Dosage formulation for a dialysis solution for the prophylaxis and treatment of creatine deficiency and the symptoms associated therewith in peritoneal dialysis patients

Abstract

The dosage formulation relates to a dialysis solution for the prophylaxis and treatment of creatine deficiency and the symptoms associated therewith in peritoneal dialysis patients. The peritoneal dialysis solution contains one or more creatine compound(s), having a total concentration equivalent to 0.8 - 3.5 mM creatine, selected from the following groups: (i) creatine and the pharmaceutically acceptable salts thereof; (v) (phospho)creatine compounds; (vi) (phospho)creatine derivatives; (vii) creatine precursors, (viii) creatine analogues, and mixtures thereof. In each case, 0.5 - 4.0 l of the peritoneal dialysis solution are used for one or more dialysis cycles per 24 hours.

Description

[0001] Dosage formulation for a dialysis solution for the prophylaxis and treatment of creatine deficiency and its associated symptoms in peritoneal dialysis patients

[0002] The present invention relates to a dosage formulation for a dialysis solution for the prophylaxis and treatment of creatine deficiency and the associated symptoms in peritoneal dialysis patients, in particular for the prophylaxis and treatment of creatine deficiency syndrome in patients with chronic kidney disease (hereinafter: dialysis patients) and the associated symptoms, according to the preamble of claim 1.

[0003] The dosage formulation refers to the intradialytic administration of creatine during peritoneal dialysis for the treatment of creatine deficiency, as occurs, for example, in patients who rely on peritoneal dialysis as chronic renal replacement therapy.

[0004] The dosage formulation presented here applies without distinction to all technical and clinical implementations of peritoneal dialysis, since the fundamental properties of detoxification, drainage and, in the present invention, supply via the peritoneum with its physiological and physical parameters remain unchanged, even if, due to clinical and / or equipment-related characteristics, various names are used, such as continuous ambulatory peritoneal dialysis, assisted peritoneal dialysis, automated peritoneal dialysis or intermittent ambulatory or assisted peritoneal dialysis.

[0005] Peritoneal dialysis is performed cyclically. A cycle consists of introducing a peritoneal dialysis solution into the abdominal cavity, leaving it there for a period of time, and then draining it. While in the abdominal cavity, the peritoneum acts as a dialysis membrane, facilitating the exchange of substances between the body and the dialysis solution. Full or partial cycles can be performed manually or automatically (by a cycler). This can be done during the day or overnight, adapted to individual needs and medical requirements. Automated exchange using a machine is often conveniently performed at night.

[0006] 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.

[0007] 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 bodies compared to the general population.

[0008] 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.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.

[0009] 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.

[0010] 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".

[0011] Creatine deficiency manifests itself in a range of physical symptoms. Replenishing or maintaining the creatine pool in the body of dialysis patients to a normal, healthy level, which is achieved through intradialytic administration of creatine at the dose disclosed herein, can positively influence a number of these symptoms:

[0012] Creatine is essential for the normal functioning of the central nervous system, particularly neurons. These exhibit a very high and highly fluctuating energy consumption, primarily due to their various energy-intensive ion pumps. Furthermore, the intracellular transport of organelles and substances over the long distances along the axons consumes a significant amount of energy.

[0013] Complex fatigue syndromes such as Chronic Fatigue Syndrome or ME / CFS (Myalgic Encephalomyelitis) can be positively influenced by intradialytic creatine administration.

[0014] Cognitive impairments affecting working memory, long-term memory, mental performance, intelligence tests, brain fog, concentration difficulties, and reduced stress resistance can be alleviated by intradialytic creatine administration. Coordination problems, depression, and sleep disturbances such as difficulty falling asleep, difficulty staying asleep, daytime sleepiness, and reduced sleep quality can also be reduced by intradialytic creatine administration.

[0015] Intradialytic creatine administration also leads to a certain degree of protection of the central nervous system against cell damage.

[0016] Paresthesia and peripheral polyneuropathy are common symptoms in chronic dialysis patients, which can be alleviated by intradialytic creatine administration. Intradialytic creatine administration also provides some protection of the peripheral nervous system against cell damage.

[0017] Intradialytic creatine administration alleviates muscle weakness such as loss of muscle mass, strength, and power, muscle hypotonia, and muscle fatigue, as well as problems associated with reduced muscle relaxation (muscle cramps). Replenishment of the creatine pool through intradialytic creatine administration counteracts muscle mass loss (sarcopenia), muscle atrophy, and catabolic muscle breakdown. Muscle fatigue, the physiological parameter for performance decline during endurance exercise, is slowed by intradialytic creatine administration. Impaired muscle relaxation, which manifests as the muscle cramps frequently experienced by dialysis patients, is improved by intradialytic creatine administration, thus reducing muscle cramps. Myalgic muscle pain is also reduced by intradialytic creatine administration.

[0018] Creatine improves muscle strength, increases muscle mass, and promotes the regeneration of muscle tissue, thus enhancing recovery after strenuous muscle activity. It is therefore a "performance enhancer / endurance enhancer / recovery enhancer".

