Dialysis solution for use in the prophylaxis and treatment of creatine deficiency in patients

Abstract

The dialysis solution is used in the prophylaxis and treatment of creatine deficiency in patients and comprises one or more creatine compound(s) selected from the following groups: (i) (phospho)creatine and the physiologically acceptable salts thereof, in each case together with any desired proportions of water of crystallization, in particular creatine monohydrate; and (ii) guanidinoacetic acid (physiological precursor of creatine) and the physiologically acceptable salts thereof, in each case together with any desired proportions of water of crystallization. The one or more creatine compound(s) is / are present in the dialysis solution in a concentration equivalent to 0.8 to 2.5 mM creatine. The dialysis solution additionally has a concentration of 0.1 to 200 μpM creatinine.

Description

[0001] Dialysis solution for use in the prophylaxis and treatment of creatine deficiency in patients

[0002] The present invention relates to a dialysis solution containing creatine and creatinine for use in the prophylaxis and treatment of creatine deficiency in patients according to the preamble of claim 1.

[0003] Creatine is a naturally occurring guanidino compound, of which the body produces approximately 50% of its daily requirement. The remaining 50% must be obtained through diet by consuming meat from vertebrates, including fish. Endogenous creatine synthesis occurs in a two-step process from arginine, glycine, and S-adenosylmethionine (SAM). The first step, producing the precursor to creatine, guanidinoacetic acid (GAA), is primarily carried out in the kidneys with the help of the enzyme L-arginine:glycine amidinotransferase (AGAT). The second step, from GAA to the end product, creatine, then takes place mainly in the liver. From there, creatine is released into the bloodstream and subsequently taken up by target organs (muscle tissue, heart, brain, etc.) into the corresponding cells via an active, specific creatine transporter.

[0004] The more or less impaired kidney function in dialysis patients results, among other things, in reduced or even absent levels and activity of the AGAT enzyme in the kidneys. This impairment of the body's own endogenous synthesis of GAA, a creatine precursor, ultimately leads to a creatine deficiency in the bodies of dialysis patients, who depend on recurring dialysis treatments for survival. In addition, the unimpeded loss of plasma creatine into the dialysis fluid during dialysis exacerbates the already existing general, chronic creatine depletion in dialysis patients. This creatine deficiency is further aggravated by the reduced intake of dietary creatine from meat and fish, because dialysis patients generally consume less meat and / or fish due to loss of appetite and prefer a more plant-based diet.Due to all these factors, a general chronic creatine deficiency results in the bodies of dialysis patients. This is all the more pronounced because the normal non-enzymatic conversion of endogenous creatine to uremic creatinine (Crn), which occurs at approximately 1.6–1.7% of the body's creatine pool per day and cannot be influenced within physiological limits, proceeds at a constant rate, and this creatinine is removed via dialysis. Because of this imbalance between the production and uptake rate of creatine, as well as the constant rate of creatine to creatinine breakdown, dialysis patients demonstrably present with a significantly more pronounced creatine deficiency in the body compared to the general population.

[0005] To compensate for the lack of kidney function in dialysis patients, life-saving dialysis treatment must be continued for life. Unfortunately, compared to the general population, the health-related quality of life (HRQoL) of dialysis patients is significantly lower, while their mortality rate is higher compared to healthy individuals. Besides the proven non-modifiable risk factors for mortality and low HRQoL (e.g., age and genetics), there are also risk factors for dialysis patients that are potentially modifiable, such as nutritional status and / or care.

[0006] The creatine deficiency generally observed in dialysis patients is one such modifiable risk factor that negatively affects several important causes of poor HRQoL, such as protein energy wasting (PEW), sarcopenia, chronic fatigue, muscle weakness, depression, cognitive impairment, as well as increased susceptibility and higher risk for an adverse course of infectious diseases.

[0007] The factors mentioned above that contribute to poor HRQoL are also reflected in the increased frailty syndrome of dialysis patients. These include increased muscle loss, progressive muscle weakness, and impaired neuromuscular coordination, leading to a higher incidence of falls and fractures. Additional complications result in delayed or prolonged bone and wound healing, often necessitating longer hospital stays. Consequently, compared to the general population, dialysis patients have a significantly higher incidence of complications, including death. Creatine can be beneficial in this context, as it can slow muscle loss during prolonged immobilization, such as with fixed fractures, and promote faster and better healing of fractures and wounds.

