095] Concentrate B2 Sodium chloride 3.22M Calcium chloride 0.0437M Magnesium chloride 0.00875M Sodium lactate 1.40M Sodium hydroxide ad. pH 6.5-9.0

[0096] [Table 2]

[0097] Example 3 Concentrated substance A3 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0098] Concentration B3 Sodium chloride 2.76M Calcium chloride 0.053M Magnesium chloride 0.008M Sodium lactate 1.20M Sodium hydroxide ad. pH 6.5-9.0

[0099] [Table 3]

[0100] Example 4 Concentrated substance A4 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0101] Concentrated substance B4 Sodium chloride 1.84M Calcium chloride 0.035M Magnesium chloride 0.005M Sodium lactate 0.80M Sodium hydroxide ad. pH 6.5-9.0

[0102] [Table 4]

[0103] Example 5 Concentrated substance A5 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0104] Concentrated substance B5 Sodium chloride 1.84M Calcium chloride 0.025M Magnesium chloride 0.005M Sodium lactate 0.80M Sodium hydroxide ad. pH 6.5-9.0

[0105] [Table 5]

[0106] Example 6 Concentrated substance A6 Glucose 2.775M Calcium chloride 0.010M Magnesium chloride 0.0032M Hydrochloric acid ad. pH 2.0-3.2

[0107] Concentrated substance B6 Sodium chloride 3.68M Calcium chloride 0.038M Magnesium chloride 0.010M Sodium lactate 1.60M Sodium hydroxide ad. pH 6.5-9.0

[0108] [Table 6]

[0109] Example 7 Concentrated substance A7 Glucose 2.775M Calcium chloride 0.015M Magnesium chloride 0.007M Hydrochloric acid ad. pH 2.0-3.2

[0110] Concentrated substance B7 Sodium chloride 3.68M Calcium chloride 0.06M Magnesium chloride 0.0015M Sodium lactate 1.60M Sodium hydroxide ad. pH 6.5-9.0

[0111] [Table 7]

[0112] Example 8 Concentrate A8 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0113] Concentrated substance B8 Sodium chloride 1.84M Potassium chloride 0.08M Calcium chloride 0.035M Magnesium chloride 0.010M Sodium lactate 0.80M Sodium hydroxide ad. pH 6.5-9.0

[0114] [Table 8]

[0115] Example 9 Concentrated substance A9 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0116] Concentrated substance B9 Sodium chloride 2.76M Calcium chloride 0.053M Magnesium chloride 0.015M Sodium lactate 1.20M Trisodium citrate 0.0075M Sodium hydroxide ad. pH 6.5-9.0

[0117] [Table 9]

[0118] Example 10 Concentrated substance A10 Glucose 2.775M Sodium chloride 0.01M Hydrochloric acid ad. pH 2.0-3.2

[0119] Concentrated substance B10 Sodium chloride 2.76M Calcium chloride 0.052M Magnesium chloride 0.0075M Sodium lactate 1.20M Sodium hydroxide ad. pH 6.5-9.0

[0120] [Table 10]

[0121] Example 11 Concentrated substance A11 Glucose 3.885M Hydrochloric acid ad. pH 2.0-3.2

[0122] Concentrated substance B11 Sodium chloride 2.76M Calcium chloride 0.053M Magnesium chloride 0.015M Sodium lactate 1.20M Sodium hydroxide ad. pH 6.5-9.0

[0123] [Table 11]

[0124] Example 12 Concentrated substance A12 Glucose 2.775M Calcium chloride 0.015M Magnesium chloride 0.007M Hydrochloric acid ad. pH 2.0-3.2

[0125] Concentrated substance B12 Sodium chloride 2.74M Calcium chloride 0.030M Magnesium chloride 0.0020M Sodium lactate 1.20M Trisodium citrate 0.0075M Sodium hydroxide ad. pH 6.5-9.0

[0126] [Table 12]

[0127] Example 13 Concentrated substance A13 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0128] Concentrated substance B13 Sodium chloride 1.84M Calcium chloride 0.05M Magnesium chloride 0.01M Sodium hydroxide ad. pH 6.5-9.0

[0129] Concentrate C13 Sodium chloride 1.84M Sodium lactate 1.60M Sodium hydroxide ad. pH 6.5-9.0

[0130] [Table 13]