[0019] Cardiomyocytes, with their high and highly fluctuating energy turnover, are strengthened by creatine administration; intradialytic creatine administration counteracts cardiac muscle disorders, myocardial insufficiency and cardiomyopathies, as well as generally left ventricular hypertrophy and other myocardial bioenergetic abnormalities.

[0020] Bone mineralization and the deposition of organic extracellular bone matrix are energy-intensive processes. Additionally, osteoblasts are restricted in their diffusion by their environment and shape. Intradialytic creatine administration counteracts osteopenia, osteoporosis, and uremic osteodystrophy, and also has a generally positive effect on bone and cartilage, as well as mineral density. Blood cell formation in general, and erythropoiesis in particular, are energy-intensive processes that are improved by intradialytic creatine administration. Renal anemia due to insufficient blood cell production can be alleviated by creatine.

[0021] Although erythrocytes themselves do not have an aerobic metabolism, a creatine transporter is found in the erythrocyte membrane. Intradialytic creatine administration protects the membranes of erythrocytes, which are particularly stressed by dialysis, against both mechanical and oxidative stress, which can lead to hemolysis, and thus extends the lifespan of the erythrocytes. Intradialytic creatine administration therefore reduces anemia in dialysis patients and has the added benefit of lowering the amount of erythropoietin required to stimulate erythropoiesis in these patients, resulting in significant cost savings in their treatment.

[0022] Movement coordination disorders can be reduced by intradialytic creatine administration through improved muscle and central nervous system function, as well as a strengthened peripheral nervous system and improved muscle relaxation. Thus, intradialytic creatine administration improves overall movement coordination.

[0023] The increased susceptibility to infection and the elevated risk of adverse outcomes from infectious diseases in dialysis patients can be reduced by intradialytic creatine administration, which also protects immune cells from mechanical, oxidative, and metabolic stress. Furthermore, the immune system is significantly strengthened by creatine through metabolic support of macrophages, neutrophils, B lymphocytes, and T cells.

[0024] Dialysis patients suffer from a significantly increased frequency of falls and a correspondingly increased frequency of bone fractures, which can be reduced by intradialytic creatine administration.

[0025] Intradialytic creatine administration reduces immobilization-induced muscle atrophy (muscle wasting due to lying down, plaster casts, etc.), promotes bone fracture healing, and also improves wound and skin healing. Furthermore, creatine can also alleviate fall-related brain injuries.

[0026] Intradialytic creatine administration reduces the effects of ischemia and anoxia on body cells by increasing the creatine pool and the associated longer energy buffer time; thus, it mitigates the consequences of thrombosis, such as stroke, heart attack, pulmonary embolism, but also of ischemia due to internal bleeding.

[0027] Creatine supplementation improves the barrier function of the intestinal epithelium and reduces inflammation in the intestinal mucosa of patients with chronic inflammatory bowel disease.

[0028] Creatine supplementation, especially in older adults, improves musculoskeletal health and slows the progressive, age-related muscle loss (sarcopenia), thereby delaying frailty in seniors. At the same time, creatine counteracts age-related vision and hearing loss. It also helps alleviate dizziness, contributing to safer mobility in daily life. All these factors contribute to an improved quality of life in old age and can postpone the need for long-term care. Overall, regular creatine supplementation contributes to healthier aging. The same applies to dialysis patients.

[0029] 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.

[0030] 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 dosage instructions 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.

[0031] The invention aims to remedy this problem. With the present invention, the intradialytic administration of creatine is integrated into the dialysis process itself. The latter represents the only consistently repetitive process in the course of dialysis patients, and this process essentially consists of a defined, dosed, and diffusive administration of creatine into the blood via the addition of creatine through the dialysis fluid, which is in direct dialytic-bidirectional exchange with the blood.

[0032] The invention solves this problem with a dosage formulation for a dialysis solution for the prophylaxis and treatment of creatine deficiency and the associated symptoms in peritoneal dialysis patients according to the features of claim 1.

[0033] The present invention allows for the simple intradialytic administration of creatine based on a desired creatine concentration in conjunction with a defined creatinine concentration in the peritoneal dialysis solution, which is introduced into the abdominal cavity of the patients.

[0034] The molar concentration (M) used in the present invention is the amount of chemically active substance in a solution, measured in moles per liter of solution. Common units and symbols for molar concentration are: mM (millimolar) and pM (micromolar).

[0035] The advantages achieved by the invention lie essentially in the fact that, thanks to the dosage formulation according to the invention, the creatine compound supplied with the dialysis solution prevents creatine deficiency in dialysis patients, or vice versa. It is clearly defined which dose of creatine is supplied to the body via the peritoneal dialysis solution during the dialysis process.

[0036] The amount of creatine compound disclosed here (during a defined time interval), in conjunction with the permissible creatinine concentration, provides a simple and sufficient indication for conducting dialysis treatment in the patient. The unavoidable, difficult-to-quantify, and always simultaneous losses of creatine—both those not yet absorbed from the peritoneal dialysis solution into the blood and those that diffused from the blood into the peritoneal dialysis solution and are thus present in the used dialysis solution drained from the abdominal cavity—need not be considered further with this dosage formulation. Differences due to varying osmolarities of the dialysis solutions used for drainage (volume control) can be disregarded.

