Peritoneal dialysis solution

Abstract

The present invention relates to a peritoneal dialysis solution, which contains a certain amount of a first solution and a certain amount of a second solution, the amount of the first solution and the amount of the second solution having a predetermined ratio, and when administered, the amount of the first solution and the amount of the second solution are mixed together, and when the amount of the first solution and the amount of the second solution are mixed, the solution has a pH of 6.9 to 7.5. The first solution is an acidic solution having a pH of 2.2 to 3.5 and contains an osmotic agent selected from the group consisting of glucose, a glucose polymer, or a mixture thereof. The second solution is an alkaline buffer solution having a pH of 7.4 to 8.2, and contains a protective agent selected from the group consisting of L-glutamine, L-alanyl-L-glutamine, L-glutaminyl-L-alanine, L-glutaminyl-L-glycine, L-glycyl-L-glutamine, or a mixture thereof, and a lactate buffer in an amount of 30 to 45 mmol / L calculated as the amount in the solution when the first solution and the second solution are mixed.

Description

Technical Field

[0001] The present invention relates to peritoneal dialysis fluid (hereinafter also referred to as "PDF").

Background Art

[0002] Peritoneal dialysis fluid removes solutes and water from uremic patients. The mechanism of PDF is known and need not be described in further detail herein.

[0003] The PDF solution contains an osmotic agent. For the purposes of the present invention, the osmotic agent is glucose. PDF containing glucose as an osmotic agent is hereinafter referred to as "glucose-based" PDF. The amount of glucose in such glucose-based PDF is typically about 0.5 to 4 g / L.

[0004] However, glucose is known to be easily decomposed and form glucose degradation products (GDP) ((1), EP2962683A1).

[0005] Therefore, it is known that glucose-containing osmotic solutions are stored at a slightly acidic pH value (1).

[0006] Known embodiments of PDF, for example, the "Dianeal® PDG4" product group manufactured by Baxter (https: / / www.baxterpi.com / pi-pdf / Dianeal_PI.pdf, retrieved on June 23, 2022), contain a single glucose solution with a pH value of approximately pH 5.0 to 5.5. However, the degree of GDP in such products is high.

[0007] Therefore, in other embodiments, the osmotic solution employs a lower pH value, for example, 3 to 5. However, peritoneal administration of a solution having such a low pH value would be impossible or at least painful.

[0008] Accordingly, in these further embodiments, a second solution is included, which is an alkaline buffer solution and is mixed with the osmotic solution prior to administration to form a ready-to-use ( "RTU") final solution having a nearly neutral pH value, e.g., 6.9 to 7.5.

[0009] The two solutions are manufactured in predetermined ratios of their respective amounts. These solutions are stored separately but are mixed together at the time of administration. As a convenient means of storage, multi-chamber bags, particularly double-chamber bags, containing the solutions in separate compartments are known, but these compartments can be connected to each other for mixing at the time of administration (e.g., by a peelable seal).

[0010] Both lactate buffers and bicarbonate buffers, as well as the aforementioned mixtures, are employed as buffers.

[0011] Various commercially available solutions of the state of the art provide different approaches with respect to - the pH values of the two solutions - the respective amounts of the two solutions and - the amount of buffer in the alkaline solution:

[0012] In the product group "Physioneal® 40 Glucose Clear-Flex" manufactured by Baxter, a glucose-containing solution and an alkaline buffer solution are mixed in a ratio of 3:1. The alkaline buffer solution contains an amount of lactate buffer such that the total amount is 15 mmol / L upon mixing of the solutions, and further, an amount of bicarbonate buffer such that the total amount is 25 mmol / L upon mixing of the solutions (https: / / www.baxter.ca / sites / g / files / ebysai1431 / files / 2018-12 / Physioneal_Clearflex_EN.pdf, accessed June 24, 2022). The pH values of the solutions are not disclosed, but are presumed to be 2.1 (glucose-containing solution) and above 9 (alkaline buffer), respectively.