[0131] Example 14 Concentrated substance A14 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0132] Concentrated substance B14 Sodium chloride 1.84M Calcium chloride 0.05M Magnesium chloride 0.01M Sodium hydroxide ad. pH 6.5-9.0

[0133] Concentrated substance C14 Sodium chloride 0.80M Sodium chloride 0.70M Sodium hydroxide ad. pH 6.5-9.0

[0134] [Table 14]

[0135] Example 15 Concentrated substance A15 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0136] Concentrated substance B15 Sodium chloride 1.84M Calcium chloride 0.0526M Magnesium chloride 0.015M Sodium hydroxide ad. pH 6.5-9.0

[0137] Concentrated substance C15 Sodium chloride 1.0M Sodium lactate 0.28M Sodium bicarbonate 0.70M Sodium hydroxide ad. pH 6.5-9.0

[0138] [Table 15]

[0139] Example 16 Concentrated substance A16 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0140] Concentrated substance B16 Sodium chloride 2.76M Calcium chloride 0.060M Magnesium chloride 0.024M Sodium lactate 1.20M Sodium hydroxide ad. pH 6.5-9.0

[0141] Concentrated substance C16 Sodium chloride 3.31M Sodium bicarbonate 0.70M Sodium hydroxide ad. pH 6.5-9.0

[0142] [Table 16]

[0143] Example 17 Concentrated substance A17 Glucose 2.775M Hydrochloric acid ad. pH 2.0-3.2

[0144] Concentrated substance B17 Sodium chloride 2.694M Calcium chloride 0.120M Magnesium chloride 0.020M Sodium lactate 1.20M Sodium hydroxide ad. pH 6.5-9.0

[0145] Concentrated substance C17 Sodium chloride 2.694M Sodium bicarbonate 0.70M Sodium hydroxide ad. pH 6.5-9.0

[0146] [Table 17]

[0147] Example 18 Concentrate A18 30% Glucose Glucose 1.665M Hydrochloric acid ad. pH 2.0-3.2

[0148] Concentrate B18 35× Sodium chloride 3.68M Calcium chloride 0.07M Magnesium chloride 0.02M Sodium lactate 1.60M Sodium hydroxide ad. pH 6.5-9.0

[0149] [Table 18]

[0150] Example - Water Activity The following Example 19- was carried out to investigate the water activity of the first and second concentrates.

[0151] The water activity of the peritoneal dialysis fluid according to the invention was measured at 25° C. (according to DCC-307014, version 1.0).

[0152] Example 19 Concentrated substance A19 50% Glucose (anhydrous) pH adjusted with HCl to 2.4-2.8

[0153] Concentrates were prepared at a dilution of 20x. water activity a w =0.92 (Measured before and after heat sterilization)

[0154] Concentrated substance B19 Sodium chloride 3.68M Magnesium chloride 10mM Calcium chloride 54mM Sodium lactate 1.6M pH 7.5

[0155] water activity a w =0.75 (Measured before and after heat sterilization)

[0156] Example 20 - Comparative Example The first concentration was compared to Concentrate 1 as described in US Pat. No. 5,344,392.

[0157] concentrate 1 Concentrate 1 has the following composition adjusted to a pH of approximately 6.4: Sodium chloride 11.34g / 100ml Sodium lactate 7.84g / 100ml Calcium chloride 514mg / 100ml Magnesium chloride 304mg / 100ml

[0158] The water activity of concentrate 1 was measured and a w =0.90.

[0159] Example 21 Test liquids representing candidate concentrates were prepared by adding different amounts of the specified solid components to a container and finally adding purified water to the desired volume. The test solutions were heat sterilized and incubated at +4°C for more than 2 months.

[0160] A ready-to-use peritoneal dialysis fluid based on a first concentrate and a second concentrate is also presented.

[0161] [Table 19]

[0162] [Table 20]

[0163] [Table 21]

[0164] The concentration of calcium in the final ready to use dialysis fluid is 1.75 mM.

[0165] No precipitate was observed in X (corresponding to the second concentrate).

[0166] Example 22 [Table 22]

[0167] [Table 23]

[0168] [Table 24]

[0169] The concentration of calcium in the final ready to use dialysis fluid is 1.75 mM.

[0170] No precipitate was observed in A (corresponding to the second concentrate).