[0037] Administering creatine directly into the abdominal cavity via the dialysis fluid is equivalent to parenteral administration, bypassing the gastrointestinal tract. This is because the patient's blood comes into direct contact with the dialysis fluid via the peritoneum, and creatine, being a low-molecular-weight compound (molecular weight = 131.13 grams), diffuses almost freely (directly into the bloodstream via the peritoneum). Low-molecular-weight byproducts and breakdown products of creatine also pass freely into the bloodstream. This contrasts with oral administration, where the gastrointestinal tract acts as a physical barrier to the blood, and creatine can only be absorbed into the blood via a specific creatine transporter.

[0038] The functioning of the creatine system depends directly on the cytosolic creatine concentration to fulfill its role as an energy buffer and endocellular energy transport system. In fact, dialysis patients without intradialytic creatine administration are severely creatine-depleted, and all the symptoms described above affect organs containing cells with high energy turnover, highly fluctuating energy consumption, or long cytosolic diffusion pathways from the mitochondria to the site of energy consumption. Optimal creatine system function is particularly important for all these cells. Synergistic interactions of various symptoms, such as fatigue and muscle weakness, which can lead to increased falls, are plausible and relevant in clinical practice and for the well-being of dialysis patients.

[0039] The dosage formulation according to the invention is particularly suitable for treating the symptoms / diseases / conditions listed below, as it supplies the body with the amount of creatine which a) in chronic dialysis patients with creatine deficiency, compensates for this deficiency to such an extent that a healthy creatine pool is achieved in the patient's body over a period of several weeks of dialysis treatment with creatine-containing dialysis solution. The exact period depends on patient-specific parameters such as lean body mass, weight, degree of deficiency, metabolic parameters, etc.However, it has been shown that the dosage according to the invention provides the body with exactly the amount that leads to a stabilization of the creatine pool, independent of the above patient-specific parameters in the body; and b) keeps the creatine pool in the body of the chronic dialysis patient stable at a healthy level in such a way that the creatine administration thus compensates well for the inevitable loss resulting from the non-enzymatic, uncontrollable conversion of creatine to creatinine in a way that is well tolerated by the patient.

[0040] This replenishment and maintenance of the creatine pool is essential for the healthy functioning of the creatine system within the cells. It is precisely those cell types with high and / or highly fluctuating energy turnover and those with diffusion-restricted energy that benefit most: myofibrils, neurons, cardiomyocytes, osteoblasts, chondroblasts, cells with many ion pumps, such as the epithelial cells of the renal tubules, as well as auditory and balance cells, but also immune cells and all cells that actively take up creatine via the creatine transporter. These are a multitude of cell types in a wide variety of tissues, which is why the indications according to claim 22 appear diverse at first glance, but share a common (co-)cause: a malfunctioning creatine system that causes a general cellular energy deficit.However, creatine deficiency can be treated with this invention.

[0041] The indications listed below therefore relate to tissues or organs, or the interaction of such organ systems, which are (co-)built from cells in which the creatine system is important for healthy functioning:

[0042] Especially for nerve cells and the brain and brain function, specifically in cases of: a) fatigue (Chronic Fatigue Syndrome, ME / CFS Myalgic Encephalomyelitis, general tiredness and exhaustion) b) cognitive impairment and reduced performance (memory, mental performance, concentration problems, mental and post-traumatic stress) c) coordination disorders d) depression, anxiety disorders, sleep disorders, as well as e) protection against cell damage from trauma f) protection against neurodegeneration g) protection against the consequences of ischemia, asphyxia and anoxia h) and, via cell and ischemia protection, to reduce the consequences of fall- and accident-related brain trauma.

[0043] As well as for the protection and regeneration of nerve cells in the spinal cord and peripheral nervous system.

[0044] And especially for myofibrils and muscles (musculoskeletal system) specifically in cases of a) muscle weakness (weak muscle tone and fatigue of muscles and the musculoskeletal system), b) sarcopenia and age-related muscle loss, c) muscle atrophy, muscle wasting and rehabilitation, d) to reduce frailty and fragility, e) in cases of movement coordination disorders, reduced (muscle) endurance and rapid fatigue and for fall prevention (through improved muscle performance), as well as for f) muscle relaxation (muscle cramps) and ischemia prevention in cases of g) myalgia (muscle pain) and for strengthening for h) an increase in muscle mass and strength, and i) improved musculoskeletal healing after injuries, especially to reduce immobilization-related muscle atrophy.

[0045] And especially in cardiomyocytes with their periodic, highly fluctuating energy consumption, therefore in the following heart and cardiovascular diseases: a) heart muscle diseases and myocardial insufficiency; b) left ventricular hypertrophy to strengthen c) cardiovascular health; and d) to protect cells, i.e., to reduce the consequences of myocardial ischemia (heart attack) and the associated ischemia-reperfusion damage.

[0046] As well as in hepatocytes (liver) to prevent fatty liver, and in kidneys: renal ischemia and to improve residual kidney function.