[0008] Due to the almost ubiquitous presence of creatine in all body cells, as well as its important function as an energy storage and energy transport form within many cell types, a creatine deficiency manifests itself in a variety of often simultaneously occurring symptoms, thus forming the so-called "creatine deficiency".

[0009] In addition to medications for treating various comorbidities that are very common and occur in combination, dialysis patients undergoing renal replacement therapy require a larger number of medications in significant quantities (polypharmacy). All orally administered medications must be taken with the smallest possible amount of fluid that this volume-controlled patient group is permitted to consume.

[0010] That creatine supplementation can have various positive effects for dialysis patients is undisputed, but the question here is how the relatively large amount of creatine can be ingested daily without excessive additional fluid intake. The fact that dialysis patients feel they have to take their very large doses of medication with far too little fluid means that adherence and compliance to medication regimens are generally a major issue for this patient group. Therefore, prescribing additional large amounts of dry creatine or creatine suspended in only a small amount of water would overwhelm many patients and result in even poorer adherence.In addition, this fragile patient group faces an increased risk of swallowing and choking, as well as frequent gastrointestinal problems, which are not conducive to regular and regulated creatine absorption under these circumstances.

[0011] Numerous dialysis solutions containing a creatine compound are already known from the prior art, but they all have the following disadvantage:

[0012] Creatinine, which always forms in aqueous solution, is a waste product that is normally excreted in urine by the kidneys in healthy individuals. In dialysis patients with impaired or absent kidney function, creatinine is excreted during dialysis into the dialysis fluid, which is then discarded.

[0013] Creatinine is inevitably formed in every aqueous solution of creatine in a non-enzymatic, non-inhibitable manner. The pH- and temperature-dependent decomposition rates of creatine to creatinine are already known, as is the fact that this process can only be slowed down, not stopped. Therefore, creatinine is always inevitably formed in every dialysis solution (as well as in and during the preparation and processing of creatine stock solutions used to produce the dialysis solution) that is enriched with creatine to supply the body with creatine, even though this dialysis solution is specifically intended to remove creatinine produced (among other things) in the body. This fact involves an intrinsic conflict of objectives, which has neither been addressed nor even partially resolved in the prior art. The invention aims to remedy this.The invention is based on the following objectives: a) to resolve the conflict of objectives that the dialysis solution, which supplies the body with creatine and removes creatinine from the body, always also contains creatinine, which inevitably arises in the creatine solution; and simultaneously b) to optimize the creatine concentration offered to the body in the dialysis solution in such a way that (i) the body is enabled to replenish its creatine pool, and (ii) the concentration of creatinine formed in the creatine-containing dialysis solution by decomposition of creatine can be kept low.

[0014] The invention solves the stated problem with a dialysis solution which has the features according to claim 1.

[0015] The advantages achieved by the invention are essentially that by combining a low creatine concentration within a narrowly defined range with a relatively high creatinine concentration, a significantly extended shelf life of the dialysis solution can be achieved, whereby the high creatinine concentration is absolutely problem-free and without disadvantages for the dialysis patients.

[0016] Based on the quality standards for commercial creatine, which exhibit very low creatinine levels (in the per mille range) for oral administration where the gastrointestinal tract still acts as a barrier, in contrast to intradialytic creatine administration via the dialysis solution, which is equivalent to paraenteral administration directly into the blood plasma, since the blood and the dialysis solution are directly subjected to osmotic exchange of smaller molecules during dialysis, where this barrier is absent. Since no creatine quality (with regard to its creatinine content) for use in dialysis solutions is currently known, the quality for oral administration represents the maximum or minimum requirement according to the state of the art.If this is used as a benchmark, only extremely short dialysis solution preparation times (including preparation, storage, and logistics times for stock solutions) are possible (as well as very narrow pH and temperature ranges). This makes it clinically, technically, and organizationally very complex and costly to achieve a clinically irrelevant goal of an unnecessarily low creatinine concentration.

[0017] By taking into account the creatine concentration according to the inventive dialysis solution and investigations on dialysis patients, a combined range of creatine and creatinine could be found which allows for a significantly higher creatinine concentration in the fresh dialysis solution and in which the creatinine from the blood plasma continues to be removed from the body, provided that the creatine concentration is kept in a low, narrowly defined range according to the inventive dialysis solution - without this having any adverse effect on dialysis patients or showing any clinically relevant negative effects.