[0013] Similarly, in the product group "Physioneal® 40 Glucose Viaflex" manufactured by Baxter, a glucose-containing solution and an alkaline buffer solution are mixed at a ratio of 725:1275. The alkaline buffer solution contains a lactate buffer in an amount such that the total amount is 15 mmol / L upon mixing of the solutions, and further contains a bicarbonate buffer in an amount such that the total amount is 25 mmol / L upon mixing of the solutions (https: / / www.baxter.ca / sites / g / files / ebysai1431 / files / 2018-11 / Physioneal_Viaflex_EN.pdf, obtained on June 24, 2022). The pH values of the solutions are not disclosed, but are presumably 4.2 (glucose-containing solution) and 7.6 (alkaline buffer), respectively.

[0014] The product group "Balance®" currently manufactured by Fresenius also contains two chambers. The glucose-containing solution and the alkaline buffer solution are mixed at a ratio of 1:1. The alkaline buffer solution contains a lactate buffer in an amount such that the total amount is 35 mmol / L upon mixing of the solutions.

[0015] The pH values of the solutions are not disclosed, but were measured based on sample products and were approximately 3.0 (glucose-containing solution) and approximately 8.6 (alkaline buffer), respectively.

[0016] According to the product information regarding this product, sodium bicarbonate is listed as an excipient.

[0017] In the brochure "Safety and biocompatibility in perfect balance" (2) published by Fresenius in 2006, it is reported that the pH value of the acidic solution is approximately 3.1 and the pH value of the buffer solution is approximately 8.0. The mixing ratio of the two solutions is not disclosed.

[0018] Thus, when using a glucose solution having a low pH value of only 3 or 2 (preferred in terms of the formation of GDP) compared to these prior art solutions, it is known that the pH value of the alkaline solution needs to be increased (up to 9 or more).

[0019] EP2962683A1 proposes a liquid prepared by mixing two or more solutions for the purpose of reducing the formation of GDP. This liquid has a low sodium content and does not contain sodium ions in the glucose-containing solution. The pH value is not disclosed.

[0020] EP1465688B2 employs a bicarbonate-based solution and an electrolyte (glucose) solution during hemodialysis and discloses several pH ranges of both solutions under moderate or extreme pH conditions.

[0021] The current state of further technologies dealing with double-chamber products for peritoneal dialysis is disclosed in EP1038552, EP1131077, EP1744768, EP2647397 and WO2018 / 201443.

[0022] From several clinical and experimental observations, it has been shown that PDF is cytotoxic and is associated with a risk of up to 30% technical failure for long-term peritoneal dialysis (PD) treatment (2).

[0023] WO2008 / 106702A1 provides a glucose-based peritoneal fluid containing a protective agent in the form of L-glutamine and a dipeptide capable of releasing L-glutamine. The dipeptide is L-glutaminyl-L-glycine, L-glycyl-L-glutamine, L-glutaminyl-L-alanine or L-alanyl-L-glutamine, or a mixture of two or more of the above dipeptides, and the concentration of the dipeptide in the dialysate is 2 mM to 25 mM.

[0024] According to this patent application, it has been found that these dipeptides, particularly L-alanyl-L-glutamine (hereinafter abbreviated as "Ala / Gln"), contribute to the prevention of technical failures.

[0025] Several publications are further investigating the effect of Ala / Gln in glucose-based PDFs ((3)-(27)).

[0026] Hereinafter, the term L-alanyl-L-glutamine or "Ala / Gln" means both Ala / Gln itself and all other protective agents within the scope of the present invention.

Prior Art Documents

Patent Documents

[0027]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Non-Patent Documents

[0028]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non - Patent Document 14

Non - Patent Document 15

Non - Patent Document 16

Non - Patent Document 17

Non - Patent Document 18

Non - Patent Document 19

Non - Patent Document 20

Non - Patent Document 21

Non - Patent Document 22

Non - Patent Document 23

Non - Patent Document 24

Non - Patent Document 25

Non-Patent Document 26

Non-Patent Document 27

Summary of the Invention

Problems to be Solved by the Invention

[0029] The problem that gives rise to the present invention is to provide the above-mentioned protective agent, particularly a glucose-based PDF containing Ala / Gln, and at the same time to bring about optimal results in terms of the formation of GDP.

