AU2016311131B2

AU2016311131B2 - Mineral compositions for stimulating the carbohydrate metabolism

Info

Publication number: AU2016311131B2
Application number: AU2016311131A
Authority: AU
Inventors: Tanja Werner
Original assignee: Protina Pharmazeutische GmbH
Current assignee: Protina Pharmazeutische GmbH
Priority date: 2015-08-25
Filing date: 2016-08-17
Publication date: 2021-06-24
Anticipated expiration: 2036-08-17
Also published as: MX2018002304A; NZ740091A; EP3135273A1; WO2017032665A1; RU2018110274A3; EP3135273B1; AU2016311131A1; RU2018110274A

Abstract

The invention relates to novel applications of mixtures of three or more citrate salts, comprising magnesium citrate, the mixture of two, three or more citrate salts additionally comprising calcium citrate and/or zinc citrate, in particular to stimulate or boost the carbohydrate metabolism, preferably the glucose metabolism, in particular to stimulate or boost the cellular energy metabolism.

Description

Mineral substance composition for stimulating the carbohydrate metabolism

Technical field

The present invention primarily relates to a mixture of three or more citrate salts, comprising magnesium citrate, wherein the mixture of three or more citrate salts additionally comprises calcium citrate and/or zinc citrate for use in a therapeutic method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, in particular for stimulating or boosting the cellular energy metabolism.

A further aspect of the present invention relates to a composition for use in a therapeutic method, wherein the composition contains a mixture of three or more citrate salts, comprising magnesium citrate as active substance, wherein the mixture of three or more citrate salts additionally, i.e. in addition to magnesium citrate, comprises two or more citrate salts selected from the group consisting of calcium citrate, zinc citrate, sodium citrate, copper citrate, iron citrate, potassium citrate, potassium-sodium-hydrogen citrate, calcium-sodium-hydrogen citrate, disodium hydrogen citrate, ammonium citrate, ammoniumhydrogen citrate, molybdenum citrate, manganese citrate, lithium citrate and chromium citrate, wherein the therapeutic method is a method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, in particular for stimulating or boosting the cellular energy metabolism; and/or for stimulating or boosting the oxidative glucose metabolism, preferably for stimulating or boosting the oxidative glucose metabolism in a muscle and/or for preventing and/or treating a lactate acidosis; and/or for treating and/or for preventing a metabolic disorder, preferably for treating and&/or preventing one, more or all metabolic disorder(s) selected from the group consisting of diabetes mellitus, obesity and metabolic syndrome; and/or for influencing the acid-base balance, in particular for influencing the carbonic acid-bicarbonate system.

Furthermore, the non-therapeutic use of a mixture of three or more citrate salts, as described herein, or of a composition, as described herein, for achieving one or more non-therapeutic/therapeutic effect(s) selected independently of each other from the group consisting of stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, in particular for stimulating or boosting the cellular energy metabolism, preferably for stimulating or boosting the oxidative glucose metabolism, preferably stimulating or boosting the oxidative glucose metabolism in a muscle; prevention and/or reduction of muscle soreness; weight reduction; increase of concentration; digestive aid; increase of the physical and mental performance; influencing the acid-base balance, in particular influencing the carbonic acid-bicarbonate system; prevention and/or reduction of cellulite, prevention and/or reduction of cracks in the connective tissue, in particular of stretch marks, is also described herein.

Further aspects of the present invention and preferred embodiments thereof result from the following description, the examples and the claims.

Background of the invention

The term metabolism represents all biochemical processes in the body, taking place in cells and is the basis for all essential processes in the body. The components of the added macro-nutrients in nutrition, comprising carbohydrates, fats, proteins and mineral substances, are broken down to their components in the stomach and intestine. Carbohydrates are processed into monosaccharides, proteins into amino acids and fats into fatty acids and glycerides, as the intestine can only resorb nutrients in their broken-down form.

Different forms of metabolism exist, the carbohydrate, the protein, the fat and the mineral substance metabolism, which are named after the substances processed therein.

At the carbohydrate metabolism, the monosaccharides obtained by digestion reach the cells via the blood. When currently no energy is required, the monosaccharide glucose is stored with the aid of insulin and via the so called glycogen synthesis as glycogen and the break down of glycogen at later energy demand is activated by glucagon or adrenaline (E. Buddecke, Grundriss der Biochemie, Walter de Gruyter Verlag, 6. Auflage, 1980).

Directly required energy is generated by the stepwise break down of the monosaccharides, obtained by nutrition or the break down of glycogen, in the cytoplasm of the cell. At this so called glycolysis, two molecules of pyruvate result among others from one glucose molecule, wherein a particularly high gain of energy is yielded. On one side, energy is generated directly in form of ATP, on the other side indirectly as NADH/H*, from which ATP is then produced in the mitochondrial respiratory chain. The break down of glucose to pyruvate equally takes place at anaerobic as well as aerobic conditions.

At sufficient availability of oxygen, the processing of pyruvate to acetyl-CoA subsequently takes place in the mitochondria with the aid of pyruvate dehydrogenase, which is further oxidized to C02 and water via the citrate cycle and thus directly participates the cellular energy metabolism. Whereas in case of lack of oxygen, pyruvate is mainly reduced to lactate at the cytosol (G. L6ffler G., P. E. Petrides, P. C. Heinrich, Biochemie & Pathobiochemie 2007, 8. Auflage, Springer Medizin Verlag Heidelberg). The lactate cannot be further metabolized in mammalian cells, but only, in case a sufficient amount of NAD is available, be re-processed into pyruvate. It is thus also called "metabolic dead end" (H. R. Horton, L. A. Moran, K. G. Scrimgeour, M. D. Perry, J. D. Rawn, Biochemie, Pearson Studium, 4. aktualisierte Auflage, 2008).

In case of strongly increased physical stress, the glycolysis is enhanced by many times for additional energy generation. This results in an increased pyruvate synthesis, which however cannot be completely processed in the citrate cycle. The excess pyruvate is then processed into lactate.

An increased lactate concentration can thus be the consequence of strong muscular stress or also of diseases, which are accompanied by reduced oxygen availability. These are particularly infections, circulatory disturbances, metabolic disorders (particularly diabetes mellitus) as well as stress situations (oxidative and nitro stress). If the energy resources are depleted, the energy reserve of the carbohydrates are mobilized. The increased break down of glucose results in increased pyruvate synthesis. The pyruvate arising in excess is, also as a result of reduced oxygen pressure, mainly reduced to lactate.

Additionally, mitochondrial disorders, in which the cellular energy metabolism is impaired, can lead to an increased lactate concentration. An increased lactate value is for example found at a defect in the oxidation of pyruvate. Due to accumulation of the metabolite pyruvate, lactate is increasingly generated. Also in case of respiratory chain deficiencies, a shift of the balance of the lactate dehydrogenase reaction of pyruvate into lactate is found (H. Renz, Integrative klinische Chemie und Laboratoriumsmedizin, Walter de Gruyter GmbH&Co., 2003).

In addition to lactate, H+ ions are generated for buffering. This results in a shift of the pH into the acid range, which can lead to substantial disturbances of the metabolism, particularly impairments in enzyme activity, the so called lactate acidosis.

The caused lactate acidosis launches a circulus vitiosus: Due to the impaired pyruvate dehydrogenase, the acetyl-CoA synthesis from pyruvate is blocked. Usually, acetyl-CoA is metabolized in the citrate cycle. Thereby the reduction equivalents NADH and FADH2 are produced, which are used for the production of ATP in the respiratory chain. If Acetyl-CoA, however, is not available in a sufficient amount for being a starting point for the citrate cycle, this leads to a reduced provision of the redox substances NADH and FADH2. The consequence thereof is a strong throttling of the energy production and an impairment of mitochondrial function. The lowered energy supply mainly affects cells with a high energy demand, such as neurons, muscles, heart muscles and immune cells.

As possible causes for increased lactate levels, also medication such as e.g. statins, Metformin or Isoniazid can come into question.

Depending on the degree of the severity, the symptoms of a present lactate excess comprise lethargy, vomiting, stomach pains, loss of appetite, dehydration, hyperventilation, hypotension, cyanosis, tachycardia, cardiovascular diseases, restlessness, mental confusion, fatigue and clouding of consciousness up to coma.

Disturbances of the carbohydrate metabolism, as they e.g. can be present in disturbances of the cellular energy metabolism caused by mitochondrial disorders, can additionally and analytically be detected by the determination of the lactate/pyruvate ratio. The ratio of the lactate and pyruvate concentrations in the blood plasma or urine reveals if aerobic or anaerobic metabolic processes prevail in the body. By the use of microdialysis methods, also in vivo examinations of the metabolism of easily accessible tissues such as e.g. skeletal muscle can take place. The determination of the lactate/pyruvate ratio in the dialysate enables in such a case to evaluate the ratio of anaerobic to aerobic metabolism state in the muscle. A lactate/pyruvate ratio of higher than 10 to 20 generally reveals an impaired carbohydrate metabolism and thus an impaired cellular energy balance, e.g. due to an insufficient oxygen supply or mitochondrial dysfunction.

