EP4687872A1 - Oral active ingredient combination containing l-arginine, l-citrulline, selenite and water-soluble boron - Google Patents

Abstract

The invention relates to an oral active ingredient combination which comprises L-arginine, L-citrulline and a selenium compound, and also water-soluble boron, wherein L-arginine, L-citrulline and selenium compound are formulated for intake at an interval of 2 to 4 hours after the boron, for animal feed, medicaments, food supplements or foods for particular medical purposes or as medicaments or animal medicaments for treating one or more of the following conditions: type-II diabetes, overweight, hypertension, lipid metabolism disorders, liver dysfunction, erectile dysfunction and libido disorders.

Description

ORAL ACTIVE INGREDIENT COMBINATION CONTAINING L-ARGININE, L-CITRULLINE, SELENITE AND WATER-SOLUBLE BORON

[0001] The present invention relates to an oral active ingredient combination as a medicament, nutritional supplement or as a food for special medical purposes with which the metabolic syndrome and general signs of aging or age-related diseases can be positively influenced. Furthermore, the oral active ingredient combination can be used as a nutritional additive in animal feed or as a veterinary drug.

[0002] With the increase in life expectancy, health problems, which usually only become noticeable after the age of 40, are increasingly coming into focus. These include, in particular, cardiovascular diseases, type II diabetes and complaints associated with the decrease in sex hormone levels. In many cases, the so-called metabolic syndrome is behind these problems. This develops unnoticed over many years and manifests itself in the following symptoms:

- high blood pressure

- increased blood lipids, especially hypertriglyceridemia

- decreasing muscle absorption capacity for sugar (peripheral insulin resistance, impaired glucose tolerance)

- increasing obesity, especially visceral obesity and fatty liver, as well as

- erectile dysfunction

- Decreased libido.

The development of metabolic syndrome is attributed to a variety of risk factors, in particular hypercaloric nutrition, lack of physical exercise, oxidative stress and smoking. This leads to obesity, which subsequently leads to insulin resistance. The main influence on the development of metabolic syndrome is the Visceral fat. This tissue, rich in fat cells, is located between the organs of the abdominal cavity. The fat cells are hormonally active and promote insulin resistance, among other things. In parallel, there is often a change in blood lipid levels (high concentrations of triglycerides and small, dense LDL particles). A diet with high levels of cell-free flour, sugar, and other refined industrial foods, which could promote an inflammatory microbiome in the intestine, is considered to be a contributing cause. Put bluntly, metabolic syndrome is the price of little exercise, (too) much food, nicotine, stress, ... and other circumstances that determine the way of life in industrialized nations.

[0003] For "treatment" it would of course be ideal to change the diet, ensure sufficient exercise and eliminate other factors such as nicotine, stress etc. As this is usually either not sufficient or not successful at all, there is no shortage of suggestions to at least compensate for the malnutrition with food supplements or foods for special medical purposes. If symptoms reach a clinically relevant level, they or their causes are regularly treated with medication. For example, statins are used as standard therapy to lower cholesterol (LDL) and in particular triglycerides to reduce the risk of heart attacks and strokes. Long-term therapy with statins, for example, often results in clinically relevant side effects such as increased blood pressure, muscular complaints, cramps, weight gain, increased blood sugar and liver values, gastrointestinal complaints, chronic fatigue, itching or headaches. These secondary diseases are often treated with other medications. This means that usually a large number of different medications are prescribed and taken.

In addition, the expected or necessary effect is not achieved in some cases. Even food supplements or foods for special medical purposes can occasionally have undesirable side effects. Often there is a lack of in these cases, there is a lack of sufficient effectiveness. The problem therefore remains of finding effective agents that are as free from undesirable effects as possible for treating the signs of aging and metabolic syndrome. The aim of the present invention was therefore to develop a product that is as free from side effects as possible for the treatment and/or support of the therapy of age- or lifestyle-related metabolic syndrome as part of diet management to regain and maintain vitality, strength and endurance.