Means for Solving the Problems

[0030] This problem is solved by the subject matter of claim 1. Preferred embodiments are disclosed in the dependent claims.

Modes for Carrying Out the Invention

[0031] Detailed Description of the Invention Problems arise when formulating a ready-to-use glucose-based peritoneal dialysis solution containing the above-mentioned protective agent.

[0032] On the other hand, it has been found that when Ala / Gln and glucose are mixed in a single solution, a reaction can occur between the dipeptide and glucose. Furthermore, at low pH values, Ala / Gln itself is liable to decompose.

[0033] Therefore, the single-solution embodiment may not be capable of long-term storage, however, long-term storage is required in PDF.

[0034] On the other hand, dipeptides such as Ala / Gln are not stable under alkaline conditions ((28), (29)) and are known to form decomposition products. This is even more applicable considering the necessity for PDF to heat-sterilize the solution at about 120°C.

[0035] However, as can be seen from the solution discussed above, when it is assumed that the pH value of the glucose-containing solution is lowered to minimize the formation of GDP, the required pH value of the alkaline buffer solution needs to be increased.

[0036] Surprisingly, it has been found that the PDF containing the two solutions defined in claim 1 solves the problems that are the starting point of the present invention.

[0037] The first solution provided by the present invention is a solution containing the penetrant glucose in a strongly acidic environment.

[0038] The second solution provided by the present invention is an alkaline buffer solution containing the protective agent, however, the pH value is of a weakly alkaline degree.

[0039] Surprisingly, even when a glucose-containing solution with a low pH value such as 2.2 to 3.5 is employed (thus minimizing the formation of GDP), the alkaline buffer solution containing Ala / Gln is found to be sufficient to establish a neutral solution upon mixing the first and second solutions with a very low alkalinity, for example, only 7.4 to 8.2. At the same time, the decomposition of Ala / Gln during storage can also be minimized due to the low alkalinity of the solution.

[0040] It should be noted that Ala / Gln itself cannot be expected to affect the pH.

[0041] In a preferred embodiment of the present invention, the pH value of the first solution is 2.2 to 2.9, more preferably 2.2 to 2.8, and most preferably 2.5 to 2.8.

[0042] In a further preferred embodiment, the pH value of the second solution is 7.4 to 7.9, more preferably 7.4 to 7.8, and most preferably 7.5 to 7.8.

[0043] The amount of lactate in the second solution is 30 - 45 mmol / L, preferably 34 - 41 mmol / L, and most preferably about 35 mmol / L. All of these values refer to the amounts in the solution obtained when the first solution and the second solution are mixed (the "ready-to-use" - RTU solution). For example, if the mixing ratio of the first solution and the second solution is 1:1 and the target amount in the RTU solution is 34 - 41 mmol / L, the amount of lactate in the second solution is 68 - 82, preferably about 70 mmol / L.

[0044] This may be similar to the amount of lactate as known from the "Balance®" product group currently sold by Fresenius. However, in this product, the glucose-containing solution has a pH value of 3.0 (i.e., less acidic than at least the preferred embodiments of the present invention), while the alkaline solution has a pH value of about 8.6 (i.e., more alkaline than in the present invention), and the respective amounts of both solutions are the same.

[0045] Lactate is preferably provided in the form of sodium lactate.

[0046] In the present invention, the ratio of the amount of the first solution to the amount of the second solution may be 3:1 to 1:3, preferably 2:1 to 1:2, and even more preferably 1.5:1 to 1:1.5.

[0047] In a particularly preferred embodiment, the ratio is about 1:1.

[0048] The term "amount" with respect to the first solution and the second solution refers to the respective volumes of these solutions.

[0049] It is also surprising that when the two solutions are mixed with each other from approximately equal amounts to even more exactly equal amounts, a neutral and thus physiologically acceptable ready-to-use PDF ("RTU") is obtained.