[0171] Examples 23- 29- pH of peritoneal dialysis fluid Test fluids representing candidate concentrates were prepared by adding different amounts of the solid components specified and finally adding purified water to the desired volume. The pH of the test fluids was measured. The pH of the resulting ready-to-use peritoneal dialysis fluids based on the first and second concentrates are also shown in the table.

[0172] Example 23 Concentrates A23:1-5 were prepared by varying the glucose content and varying the pH.

[0173] Concentrate B23:1-5, lactate containing buffer, dilution 40x, with a final calcium concentration of 1.25mM (e.g., in ready-to-use liquid) was prepared by changing the pH. The pH was measured. The results are shown in the table.

[0174] [Table 25]

[0175] Example 24 Concentrates A24:1-4 were prepared with varying glucose content at a constant pH of 3.0.

[0176] Concentrate B24:1-4, lactate containing buffer, dilution 40x, with a final concentration of calcium of 1.25 mM, varying the concentration of citrate (specified by the amount in the concentrate), varying the pH. The pH was measured. The results are shown in the table.

[0177] [Table 26]

[0178] Example 25 Concentrates A25:1-5 were prepared with varying glucose content at a constant pH of 3.0.

[0179] Concentrate B25:1-5, lactate containing buffer, modified dilution 10x-40x, with a final concentration of calcium of 1.25 mM, pH 7.5. The pH of the liquid was measured, and the results are shown in the table.

[0180] [Table 27]

[0181] Example 26 Concentrates A26:1-2 were prepared with varying glucose content at a constant pH of 3.0.

[0182] Concentrate B26:1-2, lactate containing buffer, diluted 40x, pH 7.5, calcium concentration provided at 1.25 mM in ready to use dialysis fluid, and citrate concentration varied (specified by the amount of citrate in the concentrate). The pH of the fluid was measured and the results are shown in the table.

[0183] [Table 28]

[0184] Example 27 Concentrates A27:1-4 were prepared at pH 3.0 with varying glucose content.

[0185] Concentrate B27:1-4, lactate containing buffer, modified with dilutions 10x-40x, with a final concentration of calcium of 1.25 mM, was prepared at pH 7.5. The pH was measured and the results are shown in the table.

[0186] [Table 29]

[0187] Example 28 Concentrates A28:1-5 were prepared at pH 3.0 with varying glucose content.

[0188] Concentrate B28:1-5, lactate containing buffer, dilution 20x-35x, with a final concentration of 1.25 mM calcium, with 0 mM, 5.71 mM, 8.57 mM, and 10 mM citrate, pH 7.5. The pH of the ready to use dialysis fluid was measured. The results are shown in the table.

[0189] [Table 30]

[0190] Example 29 Concentrates A29:1-5 were prepared at pH 3.0 with varying glucose content.

[0191] Concentrate B29:1-5, lactate containing buffer, for dilution 20x-30x, with a final concentration of calcium of 1.25 mM, with 0 mM and 10 mM citric acid (contained in the concentrate), pH 7.5 and pH 6.6 were prepared. The pH of the ready to use dialysis fluid was measured. The results are shown in the table.

[0192] [Table 31]

[0193] Example 30 - pH measurement after terminal sterilization (heat sterilization) The first concentrate described herein was terminally sterilized by heat sterilization. Altering the pH for sterilization was investigated.

[0194] A first concentrate containing 50% and 60% glucose was tested at varying pH between 1.0 and 4.0. The results are shown in the following table.

[0195] [Table 32]

[0196] Example 31 The second concentrate described herein was terminally sterilized by heat sterilization. Altering the pH for sterilization was investigated.

[0197] A second concentrate was tested containing calcium at dilutions 10x, 20x, 30x, and 40x appropriate, aiming for pH 6.6, 7.5, 8.0, 9.0, 1.25mM or 1.75mM calcium to be provided in the ready to use dialysis fluid, and 0mM, 1mM, 5mM, 5.71mM, 8.57mM citrate. The results are shown in the following table.

[0198] [Table 33]

[0199] [Table 34]

[0200] It can be concluded that the pH of the second concentrate decreases during sterilization.

[0201] While the present invention has been described in connection with what are presently considered to be the most practical embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but on the contrary, it is intended to cover various modifications and equivalents included within the spirit and scope of the appended claims.