[0004] Surprisingly, it has now been found that the combination of L-arginine, L-citrulline and a water-soluble selenium compound, in particular selenite, leads to a considerable reduction in blood pressure, improvement in type II diabetes, liver functions or liver metabolism, lipid metabolism and an increase in testosterone levels after taking the co-factor boron and possibly other co-factors such as other minerals and vitamins.

[0005] The above-mentioned object is therefore achieved by an oral active ingredient combination comprising L-arginine, L-citrulline and a selenium compound, in particular selenite, as well as boron, all in water-soluble form, wherein L-arginine, L-citrulline and the selenium compound are dosed for absorption from food after ingestion at an interval of 2 to 4 hours after the boron. The latter is achieved either by taking a separately packaged dose of the boron at a later time or by providing L-arginine, L-citrulline and the selenium compound in a sustained-release form with delayed release but rapid absorption in a mixture with non-sustained-release boron. The oral active ingredient combination is used as a nutritional additive for animal feed (see EU Regulation No. 1831/2003) or as a veterinary medicinal product for mammals or as a medicinal product, as a food supplement or as a food for special medical purposes (see EU Regulation No. 609/2013) for humans. [0006] The first component of the active ingredient combination according to the invention is L-arginine. This is a semi-essential amino acid that occurs in many proteins and is commercially available. L-arginine is used in water-soluble form. L-arginine is mainly produced by extraction from duck feathers. This results in an acidic L-arginine HCl that has reduced bioavailability and is not vegan. Alternatively, vegan L-arginine is obtained by fermenting sugar cane or grain as an L-arginine base. The disadvantage is the fishy taste of the L-arginine base. Preferably, vegan L-arginine alpha-ketoglutarate obtained by fermentation is used, which has high bioavailability and a neutral taste. Other physiologically acceptable and water-soluble salts of L-arginine such as citrates or malates are also possible.

[0007] A positive effect of compositions containing L-arginine on cardiovascular diseases has already been described many times, e.g. in D. Menzel et al., "L-arginine and B vitamins improve endothelial function in subjects with mild to moderate blood pressure elevation", doi.org/10.1007/s00394-016- 1342-6 and in K. Jung and O. Petrowicz, "L-arginine and folic acid in arteriosclerosis - results of a prospective, multi-center consumption study", Perfusion 2008, pp. 148-156. The effect of L-arginine intake is attributed to the formation of NO, which has a relaxing effect on blood vessels. In the body, L-arginine is converted into NO by the enzyme eNOS (endothelial NO synthase) located in the blood vessels.

[0008] However, a combination with L-citrulline and a selenium compound such as selenite and with boron as a co-factor was not considered in published studies. Nor was it suspected that a delayed dosage of L-arginine, L-citrulline and selenium compound after the intake of the co-factor boron and possibly other co-factors could be beneficial. Both However, together they showed a surprisingly increased efficacy without any adverse effects.

[0009] The active ingredient combination according to the invention comprises L-citrulline as a second component. This amino acid is also well known and commercially available. L-citrulline is also used in water-soluble form, preferably in the form of a water-soluble derivative, particularly preferably as malate.

[00010] Commercially available products such as Argilin retard (www.argilin.de), Zestval Arginin 4.0 NEM (www.zestonics.com) and aminoplus Arginin + Citrulline (www.kyberg-vital.de) also combine L-arginine and L-citrulline, sometimes with the addition of co-factors, but no boron is added.

[00011 ] The third component is a water-soluble selenium compound, in particular selenite, preferably an alkali salt of selenious acid. Sodium selenite and selenomethionine as well as selenocysteine are particularly preferred.

[00012] Well-known dietary supplements that contain selenium as a compound together with L-arginine and/or L-citrulline and in some cases also other components are Dorecfil (www.exvital.de), Arteries-Blood Vessel Support (www.biotikon.de), Vitamaze L-Arginine plus (www.vitamaze.shop), Mascupro Testo & Energy/Mascupro Fertility (www.mascupro.de), and aminoplus mann (www.kyberg-vital.de). All of these products do not contain boron.