The therapy of increased lactate levels or an acute lactate acidosis can, depending on the degree of severity, comprise the administration of coenzyme Q10, L-carnitine, alpha-lipoic acid, biotin as well as the vitamins B1, B2, B3, B5, stabilization of the blood circulation by circulation supporting medication, termination of a potentially existing Metformin-therapy, normalization of the blood glucose levels by insulin administration and possibly the implementation of a dialysis for removing lactate from the body.

A disadvantage of the supplementation of coenzyme Q10 is, however, that it promotes blood clotting. Thus, patients taking anticoagulant substances should renounce Q10 as food supplement or at least consult the physician. L-carnitine serves among others as a motor for sweat production, thus the body loses particularly in case of a too high dosage too much water, which must to be compensated by an increased water uptake. The administration of alpha-lipoic acid can lead to nausea, vomiting, stomach pain, intestinal pain, diarrhea, allergic reactions such as rash, hives (urticaria) and itching and to an alteration or distortion of sense of taste in rare cases. Biotin usually is well compatible, very rarely, however, allergic reactions of the skin (urticaria) were described. Furthermore, there are hints that the simultaneous administration of medication against cramping seizures (anticonvulsant drugs) reduces the level of biotin in the blood plasma.

Vitamin B complex compounds were partially criticized within the last years for being dosed far too high. The foundation "Okotest" has therefore negatively evaluated corresponding preparations if the dosage was clearly above the official recommendations. Additionally, the second national survey on nutrition in Germany ("nationale Verzehrstudie") of the Federal Ministry of Food, Agriculture and Consumer protection revealed that the German citizens are well supplied with B vitamins by nutrition except for folic acid (OKO-TEST Jahrbuch Gesundheit fir 2010). The supplementation of higher amounts of nicotinic acid (vitamin B3) can thus, for example, evoke severe effects on health, such as gastrointestinal undesired effects, glucose intolerance as well as hepatotoxic effects (Bundesinstitut ftr Risikobewertung, Stellungnahme Nr. 018/2012 vom 06. Februar 2012). Additionally, vitamin B2 causes a neon yellow staining of the urine, which may give an unpleasant feeling to several patients.

Summary of the invention

With regard to the aforementioned negative effects of an ineffective carbohydrate metabolism to the organism, there is a constant need for the provision of compounds or compositions, which stimulate or boost the carbohydrate metabolism, particularly the oxidative glucose metabolism and thus the cellular energy metabolism.

The primary object of the present invention was thus to provide such compounds or compositions.

The aim of the present invention was additionally, to investigate molecular mechanisms which influence the carbohydrate metabolism and thus achieve a possible beneficial effect on ubiquitous metabolic disorders such as diabetes mellitus, obesity and metabolic syndrome, ideally such having an additional beneficial effect on the carbohydrate metabolism and the acid-base balance.

Preferably, the provided compounds or compositions have a high bioavailability, to supply the active substance(s) to an individual in a suitable manner, so that an optimal supply with the active substance(s) is achieved.

In one aspect of the present invention, there is provided a method for the treatment and/or prevention of lactate acidosis and/or obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a mixture of three or more citrate salts, wherein the mixture comprises magnesium citrate, and wherein the mixture additionally comprises calcium citrate and/or zinc citrate.

In another aspect of the present invention, there is provided a use of a mixture of three or more citrate salts for the manufacture of a medicament effective in the treatment and/or prevention of lactate acidosis and/or obesity, wherein the mixture comprises magnesium citrate and additionally two or more citrate salts from the group consisting of calcium citrate, zinc citrate, sodium citrate, copper citrate, iron citrate, potassium citrate, potassium-sodium hydrogen citrate, calcium-sodium hydrogen citrate, disodium hydrogen citrate, ammonium citrate, ammonium hydrogen citrate, molybdenum citrate, manganese citrate, lithium citrate and chromium citrate

In yet another aspect of the present invention, there is provided a mixture of three or more citrate salts, wherein the mixture comprises magnesium citrate, and wherein the mixture additionally comprises calcium citrate and/or zinc citrate, when used for achieving of an effect selected from the group consisting of: preventing a non-pathological excess of lactate in the muscle by stimulating or boosting the carbohydrate metabolism and a supportive effect in weight reduction.

In a further aspect of the present invention, there is provided a method for preventing a non pathological excess of lactate in the muscle by stimulating or boosting the carbohydrate metabolism and/or providing a supportive effect in weight reduction in a subject, comprising administering to the subject a therapeutically effective amount of a mixture of three or more citrate salts, wherein the mixture comprises magnesium citrate, and wherein the mixture additionally comprises calcium citrate and/or zinc citrate.

Further objects underlying the invention, will become apparent from the following descriptions, the examples as well as the attached patent claims.

The aforementioned objects of the present invention are solved according to the invention by the herein described aspects.

Definitions

The term citrate salt, as used herein, describes salts of citric acid, i.e. compounds comprising citrates, hydrogen citrates and dihydrogen citrates as anions with one, two or three cations as counterions. Also hydrates of the citrate salts are included in the term citrate salt in the scope of the present disclosure.

The term test person(s), as used herein, relates to a person on which a scientific experiment or test is applied.

The term placebo, as used herein, describes a sham intervention, i.e. the supplementation of compositions, which cannot have a pharmacological effect, in the scope of the present disclosure.

The term verum, as used herein, describes the supplementation of compositions, which contain, contrary to the placebo, which is free of active substance, pharmacologically active substances, in the scope of the present disclosure.

The term intervention study, as used herein, relates to an experimental study in the field of epidemiology, in which the investigator examines with conscious manipulation of causal factors (intervention) their influence on an endpoint, to thus confirm or disprove an a priori raised hypothesis. In contrast to an observational study, the intervention study involves an experiment, with which the efficiency of a determined intervention, in the present disclosure a supplementation of a composition containing citrate salts, shall be examined. In the easiest case, the investigator forms two groups: In the intervention group (verum group), the intervention to be investigated is applied, in the control group (placebo group), the intervention remains undone.

The term randomized intervention study, as used herein, describes an intervention study, in which the assignment of the test persons to the intervention or control group occurs randomly. It is thus ensured that both groups are mostly equivalent to each other in terms of their composition. In the present disclosure, the randomization was performed by a person which was not involved in the implementation of the study. Therefore, the group assignments were determined by, after written declaration of consent, a previously prepared series of sealed envelopes with continuous patient numbers.

The term double blind intervention study, as used herein, describes an intervention study, in which neither the investigator (physician) nor the study participants (test persons) know about the respective group membership (intervention group or control group), i.e. neither the physician nor the patient know, who receives the active substance containing intervention agent and who receives the placebo. This serves for the prevention of a bias of the study results.

The term postprandial, as used herein, stands for "after the meal" or "after a test meal".

The term microdialysis, as used herein, describes a single, minimally invasive method, based on the principle of dialysis. It allows in vivo examinations on the regulation of the circulation and metabolism of easily accessible tissue such as the subcutaneous fatty tissue or skeletal muscle in humans. The microdialysis probe inserted into the tissue is double lumic, consisting of an outer, feeding and an inner, dissipating tube. The outer tube is semipermeable for a determined distance in its distal portion. The probe is usually perfused with a low flow velocity, for example with a physiological saline solution (perfusate). The perfusate flows over the outer tube, along the semipermeable membrane, gets via a small opening at the distal portion into the inner tube over which it exits the probe and can be fractionally collected in special microvessels (microvials). At the semipermeable membrane, different molecules can, depending on the chemical and molecular properties of the membrane and the different components of the interstitium, pass the membrane according to the concentration gradient into the perfusate, whereby such becomes the dialysate. As the probe is continuously perfused, a concentration equilibrium cannot be applied between the interstitium and the perfusate. The concentration of a molecule in the interstitium is, however, directly proportional to its concentration in the dialysate. The extent of the diffusion of substances from the interstitium into the perfusate, the so called recovery rate in the dialysate (recovery), depends on several factors. Firstly, the perfusion velocity and the length of the membrane are of importance. A long microdialysis probe combined with a slow perfusion rate result in an improved recovery. If a membrane of a length of 30 mm is perfused with a velocity of 0.3 pl/min, the recovery is almost 100%. Further factors influencing the recovery are the molecular weight as well as physical and chemical properties (e.g. charge and solubility) of the molecule to be investigated (P. Arner, Proc. Nutr. Soc. 1999, 58/04, 913-917). The pore size of the used membrane (molecular cut-off) additionally limits the size of the molecules which can pass the membrane.

The term dialysate, as used herein, describes the perfusate samples collected after the step of microdialysis.