[0050] A further embodiment of the present invention is characterized in that both the first solution and the second solution contain one or more sodium compounds in a physiologically acceptable amount (similarly, calculated based on the amount in the solution obtained upon mixing the two solutions). In other prior art proposals, the sodium compound is present in only one of the two solutions.

[0051] The total amount of sodium ions in both solutions can range from 130 mmol / L to 140 mmol / L.

[0052] The first solution of the present invention preferably further contains a physiologically active agent selected from the group consisting of physiologically acceptable compounds containing sodium ions, calcium ions, magnesium ions, and mixtures thereof.

[0053] The need for a physiologically active agent containing the aforementioned ions in the present invention is known to those skilled in the art and thus does not need to be discussed in more detail.

[0054] Typical physiologically active agents that can be employed in the above solution can be selected from sodium chloride, calcium chloride, and magnesium chloride.

[0055] For the purpose of adjusting the pH values of the first solution and the second solution to desired values, a physiologically acceptable acid (e.g., HCl) and an acceptable base (e.g., NaOH) can be employed respectively.

[0056] The amount of the protective agent, particularly the amount of Ala / Gln, is preferably 2 mM to 25 mM, more preferably 5 mM to 10 mM, and most preferably about 8 mM, calculated as the amount in the solution upon mixing the first solution and the second solution in this case as well.

[0057] Preferably, the amount of the protective agent is 95% or more of the original amount after storage for at least one year, preferably after storage for two years. The amount of decomposition of Ala / Gln in the second solution has been found to be actually very low in long-term studies.

[0058] Furthermore, it was also found that the amount of glucose decomposition, i.e., the formation of GDP in the first solution during storage, was low and basically in the same range as that of commercially available products.

[0059] In a particularly preferred embodiment, the protective agent contains, and even more preferably consists of, L-alanyl-L-glutamine.

[0060] The two solutions of the PDF of the present invention can be produced by mixing the above-described raw materials with water respectively and then heat-sterilizing the resulting solutions.

[0061] Surprisingly, it was found that with only a very small amount of addition of the bicarbonate compound to the second solution, a further effect of stabilizing the protective agent against decomposition was clearly obtained both during heat sterilization and during storage.

[0062] Furthermore, without wishing to be bound by theory, the addition of this amount of bicarbonate compound is thought to help achieve the target neutral pH value when the two solutions are mixed.

[0063] Accordingly, in a further aspect of the present invention, there is provided a method for producing the second solution of the PDF of the present invention, the method comprising the steps of mixing together the raw materials of the second solution and, further, a bicarbonate buffer in an amount of 1 mmol / L to 6 mmol / L calculated as the amount in the liquid during the mixing of the first solution and the second solution, and sterilizing the mixed solution.

[0064] The amount of the bicarbonate buffer is preferably 2 mmol / L to 4 mmol / L, and even more preferably about 3 mmol / L.

[0065] Although it is repetitive, this amount is so small that it cannot be expected to have a significant impact on the pH value when the two solutions are mixed with each other. Furthermore, since this amount is very small, bicarbonate may no longer be detected in the second solution or in the above solution after mixing, after a long storage period such as one year or two years. This is due to the equilibrium between bicarbonate anions and CO2, and the latter may be able to permeate at least partially through the film containing the solution.

[0066] Nevertheless, it may be shown that the target neutral pH value upon mixing of the first solution and the second solution can still be obtained after a long storage time.

[0067] The bicarbonate compound is preferably sodium bicarbonate.

[0068] The first solution and the second solution of the present invention preferably fill a bag containing several chambers separated from each other by a peelable seal, in particular, the previously described double-chamber bag.