[00013] As a fourth component, the active ingredient combination according to the invention comprises boron in water-soluble form, which is dosed before the components L-arginine, L-citrulline and selenium compound. Preferably, a water-soluble boron salt is used, particularly preferably an inorganic borate, in particular sodium tetraborate. Boric acid can also be used. [00014] The staggered dosing can be achieved on the one hand by separate dosage forms, which can be the same or different. For example, capsules, dragees, tablets, juice, drops, syrup, powder or granules are suitable. It is expedient to provide one of the two doses to be taken at different times in one dosage form, preferably in one or more capsules, tablets, dragees or a sachet with powder and/or granules for stirring into liquid.

[00015] In a preferred embodiment of the invention, the boron salt is provided as a tablet, capsule or dragee and the components L-arginine, L-citrulline and selenium compound are provided as a powder or granules in a sachet, wherein the dosage form preferably contains a daily dose or half a daily dose or a quarter of a daily dose.

[00016] In a particularly preferred embodiment, the components L-arginine, L-citrulline and selenium compound are provided together with the boron salt in a dosage form. The components L-arginine, L-citrulline and selenium compound are used in sustained release form with delayed release of the active ingredient. Galenic forms with delayed release of the active ingredient are known per se for pharmaceuticals. They are used to release an active ingredient at a later time after ingestion or over a longer period of time. According to the invention, delayed release is used, but not release over a longer period of time. The selected, special sustained release form ensures a delayed release of the components L-arginine, L-citrulline and selenium compound only approx. 2 to 4 hours after ingestion. This achieves the same effect as with a staggered dose, but without the need for the person being treated to take the medication twice and maintain the desired time interval between the two doses. [00017] A suitable time-delayed release of active ingredients is achieved, for example, by coating the components with pH-activated substances that are insoluble at low pH and dissolve easily in the small intestine in a basic environment at a higher pH, typically > pH 7, and release the enclosed active ingredients. These conditions are met, for example, by shellac-coated microgranules and ethyl cellulose or alginate-based micro- or nanoparticles. Alternatively, starch-coated microgranules or nanoparticles can be used, for example, which are released by alpha-amylase digestion after passage through the stomach in the duodenum/jejunum. According to the invention, the effect of the uncoated active ingredients occurs through rapid absorption in the upper digestive tract, in particular during passage through the stomach, with rapid bioavailability of the boron and, if applicable, the other cofactors contained in water-soluble form. The release and rapid absorption of the coated components in the small intestine then occurs approximately 2 to 4 hours later, e.g. through pH-activated or alpha-amylase-induced release. The rapid bioavailability of the delayed-release, delayed-release components is preferably ensured by using appropriate, readily water-soluble derivatives such as inorganic or organic salts or e.g. as esters.

[00018] The active ingredient combination in a dosage form preferably comprises a water-soluble boron salt or boric acid as a powder, optionally with other easily water-soluble co-factors, and the components L-arginine, L-citrulline and selenium compound in water-soluble form as microgranules coated with shellac in a sachet. For ingestion, the sachet contents are stirred into water to produce a drinking solution.

[00019] A suitable daily dose is usually divided into 1 to 3 individual doses, preferably into 1 to 2 individual doses and particularly preferably as 1 individual dose taken in the morning. [00020] A daily dose or sustained-release, time-delayed amount of the components L-arginine, L-citrulline and selenium compound in the active ingredient combination usually comprises, based on a person with a body weight of 80 kg, from 0.5 to 10.0 g L-arginine, from 1.0 to 10.0 g L-citrulline and from 10 to 150 pg selenium compound. Preference is given to 1.0 to 3.0 g L-arginine, from 2.0 to 8.0 g L-citrulline and from 20 to 100 pg selenium compound, particularly preferably from 1.5 to 2.5 g L-arginine, from 3.0 to 4.0 g L-citrulline and from 35 to 70 pg selenium compound. The amounts stated refer to the amounts calculated as free amino acid or selenium; the preferred compounds are used in correspondingly greater quantities. It is advantageous if the amount of L-citrulline is 1.5 to 3 times the amount of L-arginine. As a further component, the active ingredient combination comprises a separate or non-sustained-release daily dose of boron containing 1 to 9 mg, preferably 2 to 5 mg, particularly preferably around 3 mg of boron. The daily dose calculated for a body weight of 80 kg can usually also be used for a lower or higher body weight, e.g. for a body weight of 60 to 100 kg or up to 120 kg. With a very high body weight, from around 110 kg or 120 kg, taking two doses calculated for a weight of 80 kg should be considered; from around 140 or 150 kg this is preferred.