The term EtOH ratio (ethanol ratio), as used herein, describes the quotient of the ethanol concentration in the dialysate and the ethanol concentration in the perfusate. With the EtOH ratio, the circulation within the tissue can be assessed semiquantitatively. Therefore, a defined amount of ethanol is added to the perfusate. Ethanol diffuses according to its concentration gradient from the perfusate into the interstitium and is cart off via the blood capillaries faster or more slowly, depending on the strength of tissue perfusion. Thus, the ethanol concentration in the dialysate is always lower than in the perfusate and can be used for the semiquantitative analysis of the tissue perfusion.

The energy turnover (ET), as described herein, is composed of the basal metabolic rate (BR) and the active metabolic rate. The BR is the amount of energy, which is required for the maintenance of all fundamental, vital functions of the body and the muscle tone. The BR is measured in the morning, directly after waking up and in a lying position, 12-14 h after consumption of the last meal and at comfortable room temperature. The active metabolic rate is the amount of energy, which is needed by the body within a day, to do its work. The energy exceeding the basal metabolic rate is thereby described as the active metabolic rate. The resting sober metabolic rate (RSR), as used herein, describes the energy turnover, which is, contrary to the basal metabolic rate measured in a lying position, measured while sitting and is approximately 10 % higher than the basal metabolic rate (G. Pschel, H. Khn, T. Kiethmann, Taschenlehrbuch der Biochemie 2011; Georg Thieme Verlag KG, Stuttgart).

The term postprandial thermogenesis (ppTh), as used herein, describes the increase of the energy turnover after the intake of food. It results from the energy required for digestion, resorption, transport and storage of the nutrients. The ppTh depends on the composition and amount of the nutrition taken in and results in the same increases of metabolism independent of age and sex. For the single macronutrients, the following increases of metabolism are measured: fats 2-4%, carbohydrates 4-7% and proteins 18-25% (H. K. Biesalski, P. Frst, H. Kasper, Ernshrungsmedizin: Nach dem Curriculum Ernshrungsmedizin der Bundessrztekammer. 2004, 3. erweiterte Auflage, Georg Thieme Verlag, Stuttgart). Thus, proteins have the highest thermogenic potential, followed by carbohydrates and fats. Related to the 24 h total energy turnover, the proportion of the RSR is about -70%, the proportion of the ppTH is about 5-10% and the proportion of physical activity is 20-30%.

The term carbohydrate oxidation rate (CHO), as used herein, describes the rate with which the carbohydrates are oxidatively metabolized while generating carbon dioxide.

The term oxidative glucose metabolism, as used herein, relates to, as extensively described above, the break down of the monosaccharide glucose obtained from nutrition under aerobic metabolic state. The first part of the glucose metabolism is the glycolysis - a biochemical break down pathway, which metabolizes a molecule of glucose into two molecules of pyruvate and equally takes place under anaerobic and aerobic conditions. Aerobically working tissues subsequently break down the pyruvate in the citrate cycle und the subsequent respiratory chain while gaining energy to the endproducts carbon dioxide and water.

Detailed description

A primary aspect of the present invention relates to a mixture of three or more citrate salts, comprising magnesium citrate, wherein the mixture of three or more citrate salts additionally comprises calcium citrate and/or zinc citrate, preferably at least zinc citrate, for use in a therapeutic method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism. According to a preferred embodiment of the present invention, the mixture to be applied according to the invention, particularly one that in addition to magnesium citrate also comprises zinc citrate, furthermore comprises also potassium and/or sodium citrate. Further citrate salts to be (additionally) advantageously used preferably in the scope of the present invention, be it in a herein described mixture or a herein described composition, are described below.

An embodiment thus relates to a mixture of or comprising magnesium citrate and calcium citrate for use in a therapeutic method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism.

A further embodiment relates to a mixture comprising magnesium citrate and zinc citrate for use in a therapeutic method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism.

A further embodiment relates to a mixture comprising magnesium citrate, calcium citrate and zinc citrate for use in a therapeutic method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism.

A further embodiment thus relates to a mixture of or comprising magnesium citrate, zinc citrate, potassium citrate and sodium citrate for use in a therapeutic method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism.

According to a further embodiment, the mixture for use in a therapeutic method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism comprises three, four, five, six, seven, eight, nine, ten or more different citrate salts, which are combined with each other, or it consists thereof, wherein one or more, preferably all, citrate salt(s) is/are preferably selected from the group consisting of magnesium citrate, calcium citrate, zinc citrate, sodium citrate, copper citrate, iron citrate, potassium citrate, potassium-sodium-hydrogen citrate, calcium-sodium-hydrogen citrate, disodiumhydrogen citrate, ammonium citrate, ammoniumhydrogen citrate, molybdenum citrate, manganese citrate, lithium citrate and chromium citrate, and wherein at least magnesium citrate as well as additionally zinc citrate and/or calcium citrate are comprised, and wherein relating to the remaining citrate salts any combinations of the preceedingly named salts are comprised by the scope of the present disclosure. Preferably and in addition to magnesium citrate, two or more citrate salts selected from the group consisting of calcium citrate, zinc citratee, sodium citrate and potassium citrate, preferably selected from the group consisting of zinc citrate, sodium citrate and potassium citrate are present.

What was previously said for preferably used or comprised citrate salts for mixtures to be applied according to the invention, is accordingly valid for the herein and below described compositions.

The mineral substances potassium, calcium, magnesium and sodium belong to the so called bulk elements, hence to the mineral substances the boy resorbs from nutrition and from which the body requires high amounts.

Potassium is among others involved in the regulation of blood pressure as well as in the maintenance of the membrane potential, it controls the fluid content of the cells and has numerous further metabolic functions such as the synthesis of proteins and glycogen. In neurons, potassium accounts for the signal transmission, in the muscles it is involved in the control of contractions.

Calcium is present to 99% in the bones. The remaining 1% are important as intra- as well as extracellularly dissolved Ca 2 * ions in the blood as well as in the interstitium for the extra- and intracellular signal transmission (e.g. transmission of nerve impulses or muscular contractions), for blood clotting and the activation of enzymes (M. Peacock, Clin. J. Am. Soc. Nephrol. 2010, 5, 23-30).

Magnesium is predominantly present in the intracellular compartment of the body and is essential for the function of enzymes, particularly for the function of enzymes transmitting phosphate groups. Magnesium is required for the cellular energy metabolism and is important for the stabilization of membranes, the velocity of nervous transmission, ion transport and calcium channel activity (J. R. Weisinger, Lancet 1998, 352, 391-396).

Sodium has a significance for the concentration gradient in neurons (together with potassium), the resorption and transport of nutrients, the regulation of the water balance and the acid-base balance. Sodium additionally promotes the resorption of nutrients such as glucose and amino acids.

The mineral substances chromium, iron, copper, manganese, molybdenum and zinc belong to the so called trace elements, hence to the mineral substances of which the body only needs a small amount, which however are essential for the organism and which the organism resorbs from nutrition.

Chromium is one of the most frequent elements on earth and is present as Cr 3 * in most nutrition. A lack of chromium therefore hardly arises. It was discovered only by patients with parenteral nutrition that a lack of chromium can lead to diabetes-like symptoms. Numerous subsequent studies showed the result that chromium is important in the glucose and lipid metabolism (W. T. Cefalu, F. B. Hu, Diabetes Care 2004, 27, 2741-2751).

Iron is required among others for the synthesis of haemoglobin in erythrocytes, for the transport of oxygen, the production of metabolism stimulating enzymes and the gain of energy during endurance performance.

Copper is together with iron necessary for the activation of important enzymes, the colour formation in skin and hair, the production of erythrocytes and maintenance of the nervous system.

Manganese is predominantly involved in the construction of connective tissue in the body, which is taking place by the synthesis of proteoglycans in cartilage and bone tissues. Manganese further contributes to the synthesis of proteins and fats and is required for the synthesis and secretion of insulin as well as the generation of urea. Furthermore, manganese is involved in the production of melanine and dopamine. Manganese further activates a series of enzymes, which for example act as antioxidants (Mn-superdismutase), contribute to the utilization of vitamin B1 (phosphatise) and are required for the gluconeogenesis, i.e. the synthesis of glucose.

Molybdenum is a transition element and can, due to its high oxidation number, transfer several electrons simultaneously and is capable of transferring oxygen to different substrates. Thus, molybdenum is an important co-factor for oxidases, such as e.g. the xanthin oxidase, which is involved in the purin metabolism, or the sulphite oxidase, which is involved in the metabolism of sulphurous amino acids (R. R. Mendel, J. Biol. Chem. 2013, 288 (16), 13165-13172).

Zinc has catalytic as well as structural functions in zinc enzymes and participates redox reactions without changing its redox state. As a component of zinc finger proteins imparts this protein a special scaffold and thus interacts with the DNA or proteins (W. Maret, J. Nutr. 2000, 130, 1455-1458). It furthermore has in important function in wound healing, in growth and the strengthening of the immune system. Zinc additionally is a co-factor of the carboanhydrase. These enzymes catalyse the hydratization of carbon dioxide to carbonic acid and vice versa. The carbonic acid dissociates to hydrogen carbonate and H*. Via this reaction, the pH value of the blood plasma and thus the acid base balance as well as the pH value of the gastric acid is regulated.