[0069] After filling the bag, the solution is sterilized, optionally further packaged using an over pouch, and stored. Examples

Examples

[0070] pH shift of the sterilized alanyl-glutamine dipeptide (AGD)-containing solution: The pH value of the AGD-containing solution was adjusted in steps of pH 0.5. These samples were used to analyze the pH behavior of the solution during sterilization and to find the most appropriate formulation of the AGD-containing alkaline solution to reach the pH range required for the ready-to-use solution (RTU solution). The final target composition of the AGD-containing alkaline solution in the RTU solution after mixing and the actual composition of the alkaline solution before mixing were as follows (based on a 1:1 mixing ratio of the acidic solution and the alkaline solution):

[0071]

Table 1

[0072] For the preparation of 1 L of solution, the following amounts of raw materials were weighed using a calibrated balance:

[0073]

Table 2

[0074] To prepare the alkaline solution containing AGD, approximately 250 mL of deionized water was placed in a beaker. All the raw materials were added while stirring, and the solution was transferred to a plastic canister. Deionized water was added while stirring, and the pH value was adjusted using 1 M NaOH solution until the required value was reached. Deionized water was poured to a final volume of 1 L and the pH was adjusted. The required volume of the solution was transferred to a bag through a filling tube. Sterilization (steam-air mixing method) was carried out using the standard program for a sterilizable overwrapped 5000 ml bag under the conditions shown in Table 3:

[0075]

Table 3

[0076] The solutions were prepared at six different pH values (pH 6.0 - 8.5 in 0.5 steps), and the pH values were measured before and after sterilization to determine the pH shift after sterilization.

[0077] All pH examinations were carried out in accordance with the currently valid monograph 2.2.3 "Potentiometric Measurement of pH" of the European Pharmacopoeia, using a certified pH electrode calibrated in the corresponding pH range (alkaline, neutral or acidic) with certified NIST traceable buffer solutions of pH 1.0, 4.0, 7.0, 9.0, and 10.0.

[0078]

Table 4

[0079] From the results in Table 4, it is shown that the sterilization process has a significant effect of about 1 to 1.5 units on the pH value of the alkaline solution within the acidic range of pH 6 to 7.5. At the high pH values of 8.00 and 8.50, the difference became smaller (about 0.3 units). These results indicate that the stabilization of the solution pH by AGD is excellent at alkaline pH values.

Example

[0080] Stabilization of AGD by addition of a small amount of bicarbonate compound (sodium bicarbonate): To determine the effect of sodium bicarbonate on the pH shift during sterilization, solutions with a constant bicarbonate content and different pH values were prepared. The final concentrations of the RTU solutions were as follows:

[0081]

Table 5

[0082] For the preparation of 1 L of alkaline solution (similarly based on a 1:1 mixing ratio), the following amounts of raw materials were weighed using a calibrated balance:

[0083]

Table 6

[0084] Approximately 500 mL of deionized water was placed in a beaker. All the raw materials were added while stirring, and the solution was transferred to a plastic canister. Deionized water was added while stirring, and the pH value was adjusted using 1 M NaOH solution until the required value was reached. Deionized water was poured to a final volume of 1 L, and the pH was adjusted. The required volume of the solution was transferred to the bag through a filling tube. Sterilization was carried out using the standard program for the 3000 ml bag with a sterilized overwrap.

[0085]

Table 7

[0086] The pH value was measured before and after sterilization to determine the pH shift after sterilization.

[0087]

Table 8

[0088] From the results in Table 8, it is shown that the sterilization process does not significantly affect the pH value of the alkaline solution in the presence of 3 mmol / L NaHCO3. In comparison with Example 1, the presence of a small amount of bicarbonate clearly affects the pH value during the sterilization process. Bicarbonate is considered to have a kind of buffering effect on the solution.

Examples

[0089] Mixing of acidic and alkaline solutions: For the pH mixing experiment, an acidic glucose-containing solution and a basic AGD-containing solution were prepared. In the first step, the pH value of the solution was adjusted in steps of pH 0.5. These samples were used to analyze the pH behavior of the solution during sterilization and also to analyze the results of the combination of acidic and basic solutions with respect to the pH range of the mixed solution. A range of 6.9 - 7.5 was set as the target pH value for the mixed solution, i.e., the ready-to-use solution (RTU solution).