[00021] The oral active ingredient combination according to the invention can contain further amino acids and/or further co-factors, ie minerals and/or vitamins and/or antioxidants. Preferably one, in particular several, of magnesium, manganese, zinc, molybdenum, copper, chromium, calcium, folic acid, vitamin C, vitamin B2, vitamin B6, vitamin B12, vitamin B1, vitamin B5, vitamin D, vitamin K, coenzyme Q10, glutathione, biotin, niacinamide, omega-3 fatty acids, alpha-linolenic acid, DHA (docasahexaenoic acid), curcumin, OPC (oligomeric proanthocyanides), pycnogenol, lutein, rutin or spermidine are included. The further amino acids or the co-factors can be combined with the boron compound be combined/mixed together in one dosage form or be present in whole or in part in another dosage form, for example in another capsule or tablet or another sachet. Preferably, the additional co-factor(s) is/are used in a form that is readily soluble in water.

[00022] A first preferred additional co-factor is magnesium. A daily dose is generally from 100 or 200 to 800 or 1000 mg of magnesium, preferably from 120 to 150 mg. The use of a water-soluble magnesium salt is advantageous, magnesium citrate, magnesium gluconate, magnesium L-threonate or magnesium bisglycinate are preferably used, magnesium bisglycinate is particularly preferred.

[00023] A second preferred additional co-factor is zinc. From 10 to 25 mg of zinc per daily dose is well suited, preferably about 15 mg. Zinc is often used as zinc oxide but preferably in the form of a readily water-soluble salt, in particular as zinc glycinate, zinc citrate, zinc gluconate and most preferably as zinc glycinate.

[00024] A third preferred additional co-factor is manganese. A daily dose is usually from 0.5 to 5 mg manganese, preferably about 3 mg.

Manganese is preferably used in the form of a water-soluble salt, in particular as manganese glycinate or manganese gluconate.

[00025] A fourth preferred further co-factor is folic acid or folate. In particular, from 200 to 1000 pg of folic acid or folate, calculated as folic acid, preferably about 400 pg, are used per daily dose. A preferably used water-soluble form is methyl tetrahydrofolate.

[00026] A fifth preferred further co-factor is vitamin C. Preferably, from 200 to 1000 mg of vitamin C, particularly preferably about 200 to 300 mg, are used per daily dose. A preferred form is calcium ascorbate or Vitamin C ester or vitamin C complex consisting of calcium ascorbate and L-threonate.

[00027] A sixth preferred additional co-factor is vitamin B2. Preferably, 1 to 5 mg of vitamin B2 are used per daily dose, particularly preferably about 3 to 5 mg.

[00028] A seventh preferred additional co-factor is vitamin B6. Here, a daily dose of 1 to 20 mg of vitamin B6 is preferred, in particular about 5 mg.

[00029] An eighth preferred additional co-factor is vitamin B12. Preferably, from 1 to 50 pg of vitamin B12, particularly preferably about 25 pg, are used per daily dose.