Lithium is so far believed to be non-essential for humans, however a series of therapeutic effects especially effects on mind are proven (A. Cipriani, K. Hawton, S. Stockton, J. R. Geddes, BMJ 2013, 346, f3646).

The bioavailability of the mineral substance cations strongly depends on their counterions. It could be shown that cationic mineral substances in connection with organic counterions can be better resorbed by the body than anorganic compounds. In a comparative study with different magnesium compounds it turned out that magnesium citrate as the only compound led to an increase of the magnesium plasma concentration, both after single application and after chronic supplementation (60 days) (A. F. Walker, G. Marakis, S. Christie, M. Byng, Magnesium Research 2003, 16, 183-191).

The stimulation or boosting of the carbohydrate metabolism and thus the cellular energy metabolism by means of the citrate salts to be used according to the invention, as described herein, is thus particularly advantageous, as the previously described mineral substance cations represent essential bulk or trace elements for the organism and the citrate counterion ensures the bioavailability of the cations.

The activity of the carbohydrate metabolism can be observed with the concentration values of certain analytes. Among these is the concentration of blood glucose, insulin, glucose in the interstitial fluid as well as the concentration of the glucose metabolites lactate and pyruvate in the blood and the interstitial fluid.

Furthermore, the oxygen consumption and the production of carbon dehydrate are indirectly informative about the activity of the energy metabolism, under the assumption that the total consumed oxygen and the total produced carbon dehydrate exclusively arise from the oxidation of the main nutrients. The measurement and determination of the above mentioned analytes with the use of common machines and using common sample materials, such as arterial, venous or capillary blood, blood serum, dialysate as defined above or inhalation and exhalation air, is well known to the person skilled in the art, possibly an expert in clinical diagnostics.

The blood glucose (also called "blood sugar") describes the concentration of glucose in the blood. The concentration values of the blood glucose can be expressed in mg/dl or mmol/l.

For humans without diabetes, the blood glucose in the blood is under sober condition, i.e. after 8 to hours without food, usually between 55-110 mg/dl (3.1 - 6.1 mmol/I). After the meal, the blood glucose value usually does not exceed 140 mg/dl (7.8 mmol/).

A blood glucose value under sober condition between 100 and 125 mg/dl (5.6 to 6.9 mmol/) may indicate a type 2 diabetes preparatory stage (prediabetes). The diagnosis can be clarified with further tests, particularly an oral glucose tolerance test. A diabetes mellitus is often present if the blood glucose value under sober conditions is higher than 126 mg/dl (7.0 mmol/I) or at an arbitrary time point higher than 200 mg/dl (11.1 mmol/).

Instead of in the blood, the glucose concentration can also be determined in the interstitial fluid. Studies have shown that the measured glucose concentration in the interstitial fluid does not directly correlate with the values measured in the blood. In the steady state, the glucose concentration in the interstitium, however, reaches a certain, usually constant, percentage of the blood glucose concentration. Thereby, the interstitial glucose concentration is under steady state conditions between 67 and 106% relative to the blood glucose. In case of timely alterations of the glucose concentration in the organism, a timely shift of 2 to 60 minutes between the changes in the blood and in the interstitium is observed, wherein the glucose concentration in the interstitium catches up with the blood glucose concentration (WO 2001047408 Al).

The basal insulin concentration in the blood is under sober conditions and for healthy people usually between 5 and 30 pU/mL. Between the meals and depending on the composition and the amount of the carbohydrates taken in with the meal, a timely highly variable, quick and short-term stimulation of the insulin concentration up to a range of 50 - 100 pU/ml takes place between 30 and 60 minutes postprandially (C. H6germann, MNU 68/1 (15.1.2015) Seiten 1-3, ISSN 0025-5866, Verlag Klaus Seeber-ger, Neuss).

The lactate concentration in the plasma usually is between 5.7 and 22 mg/dl (0.63 - 2.44 mmol/I). In the arterial blood, the values are clearly lower at usually < 16 mg/dl (< 1.8 mmol/I) and in the cerebrospinal fluid at usually 11 to 19 mg/dl (1.2 - 2.1 mmol/I). Plasma values are higher than values derived from whole blood. One hour after a meal rich in carbohydrates, an increase to 120-150% of the values under sober conditions takes place (K. D6rner, Klinische Chemie und Hsmatologie (Taschenlehrbuch), 7. Auflage, Thieme Verlag). An increase of lactate over the standard value points towards a reduction of the amount of oxygen in certain tissue areas, but the lactate value can also be increased following much movement. In case the lactate value in the blood increases to > 45 mg/dl (5 mmol/I), usually a lactate acidosis is assumed.

The pyruvate concentration in the plasma usually is between 0.4 and 0.8 mg/dl (45-91 pmol/). One hour after a meal rich in carbohydrates, the values are higher by up to 114 pmol/1 (1 mg/dl). The quotient lactate/pyruvate usually is (10-20)/1 (K. D6rner, Klinische Chemie und Hsmatologie (Taschenlehrbuch), 7. Auflage, Thieme Verlag).

By stimulating or boosting the carbohydrate metabolism in the sense of the present invention, preferably a, preferably statistically significant, change in the direction of an increase of the carbohydrate metabolism rate of one or more measurement parameter(s), which are brought into contact with the carbohydrate metabolism, after the intervention (V2) compared to before the intervention (V1) is meant to be understood. Among that, the glucose and insulin values in venous blood or serum (basal and prostprandial), the urea and magnesium values in the venous blood or serum (basal and postprandial), the carbon dioxide and oxygen partial pressure in the capillary blood or serum (basal and postprandial), the bicarbonate ion concentration in the capillary blood or serum (basal and postrprandial), the postprandial thermogenesis as defined above, the carbohydrate oxidation rate (basal and postprandial), the fat oxidation rate (basal and postprandial), the circulation in tissues such as e.g. in the muscle (basal and postprandial), the EtOH ratio as defined above (basal and postprandial), the glucose, lactate, pyruvate and glycerol concentration (basal and postprandial) in the dialysate as defined above or in the blood or the urine, the pH value in the dialysate as defined above (basal and postprandial), the carbon dioxide and oxygen partial pressure (basal and postprandial) in the dialysate as defined above or in the blood, the bicarbonate ion concentration (basal and postprandial) in the dialysate as defined above or in the blood, the resting sober metabolic rate as defined above, the relative energy turnover (basal and postprandial), the respiratory quotient as defined above (basal and postprandial) can among others be ranked. The measurement and determination of the above mentioned parameters with the use of common machines and using common sample materials, such as arterial, venous or capillary blood, blood serum, dialysate as defined above or inhalation and exhalation air and the analysis of the parameters with regard to the carbohydrate metabolism activity is well known to the person skilled in the art, possibly an expert in clinical diagnostics.

An embodiment of the present invention relates to a mixture of three or more citrate salts for use as described herein, wherein the therapeutic method comprises stimulating or boosting the oxidative glucose metabolism, preferably stimulating or boosting the oxidative glucose metabolism in the muscle and/or the prevention and/or treatment of a lactate acidosis.

In the scope of the present invention, it could surprisingly been shown that the lactate/pyruvate ratio can be influenced by a treatment of the verum group according to the invention with citrate salts as described herein. For the detection of the lactate/pyruvate ratio a dialysate was obtained after a test meal with a microprobe inserted into the right thigh muscle and the dialysate was subsequently analysed with regard to the contained concentration of glucose, lactate and pyruvate. It unexpectedly turned out that the treatment of the verum group of the test persons with citrate salts as described herein leads to a significant increase of both the basal and the postprandial pyruvate concentration in the dialysate and thereby the lactate/pyruvate ratio was strongly reduced. This indicates a significantly improved oxidative glucose metabolism in case of a treatment with the herein described citrate salts.

By the application of the citrate salts to be used according to the invention, thus the occurrence of symptoms of a lactate acidification in the organism can be prevented or such symptoms can be reduced.

Stimulating or boosting of the oxidative carbohydrate metabolism in the muscle is thereby particularly advantageous, as it leads to a particularly high provision of energy in the muscle cells.

A further embodiment relates to a mixture of three or more citrate salts for use as described herein, wherein the therapeutic method comprises the treatment and/or prevention of a metabolic disorder, wherein the metabolic disorder comprises at least one selected from the group consisting of diabetes mellitus, obesity and metabolic syndrome.

As described above, stimulating or boosting of the carbohydrate metabolism with the citrate salts to be used according to the invention leads to an increased aerobic, i.e. complete metabolization of the glucose to carbon dioxide and water and thus to a more effective provision of energy. This can be used for the prevention and/or treatment of common metabolic disorders such as e.g. diabetes mellitus, obesity and the metabolic syndrome.