[0090]

Table 9

[0091]

Table 10

[0092] The pH value of the acidic solution was adjusted by adding 1M HCl until the desired pH value was reached.

[0093] The alkaline solution was prepared as described in Example 2.

[0094] The ready-to-use solution was prepared by mixing the samples (acidic and basic) in a 1:1 ratio and then immediately analyzing the pH value.

[0095]

Table 11

[0096] The results in Table 11 show that the target pH range of 6.9 - 7.5 could not be reached after mixing the acidic and alkaline solutions.

Example

[0097] Mixing of acidic and alkaline solutions: In further trials, the pH values were set as follows: - Acidic solution pH 2.0 - 3.4 (0.2 step) - Alkaline solution pH 7.6 - 9.0 (0.2 step)

[0098] Furthermore, 3 mmol / L NaHCO3 (referred to as the ready-to-use solution) was added to the alkaline solution before adjusting the pH value.

[0099] The acidic solution was prepared in the pH range of 2.0 - 3.4 in 0.2 steps as described in Example 3. The basic solution was prepared according to Example 2 and the pH value was adjusted in the range of 7.2 - 9.0 in 0.2 steps. Sterilization of both solutions was carried out using the standard program for 3000 mL bags as shown in Table 7.

[0100] The ready-to-use solution was prepared by mixing the acidic and alkaline solutions in a 1:1 ratio and then immediately analyzing the pH value.

[0101]

Table 12

[0102] The pH value applied with gray corresponds to the pH range of 6.9 - 7.5 defined as the target range of the final product. Based on the results of the mixing test, there are several possibilities regarding the adjustment of the pH values of the acidic and alkaline solutions to achieve the desired target range of 6.9 - 7.5 for the pH value of the RTU solution.

Example

[0103] Examples of acidic and alkaline solutions and the solution ready for mixed use: Three examples of acidic and alkaline solutions according to the present invention have different glucose contents and are shown below. In all examples, the mixing ratio of the acidic and alkaline solutions is set to 1:1 (volume basis).

[0104]

Table 13

[0105]

Table 14

[0106]

Table 15

[0107]

Table 16

[0108] The pH value of the mixed solution, i.e., the RTU solution, was within the target pH range of 6.9 - 7.5 in each case.

Example

[0109] Long-term stability of AGD: The long-term stability test of AGD in an alkaline solution according to the present invention was carried out. Two sample solutions with pH values of 7.4 and 7.8 respectively were prepared, which contained the same amounts of AGD (16 mmol / L), NaHCO3 (6 mmol / L) and sodium lactate (70 mmol / L). The pH of each sample was adjusted using 1M NaOH. A fixed amount of each sample was prepared under adjusted conditions and stored under the specified conditions of 25°C / 60% rH.

[0110] Sterilization was carried out under the following conditions:

[0111] [Table 17]

[0112] The stability of AGD was examined by AS analysis. The analysis was carried out by qualitative amino acid analysis using IEX and post-column derivatization with ninhydrin.

[0113] Both samples examined showed the same tendency in that, after storage at 25°C / 60% rH for a storage time of 52 weeks, very little AGD decreased (less than 5% of the original amount).

[0114] The sample with a pH value of 7.4 was found to have the least decrease in AGD (98% of the original amount), and the sample with a pH value of 7.8 had a decrease in AGD of more than 95% of the original amount.