[0018] According to the combinatorial optimization of the two opposing parameters, i.e., creatine supply on the one hand and creatinine excretion on the other, it is permissible, taking into account the creatine concentration according to the invention in the dialysis solution, that ~10 mol-% of the creatine may already have been converted into creatinine at the time when the dialysis solution is actually applied.

[0019] This development is of the greatest practical and technical importance, as it significantly simplifies the process of how and when exactly the creatine is added to the dialysis solution, how exactly stock solutions can be introduced, how exactly stock solutions are prepared and how long they can be stored under which conditions, and thus also creates new options that would not be possible without the invention.

[0020] The rate constant of the conversion of creatine to creatinine in aqueous solution, like the solubility of creatine itself, is strongly pH- and temperature-dependent. The overall process of how exactly (and in what technical implementation) creatine is added to the dialysis solution comprises several steps, from dissolving a creatine compound to producing a stock solution, its storage, and its incorporation into a dialysis solution component (or into the dialysis solution itself), which is then mixed to form the finished dialysis solution. Thanks to the invention, entirely new temperature ranges within the process, as well as storage and transport temperatures, and especially shelf life, are explored for the entire process.The invention also makes it possible for the first time to traverse and use acidic or basic pH ranges (pH 2 to neutral and pH 14 to neutral) during the introduction process, which was not possible with the previous state of the art (for example, the addition of creatine via the acidic or basic dialysis solution concentrate).

[0021] The invention enables, for example, a 50 mM stock solution of creatine in water (WFI) to be used as an intermediate step in the technical implementation for enriching the dialysis solution with creatine by adding the stock solution to a prepared dialysis fluid stream, which, according to the prior art, could only be used for a few days. According to the invention, this can now be stored for 9 months under refrigeration (4°C) and transported at room temperature (with a total transport time of 5 days). This eliminates: a) The need to prepare the stock solution close to the time of dialysis, which had to be done locally without long transport routes and was therefore labor-intensive and costly (due to the limited number of dialysis treatments performed in a hospital); b) The costly transport cold chain, since room temperature can be used for transport logistics.This also enables a significant cost reduction through the use of large, automated, high-throughput equipment to produce the stock solution, which can be conveniently stored and distributed.

[0022] Only the present invention makes it possible to use a creatine concentrate solution delivered to the patient's home for the preparation of the dialysis solution according to the invention in a home dialysis device, which is decomposed to a maximum of 5% at the time of delivery, in such a way that he can store it for an additional 5 weeks at room temperature (20°C) without having to store it in a specially purchased and operated refrigerator.

[0023] The invention makes it possible to enrich the water supplied to the dialysis machines with creatine at a dialysis station equipped with a central water treatment system that supplies the existing dialysis machines. This enrichment is achieved by means of an additional device, allowing the dialysis solution according to the invention to be prepared by the existing dialysis machines without any modification of the existing hardware (resulting in cost reduction). The concentrates (typically acidic or alkaline) used by existing dialysis machines to mix the finished dialysis solution with water can continue to be used unchanged according to the invention (as the creatine enrichment according to the invention is achieved through the water) to prepare the dialysis solution according to the invention.This is achieved by first mixing the creatine, which is dissolved in the water (normally), with one of the concentrates and then neutralizing it with the other, thus allowing it to be exposed to a very acidic or very basic pH for a certain period of time without leaving the creatine to creatinine parameter range optimized according to the invention.

[0024] This fact is relevant because the solution according to the invention allows for approximately one hour of processing time at the extreme pH of the acidic or alkaline side. This enables significant economies of scale and cost savings for dialysis centers with centralized water treatment, as well as considerably simplifying distribution logistics. The invention enables a new technical implementation such that the creatine is added upstream of an inlet of the dialysis machine via one of the two concentrate inlets as a pre-prepared stock solution or as a freshly prepared stock solution, without requiring extensive modifications to the dialysis machine itself, yet still producing the dialysis solution according to the invention. This allows the expensive equipment already present in dialysis centers to continue to be used without requiring modifications or replacements, and without altering the water treatment process, resulting in substantial cost savings.

[0025] The invention makes it possible to use creatine stock solutions for mixing the dialysis solution according to the invention for dissolving creatine (for example, in or on a dialysis machine or at the dialysis station) at higher temperatures in order to achieve higher concentrations and faster dissolution times, since approximately 1-3 days of processing time are available, which simplifies handling on the one hand and reduces the process duration, thus having a doubly complexity- and cost-reducing effect.