Diabetes mellitus is a metabolic disorder, at which the concentration of the glucose levels in the blood is too high as an absolute lack of insulin (type 1 diabetes) or a resistance against insulin, a hyperinsulinism, a relative lack of insulin or disturbances in the secretion (type 2 diabetes) are present.

Obesity, also known as adiposity, adiposis, adiposeness or obeseness leads to an increased risk to come down with type 2 diabetes. Due to the oversupply of glucose taken up by a food quantity exceeding the energy demand and the constantly increased insulin level resulting thereof, the sensibility and the amount of insulin recptors decrease. The secreted insulin is no longer sufficient to take down the insulin. Thus the body suffers from a relative lack of insulin and needs to increasingly synthesize new insulin. This results in an overstrain of the insulin producing beta cells of the pancreas, which in turn leads to an exhaustion of the organ and to the development of a type 2 diabetes mellitus. Furthermore, not only the oversupply of glucose but also the blood fats have a significant influence on the risk of developing a type 2 diabetes. The amount of free fatty aids present in the blood is associated with the development of the insulin resistance in muscles and the liver. More insulin is required for the maintenance of a normal blood glucose level. Thereby, the oversupply of fatty acids taken up by excessive consumption further have a negative effect on the insulin producing beta cells of the pancreas.

The term metabolic syndrome describes the combination of disturbed carbohydrate metabolism, which manifests by an insulin resistance or elevated glucose concentrations in the blood, high blood pressure, dyslipoproteinemia, i.e. increase of the VLDL with a simultaneous decrease of the HDL lipoproteins, and abdominal obesity. The probably underlying cause for the metabolic syndrome is a peripheral insulin resistance and the chronic hyperinsulinemia relating thereto. The metabolic syndrome is considered as the preliminary stage of the type 2 diabetes.

The previously described metabolic disorders have in common that they are associated with an elevated blood glucose level. Stimulating or boosting the carbohydrate metabolism by means of the citrate salts to be used according to the invention can thus have positive effects on an elevated blood glucose level. A lower increase of the blood glucose values by a stimulated or boosted carbohydrate metabolism and a lower required concentration of insulin after a meal, related thereto, can assist to prevent the development of the previously mentioned metabolic disorders or to reduce the degree of severity of the symptoms of the aforementioned metabolic disorders.

A further embodiment relates to a mixture of three or more citrate salts for use as herein described, wherein stimulating or boosting the carbohydrate metabolism or stimulating or boosting the oxidative glucose metabolism additionally results in the influence of the acid-base balance, particularly the influence of the carbonic acid-bicarbonate system, due to the selected citrate salt(s).

As previously described, stimulating or boosting the oxidative carbohydrate metabolism according to the invention results in an increased break down of glucose via pyruvate instead of lactate. Lactate is the acid anion of lactic acid and leads to a reduction of the pH value in the blood or in tissues. It is referred to a lactate acidosis if the pH value is reduced (< 7.36) and simultaneously the lactate concentration is increased (> 5 mmol/I). A reduction of the lactate/pyruvate ratio by stimulating or boosting the oxidative carbohydrate metabolism and thus a reduced synthesis of lactate from glucose has therefore positive effects on the pH value or the acid-base balance in the body.

The citrate salts to be used according to the invention do thereby not only stimulate the carbohydrate metabolism, their use is further advantageous as citrates and hydrogen citrates themselves have an alkaline effect in the body. They are anions of citric acid, i.e. they can bind acid in the form of protons and are subsequently broken down to the pH neutral metabolites carbon dioxide and water.

The precise active principle of a citrate salt as defined above shall be exemplarily explained by means of magnesium citrate. Ingested magnesium citrate is not affected by the gastric acid and gets to the upper portion of the small intestine. In case of a slightly alkaline pH value of 8, which is present in this proportion of the intestine, magnesium citrate dissociates into the magnesium cation, which is on the same time an important mineral substance, and the anion citrate and can then be resorbed by the body. In the cell, the citrate molecule actively binds protons, forming citric acid. The citric acid is implemented into the citric acid cycle and finally broken down to water and carbon cioxide. The carbon dioxide is breathed out via the lung, water is excreted via the urine. Via the citrate, acid is thus bound and actively removed from the body by forming neutral end products.

The reduced formation of lactate by stimulating the oxidative glucose metabolism combined with the effect of the citrate anion on the pH value prevents or reduces a chronic acidification of the body, which otherwise would result in the deposit of excess acid in the connective tissue or in dissolving out alkaline mineral substances from the bone.

Connective tissue depositing acid changes its physical-chemical properties. In bone and joint cartilage, the connective tissue serves as collagenous supporting tissue. In case of an acidification, protons instead of water molecules would accumulate at the scaffold molecules (proteoglycanes) of the connective tissue and it would lose its capability of binding water. Thereby, the connective tissue would lose elasticity, mechanical stress could be less absorbed and the tendency for infections would be increased. This could be expressed by muscular and joint pains.

To compensate the acid load in case of an acidification, calcium and magnesium would among other be released from the bone. Over a long period, this would lead to bone dissolving.

A preferred embodiment relates to a mixture of three or more citrate salts for use as herein described, wherein the mixture at least comprises magnesium citrate, calcium citrate and zinc citrate, or wherein the mixture consists of magnesium citrate, calcium citrate and zinc citrate.

A mixture at least comprising magnesium citrate, calcium citrate and zinc citrate, or consisting of magnesium citrate, calcium citrate and zinc citrate for use in a therapeutic method for stimulating or boosting the carbohydrate metabolism has particularly advantageous effects, as magnesium, calcium and zinc, as mentioned above, are important bulk or trace elements, which are required in a sufficient amount by the body for a healthy function.

A further embodiment relates to a mixture of three or more citrate salts for use as described herein, wherein, related to the total weight of the citrate salts, the proportion of magnesium citrate is in a range of 2 to 100 wt.-%, preferably in a range of 2 to 40 wt.-%, particularly preferably in a range of 9 to 36 wt.-%, especially preferably in a range of 15 to 36 wt.-%. According to an alternative, particularly preferred embodiment, the proportion of magnesium citrate is in a range of 30 to 40 wt.

In a preferred embodiment, the proportion of magnesium citrate related to the total weight of the citrate salts is (at least) 2 wt.-%, 3 wt.-%, 4 wt.-%, 5 wt.-%, 6 wt.-%, 7 wt.-%, 8 wt.-%, 9 wt.-%, 10 wt. %,11 wt.-%, 12 wt.-%, 13 wt.-%, 14 wt.-%, 15 wt.-%, 16 wt.-%, 17 wt.-%, 18 wt.-%, 19 wt.-%, 20 wt. %,21 wt.-%, 22 wt.-%, 23 wt.-%, 24 wt.-%, 25 wt.-%, 26 wt.-%, 27 wt.-%, 28 wt.-%, 29 wt.-%, 30 wt. %,31 wt.-%, 32 wt.-%, 33 wt.-%, 34 wt.-%, 35 wt.-% or 36 wt.-%.

A further aspect of the present invention relates to a composition for use in a therapeutic method, wherein the composition contains a mixture of three or more citrate salts, comprising magnesium citrate, as active substance, wherein the mixture of three or more citrate salts additionally, i.e. additional to magnesium citrate, comprises two or more citrate salts of the group consisting of calcium citrate, zinc citrate, sodium citrate, copper citrate, iron citrate, potassium citrate, potassium sodium hydrogen citrate, calcium-sodium hydrogen citrate, disodium hydrogen citrate, ammonium citrate, ammonium hydrogen citrate, molybdenum citrate, manganese citrate, lithium citrate and chromium citrate, preferably at least zinc citrate as well as another citrate of the preceding list, wherein the therapeutic method is a method for stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism; and/or for stimulating or boosting the oxidative glucose metabolism, preferably for stimulating of boosting the oxidative glucose metabolism in the muscle and/or for preventing and/treating a lactate acidosis; and/or for treating and/or preventing one, more or all metabolic disorder(s) selected from the group consisting of diabetes mellitus, obesity and metabolic syndrome; and/or for influencing the acid-base balance, particularly for influencing the carbonic acid bicarbonate system.

An active substance in the sense of this application is preferably a substance of a mixture of substances, which is/are capable of effecting the previously defined stimulation or boost of the carbohydrate metabolism or the oxidative glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism, preferably the oxidative glucose metabolism in a muscle, and/or the prevention and/or treatment of a lactate acidosis and/or the treatment and/or prevention of a metabolic disorder and/or the influence of the acid-base balance, particularly the influence of the carbonic acid-bicarbonate system, in a dose required for this. Traces of tese substances or mixtures of substances are thus regularly not to be understood as active substance. I.e. the herein described compositions to be used according to the invention contain an amount of citrate salts as herein described, which is sufficient to effect the herein describe effect(s).

According to the German Nutrition Association, the recommended daily dose of magnesium for young people and young adults in the age of 15 to 19 years is 400 mg (male) or 350 mg (female) and for adults older than 25 years 350 mg (male) or 300 mg (female).

