METHOD FOR STABILIZING A DIALYSIS SOLUTION

Description

[0001] The invention relates to a method for the subsequent stabilization of a dialysis solution against the precipitation of calcium carbonate.

[0002] WO 2016 / 041634 A1 discloses that small amounts of orthophosphate in the millimolar concentration range can prevent the precipitation of poorly soluble calcium carbonate from dialysis solutions. Furthermore, WO 2016 / 202462 A1 discloses that organic phosphates such as glycerophosphate can also exert a stabilizing effect, as can mixtures of orthophosphates and organic phosphates. Stabilization is achieved in the prior art by initially adding a defined amount of phosphate during solution preparation.

[0003] Many dialysis solutions available on the market do not contain phosphates as stabilizing agents and are therefore susceptible to precipitation reactions.

[0004] The object of the invention is to provide a method to reduce the susceptibility of such solutions to undesirable precipitation reactions.

[0005] Against this background, the invention relates to a method for stabilizing a dialysis solution containing calcium ions and bicarbonate ions, wherein a phosphate in an amount of up to 0.4 mmol / l and / or an organic phosphate ester in an amount of up to 1.25 mmol / l is added to the dialysis solution at a time interval after its preparation, the time interval after preparation is more than 30 minutes, more than 60 minutes, more than 90 minutes or more than 105 minutes and the pH of the solution at the time of the subsequent addition is greater than 7.2.

[0006] The invention thus relates to the delayed addition (spiking) of a phosphate or an organic phosphate ester to stabilize existing dialysis solutions. It was surprisingly discovered that a stabilizing effect against calcium carbonate precipitation can be achieved not only through initial but also through subsequent addition of a phosphate or organic phosphate ester. Thus, the subsequent addition of the phosphate inhibits further precipitation despite the presence of nuclei. No dissolution of existing precipitate was observed.

[0007] The term "dialysis solution" is to be understood broadly and encompasses all solutions that can be used during dialysis treatment, i.e., in addition to solutions for hemodialysis, for example, also substitution solutions or solutions for peritoneal dialysis. However, the method according to the invention is particularly preferred for use with solutions for continuous renal replacement therapy (CRRT), in particular substitution solutions. Substitution solutions are infused directly into the patient's blood and therefore must not contain any particles.

[0008] According to the understanding of the present disclosure, the term "dialysis solution" also encompasses dialysis solutions that are still in the form of two or more separate individual solutions, the mixing of which results in a ready-to-use dialysis solution. Such individual solutions can, for example, be present in a dual-chamber bag. Thus, within the scope of the method according to the invention, it may be provided to spike an individual solution with a phosphate or organic phosphate ester. In this case, addition to an individual solution that contains bicarbonate ions and / or contains no calcium ions may be preferred.

[0009] Whenever phosphates or phosphate esters are mentioned in this disclosure, this term always encompasses both fully protonated and partially protonated acids as well as salts. The addition of salts, in particular sodium salts of the phosphates or phosphate esters, is particularly preferred within the scope of the invention.

[0010] In In one embodiment, the phosphate is ortho- phosphate and / or that the organic phosphate ester is an organic ester of ortho-phosphate.

[0011] In In one embodiment, the organic ester of the orthophosphate is a glycerol orthophosphate. This substance is already established as an active ingredient, for example, in parenteral nutrition and is also monographed in the European Pharmacopoeia (01 / 2009:1995). This relatively small molecule can be rapidly metabolized with the release of orthophosphate. The glycerol orthophosphate can be a glycerol-2- ortho -phosphate, a glycerol-3- ortho- phosphate or a mixture thereof.

[0012] According to the invention, the phosphate is added in an amount of up to 0.4 mmol / l. An addition of up to 0.375 mmol / l, up to 0.25 mmol / l, or up to 0.2 mmol / l may be preferred. In one embodiment, the phosphate is added in an amount of at least 0.05 mmol / l. Such phosphate concentrations are below physiological concentration values, so the medical efficacy of the dialysis solution is not affected.

[0013] According to the invention, it is provided that the organic phosphate ester is added in an amount of up to 1.25 mmol / l. An addition of up to 1.2 mmol / l can be preferred. In one embodiment, it is provided that the organic phosphate ester is added in an amount of at least 0.8 mmol / l. An addition of at least 1.0 mmol / l can be preferred. A phosphate concentration of 0.8 to 1.25 mmol / l and preferably of 1 to 1.2 mmol / l corresponds to a concentration that can be used to regulate the phosphate balance of dialysis patients and, for example, to prevent hypophosphatemia. Thus, in the case of phosphate-free dialysis solutions, a physiologically desirable phosphate concentration can be subsequently adjusted by subsequent addition of organic phosphate esters and, in particular, glycerophosphate, while simultaneously increasing stability against precipitation reactions of calcium carbonates.