[0026] The invention further enables the temperature for the dissolution process to be increased in a factory for the production of containers filled with creatine stock solution for the preparation of the dialysis solution according to the invention, in order to increase the throughput of dissolution / filling lines, in order to accelerate this production process and reduce costs, since this reduces the available "shelf life" of the stock solution for the dialysis solution according to the invention within an economic framework.

[0027] Only through this invention will it be possible to provide finely crystalline creatine monohydrate in a solid mixture or a multi-chamber system with bicarbonate for the basic side of the dialysis solution preparation in such a way that the dialysis machine dissolves the bicarbonate as well as the creatine substance(s) and mixes them with the other components to form the finished dialysis solution according to the invention, thus allowing such cost-saving integration.

[0028] These examples illustrate that only the dialysis solution according to the invention, with its harmless creatinine but simultaneously beneficial narrow creatine concentration, makes it possible to simplify the technical and procedural implementation of how creatine is added to the dialysis solution to such an extent that many different technical implementation options are opened up and can be designed in such a way that the existing dialysis treatment infrastructure only needs to be minimally adapted, which significantly reduces system costs for the healthcare system. Surprisingly, clinical trials have shown that a very narrow concentration range of 0.8 to 2.5 mM creatine proves to be optimal for the practical treatment of creatine deficiency in chronic dialysis patients. This is surprisingly largely independent of the patients' body weight, which varied by more than a factor of 2 (~50 to -115 kg).The absorption of creatine offered in the dialysis solution and transported into the body via the blood plasma largely converged after a few weeks of treatment at concentrations high enough to supply the body with creatine to such an extent that the creatine pool of the dialysis patients could be replenished physiologically optimally. Since the aim of the invention is the treatment of creatine deficiency within a chronic, i.e., permanent until death (or transplantation), life-saving therapy that replaces vital kidney function, the goal is not a rapid replenishment of the body's own creatine pool, but rather to maintain it at a healthy physiological level with intradialytic creatine administration until the end of life (or until transplantation). Therefore, an overdose of creatine is not necessary.Furthermore, it has been shown that creatine uptake decreases with continued treatment (i.e., an increasing creatine pool in the patient's body). This means that the greater the creatine deficiency at the start of treatment, the more creatine is automatically absorbed into the body. Subsequently, the creatine pool stabilizes on its own if the concentrations of creatine and creatinine according to the invention are maintained throughout the entire dialysis session (especially until the end of the session). Therefore, adjusting the creatine concentration based on various patient characteristics such as weight, lean body mass, sex, etc., is unnecessary. This finding is entirely novel and unexpected and has great practical significance for the clinical application of creatine in dialysis patients, as a standardized treatment can be used effectively regardless of body weight, lean body mass, or other physiological parameters.

[0029] The molar concentration (M) used in the claims is the amount of chemically active substance in a solution, measured in moles per liter of solution. Common units and symbols are: mM (millimolar) and pM (micromolar).

[0030] Creatinine (Crn), a cyclized, non-enzymatic breakdown product of creatine excreted in healthy individuals, is removed from the body of dialysis patients via the dialysis solution. Simultaneously, it is inevitably produced as a breakdown product of creatine before and during every intradialytic administration process in varying amounts, including during formulation (e.g., creatine synthesis, preparation), in creatine-containing stock solutions, and in the dialysis solution itself. Therefore, creatine is never truly completely free of creatinine. The technically feasible implementation of intradialytic creatine administration thus requires experimental investigations to determine the permissible creatinine levels or concentrations in the dialysis solution without endangering patients.

[0031] The common perception among physicians that creatinine is supposedly harmful to the kidneys (presumably based on the fact that plasma creatinine concentration is the most frequently used clinical proxy marker for the glomerular filtration rate of the kidneys) stems from the misconception that the marker itself is a harmful substance, which has proven to be false. This has led to considerable technical effort being made to keep the creatinine concentration in creatine as low as possible for certain applications, which is complex and expensive.