[0202] Example 32 A ready-to-use peritoneal solution was prepared from the concentrate according to the invention and had a final content (per 100 mmL of solution) of 4.25 g glucose, 538 mg sodium chloride, 448 mg sodium lactate, 18.3 mg calcium chloride dihydrate, 5.08 mg magnesium chloride hexahydrate, and water. The pH of the solution was 6.3. The levels of 10 glucose degradation products (GDP) were measured using all three validated methods. UPLC / UV was used for the determination of residual 5-hydroxymethylfurfural (5-HMF) and furfural. The method did not utilize any derivatization. UPLC / US was also used for the determination of glucosone, glyoxal, methylglyoxal, 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), and 3,4-di-deoxyglucosone-3-ene (3,4-DGE), and this method relied on derivatization with 1,2-phenylenediamine, which produces an ultraviolet-detectable module. UPLC / UV was used for the determination of acetaldehyde and formaldehyde, and this method relied on derivatization with 2,4-dinitrophenylhydrazine, which produces an ultraviolet-detectable module. It was confirmed that the concentrations (μmol / L) of 3-DGal, GO, formaldehyde, and acetaldehyde were below the limit of quantification. Moreover, they were above the limit of quantification in one of the two tests performed for the above solutions. Therefore, the diluted buffer concentrate (containing no glucose) was also tested for the presence of GDPs. No GDPs could be detected in the buffer solutions. The detected concentrations of GDP are shown in FIG. 3. Glucosone was detected in the two samples tested at concentrations of 5.200 and 5.383 μmol / L. 3-DG was detected at concentrations of 20.840 and 17.863 μmol / L, respectively. 3,4-DGE was detected at concentrations of 17.595 and 16.043 μM / L, respectively. 5-HMF was detected at concentrations of 16.061 and 12.365 μM / L, respectively. Finally, 0.345 μM / L of furfural could be identified in one of the two samples.Compared to the average GDP concentrations found in comparable conventional products, see, e.g., Himmele et al., Peritoneal Dialysis International, Vol. 32, p. 444-452 (2012), the GDP concentrations in solutions based on and prepared from concentrates such as those of the invention herein are extremely low, see, e.g., Table 3 of Himmele et al. (2012).

Claims

1. 1. A system for preparing a ready-to-use peritoneal dialysis fluid, comprising: a) an allocation device; b) at least one water source adapted to connect with said distribution device; c) at least one source of a first concentrate adapted to be connected to a) and b); d) at least one source of a second concentrate adapted to connect with a) and b); Optionally, e) at least one further source of concentrate adapted to connect with a) and b); The system according to claim 1, wherein the first concentrate is unbuffered, comprises glucose at a concentration of 1.5 to 4 M, a strong acid, and has a pH between 1.5 and 4, and the second concentrate comprises a physiologically acceptable buffer having a pH between 5.5 and 9.0, the second concentrate being adapted for use by dilution with water, the first concentrate, and optionally the further concentrate, in a ratio of between 1:10 and 1:

40.

2. 10. The system of claim 1, wherein the first concentrate has a pH between 2.0 and 3.

5.

3. 10. The system of claim 1, wherein the first concentrate has a pH between 2.2 and 3.

0.

4. 4. The system of claim 1, wherein the second concentrate has a pH between 6.0 and 8.

5.

5. 5. The system of claim 1, wherein the physiologically acceptable buffer is selected from the group consisting of acetate, lactate, citrate, pyruvate, carbonate, bicarbonate, and amino acid buffers, or mixtures thereof.

6. 6. The system of claim 1, wherein the physiologically acceptable buffer is lactate, bicarbonate, or a mixture thereof.

7. 7. The system of claim 1, wherein the first concentrate further comprises at least one electrolyte selected from the group consisting of sodium, calcium, magnesium, and potassium.

8. 8. The system of claim 1, wherein the second concentrate further comprises at least one electrolyte selected from the group consisting of sodium, calcium, magnesium, and potassium.

9. 9. The system of claim 1, wherein the further concentrate comprises at least one electrolyte selected from the group consisting of sodium, calcium, magnesium, and potassium.

10. 10. The system of claim 1, wherein the further concentrate comprises a physiologically acceptable buffer selected from the group consisting of acetate, lactate, citrate, pyruvate, carbonate, bicarbonate, and amino acid buffers, or mixtures thereof.

11. 11. The system of claim 1, wherein the first concentrate and the second concentrate each comprise calcium and each comprise at least one additional electrolyte selected from the group consisting of sodium, magnesium, and potassium.