[0014] In one embodiment, both a phosphate and an organic phosphate ester are added to the solution at intervals after its preparation, preferably with the concentration ratio between the phosphate and the organic phosphate ester being between 0.3 / 0.7 and 0.9 / 0.1. When adding both an organic ester of phosphoric acid and orthophosphate, a synergistic effect can occur, which can lead to even better stabilization of the solution against the precipitation of calcium carbonate.

[0015] In one embodiment, the time interval between preparation and storage is more than 60 minutes, more than 90 minutes, or more than 105 minutes. Even aged solutions with an already elevated pH value can thus be subsequently stabilized and thus made safer using a method according to the invention.

[0016] In one embodiment, the time interval between preparation and use is more than one week, more than one month, more than six months, or more than one year. Even aged solutions with an already elevated pH value can therefore be subsequently stabilized and thus made safer using a method according to the invention.

[0017] According to the invention, the pH of the solution at the time of subsequent addition is greater than 7.2. Values ​​greater than 7.4 or greater than 7.6 are preferred. The pH of freshly prepared dialysis solutions is typically lower and can, for example, be between approximately 7.0 and 7.6. However, the pH of the solution at the time of subsequent addition should, if possible, still be below 8.0, since at a pH of 8.0, calcium carbonate has often already precipitated to a significant extent, and thus the addition would no longer be effective.

[0018] In one embodiment, the dialysis solution contains, in addition to calcium ions, other electrolytes, preferably sodium ions, potassium ions, magnesium ions, and / or chloride ions. Magnesium can also precipitate as a poorly soluble carbonate, and this precipitation reaction can also potentially be inhibited by the phosphate or phosphate ester.

[0019] In one embodiment, the dialysis solution or substitution solution further contains at least one osmotic agent, for example a saccharide such as glucose or a derivative thereof.

[0020] For example, in the dialysis solution, the solution components mentioned can be present independently of one another in the concentrations listed in Table 1. Table 1 Calcium ions: 1-2 mmol / l, for example 1.5 mmol / l Magnesium ions: 0.2-0.8 mmol / l, for example 0.5 or 0.75 mmol / l Potassium ions: up to 8 and preferably up to 4 mmol / l Sodium ions: 120-160 mmol / l, for example 140 mmol / l Bicarbonate ions (including carbonate ions and dissolved CO 2 ): 30-40 mmol / l, for example 35 mmol / l Osmotic agent: 4-12 mmol / l, for example 5.6 mmol / l Chloride ions: 100-120 mmol / l, for example 109 mmol / l

[0021] Further details and advantages of the invention will become apparent from the experiments and exemplary embodiments described below with reference to the figures. The figures show: Figure 1: An exemplary pH value curve of a dialysis solution over its lifetime; Figure 2: A schematic representation of chemical processes during the production and life cycle of a dialysis solution; Figure 3: Values ​​for pH max and t G in the experiment of Example 1; Figure 4: Phototrode signal for selected data points in the experiment of Example 1; Figure 5: Values ​​for pH max and t G in the experiment of Example 2; and Figure 6: Phototrode signal for selected data points in the experiment of Example 2.

[0022] The CO2 release from a bicarbonate-buffered dialysis solution increases the pH of the solution, which in the case of calcium-containing solutions promotes the precipitation of calcium carbonate. The pH value at which significant precipitation of calcium carbonate begins is a criterion for the stability of the solution and is referred to below as pH max. The higher the pH max value, the more stable the solution. The point in time at which significant precipitation of calcium carbonate begins is referred to below in reference to the English term "time of germination" referred to as t G. An example of the pH value of a dialysis solution over its lifetime is shown in Figure 1 where the pH max in this illustration is assumed to be 8.0 and t G is not yet reached in the time period shown.

[0023] The stabilizing effect of subsequent addition of phosphate or a phosphate ester to existing dialysis solutions was investigated using the rapid degassing method in a carousel setup. This variant of the rapid degassing method allows for accelerated aging of dialysis solutions by outgassing CO2 from the bicarbonate buffer. CO2 outgassing, which normally occurs slowly over the lifespan of the products, can be simulated within a few hours using this experimental setup.