[0047] As well as, in particular, osteoblasts, osteoclasts, and chondrocytes, and bone and cartilage, especially in a) osteopenia and osteoporosis, and also b) for bone and cartilage calcification and bone healing in fractures.

[0048] As well as in the intestines in cases of: intestinal inflammation, colitis, Crohn's disease

[0049] As well as for improved skin and wound healing.

[0050] As well as the hair cells in the ear and inner ear: a) hearing loss, tinnitus; b) dizziness, orthostatic intolerance

[0051] As well as in the case of the retina: degeneration and vision loss.

[0052] And especially in the case of erythrocytes, their formation (blood formation) and their lifespan against anemia and anemia, as well as for the mechanical and osmotic protection of the erythrocyte cell membranes.

[0053] As well as strengthening and activating immune cells such as macrophages, neutrophils, and T cells. Effective against inflammation and generally as cell protection against ischemia and asphyxia, against reactive oxygen species (ROS), and against radiation damage.

[0054] Further advantageous embodiments of the invention can be commented on as follows:

[0055] Another embodiment is a creatine compound which exists in solution in the form of creatine molecules.

[0056] Preferably, the creatine compound is: creatine, creatine monohydrate or a physiologically acceptable creatine salt.

[0057] Peritoneal dialysis uses the peritoneum, which lines the abdominal cavity, as a dialysis membrane. This occurs, on the one hand, through the exchange of low-molecular-weight substances. These substances are diluted from body fluids and blood plasma into the peritoneal dialysis solution via dialysis (osmosis) and then removed from the body. On the other hand, the peritoneum also acts as a dialysis membrane, drawing water from the body into the highly osmolar peritoneal dialysis solution via osmosis, thus ensuring fluid control, i.e., dehydration. The osmolarity, the number of cycles, the dwell time, and the exchange volumes are determined individually for each patient. Since the exchange of low-molecular-weight dialytic substances is always bidirectional, detoxification into the peritoneal dialysis solution occurs simultaneously with the supply of creatine from the peritoneal dialysis solution into the bloodstream.The prescribed dialysis dose therefore does not need to be changed for creatine supplementation, nor does the composition of the peritoneal dialysis solution enriched with creatine according to the invention need to be adjusted, as this is already done by the patient-specific dwell times, volumes and osmolarity.

[0058] Due to inter-patient variability, the number of cycles, dwell times, and volumes used vary considerably. Typically, the peritoneal dialysis solution simply remains in the abdominal cavity for the majority of the time.

[0059] Advantageously, the peritoneal dialysis solution according to the invention is changed manually 1-6 times per 24 hours with varying day-night rhythms or automatically by a device up to 15 times, primarily at night and partially during the day (patient-specific with various rhythms and partial exchange, typically 50% tidal). Many patterns exist, differing from each other: CAPD (Continuous Cycled PD), Dry Day APD, APD with long dwell, APD with two-day dwell, APD with short-day dwell, and tidal APD. Dwell times range from 45 minutes to 3 hours or up to 12 hours overnight. The volume exchanged is determined individually for each patient and can generally range from 0.The volume of 4 to 4 liters varies depending on the number of cycles, constitution, body type and preference, and especially whether tidal peritoneal dialysis is performed (i.e., partial exchange of the peritoneal dialysis solution located in the abdominal cavity; 50% of the volume is common, but other ratios such as 70 or 90% are also used).

[0060] In one particular dosage formulation, 1.5 to 2.5 liters of peritoneal dialysis solution are used in 1 to 5 cycles per 24 hours. In another embodiment, 1.5 to 2.5 liters of peritoneal dialysis solution are used in 1 to 5 cycles on 3 to 4 days (24 hours) per week. In a further embodiment, 0.5 to 2 liters, preferably 1.0 to 2 liters of peritoneal dialysis solution are used in 2 to 10 cycles per day (14 hours). In a special embodiment, 0.5 to 2 liters, preferably 1.0 to 2 liters of peritoneal dialysis solution are used in 2 to 10 cycles on 3 to 4 days (24 hours) per week.

[0061] In a particular embodiment, the (phospho)creatine compounds comprise the group consisting of (phospho)creatine, (phospho)creatine monohydrate, (phospho)cyclocreatine, and homocyclocreatine. The (phospho)creatine derivatives may include the group consisting of (phospho)creatine salts, and preferably creatine pyruvate, lactate, ascorbate, acetate, citrate, hydroxycitrate, laureate, phytate, mandelate, malate, glycolate, cinnamate, salicilate, hyaluronate, and β-hydroxygutyrate. -gluconate, -choline, -carnitine, -propionylcarnitine, -coenzyme Q10, -adenosine, -fructose, -fructose-1,6-bisphosphate, -adenosine ester, -acid anhydrous, and -glutamine.

[0062] Creatine precursors can include guanidinoacetic acid, 3-guanidinopropionic acid, guanidinobenzoic acids, and the combination of glycine, arginine, and methionine, as well as their physiologically acceptable salts and derivatives. Creatine analogs can include guanidinoacetic acid and guanidinoacetate.