[0032] The creatinine concentrations according to the invention significantly simplify processing, logistics, and storage requirements (e.g., refrigerated storage). Furthermore, they can save costs, extend the shelf life of the creatine-containing solution, and, most importantly, offer many cost-relevant and complexity-reducing degrees of freedom with regard to technical implementation options, such as increasing the pH range (the rate constant for creatine to creatinine conversion and the position of the creatine-creatinine equilibrium are strongly pH-dependent), allowing for different processing times and temperatures (creatine solubility, the rate constant for creatine to creatinine conversion, and the position of the creatine-creatinine equilibrium are strongly temperature-dependent), reducing volume (logistics and production), etc.of precursors, components, stock solutions, solid stock preparations and other dialysis solution precursors, which are prepared to form a finished dialysis solution.

[0033] The maximum limits for creatinine concentration according to the invention during intradialytic creatine administration have surprisingly proven to be optimal for safe treatment. Given that intradialytic creatine administration is a parenteral administration bypassing the natural gastrointestinal barrier, this is essential for practical application in patients, as creatinine, as well as other low-molecular-weight substances, pass directly into the bloodstream unfiltered. The high limits for creatinine concentration according to the invention eliminate the need for technically complex and therefore expensive methods for minimizing creatinine concentration.

[0034] Furthermore, there is no known process that actively pumps creatinine from the dialysis solution into the body. Nevertheless, the administration of the dialysis solution according to the invention still allows creatinine to be removed from the body in any case (albeit more slowly), without any disadvantages for the patients.

[0035] Creatinine concentration is measured in the freshly prepared dialysis solution, which is fed into the dialysis filter. Reverse-phase HPLC is the standard method, but care must be taken to avoid interference with other components, particularly creatine, in the dialysis solution. Therefore, clinical tests that use enzyme-linked assays via creatinine nitric oxide to produce creatine, which is then broken down and measured, cannot be used. Similarly, the classic Jaffe method is not ideally suited due to the potential for interference.

[0036] Further advantageous embodiments of the invention can be commented on as follows:

[0037] In a particular embodiment of the invention, the dialysis solution has a concentration of 0.9–2.3 mM, preferably 1.0–1.9 mM, of one or more creatine compounds. In a further embodiment, the concentration of the creatine compound(s) in the dialysis solution is 1.2–1.8 mM, preferably 1.25–1.7 mM.

[0038] In a particular embodiment of the invention, (i) at least 80 mol% creatine - but excluding the decomposition product creatinine - is present in the dialysis solution as (phospho)creatine and (ii) a maximum of 20 mol% as creatine precursor in the dialysis solution, preferably 90 mol% (i) to 10 mol% (ii).

[0039] The dialysis solution should preferably contain no more than 100 ppm creatinine, preferably no more than 50 ppm creatinine.

[0040] In a particular embodiment of the invention, the dialysis solution has a maximum concentration of 200 pM of phosphates bound or dissociated to one or more creatine compounds.

[0041] In a particular embodiment of the invention, the concentration of bound or dissociated phosphates in the dialysis solution is a maximum of 100 ppm, preferably a maximum of 50 ppm. Due to the impaired or absent renal function in dialysis patients, clinical monitoring of the phosphate level (and the calcium-phosphate product) is important to prevent excessive hyperphosphatemia in these patients. A key component of this monitoring is the removal of dietary phosphate from the gastrointestinal tract using phosphate binders. Intradialytic administration of (phospho)creatine compounds such as (phospho)creatine, (phospho)creatine monohydrate, and (phospho)creatine salts delivers bound phosphate directly into the bloodstream of dialysis patients, thus directly introducing phosphate into the body. This bound phosphate is released over time, contributing to the total phosphorus in the body and further increasing the serum phosphorus concentration.Since dialysis patients already suffer from excessive phosphate levels in their bodies, additional phosphate intake, which is carried out regularly and chronically (dialysis treatment for CKD patients must be carried out permanently to sustain life), is critical to consider and can even be harmful to the body in the long run, as the calcium-phosphate product is also increased.

[0042] In some regions, phosphocreatine has been and is still being administered intravenously for the treatment of acute heart failure. However, this is a one-time, short-term acute intervention, not a chronic one, and is generally used in patients who are not on dialysis and have functioning renal excretion. Furthermore, the production of the aforementioned phosphocreatine compounds is relatively complex and expensive compared to the unphosphorylated compounds, which significantly increases the cost of the therapy. This cost can only be justified by an additional clinical benefit, which, however, must be weighed against the risks and benefits of the additional phosphate intake. Additionally, the phosphocreatine compounds are less stable. On the one hand, the bond between the phosphate and the rest of the compound is not very stable in aqueous solution and decomposes easily; on the other hand, phosphocreatine cyclizes more rapidly to creatinine, which is excreted.Based on all these findings in combination, it has proven advantageous to establish the maximum limits according to the invention for the use of these substances for intradialytic creatine administration for the treatment of creatine deficiency in dialysis patients.