[00030] In a preferred embodiment, several of the preferred additional co-factors are included in the oral active ingredient combination according to the invention, for example two, three or even more. Particularly preferably, all eight preferred additional co-factors are included. Also particularly preferably, vitamin C, folic acid, manganese, zinc and magnesium are included as additional co-factors, in particular in an intestinally compatible form with high bioavailability (e.g. as calcium ascorbate, methyl tetrahydrofolate and the minerals as glycinate or citrate). The preferred additional co-factor(s) are included in particular in the amounts mentioned and/or in the form of the compounds mentioned. According to the invention, the additional co-factors are preferably combined with boron in a dosage form. It is also possible to combine individual additional co-factors with the components L-arginine, L-citrulline and selenium compound. For example, magnesium can also be combined in part with the components L-arginine, L-citrulline and the selenium compound. A separate dosage form of the other co-factor(s) is also possible, but not preferred. [00031] The dosage form of the oral active ingredient combination is produced in a manner known per se. Excipients are often used for this purpose. These are normally inert and are used to improve shelf life, stability, for shaping, for adjusting the weight and consistency, for taste and appearance. In addition, excipients can be important for promoting release, absorption and bioavailability, for adjusting the pH value and osmolarity, for protection and for the manufacturing process. Typical excipients include antioxidants, flavorings, binders, fragrances, emulsifiers, colorants, film formers, fillers, gelling agents, taste correctors, complexing agents, preservatives, solvents, solubilizers, buffers, ointment bases, acidifiers, acidity regulators, acids and bases, lubricants, sweeteners, coating agents, thickeners and disintegrants.

[00032] With the oral active ingredient combination according to the invention, all relevant symptoms or diseases of the metabolic syndrome could be influenced in a surprisingly positive way when the time-staggered intake was observed. In particular, the active ingredient combination supports the reduction of LDL cholesterol and especially triglycerides, and also improves blood pressure, testosterone levels and liver function or liver metabolism, expressed in an unexpectedly high reduction in the liver markers gamma-GT and GPT. The treatment showed no side effects, and no additive oxidative stress (radical stress) occurred during the study period. In addition to use in humans, the areas of application also include use as a nutritional additive for animal feed and as a veterinary drug for mammals, particularly horses, dogs and cats.

[00033] The invention will be explained by means of the following examples, without, however, being restricted to the specifically described embodiment. The invention also relates to all combinations of preferred Forms of implementation, provided that they are not mutually exclusive. The terms "about" or "approx." in conjunction with a numerical specification mean that values that are at least 10% higher or lower, or 5% higher or lower, and in any case 1% higher or lower, are included.

[00034] Examples

For an application study, a dosage form containing boron salt and the other co-factors magnesium, manganese, zinc, folic acid, vitamin C, vitamin B2 and vitamin B12 was provided in the form of capsules and a second dosage form containing L-arginine, L-citrulline and selenium compound in the form of a powder for dissolving in sachets. The 2 capsules as a daily dose for morning intake contained together:

3.0 mg boron (as sodium tetrahydroborate)

400 mg magnesium (as magnesium oxide)

3.0 mg manganese (as manganese glycinate)

15.0 mg zinc (as zinc glycinate)

0.4 mg folic acid (as methyltetrahydrofolate)

200 mg vitamin C (as calcium ascorbate)

5.0 mg vitamin B2

25.0 pg vitamin B12 (as methylcobalamin) and

4.0 mg citrus bioflavonoids.

The powder for 2 to 4 hour delayed administration contained per sachet as a daily dose:

L-arginine 1.8 g (as arginine alpha-ketoglutarate 2:1)

L-Citrulline 3.6 g (as citrulline malate)

Selenium 70 pg (as sodium selenite) as well as flavor and erythritol.

[00035] 20 subjects were examined based on the criteria of drug or other medical treatment of at least one of the following diseases or functional disorders were selected: high blood pressure, lipid metabolism disorder, type II diabetes, overweight/obesity, libido and potency disorders, menopausal symptoms. The age of the subjects was between 40 and 85 years. None of the subjects had any of the following exclusion criteria: systemic active autoimmune disease (including rheumatoid arthritis, Crohn's disease), active malignant tumor disease, active infectious disease, pregnancy, condition after myocardial infarction.

[00036] The subjects were divided into 2 groups A and B. Group B received the oral active ingredient combination according to the invention with an intake of the co-factors in the morning and approximately 2 to 4 hours later the intake of the components L-arginine, L-citrulline and selenium compound. For comparison, group A took all components simultaneously in the morning.