[0063] The amount of creatine compound to be added to the hemodialysis solution is expediently adjusted according to the molar mass ratio to creatine.

[0064] The creatine compound(s) is preferably in solid form or in the form of a dialysis concentrate or dialysis solution.

[0065] Creatinine concentration is measured in the freshly prepared dialysis solution before it is introduced into the abdominal cavity. 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 using enzyme-linked assays via creatinine nitric oxide (CRISO) that 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.

[0066] According to the invention, the creatine compound contains at most 10 mol% creatinine (based on creatine + creatinine or on the total concentration of all creatine compounds plus creatinine), preferably at most 5 mol% creatinine. Creatinine (Crn), a cyclized, non-enzymatic breakdown product of creatine that is excreted in urine in healthy individuals, is removed from the body of dialysis patients by the dialysis solution. Simultaneously, it is inevitably produced as a breakdown product of creatine before and during every intradialytic administration process in varying amounts, also at the formulation stage, e.g., during creatine synthesis, preparation, as well as in creatine-containing stock solutions and also in the dialysis solution itself, so that creatine is never truly completely free of creatinine.A technically feasible implementation of intradialytic creatine administration therefore required experimental investigations to determine the permissible creatinine levels or concentrations in the dialysis solution without endangering patients. The common perception among physicians that creatinine is supposedly nephrotoxic (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 the creatine as low as possible for certain applications, which can be complex and expensive.

[0067] The preferred creatinine concentrations dramatically simplify processing, logistics, and storage requirements (e.g., refrigerated storage), thus saving costs, extending shelf life, and, above all, also improving technical aspects.

[0068] Implementation options have gained many cost-relevant and complexity-reducing degrees of freedom, such as increasing the pH range (strongly pH-dependent).

[0069] Rate constant for creatine to creatinine conversion and the position of the creatine-creatinine equilibrium), possible processing times and temperatures (strong temperature dependence of creatine solubility and the rate constant for creatine to creatinine conversion, as well as the position of the creatine-creatinine equilibrium), volume reduction (logistics and production), etc. of precursors or components, stock solutions, solid stock preparations, and other dialysis solution precursors that are prepared to form a finished dialysis solution.

[0070] The maximum creatinine limits listed here for intradialytic creatine administration have surprisingly proven optimal for safe treatment. Given that intradialytic creatine administration is a parenteral method bypassing the natural gastrointestinal barrier, this is essential for practical application in patients, as creatinine, along with other low-molecular-weight substances, passes directly into the bloodstream unfiltered. The surprisingly high creatinine concentration limits we determined eliminate the need for technically complex and therefore expensive methods to minimize creatinine levels. Furthermore, there is no known process that actively pumps creatinine from the dialysis solution into the body, and since creatinine is present in the body (in the blood plasma) at a higher concentration than the defined 10⁻⁵ M, this limit is not a significant factor.Even with a creatinine concentration of -% in the dialysis solution, the creatinine is still removed from the body (albeit marginally more slowly) using the present dosage regimen for creatine according to the invention. It is important that the dialysis process with creatine is not negatively affected by setting a maximum creatinine concentration. Preferably, the dialysis solution contains a creatinine concentration of no more than 100 pM, and preferably no more than 50 pM.

[0071] 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.

[0072] In a further embodiment of the invention, the dialysis solution has a concentration of at most 786 ng / l, preferably at most 542 ng / l dihydrotriazine.

[0073] The maximum concentration of impurities with synthesis by-products that can arise during the production of creatine serves to ensure that the health of dialysis patients is not endangered.

[0074] In a particular embodiment of the invention, the dialysis solution has a concentration of at most 100 pM, preferably at most 50 pM, of phosphates bound (or dissociated) to creatine substances.

[0075] In a further embodiment of the invention, 1.5 - 2.5 l of peritoneal dialysis solution is used in 1 - 5 cycles per 24 hours, and in a further embodiment of the invention, 1.5 - 2.5 l of peritoneal dialysis solution is used in 1 - 5 cycles on 3 to 4 days (24 hours) per week.

[0076] In a particular embodiment of the invention, 0.5 - 2.0 l, preferably 0.75 - 1.50 l of peritoneal dialysis solution is used in 2 - 10 cycles per day (24 hours), and in a further embodiment of the invention, 0.5 - 2.0 l, preferably 0.75 - 1.50 l of peritoneal dialysis solution is used in 2 - 10 cycles on 3 to 4 days (24 hours) per week.

[0077] The invention also relates to a manufacturing process for a dialysis solution according to the dosage instructions of the invention. It consists in the addition of one or more creatine compounds to the peritoneal dialysis solution by means of a predetermined or in situ prepared solution of one or more creatine compounds, preferably in the form of a stock solution.