[0115] Non-patent documents cited in the specification: (1)How to avoid glucose degradation products in peritoneal dialysis fluids. Perit Dial Int. 2006 Jul; 26(4):490-7. (2)Safety and biocompatibility in perfect balance. Fresenius Medical Care Deutschland GmbH. 2006. (3)What really happens to people on long-term peritoneal dialysis? Kidney Int. 1998 Dec;54(6):2207-17. (4)A randomized controlled trial of alanyl-glutamine supplementation in peritoneal dialysis fluid to assess impact on biomarkers of peritoneal health. Kidney Int. 2018 Dec;94(6):1227-1237. (5)Biomarker research to improve clinical outcomes of peritoneal dialysis: consensus of the European Training and Research in Peritoneal Dialysis (EuTRiPD) network. Kidney Int. 2017. (6)Functional and Transcriptomic Characterization of Peritoneal Immune-Modulation by Addition of Alanyl-Glutamine to Dialysis Fluid. Sci Rep. 2017 Jul 24;7(1):6229 (7)Addition of Alanyl-Glutamine to Dialysis Fluid Restores Peritoneal Cellular Stress Responses - A First-In-Man Trial. PloS One. 2016 Oct 21;11(10):e0165045. (8)Dynamic O-linked N-acetylglucosamine modification of proteins affects stress responses and survival of mesothelial cells exposed to peritoneal dialysis fluids. J Am Soc Nephrol. 2014 Dec;25(12):2778-88. (9)Interleukin-1 receptor-mediated inflammation impairs the heat shock response of human mesothelial cells. Am J Pathol. 2011 Apr;178(4):1544-55. (10)Alanyl-glutamine dipeptide restores the cytoprotective stress proteome of mesothelial cells exposed to peritoneal dialysis fluids. Nephrol Dial Transplant. 2012 Mar;27(3):937-46. (11)Peritoneal dialysis fluids induce the stress response in human mesothelial cells. Perit Dial Int. 2001 Jan-Feb;21(1):85-8. (12)Peritoneal dialysate fluid composition determines heat shock protein expression patterns in human mesothelial cells. Kidney Int. 2001 Nov;60(5):1930-7. (13)Alanyl-Glutamine Restores Tight Junction Organization after Disruption by a Conventional Peritoneal Dialysis. Biomolecules. 2020 Aug 13;10(8). (14)The Peritoneal Surface Proteome in a Model of Chronic Peritoneal Dialysis Reveals Mechanisms of Membrane Damage and Preservation. Front Physiol. 2019 May 14;10:472. (15)Composite Outcome Improves Feasibility of Clinical Trials in Peritoneal Dialysis. Perit Dial Int. 2019 May 23. (16)Does alanyl-glutamine supplementation offer potential to improve peritoneal dialysate biocompatibility? Kidney Int. 2018 Dec;94(6):1050-1052. (17)Injury-induced inflammation and inadequate HSP expression in mesothelial cells upon repeat exposure to dual-chamber bag peritoneal dialysis fluids. Int J Artif Organs. 2015 Oct;38(10):530-6. (18)Is there such a thing as biocompatible peritoneal dialysis fluid? Pediatr Nephrol. 2016 Oct 8. (19)HSP-mediated cytoprotection of mesothelial cells in experimental acute peritoneal dialysis. Perit Dial Int. 2010 May-Jun;30(3):294-9. (20)Peritoneal dialysis fluids can alter HSP expression in human peritoneal mesothelial cells. Nephrol Dial Transplant. 2011 Mar;26(3):1046-52. (21)Effects of epithelial-to-mesenchymal transition on acute stress response in human peritoneal mesothelial cells. Nephrol Dial Transplant. 2008 Nov;23(11):3494-500. (22)Evidence for HSP-mediated cytoskeletal stabilization in mesothelial cells during acute experimental peritoneal dialysis. Am J Physiol Renal Physiol. 2007 Jan;292(1):F47-56. (23)Overexpression of HSP-72 confers cytoprotection in experimental peritoneal dialysis. Kidney Int. 2004Dec;66(6):2300-7. (24)The dipeptide alanyl-glutamine ameliorates peritoneal fibrosis and attenuates IL-17 dependent pathways during peritoneal dialysis. Kidney Int. 2016 Mar;89(3):625-35. (25)Effects of Alanyl-Glutamine Treatment on the Peritoneal Dialysis Effluent Proteome Reveal Pathomechanism-Associated Molecular Signatures. Mol Cell Proteomics. 2018 Mar;17(3):516-532. (26)Peritoneal Dialysis Fluid Supplementation with Alanyl-Glutamine Attenuates Conventional Dialysis Fluid-Mediated Endothelial Cell Injury by Restoring Perturbed Cytoprotective Responses. Biomolecules. 2020 Dec 15;10(12). (27)Targeted Metabolomic Profiling of Peritoneal Dialysis Effluents Shows Anti-oxidative Capacity of Alanyl-Glutamine. Front Physiol. 2019 Jan 21;9:1961. (28)Degradation kinetics of L-alanyl-L-glutamine and its derivatives in aqueous solution. Eur J Pharm Sci. 1999 Jan;7(2):107-12. (29)Quantitative high-performance liquid chromatography-tandem mass spectrometry impurity profiling methods for the analysis of parenteral infusion solutions for amino acid supplementation containing L-alanyl-L-glutamine. J Chromatogr A. 2012 Oct 12;1259:111-20.