The proportion of magnesium citrate in the composition according to the invention is thereby advantageously selected such that the recommended daily dose of magnesium is reached by the administration of magnesium citrate or a mixture to be used according to the invention of three or more citrate salts or a composition to be used according to the invention. Here, the daily dose can be achieved by an administration of the substances, mixtures or compositions to be used according to the invention once, twice, triple or more than triple a day. Preferably, the administration is once, twice or triple a day.

In a preferred embodiment, the daily dose of magnesium citrate in a method described herein is 15 to 1000 mg.

An embodiment relates to a composition for use in a therapeutic method as described herein, wherein the composition additionally and independent from each other comprises one or more further components selected from the group consisting of sweeteners, preferably lactose, saccharose or sorbitol; acidity regulators, preferably potassium tartrate; separating agents, preferably salts, particularly magnesium or calcium salts, of fatty acids, cross-linked sodium carboxymethyl cellulose or silicon dioxide; acidifying agents, preferably citric acid; aromas, preferably natural aromas; fillers, preferably hydroxypropyl cellulose; magnesium oxide; further citrate salts, preferably sodium citrate, potassium citrate, potassium-sodium hydrogen citrate, calcium-sodium hydrogen citrate, copper citrate and/or iron citrate; calcium carbonate, calcium lactate (particularly for the case, that the mixture or composition to be used according to the invention does not contain calcium citrate), magnesium carbonate and/or sodium hydrogen carbonate; vitamins, preferably riboflavin, cholecalciferol (vitamin D) and/or ascorbic acid; L-carnitine; maltodextrine; molybdenum, preferably sodium molybdenum; chromium, preferably chromium chloride; and selenium, preferably sodium selenite, sodium selenate or selenium yeast.

Further pharmaceutically compatible additives, which can be comprised by the composition according to the present disclosure, are known to the person skilled in the art.

A further embodiment relates to a composition for use in a therapeutic method as described herein, wherein the total amount of citrate salts in the composition related to the total weight of the composition is in a range of 4 to 70 wt.-%, preferably in a range of 8 to 67 wt.-%, particularly preferably in a range of 19 to 44 wt.-%, especially preferably in a range of 25 to 35 wt.-%, particularly in a range of 30 to 35 wt.-%.

In an embodiment the total amount of citrate salts in the composition is, related to the total weight of the composition, (at least) 4 wt.-%, 5 wt.-%, 6 wt.-%, 7 wt.-%, 8 wt.-%, 9 wt.-%, 10 wt.-%, 11 wt.-%, 12 wt.-%, 13 wt.-%, 14 wt.-%, 15 wt.-%, 16 wt.-%, 17 wt.-%, 18 wt.-%, 19 wt.-%, 20 wt.-%, 21 wt.-%, 22 wt.-%, 23 wt.-%, 24 wt.-%, 25 wt.-%, 26 wt.-%, 27 wt.-%, 28 wt.-%, 29 wt.-%, 30 wt.-%, 31 wt.-%, 32 wt.-%, 33 wt.-%, 34 wt.-%, 35 wt.-%, 36 wt.-%, 37 wt.-%, 38 wt.-%, 39 wt.-%, 40 wt.-%, 41 wt.-%, 42 wt.-%, 43 wt.-%, 44 wt.-%, 45 wt.-%, 46 wt.-%, 47 wt.-%, 48 wt.-%, 49 wt.-%, 50 wt.-%, 51 wt.-%, 52 wt.-%, 53 wt.-%, 54 wt.-%, 55 wt.-%, 56 wt.-%, 57 wt.-%, 58 wt.-%, 59 wt.-%, 60 wt.-%, 61 wt.-%, 62 wt.-%, 63 wt.-%, 64 wt.-%, or 65 wt.-%.

A further embodiment relates to a composition for use in a therapeutic method as described herein, wherein the composition is selected from the group consisting of granules, preferably for direct consumption, for dissolving or for stirring into meals, tablets, capsules and lozenges, preferably tablets, capsules and lozenges for swallowing, sucking or chewing, powder, preferably for direct consumption and water soluble powders for drinking, drinking vials and micropearls, preferably for direct consumption without water.

Further dosage forms of a peroral or also topical composition, which can be comprised by the present disclosure, and the according techniques for the formulation of the drug substance are known to the person skilled in the art on the field of pharmaceutical technology and can be readily provided by consulting general knowledge on the field.

A further embodiment relates to a composition for use in a therapeutic method as described herein, wherein the composition is free of one, more or all of the components selected from the group consisting of lactose, iodine gluten, fragrances and sweeteners, preferably free of lactose, iodine and gluten.

A further embodiment relates to a composition for use in a therapeutic method as described herein, wherein the therapeutic method comprises the controlled release of the active substances of the composition administered as depot version.

The depot version of a pharmaceutical leads to a delayed, preferably even release of the active substance from a reserve of active substance with the prevention of peaks in the plasma concentration over a defined time. Thus, the total amounts of substance can often be decreased, side effects of the pharmaceutical can be reduced and a repeated dosage per day can be replaced by a single administration. These advantages improve the compliance of the patients.

The requirements for an ideal depot dosage form can substantially be summed up: - After the administration, a quick achievement of the therapeutically optimal blood level is desired from the composition.

- A constant level of blood levels has to be ensured.

- An even biological effect must be maintained along the desired time period.

- By the prevention of peaks in the concentration, i.e. prevention of an increase of the concentration of active substance into a toxic range, intensity and frequency of undesired side effects are to be reduced.

After the comprehensive definition of the FDA (Food and Drug Administration), "controlled release products" are to be understood as formulations, which are meant to release the active component in a way that significantly differs from corresponding compositions with immediate release. This definition includes all types of modified-release(-depot) pharmaceuticals as well as those with a timely limited release. Also the term "pharmaceuticals with modified release" sums up all dosage forms which intentionally show a different release than a normal, quick release.

The term depot pharmaceutical is often used as a superior denotation for dosage forms with prolonged effect or as a synonym for modified-release-pharmaceuticals.

Four types of depot pharmaceuticals can be differed: - Sustained release type (synonyms: evenly stalling active substance release, sustained action): From a pharmaceutical and by an initial dose, the active substance is provided to the body in a concentration resulting in the desired pharmacodynamic effect and ensuring a maintenance of this pharmacologically optimal concentration for a certain time higher than the time of the effect of a single dose.

- Prolonged release type (synonyms: prolonged active substance release, prolonged action): From a pharmaceutical and by an initial dose, the active substance is provided to the body in a concentration which is sufficient but not undesirably high and exerts the desired pharmacodynamic effect. Additionally, this type of pharmaceutical shall constantly release the active substance in a way that it results in a measurable prolongation of the effect compared to a normal single dose.

- Repeat release type (synonyms: staggered active substance release, repeat action): From a pharmaceutical, firstly an initial dose of the active substance and after some time a further single dose is released intermittently. Possibly, further doses can follow in due course.

- Delayed release type (synonym: delayed active substance release): From a pharmaceutical, the active substance is released only a long time after the application.

(R. Voigt, Pharmazeutische Technologie, 10. Auflage, Deutscher Apotheker Ver-band Stuttgart).

The common techniques of the formulation of pharmaceuticals from active substance to depot versions, the use of equipment needed therefore and the use of common substances are known to a person skilled in the art in the field of pharmaceutical technology and can be readily provided by consulting general knowledge on the field.

Furthermore, the non-therapeutic use of a mixture of three or more citrate salts as herein described or of a composition as herein described for achieving one or more non-therapeutic/therapeutic effect(s) selected independently of each other from the group consisting of stimulating or boosting the carbohydrate metabolism, preferably the glucose metabolism, in particular for stimulating or boosting the cellular energy metabolism, preferably for stimulating or boosting the oxidative glucose metabolism, preferably stimulating or boosting the oxidative glucose metabolism in a muscle; prevention and/or reduction of muscle soreness; weight reduction; increase of concentration; digestive aid; increase of the physical and mental performance; influencing the acid-base balance, in particular influencing the carbonic acid-bicarbonate system; prevention and/or reduction of cellulite, prevention and/or reduction of cracks in the connective tissue, in particular of stretch marks, is also described herein.

The use of a mixture of three or more citrate salts as described herein or of a composition as described herein for stimulating of boosting the carbohydrate metabolism, preferably the glucose metabolism, particularly for stimulating or boosting the cellular energy metabolism can be used for improving the symptoms of a series of non-pathological conditions.

Stimulating or boosting the glucose metabolism, particularly the oxidative glucose metabolism, results in, as previously described in a comprehensive way, a reduced break down of glucose via the anaerobic glucose metabolism and thus in a reduced generation of lactate. The prevention of the metabolic dead end lactate and the complete use of glucose with the break down to pyruvate and the subsequent metabolism at aerobic conditions to acetyl-Co, which is further oxidized to C02 and water in the citrate cycle, is particularly advantageous with regard to the energy production of the organism. Within the aerobic oxidation of one mole glucose toC02, about 20 times more energy in form of the energy equivalent ATP (adenosine triphosphate) is gained compared to the anaerobic break down to lactate, i.e. the cellular energy metabolism is stimulated or boosted with the citrate salts to be used according to the invention.