[0078] The creatine compound according to the invention serves for the prophylaxis and treatment of the following symptoms in hemodialysis patients:

[0079] I. Brain & Brain Function: a) Symptoms of Fatigue:

[0080] 1. Chronic Fatigue Syndrome

[0081] 2. ME / CFS Myalgic Encephalomyelitis

[0082] 3. General fatigue, exhaustion b) Cognitive impairment, cognitive performance of the / the / of

[0083] 1. Working memory

[0084] 2. Long-term memory

[0085] 3. Mental performance

[0086] 4. Brain fog

[0087] 5. Concentration difficulties

[0088] 6. Reduced stress resistance c) Coordination disorders d) Depression, anxiety disorders e) Sleep disorders:

[0089] 1. Difficulty falling asleep

[0090] 2. Sleep disturbance

[0091] 3. Daytime sleepiness

[0092] 4. Reduced sleep quality f) to protect against cell damage from trauma g) to protect against neurodegeneration

[0093] II. Spinal Cord & Peripheral Nervous System: a) Paresthesias b) Peripheral Polyneuropathies c) for the protection and regeneration of the spinal cord and peripheral nervous system

[0094] III. Muscles: a) Muscle weakness

[0095] 1. Muscle tone weakness

[0096] 2. Muscle fatigue b) Sarcopenia, age-related loss of muscle mass c) Muscle atrophy, muscle wasting & rehabilitation d) Frailty & fragility e) Movement coordination disorders & fall prevention Muscle endurance & fatigue f) Muscle relaxation, muscle cramps & ischemia g) Myalgia, muscle pain h) For increasing muscle mass and strength i) For improved musculoskeletal healing,

[0097] IV. Heart & Cardiovascular System: a) Cardiac muscle diseases, myocardial insufficiency, cardiac ischemia, heart failure, myocardial infarction b) Left ventricular hypertrophy c) Cardiovascular health d) Myocardial ischemia, ischemia and reperfusion injury

[0098] V. Liver: a) to prevent fatty liver

[0099] VI. Kidneys: a) Follow renal ischemia, b) to improve residual renal function

[0100] VII. Bones and cartilage: a) Osteopenia b) Osteoporosis c) Uremic osteodystrophy d) for improved bone and cartilage mineralization

[0101] VIII. Blood and blood cells: a) Anemia b) Renal anemia

[0102] 1. reduced blood cell production

[0103] 2. the reduced lifespan of erythrocytes

[0104] 3. and to protect erythrocytes from osmotic and mechanical stress

[0105] IX. Immune system: a) Increased susceptibility to infection b) Increased risk of an unfavorable course of infectious diseases c) and to protect immune cells from mechanical, oxidative and osmotic stress d) to strengthen the immune system by supporting macrophages, B lymphocytes and T cells

[0106] X. Movement coordination disorders

[0107] XI. Fall prevention: a) increased frequency of falls b) increased frequency of bone fractures

[0108] XII. Fall prevention: a) Reduction of immobilization-induced muscle atrophy b) Impaired bone healing c) Impaired wound healing d) Impaired skin healing e) Fall-related brain trauma

[0109] XIII. Prevention of the consequences of ischemia to reduce the effects of ischemia and anoxia on body cells: a) Thrombosis

[0110] 1. Stroke

[0111] 2. Heart attack

[0112] 3. Pulmonary embolism b) and in cases of ischemia due to bleeding

[0113] XIV. Intestine: a) Intestinal inflammation, colitis, Crohn's disease b) Reduced intestinal health c) Colitis

[0114] XV. Frailty (Fragility)

[0115] XVI. Orthostatic problems and dizziness a) In the ear, energy for ion transport against ear cell loss b) Against dizziness

[0116] XVII. General cell protection: a) against ischemia & asphyxia b) against oxygen radicals (ROS) c) against radiation damage

[0117] The invention and further developments of the invention will be explained in more detail below using several non-restrictive exemplary embodiments.

[0118] Example 1

[0119] A patient undergoing continuous outpatient peritoneal dialysis performs five cycles daily, four times a day (at intervals of approximately 3-5 hours, depending on daily routine) plus overnight (8 hours). Each cycle involves the self-exchange of 1.5 liters of fresh peritoneal dialysis solution containing 0.227 g of creatine monohydrate per liter of peritoneal dialysis solution, corresponding to 1.5 mM creatine, and 75 M creatinine (corresponding to 5 mol% of the creatine monohydrate). The patient drains the old dialysis fluid and then adds fresh fluid. The creatinine concentration in the fresh peritoneal dialysis solution can be determined using HPLC, taking into account potential interferences (osmolytes, creatine, etc.). The patient's creatine pool replenishes to a normal level within a few weeks and remains within a healthy range thereafter. Creatinine excretion into the peritoneal dialysis solution proceeds without adverse effects on the patient.

[0120] Example 2

[0121] A patient undergoing nocturnal peritoneal dialysis using automated peritoneal dialysis (APD) on a dry-day schedule is treated with a device that delivers six 1.5-liter doses of peritoneal dialysis solution (141.5 mg creatine monohydrate per liter of dialysis solution, corresponding to 0.95 mM, and 58.5 µg guanidinoacetic acid per liter of dialysis solution, corresponding to 0.05 mM) of which 5 mol% (corresponding to 50 pM) is metabolized to creatinine. The patient's creatine pool replenishes to a normal level within a few weeks and remains within a healthy range thereafter. Creatinine excretion into the peritoneal dialysis solution occurs without adverse effects on the patient.