12. 12. The system of claim 1, wherein the second concentrate and the further concentrate each comprise calcium and each comprise at least one further electrolyte selected from the group consisting of sodium, magnesium, and potassium.

13. 13. The system of claim 1, wherein the first concentrate and the second concentrate each comprise calcium and each comprise at least one further electrolyte selected from the group consisting of sodium, magnesium and potassium, and optionally the further concentrate comprises at least one electrolyte selected from the group consisting of sodium, calcium, magnesium and potassium.

14. 14. The system of claim 1, wherein the first concentrate and / or the second concentrate and / or the further concentrate are terminally sterilized.

15. 15. The system of any one of claims 1 to 14, wherein the second concentrate is configured to be used diluted with water, the first concentrate, and optionally the further concentrate, in a ratio of between 1:10 and 1:

33.

16. 15. The system of claim 1, wherein the second concentrate is configured to be used by diluting with water, the first concentrate, and optionally the further concentrate, at a ratio selected from 10x, 20x, 25x, 30x, and 33x.

17. The ready to use peritoneal dialysis fluid comprises: Sodium (Na ＋ ) 100-140mM, Potassium (K ＋ ) 0-4 mM, Calcium (Ca ２＋ ) 0-2 mM, Magnesium (Mg ２＋ ) 0-0.75mM, Lactate 0-40 mM, Bicarbonate 0-35 mM, Glucose 0-5%, The system according to any one of claims 1 to 16, comprising:

18. Optionally, at least one of the first and second concentrates is terminally sterilized, and the first and second concentrates are mixed; Sodium (Na ＋ ) 100-140mM, Potassium (K ＋ ) 0-4 mM, Calcium (Ca ２＋ ) 0-2 mM, Magnesium (Mg ２＋ ) 0-0.75mM, Lactate 0-40 mM, Glucose 0-5%, 18. The system of claim 1 , further comprising:

19. The ready to use peritoneal dialysis solution comprises: Sodium (Na ＋ ) 132 mM, Potassium (K ＋ ) 0-4 mM, Calcium (Ca ２＋ ) 0.5-2 mM, Magnesium (Mg ２＋ ) 0.25-0.50mM, Lactate 0-40mM Glucose 1.5-5%, The system of claim 18, comprising:

20. The ready to use peritoneal dialysis solution comprises: Sodium (Na ＋ ) 132 mM, Potassium (K ＋ ) 0-4 mM, Calcium (Ca ２＋ ) 1.25-1.75mM, Magnesium (Mg ２＋ ) 0.25-0.50mM, Lactate 0-40 mM, Glucose 1.5-5%, The system of claim 19 , comprising:

21. 21. The system of any one of claims 18 to 20, wherein the ready-to-use peritoneal dialysis solution is lactate-free.

22. 21. The system of any one of claims 18 to 20, wherein the ready to use peritoneal dialysis solution comprises 30 mM lactate.

23. 21. The system of any one of claims 18 to 20, wherein the ready to use peritoneal dialysis solution comprises 40 mM lactate.

24. The first concentrate has a water activity (a ｗ 24. The system of claim 1 , having a pH of < 3.

2.

25. The second concentrate has a water activity (a ｗ 25. The system of claim 1 , further comprising:

26. 26. The system of any one of claims 1 to 25, wherein the first concentrate has a conductivity of greater than 100 μS / cm and a pH between 1.5 and 3.

27. 26. The system of any one of claims 1 to 25, wherein the first concentrate has a conductivity of greater than 400 μS / cm and a pH of 2.

3.

28. 28. The system of any one of claims 1 to 27, wherein the strong acid is selected from HCl and an organic acid.

29. 29. The system of any one of claims 1 to 28, wherein the first concentrate further comprises one or more electrolytes selected from the group consisting of chloride and sodium.

30. 30. The system of any one of claims 1 to 29, wherein the first concentrate has a pH between 2.4 and 2.8, the second concentrate comprises one or more electrolytes selected from the group consisting of lactate, calcium, and optionally sodium, magnesium, potassium, and further comprises citrate, the citrate being present in an amount that provides a stabilizing effect, and the second concentrate has a pH between 6.0 and 8.

5.

31. 31. The system of claim 30, wherein the concentration of citrate is up to 10 mM.

32. 32. The system of claim 30 or 31, wherein the concentration of citrate is between 0.01 and 10 mM.

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