In an embodiment, stimulating or boosting of the carbohydrate metabolism, particularly the oxidative glucose metabolism, leads, by means of the citrate salts to be used according to the invention, to an improved use of the carbohydrates absorbed from nutrition and thus to a lower lactate concentration and to an increased energy provision, both systemic and local, such as for example in the muscle. This in turn results in a general improvement of the physical and mental performance and in an increase of concentration, particularly in times of elevated energy demand. Fatigue and exhaustion are also reduced.

One embodiment relates to the prevention of a non-pathological excess of lactate in the muscle by stimulating or boosting the carbohydrate metabolism with the citrate salts to be used according to the invention.

The simultaneous addition of essential and non-essential bulk and trace elements, which are present in the citrate salts to be used according to the invention, further leads to, as previously described, an improvement of various body functions, such as for example the cellular energy metabolism, to an improvement of overall wellness and a reduction of fatigue and exhaustion.

In a further embodiment, stimulating or boosting the carbohydrate metabolism by means of the citrate salts to be used according to the invention can also be associated with an aid in digestion and a supportive effect in weight reduction. The term weight reduction is in this context meant to be understood as a reduction of body weight of a few kilograms due to cosmetic, non-therapeutic reasons.

Carbohydrates absorbed with nutrition are firstly broken down to monosaccharides such as glucose in the intestine, subsequently the monosaccharides obtained from digestion are transported to cells via the blood. Due to a stimulated or boosted carbohydrate metabolism or cellular energy metabolism by means of the citrate salts to be used according to the invention, the absorbed glucose is directly used by energy production and not stored in the organism, which has an advantageous effect on a desired reduction in weight.

As previously described, an acidification of the body can be prevented or reduced with the citrate salts to be used according to the invention due to a reduction of the production of lactate by stimulating the oxidative carbohydrate metabolism and by the influence of the citrate anion on the pH value in the organism.

An embodiment relates to the use of the herein described citrate salts for influencing the acid-base balance, particularly for influencing the carbonic acid-bicarbonate system, for preventing and/or improving of non-pathologic states of the connective tissue such as for example cellulite or cracks in the connective tissue, especially during pregnancy (so called stretch marks). As previously described, an acidification of the body results in an accumulation of protons instead of water molecules to the proteoglycanes of the connective tissue, resulting in a reduction of the elasticity of the connective tissue. This state can be prevented or improved by the regulatory effect of the citrate salts to be used according to the invention on the acid-base balance of the body.

What was said in the scope of a herein described embodiment of the present invention (e.g. relating to (preferred) components of mixtures and components to be used according to the invention and type and amount of the herein described citrate salts or their use) is obviously also valid for other herein described embodiments. Thus, the herein described embodiments are arbitrarily - provided that it is reasonable for the person skilled in the art - combinable with each other.

In the following, the present invention is described with selected examples without restricting the subject-matter according to the claims thereto.

Examples:

1. Compositions:

1. Micropearls Substance Amount [mg] Sorbitol 1078,16 Calcium citrate 569,26 Potassium tartrate 481,23 Magnesium citrate 317,65 Magnesium oxide 286,90 E 470a 28,00 Zinc citrate 8,01 Citrus fruit extract on the carrier 3,00 maltodextrine and antioxidants Sodium molybdate 0,06 Chromium chloride 0,10 Sodium selenite 0,03

Production: A mixture of the substances is obtained and subsequently granulated.

2. Granulate

Substance Amount [mg] Lactose 25388,49 Calcium citrate 2609,70 Sodium citrate 1598,90 Magnesium citrate 966,73 Potassium citrate 975,80 Maltodextrine 408,70 Zinc citrate 16,18 Iron citrate 23,81 Copper citrate 8,33 Chromium chloride 0,21 Sodium molybdate 0,13 Sodium selenite 0,07

Production: Aqueous mixture of trace elements is sprayed on the carrier substance and granulated. The final mixture is produced from this granulate and is granulated.

3. Drinking powder

Substance Amount [mg] Inuline 2599,87 Sodium citrate 1172,71 Potassium citrate 829,65 Calcium lactate 769,23 Magnesium citrate 618,81 Zinc citrate 8,01 Copper citrate 1,42 Chromium chloride 0,15 Sodium molybdate 0,10 Sodium selenite 0,05

Production: Aqueous mixture of trace elements is sprayed on the carrier substance and granulated. The final mixture is produced from this granulate.

II. Study results:

1. Conduct

Using a composition as defined in example 1 as verum, as defined above, a randomized, two-armed, double blind intervention study, as defined above, was conducted on 40 test persons, to investigate the influence of the composition to be used according to the invention on the carbohydrate metabolism as well as on the cellular energy metabolism.

The test persons participated at two days of examination (V1 before the intervention, V2 after the intervention) being identical with regard to the study protocol, separated by 4 weeks. Figure 1 thereto shows a detailed overview on the sequence of a day of examination.

After completion of the first day of examination (V1), the test persons either received the verum, as defined above, (composition as defined in example 1) or the placebo, as defined above, which they took within the following four weeks in the morning and in the evening. The appearance and the packaging of the verum and the placebo was identical.

The test persons arrived at 8 a.m. at the respective day of examination (V1 or V2) and were instructed to have their last meal at the latest until 8 p.m. the night before. Additionally, they were asked to renounce drinks and food containing caffeine or alcohol within 24 hours before the examinations.

After a 30 minute resting period, a microdialysis probe, as defined above, was placed in the right thigh muscle of the test persons. The probe was subsequently perfused firstly for 30 min, to restore the inter-/extracellular balance of the tissue. Afterwards, the resting sober metabolic rate, as defined above, was measured for 30 min via indirect calorimetry by means of a hood placed on the head. Subsequently, the test persons had a meal rich in proteins. The postprandial energy turnover was measured for 180 min (3 intervals A 45 min with 15 min pause each). Before and after the test meal, capillary blood was obtained in determined time intervals from the earlobe of the test persons. Additionally, venous blood was obtained also in determined time intervals before and after the test meal. The microdialysis continuously ran up till the end of the examination (see Figure 1).

2. Results

2.1 Blood parameters

In Figure 2, the basal and postprandial blood glucose concentrations before (V1) and after (V2) the intervention (A) and the basal and postprandial insulin (B) concentrations before (V1) and after (V2) the intervention (B) are depicted.

For the test persons of both groups, the values of the blood glucose and the insulin concentration were in a normal range of sober, healthy people, as defined above, so that a diabetic metabolic state could be excluded. After the test meal, the blood glucose levels slightly increased - the values however did not exceed the normal range for glucose in a sober condition at any time. As can be seen in Figure 2, the basal and postprandial glucose values were reduced after a supplementation for four weeks with the composition as defined in example 1 (verum). The postprandial increase of insulin in the serum was also lower in the case of verum supplementation compared to placebo.

Figure 3 shows the basal serum magnesium concentration before (V1) and after (V2) intervention.

In the verum as well as the placebo group, the serum magnesium concentrations were in a normal range of 0.75 to 0.95 mmol/L, however increased though significantly in the verum group after a supplementation for four weeks with the composition as defined in example 1.

Figure 4 shows the basal and postprandial bloodp02values before (V1) and after (V2) intervention.

The arterial oxygen partial pressure usually is between 70-100 mmHg and decreases with increasing age. In the present study however, capillary blood was used. Hints in literature exist, showing that values obtained from the capillary blood do not correspond to arterial blood. The sober p02 though corresponded to the standard value (83± 5 mmHg) in both groups. After the test meal, the p02 equally decreased in V1 and V2 in the case of placebo, in the case of verum it decreased in V1 and even more in V2. This reveals that the metabolic activity and thus the oxygen consumption with verum was significantly stronger than before.

2.2 Energy turnover

Figure 5 shows the relative changes in the energy turnover (ET) before (V1) and after (V2) intervention.

The RSR, as defined above, was 3.9 kJ/min for V1 in the verum group and 3.8 kJ/min for V1 in the placebo group. After consuming the test meal rich in protein, a clear increase in the energy turnover as defined above occurred as expected. This process is called postprandial thermogenesis (as defined above). The percentage postprandial increase in metabolism was 15% to 23%, which indeed corresponds to the thermogenic potential of the proteins in the test meal.

The relative increase of the postprandial energy turnover was rather higher after verum administration, rather lower after placebo administration. One reason for the lower postprandial increase in the energy turnover in the case of placebo could be that the elderly test persons, normally inexperienced with studies, in V1 were slightly excited and thus the postprandial thermogenesis was additionally superimposed with a stress-related increase of the energy turnover. In V2, the test persons were possibly less excited so that the postprandial increase in total was lower. If the same is considered for the verum group, the higher thermogenesis results from an effect of the verum and such was possibly higher than manifested, particularly if the postprandial thermogenesis in V2 is directly compared between verum and placebo.