[0122] Example 3

[0123] This concerns a patient who performs intermittent self-dialysis three times a week (skipping two days twice a week and one day skipping two days). The dialysis solution contains 1.5 liters of peritoneal dialysis fluid three times a day and 2 liters overnight. This fluid contains 1.8 mM creatine (0.236 g anhydrous creatine per liter of peritoneal dialysis solution) and 80 pM (corresponding to 4.4 mol% of creatine) creatinine. The patient's creatine pool replenishes to a normal level within a few weeks and remains within a healthy range thereafter. Creatinine excretion into the peritoneal dialysis solution proceeds without adverse effects for the patient.

[0124] Example 4

[0125] This concerns a patient with automated tidal peritoneal dialysis, in which the peritoneal dialysis machine performs a (partial) exchange of the blood 12 times each night.

[0126] Peritoneal dialysis solution is performed, whereby 1.5 l of peritoneal dialysis solution is added during the first filling of the abdominal cavity, followed by 11 times 0.75 l of the

[0127] Peritoneal dialysis solution is drained and replaced with 0.75 liters of fresh peritoneal dialysis solution (50% tidal) until the entire 1.5 liters are drained in the morning (dry day). The peritoneal dialysis solution contains 2.3 mM creatine (corresponding to 0.301 g creatine monohydrate per liter of peritoneal dialysis solution) and 100 pM (corresponding to 4.34 mol%) creatinine. The patient's creatine pool replenishes to a normal level within a few weeks and remains within a healthy range thereafter, and creatinine excretion into the peritoneal dialysis solution occurs without adverse effects for the patient.

Claims

Patent claims 1. Dosage formulation for a dialysis solution for the prophylaxis and treatment of creatine deficiency and its associated symptoms in peritoneal dialysis patients, characterized in that a) the peritoneal dialysis solution contains one or more creatine compounds with a total concentration equivalent to 0.8 - 3.5 mM creatine, selected from the following groups: (i) Creatine and its pharmaceutically acceptable salts; (i) (Phospho)creatine compounds; (ii) (Phospho)Creatine derivatives; (iii) creatine precursors, (iv) Creatine analogues, and Mixtures thereof; and b) 0.5 - 4.0 I of the peritoneal dialysis solution is used for one or more dialysis cycles per 24 hours.

2. Dosage formulation according to claim 1, characterized in that the concentration of creatine compound(s) is 1.0 - 3.1 mM, preferably 1.2 - 2.8 mM.

3. Dosage formulation according to claim 2, characterized in that the concentration of creatine compound(s) is 1.5 - 2.5 mM, preferably 1.8 - 2.4 mM.

4. Dosage formulation according to one of claims 1 to 3, characterized in that the dialysis solution has a creatinine concentration of 0.1 to 200 pM.

5. Dosage formulation according to claim 4, characterized in that the dialysis solution has a concentration of at most 100 pM creatinine, preferably at most 50 pM creatinine.

6. Dosage formulation according to one of claims 1 to 5, characterized in that it is a creatine compound which is present in solution in the form of creatine molecules.

7. Dosage formulation according to claim 6, characterized in that the creatine compound is: creatine, creatine monohydrate or a physiologically acceptable creatine salt.

8. Dosage formulation according to one of claims 1 to 7, characterized in that the (phospho)creatine compounds comprise the group consisting of (phospho)creatine, (phospho)creatine monohydrate, (phospho)cyclocreatine, and homo-cyclocreatine.

9. Dosage formulation according to any one of claims 1 to 8, characterized in that the (phospho)creatine derivatives comprise the group of (phospho)creatine salts, and preferably creatine pyruvate, lactate, ascorbate, acetate, citrate, hydroxycitrate, laureate, phytate, mandelate, malate, glycolate, cinnamate, salicilate, hyaluronate, β-hydroxygutyrate, gluconate, choline, carnitine, propionylcarnitine, coenzyme Q10, adenosine, fructose, fructose-1,6-bisphosphate, adenosine ester, acid anhydrous dihydrogenase, and glutamine.

10. Dosage formulation according to any one of claims 1 to 9, characterized in that the creatine precursors comprise the group consisting of guanidinoacetic acid, 3-guanidinopropionic acid, guanidinobenzoic acids and the combination of glycine, arginine, and methionine as well as their physiologically acceptable salts and derivatives.

11. Dosage formulation according to any one of claims 1 to 10, characterized in that the creatine analogues comprise guanidinoacetic acid and guanidinoacetate.

12. Dosage formulation according to one of claims 1 to 11, characterized in that the amount of creatine compound to be added to the peritoneal dialysis solution is adapted according to the molar mass ratio to creatine.

13. Dosage formulation according to one of claims 1 to 12, characterized in that the one or more creatine compound(s) are in solid form or in the form of a dialysis concentrate or a dialysis solution.

14. Dosage formulation according to one of claims 1 to 13, characterized in that the dialysis solution contains at most 10 mol% creatinine (based on creatine + creatinine), preferably at most 5% mol% creatinine.