Claims

1. A peritoneal dialysis solution comprising an amount of a first solution and an amount of a second solution, wherein the amount of the first solution and the amount of the second solution have a predetermined ratio, and upon administration, the amount of the first solution and the amount of the second solution are mixed together, and when the amount of the first solution and the amount of the second solution are mixed, the solution has a pH of 6.9 to 7.5, wherein the first solution is an acidic solution having a pH of 2.2 to 3.5 and contains an osmotic agent selected from the group consisting of glucose, a glucose polymer, or a mixture thereof, wherein the second solution is an alkaline buffer solution having a pH of 7.4 to 8.2, a protective agent selected from the group consisting of L-glutamine, L-alanyl-L-glutamine, L-glutaminyl-L-alanine, L-glutaminyl-L-glycine, L-glycyl-L-glutamine, or a mixture thereof, and a lactate buffer in an amount of 30 to 45 mmol / L calculated as the total amount in the solution when the amount of the first solution and the amount of the second solution are mixed.

2. The solution according to claim 1, wherein the pH value of the first solution is 2.2 to 2.9, more preferably 2.2 to 2.8, and most preferably 2.5 to 2.

8.

3. The solution according to any one of claims 1 to 2, wherein the pH value of the second solution is 7.4 to 7.9, more preferably 7.4 to 7.8, and most preferably 7.5 to 7.

8.

4. The solution according to any one of claims 1 to 3, wherein the amount of the lactate buffer is 34 to 41 mmol / L, preferably about 35 mmol / L.

5. The solution according to any one of claims 1 to 4, wherein the ratio of the amount of the first solution to the amount of the second solution is 3:1 to 1:3, preferably 2:1 to 1:2, and even more preferably 1.5:1 to 1:1.

5.

6. The solution according to claim 5, wherein the ratio is about 1:

1.

7. The solution according to any one of claims 1 to 6, wherein both the first solution and the second solution contain one or more physiologically acceptable amounts of sodium compounds calculated as the total amount in the solution when the amount of the first solution and the amount of the second solution are mixed.

8. The liquid according to any one of claims 1 to 7, characterized in that the first solution further comprises a physiologically active agent selected from the group consisting of physiologically acceptable compounds containing sodium ions, calcium ions, magnesium ions, and mixtures thereof.

9. The liquid according to any one of claims 1 to 8, characterized in that the amount of the protective agent is 2 mM to 25 mM, preferably 5 mM to 10 mM, most preferably about 8 mM, calculated as the amount in the liquid during the mixing of the first solution and the second solution.

10. The liquid according to any one of claims 1 to 9, characterized in that the amount of the protective agent in the second solution is 95% or more of the original amount after storage for at least one year, preferably after storage for two years.

11. The liquid according to any one of claims 1 to 10, characterized in that the protective agent is L-alanyl-L-glutamine or contains the same.

12. A method for producing the second solution of the liquid according to any one of claims 1 to 11, comprising the steps of: mixing together the raw materials of the second solution, and further a bicarbonate compound in an amount of 1 mmol / L to 6 mmol / L calculated as the amount in the liquid during the mixing of the first solution and the second solution; and sterilizing the mixed solution.

13. The method according to claim 12, characterized in that the amount of the bicarbonate compound is 2 mmol / L to 4 mmol / L, preferably about 3 mmol / L.

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