[0024] The chemical processes during the production and outgassing of the solution are shown schematically in Figure 2 For example, during production, CO2 is introduced into the solution to lower the pH. During the solution's life cycle, this process is gradually reversed by outgassing, which, at a certain point, leads to undesirable precipitation of calcium carbonate at the resulting higher pH. Example 1:

[0025] The dialysis solution DUOSOL 4551 from B. Braun is subjected to simulated aging in several experiments with and without the addition of orthophosphate using the rapid degassing procedure described above at 40°C. The calcium-containing dialysis solution DUOSOL 4551 does not contain phosphates as stabilizing agents and is therefore susceptible to precipitation reactions.

[0026] After a certain period of time, 250 µl of a stock solution containing 100 mmol / l ortho-phosphate is added to several flasks containing 250 ml of DUOSOL 4551, resulting in a concentration of 0.1 mmol / l ortho-phosphate in the flask. Three separate experiments are conducted for each data point, and the mean value is used. The results regarding pH max and t G are shown in Figure 3 The phototrode signal for selected data points is shown in Figure 4 shown.

[0027] Without the addition of ortho-phosphate, precipitation of calcium carbonate begins after about two hours, which is indicated by the decrease in the transmission of the Figure 4 is evident. The addition of orthophosphate after the onset of precipitation has an inhibitory effect. Dissolution of the precipitate is not observed. Therefore, adding it after the onset of precipitation slows the further precipitation process.

[0028] The Figure 3 It can be seen that there is no interaction between the stabilizing effect and the time of addition of ortho-phosphate. Figure 3 The large standard deviation observed for the measurement point at 105 minutes results from the fact that significant precipitation had already begun in two of the three repetitions of the experiment. Example 2:

[0029] The experiment of Example 1 is repeated in the same way, with the only difference that this time glycerophosphate is added instead of orthophosphate. Namely, after a certain period of time, 2.5 ml of a stock solution containing 100 mmol / l glycerophosphate is added to the flasks containing 250 ml of DUOSOL 4551, resulting in a concentration of 1.0 mmol / l glycerophosphate in the flask. The results regarding pH max and t G are shown in Figure 5 The phototrode signal for selected data points is shown in Figure 6 Similar conclusions can be drawn from these graphs as for Example 1 from the graphs of the Figures 3 and 4 was made.

[0030] In summary, the delayed addition of phosphates or phosphate esters to calcium-containing and bicarbonate-buffered dialysis solutions has the same stabilizing effect against calcium carbonate precipitation as an initial addition during solution preparation. Even aged solutions with an elevated pH can be stabilized and thus made safer using this approach. This principle works before and during dialysis treatment.

[0031] In the case of organic phosphate esters and especially glycerophosphate, the addition of approximately 1 mmol / l allows the establishment of a physiological phosphate concentration while simultaneously increasing stability against precipitation reactions of calcium carbonates.

Claims

1. A method of stabilizing a dialysis solution that includes calcium ions and bicarbonate ions, characterized in that a phosphate is added to the dialysis solution at a time interval from its preparation in an amount of up to 0.4 mmol / l and / or an organic phosphate ester is added to the dialysis solution at a time interval from its preparation in an amount of up to 1.25 mmol / l.; the time interval from the preparation amounts to more than 30 minutes, more than 60 minutes, more than 90 minutes, or more than 105 minutes; and the pH .of the solution at the time of the subsequent addition is greater than 7.2.

2. A method in accordance with claim 1, characterized in that the phosphate is an orthophosphate; and / or in that the organic phosphate ester is an organic ester of the orthophosphate.

3. A method in accordance with claim 2, characterized in that the organic ester of the orthophosphate is a glycerol orthophosphate.

4. A method in accordance with one of the preceding claims, characterized in that the phosphate is added in an amount of at least 0.05 mmol / l.

5. A method in accordance with one of the preceding claims, characterized in that the organic phosphate ester is added in an amount of at least 0.8 mmol / l.

6. A method in accordance with one of the preceding claims, characterized in that both a phosphate and an organic phosphate ester are added to the solution at a time interval from its preparation, with provision preferably being made that the concentration ratio between the phosphate and the organic phosphate ester is between 0.3 / 0.7 and 0.9 / 0.1.

7. A method in accordance with one of the preceding claims, characterized in that the time interval from the preparation amounts to more than one week, more than one month, more than six months, or more than one year.

8. A method in accordance with one of the preceding claims, characterized in that the pH of the solution at the time of the subsequent addition is greater than 7.4 or greater than 7.6