15. Dosage formulation according to one of claims 1 to 14, characterized in that the dialysis solution has a concentration of at most 13.1 pg / l, preferably at most 6.55 pg / l dicyandiamide.

16. Dosage formulation according to one of claims 1 to 15 characterized in that the dialysis solution has a concentration of at most 786 ng / l, preferably at most 542 ng / l dihydrotriazine.

17. Dosage formulation according to one of claims 1 to 16, characterized in that the dialysis solution contains a concentration of at most 100 pM, preferably at most 50 pM, of phosphates bound (or dissociated) to creatine substances.

18. Dosage formulation according to any one of claims 1 to 17, characterized in that 1.5 - 2.5 l of peritoneal dialysis solution is used in 1 - 5 cycles per 24 hours.

19. Dosage formulation according to any one of claims 1 to 18, characterized in that 1.5 - 2.5 l of peritoneal dialysis solution is used in 1 - 5 cycles on 3 to 4 days (24 hours) per week.

20. Dosage formulation according to one of claims 1 to 19, characterized in that 0.5 - 2.0 I, preferably 0.75 - 1.5 I peritoneal dialysis solution is used in 2 - 10 cycles per day (14 hours).

21. Dosage formulation according to one of claims 1 to 20, characterized in that 0.5 - 2.0 I, preferably 0.75 - 1.5 I peritoneal dialysis solution is used in 2 - 10 cycles on 3 to 4 days (24 hours) per week.

22. Manufacturing process for a dialysis solution according to the dosage instruction according to one of claims 1 to 21, characterized in that the addition of one or more creatine compounds to the peritoneal dialysis solution is carried out by means of a predetermined or in situ prepared solution of one or more creatine compounds, preferably in the form of a stock solution.

23. Dosage formulation according to any one of claims 1 to 21 for the prophylaxis and treatment of the following symptoms in hemodialysis patients: I. Brain & Brain Function: a) Symptoms of Fatigue:

1. Chronic Fatigue Syndrome 2. ME / CFS Myalgic Encephalomyelitis 3. General fatigue, exhaustion b) Cognitive impairment, cognitive performance of the / the / of 1. Working memory 2. Long-term memory 3. Mental performance 4. Brain fog 5. Concentration difficulties 6. Reduced stress resistance c) Coordination disorders d) Depression, anxiety disorders e) Sleep disorders:

1. Difficulty falling asleep 2. Sleep disturbance 3. Daytime sleepiness 4. Reduced sleep quality f) to protect against cell damage from trauma g) to protect against neurodegeneration II. Spinal Cord & Peripheral Nervous System: a) Paresthesias b) Peripheral Polyneuropathies c) for the protection and regeneration of the spinal cord and peripheral nervous system III. Muscles: a) Muscle weakness 1. Muscle tone weakness 2. Muscle fatigue b) Sarcopenia, age-related loss of muscle mass c) Muscle atrophy, muscle wasting & rehabilitation d) Frailty & fragility e) Movement coordination disorders & fall prevention Muscle endurance & fatigue f) Muscle relaxation, muscle cramps & ischemia g) Myalgia, muscle pain h) For increasing muscle mass and strength i) For improved musculoskeletal healing, IV. Heart & Cardiovascular System: a) Cardiac muscle diseases, myocardial insufficiency, cardiac ischemia, heart failure, myocardial infarction b) Left ventricular hypertrophy c) Cardiovascular Health d) Myocardial Ischemia, Ischemia and Reperfusion Injury V. Liver: a) to prevent fatty liver VI. Kidneys: a) Follow renal ischemia, b) to improve residual renal function VII. Bones and cartilage: a) Osteopenia b) Osteoporosis c) Uremic osteodystrophy d) for improved bone and cartilage mineralization VIII. Blood and blood cells: a) Anemia b) Renal anemia 1. reduced blood cell production 2. the reduced lifespan of erythrocytes 3. and to protect erythrocytes from osmotic and mechanical stress IX. Immune system: a) Increased susceptibility to infection b) Increased risk of an unfavorable course of infectious diseases c) and to protect immune cells from mechanical, oxidative and osmotic stress d) to strengthen the immune system by supporting macrophages, B lymphocytes and T cells X. Movement coordination disorders XI. Fall prevention: a) increased frequency of falls b) increased frequency of bone fractures XII. Fall prevention: a) Reduction of immobilization-induced muscle atrophy b) Impaired bone healing c) Impaired wound healing d) Impaired skin healing e) Fall-related brain trauma XIII. Prevention of the consequences of ischemia to reduce the effects of ischemia and Anoxia on body cells: a) Thrombosis 1. Stroke 2. Heart attack 3. Pulmonary embolism b) and in cases of ischemia due to bleeding XIV. Intestine: a) Intestinal inflammation, colitis, Crohn's disease b) Reduced intestinal health c) Colitis XV. Frailty (Fragility) XVI. Orthostatic problems and dizziness a) In the ear, energy for ion transport against ear cell loss b) Against dizziness XVII. General cell protection: a) against ischemia & asphyxia b) against oxygen radicals (ROS) c) against radiation damage