[0043] In a particular embodiment of the invention, the dialysis solution has a concentration of at most 13.1 pg / l, preferably at most 6.55 pg / l dicyandiamide.

[0044] In another embodiment, the dialysis solution contains at most 786 ng / l, preferably at most 542 ng / l dihydrotriazine.

[0045] In another embodiment, the dialysis solution contains – based on the molar ratio relative to creatine monohydrate – no more than 40 mg of dicyandiamide per kg of creatine compound used. In a particular embodiment of the invention, the dialysis solution contains – based on the molar ratio relative to creatine monohydrate – no more than 30 mg of dicyandiamide per kg of creatine compound used, preferably no more than 25 mg / kg.

[0046] In another embodiment, the dialysis solution contains—based on the molar ratio relative to creatine monohydrate—no more than 3 mg of dihydrotriazine per kg of creatine compound used, preferably no more than 2 mg / kg per kg of creatine compound used. When creatine is administered intradialytically to treat creatine deficiency, low-molecular-weight byproducts and degradation products of creatine also enter the bloodstream practically unimpeded. This contrasts with oral administration, where the gastrointestinal tract presents a physical barrier to the blood. Any synthesis of a substance inevitably involves certain amounts of byproducts, some of which can be toxic. This must be avoided. Since the creatine substance is administered directly into the bloodstream in this invention, it proved advantageous to further reduce risk by limiting the DCD concentration to a maximum value according to the invention.

[0047] In a specific embodiment of the invention, the concentration(s) of the creatine compound(s) and / or creatinine is / are defined independently of the patient.

[0048] Finally, in another embodiment, the ratio K a : Kb of the creatine concentration Ka to the creatinine concentration Kb in the dialysis solution in the range of 6 - 100, preferably from 8 - 50.

[0049] The invention and further developments of the invention will be explained in more detail below using several non-restrictive exemplary embodiments.

[0050] Example 1 (according to the invention)

[0051] A female patient weighing 55 kg with a lean body mass of approximately 38 kg, who had been on dialysis for an extended period (3 times per week for 4 hours each session), is now being treated with a dialysis solution containing 1.5 mM creatine and 75 pM creatinine (measured in the fresh dialysis solution, before the dialysis filter, using reverse-phase HPLC). Creatine uptake is initially high, between 6.5 and 7 g per session, and stabilizes after a few weeks at approximately 3 to 3.6 g per session, which corresponds to a healthy creatine pool given this treatment interval and body mass. Creatinine excretion from the body into the dialysis solution occurs without problems during the dialysis sessions.

[0052] Example 2 (according to the invention)

[0053] A 67 kg male patient with a lean body mass of approximately 50 kg, who had been on dialysis for an extended period (3 times per week for 3 hours each session), is now being treated with a dialysis solution containing 2 mM creatine and 100 pM creatinine. Initially, creatine uptake is very high at approximately 9.5 g per dialysis session, but after 3 weeks it drops to 5.5-6 g per session and stabilizes early on at approximately 4 g per session. This leads to a rapid replenishment of the creatine pool. Creatinine excretion into the dialysis solution occurs without problems during the dialysis sessions.

[0054] Example 3 (state-of-the-art hemodialysis)

[0055] A 100 kg male patient with a lean body mass of approximately 65 kg, who had been on hemodialysis for an extended period (3 times per week for 3.5 hours each session), was newly treated with a dialysis solution containing 0.5 mM creatine and 50 pM creatinine. The patient absorbed 2.9 g in the first session and, after 6 weeks, still only 2.5 g per session, a value clearly below what is needed for a healthy creatinine balance. The patient remained creatine deficient.