Figure 6 shows the basal and the postprandial carbohydrate oxidation rate (CHO) before (V1) and after (V2) intervention.

At the test meal, 72% of the energy originated from the protein and 24% from the carbohydrates. Interestingly, the increase in the postprandial energy turnover was mainly fed by an increase in the carbohydrate oxidation. This effect was rather enhanced with verum, rather reduced with placebo.

2.3 Microdialysis

In the present study, the microdialysis technique, as defined above, was used to investigate the effect of the verum on the metabolism particularly in the muscle. The obtained dialysate, as defined above, was subsequently analyzed. For this "tissue monitoring technique" it is also always important to detect the changes in the local circulation, as the local circulation does not only significantly influence the substrate supply but also the removal of the products and thus the local interstitial metabolite concentrations. In the present study, the ethanol dilution technique, as previously described at the definition of the EtOH ratio, was used for being able to semiquantitatively estimate the relative changes in the circulation in tissue. As the test persons were lying in bed during the examinations and did not substantially change their position, no change of the circulation due to muscular work was expected. In the postprandial phase, the digestive organs are more supplied with blood than the periphery, as for example the muscles. This is the cause for the short-term slight postprandial increase of the EtOH ratio in the muscle, which can be traced back to a slightly reduced circulation in the muscle.

Figure 7 shows the basal and the postprandial EtOH ratio as previously defined before (V1) and after (V2) intervention (A) and the basal and the postprandial dialysate glucose concentration before (V1) and after (V2) intervention (B).

In the verum group, the values of the EtOH ratio in V1 and V2 were almost congruent, the values in the placebo group were higher in V2 than in V1. This difference was mathematically significant, however not of clinical relevance and was not taken into further consideration.

The dialysate glucose postprandially increased in the muscle for a short time and this increase was stronger in the verum group than in the placebo group both, in V1 and V2. Possibly, this difference is related to the composition of the group: The female/male ratio in the verum group was 17/3, in the placebo group 14/6. In the verum group, the dialysate glucose quickly decreased in V2. As the circulation, as previously described in the discussion of the EtOH ratio, was rather unchanged, it can be assumed that with verum glucose is increasingly taken up and metabolized by the muscle.

Figure 8 shows the basal and the postprandial dialysate lactate concentrations before (V1) and after (V2) intervention (A), the basal and the postprandial pyruvate concentrations before (V1) and after (V2) intervention (B) as well as the basal and the postprandial lac/pyr ratio before (V1) and after (V2) intervention (C).

As previously described, glucose is firstly broken down to pyruvate and then, depending on the oxygen supply, either anerobically to lactate or aerobically to carbon dioxide and water in the muscle. Postprandially, the dialysate lactate was increased to the 1.5-fold both, in the verum group and in the placebo group - both, in V1 and in V2. The dialysate pyruvate was as well increased in both groups and equally in V1 and V2 to the 2-fold. However, in V2 of the verum group both, the basal and the postprandial pyruvate concentrations in the dialysate, as previously defined, were significantly higher than in V1. The lactate/pyruvate ratio hardly changed postprandially in V1 and V2 of the placebo group and in V1 of the verum group. However, it clearly decreased in V2 of the verum group. All these changes in V2 of the verum group point towards a clearly improved oxidative glucose metabolism with verum supplementation.

Short description of the attached figures:

Figure 1 shows an overview on the sequence of a day of examination: A) schematic sequence of the applied tests, B) temporal sequence of the applied tests at 40 test persons.

Figure 2 shows: A) the basal and the postprandial blood glucose concentrations before (V1) and after (V2) intervention and B) the basal and the postprandial insulin (B) concentrations before (V1) and after (V2) intervention.

Figure 4 shows the basal and the postprandial blood p02 values before (V1) and after (V2) intervention.

Figure 5 shows the relative changes in the energy metabolism (EM) before (V1) and after (V2) intervention.

Figure 7 shows: A) the basal and the postprandial EtOH ratio before (V1) and after (V2) intervention and B) the basal and the postprandial dialysate glucose concentration before (V1) and after (V2) intervention.

Figure 8 shows; A) the basal and the postprandial dialysate lactate concentrations before (V1) and after (V2) intervention and B) the basal and the postprandial pyruvate concentrations before (V1) and after (V2) intervention as well as C) the basal and the postprandial lac/pyr ratio before (V1) and after (V2) intervention.

Claims

1. A method for the treatment and/or prevention of lactate acidosis and/or obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a mixture of three or more citrate salts, wherein the mixture comprises magnesium citrate, and wherein the mixture additionally comprises calcium citrate and/or zinc citrate.

2. The method according to claim 1, wherein the mixture comprises or consists of at least magnesium citrate, calcium citrate and zinc citrate.

3. The method according to one of the preceding claims, wherein, related to the total weight of the citrate salts, the proportion of magnesium citrate is in a range of 2 to 100 wt.-%, or 2 to 40 wt.-%, or 9 to 36 wt.-%.

4. The method according to claim 3, wherein, related to the total weight of the citrate salts, the proportion of magnesium citrate is in a range of 15 to 36 wt.-%.

5. Use of a mixture of three or more citrate salts for the manufacture of a medicament effective in the treatment and/or prevention of lactate acidosis and/or obesity, wherein the mixture comprises magnesium citrate and additionally two or more citrate salts from the group consisting of calcium citrate, zinc citrate, sodium citrate, copper citrate, iron citrate, potassium citrate, potassium-sodium hydrogen citrate, calcium-sodium hydrogen citrate, disodium hydrogen citrate, ammonium citrate, ammonium hydrogen citrate, molybdenum citrate, manganese citrate, lithium citrate and chromium citrate.

6. The use according to claim 5, wherein the medicament additionally and independent from each other comprises one or more further components selected from the group consisting of sweeteners, acidity regulators, separating agents, acidifying agents, aromas, fillers, magnesium oxide, further citrate salts, calcium carbonate, calcium lactate, magnesium carbonate and/or sodium hydrogen carbonate, vitamins, L-carnitine, maltodextrin, molybdenum, chromium and selenium.

7. The use according to claim 6, wherein the sweetener is lactose, saccharose or sorbitol.

8. The use according to claim 6 or claim 7, wherein the acidity regulator is potassium tartrate.

9. The use of any one of claims 6 to 8, wherein the separating agents are magnesium or calcium salts of fatty acids, cross-linked sodium carboxymethyl cellulose or silicon dioxide.

10. The use according to any one of claims 6 to 9, wherein the acidifying agent is citric acid.

11. The use according to any one of claims 6 to 10, wherein the aromas are natural aromas.

12. The use according to any one of claims 6 to 11, wherein the filler is hydroxypropyl cellulose.

13. The use according to any one of claims 6 to 12, wherein the further citrate salts are sodium citrate, potassium citrate, potassium-sodium hydrogen citrate, calcium-sodium hydrogen citrate, copper citrate and/or iron citrate.

14. The use according to any one of claims 6 to 13, wherein the vitamins are riboflavin, cholecalciferol (Vitamin D) and/or ascorbic acid.

15. The use according to any one of the claims 5 to 14, wherein the total amount of citrate salt(s) in the medicament related to the total weight of the medicament is in a range of 4 to 70 wt.-%, or 8 to 67 wt.-%, or 19 to 44 wt.-%.

16. The use according to claim 15, wherein the total amount of citrate salt(s) in the medicament related to the total weight of the medicament is in a range of 25 to 35 wt.-%.

17. The use according to one of the claims 6 to 16, wherein the medicament is formulated to be in a form selected from the group consisting of: granules for direct consumption or for dissolving or stirring into meals; tablets, capsules and lozenges for swallowing, sucking or chewing; powder for direct consumption; water soluble powders for drinking; drinking vials; and micropearls for direct consumption without water.

18. The use according to claim 5, wherein the medicament is free of one, more or all of the components selected from the group consisting of lactose, iodine, gluten, fragrances and sweeteners.

19. A mixture of three or more citrate salts, wherein the mixture comprises magnesium citrate, and wherein the mixture additionally comprises calcium citrate and/or zinc citrate, when used for achieving of an effect selected from the group consisting of: preventing a non-pathological excess of lactate in the muscle by stimulating or boosting the carbohydrate metabolism and a supportive effect in weight reduction.

20. A method for preventing a non-pathological excess of lactate in the muscle by stimulating or boosting the carbohydrate metabolism and/or providing a supportive effect in weight reduction in a subject, comprising administering to the subject a therapeutically effective amount of a mixture of three or more citrate salts, wherein the mixture comprises magnesium citrate, and wherein the mixture additionally comprises calcium citrate and/or zinc citrate.

PROTINA Pharmazeutische Gesellschaft mbH Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON

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