[0056] Example 4 (according to the invention)

[0057] A patient population of 9 people (male and female) weighing between 50-120 kg and with a lean body mass between 35-75 kg, all of whom had been on dialysis for a long time (2-3 times per week for 2.5-4 hours each), were newly treated (3 patients each) with the following dialysis solutions, which contain the following concentrations of creatine and creatinine:

[0058] (i) 1.0 mM creatine and 35 pM creatinine;

[0059] (ii) 1.5 mM creatine and 50 pM creatinine;

[0060] (iii) 2.0 mM creatine and 75 pM creatinine;

[0061] All patients followed the pattern of initially having higher creatine levels, which normalized after a few weeks of dialysis treatment. Creatinine excretion was unaffected in all patients.

[0062] Example 5 (according to the invention)

[0063] A creatine stock solution of creatine monohydrate in water (for injection) containing 50 mM creatine at the time of preparation was used in a 1:49 ratio to produce a ready-to-use dialysis solution containing 1 mM creatine. This was done using a standard dialysis machine, which mixed the dialysis solution online and supplied it to and discharged from the dialysis filter, where the dialytic exchange with the blood took place. After preparation and packaging, the stock solution was stored at room temperature for 8 months at 4°C. It was then transported from the manufacturer to the clinic at room temperature and used there after a further month of storage at 4°C. During this time, approximately 9% creatinine was formed, so that the ready-to-use dialysis solution contained 0.91 mM creatine and 90 pM creatinine.

Claims

Patent claims 1. Dialysis solution for use in the prophylaxis and treatment of creatine deficiency in patients, comprising one or more creatine compounds selected from the groups consisting of: (i) (Phospho)creatine and its physiologically acceptable salts, both with any proportion of water of crystallization, in particular creatine monohydrate; and (ii) Guanidinoacetic acid (physiological precursor of creatine), and its physiologically acceptable salts, both with any proportion of water of crystallization, characterized in that a) the one or more creatine compound(s) is / are present in the dialysis solution in a concentration equivalent to 0.8 to 2.5 mM creatine; and b) the dialysis solution has a creatinine concentration of 0.1 to 200 pM.

2. Dialysis solution according to claim 1, characterized in that the dialysis solution has a concentration of 0.9 - 2.3 mM, preferably 1.0 - 1.9 mM of the one or more creatine compound(s).

3. Dialysis solution according to claim 2 characterized in that the concentration of the creatine compound(s) in the dialysis solution is 1.2 - 1.8 mM, preferably 1.25 - 1.7 mM.

4. Dialysis solution according to claim 3, characterized in that at least 80 mol-% creatine according to group (i) - but excluding the decomposition product creatinine - is present in the solution as (phospho)creatine and a maximum of 20 mol-% as creatine precursor according to group (ii) is present in the solution, preferably 90 mol-% (i) to 10 mol-% (ii).

5. Dialysis solution according to one of claims 1 to 4, characterized in that the dialysis solution contains at most 100 pM creatinine, preferably at most 50 pM creatinine.

6. Dialysis solution according to claims 1 to 5, characterized in that it has a concentration of at most 200 pM of phosphates bound or dissociated to one or more creatine compounds.

7. Dialysis solution according to claim 6, characterized in that the concentration of bound or dissociated phosphates in the dialysis solution is a maximum of 100 pM, preferably a maximum of 50 pM.

8. Dialysis solution according to one of claims 1 to 7, characterized in that the dialysis solution contains at most 13.1 pg / l, preferably at most 6.55 pg / l dicyandiamide.

9. Dialysis solution according to one of claims 1 to 8, characterized in that the dialysis solution contains at most 786 ng / l, preferably at most 542 ng / l dihydrotriazine.

10. Dialysis solution according to one of claims 1 to 9, characterized in that it contains - according to the molar ratio based on creatine monohydrate - not more than 40 mg dicyandiamide per kg of creatine compound used.

11. Dialysis solution according to claim 10, characterized in that it contains - according to the molar ratio based on creatine monohydrate - no more than 30 mg dicyandiamide per kg of creatine compound used, preferably no more than 25 mg / kg.

12. Dialysis solution according to one of claims 1 to 11, characterized in that it contains - according to the molar ratio based on creatine monohydrate - no more than 3 mg dihydrotriazine per kg of creatine compound used, preferably no more than 2 mg / kg.

13. Dialysis solution according to one of claims 1 to 12, characterized in that the concentration of the creatine compound(s) and / or creatinine is defined independently of the patient.

14. Dialysis solution according to one of claims 1 to 13, characterized in that the ratio K a : Kb of the creatine concentration Ka to the creatinine concentration Kb is in the range of 6 - 100, preferably 8 - 50.