[00037] At the beginning of the study, weight and blood values were determined. At the end of the study period of 8 weeks, weight and blood values were determined again and the subjects were asked in a final interview about a range of conditions such as fatigue, physical fitness or mental stability/stress resistance. In group B, 4 women and 6 men were recruited. During the course of the study, 1 subject in group A stopped participating; of the remaining subjects, 6 were men and 3 were women in group A. The blood values determined were: HbA1 c, total bilirubin as well as indirect and direct, GPT, gamma GT, LDH, HDL, LDL, triglycerides, creatinine, urea, uric acid, iron, albumin, 17-beta-estradiol (in women, all of whom showed no stimulation of estradiol levels during menopause), testosterone (in men without medicinal testosterone substitution), SHBG, CRP, IL6, IP 10, Lp-PLA2, MDA-LDL, nitrotyrosine, AGE, Lp-PLA 2. Significant differences between groups A and B were found for HbA1 c, LDL cholesterol, triglycerides, GPT, gamma GT, testosterone (men) and nitrotyrosine. [00038] Example 1 : Blood pressure

All study patients with high blood pressure (this was 8/10 of the subjects in group B and 5/9 of the subjects in group A) remained on unchanged drug therapy with up to 3 anti-hypertensive preparations during the study. Of the 19 subjects, 7 measured and recorded their blood pressure daily during the study using their own measuring devices. The changes in blood pressure values found for these 7 patients are shown in Table 1. The values from the 3rd day after the start and end of the study were taken into account. The other subjects from groups A and B who did not regularly check their blood pressure also reported that their high blood pressure decreased during the study.

[00039] Table 1

[00040] The table values show that the blood pressure could be reduced by an average of 15% for the systolic blood pressure and 10% for the diastolic blood pressure in both groups B and A by the oral drug combination in addition to the existing drug therapy. After the end of the study, there was a return to the mean blood pressure values before the study.

[00041] As a result, the oral active ingredient combination according to the invention is therefore very well suited to support high blood pressure therapy, so that if necessary, the dosage of the drugs can be reduced and/or in the case of several of the “blood pressure medication” can be omitted. If blood pressure values are in the upper normal range or if blood pressure is slightly elevated, taking the oral combination of active ingredients may be sufficient to prevent or delay the development of manifest high blood pressure.

[00042] Example 2: Application security

The safety of use was tested by measuring the nitrotyrosine blood levels. The laboratory parameter nitrotyrosine indicates nitrosative stress. It is known that in the context of inflammatory diseases, especially those caused by bacteria, the eNOS enzyme system and thus the NO supply for vascular regulation can be destabilized. As a result, reactive oxygen radicals can intensify the inflammatory processes. Inflammatory vascular wall reactions are crucial for the development or intensification of atherosclerotic vascular changes and their secondary diseases. Therefore, sufficient stabilization and activation of the vascular wall-regulating enzyme eNOS is very important for sufficient and regulated NO supply over the course of the day.

[00043] In group B, no new increase in nitrotyrosine beyond the limit was observed during the 8-week study period. In contrast, in group A, nitrosative stress was measured in 2 subjects that did not exist before the start of the study. This represents a significant advantage in terms of high application safety when taking co-factor(s) and substrates at different times.

[00044] Example 3: Diabetes, liver function, lipid metabolism, sex hormones The blood value measurements for blood lipids, the "liver values", sugar and sex hormones are summarized in Table 2. In each case, the difference between the measured blood value at the end of the study minus the value at the beginning of the study before starting to take the test medication is given. [00045] Table 2

[00046] From Table 2 it can be seen that an improvement was achieved in terms of HbA1 c as a long-term blood sugar value. In group B, 5/10

(50%) subjects achieved a reduction in HbA1c value between -0.10 and -0.30%. In the comparison group A, the HbA1c value improved in 5/9

(56%) subjects by between -0.10 and -0.20%. The time-delayed dosing according to the invention in group B was therefore somewhat more effective. This positive effect is surprising, since the measured HbA1 c value corresponds to the reaction of blood sugar with the hemoglobin of the erythrocytes. The average lifespan of the erythrocytes is 120 days. With a study duration of 56 days, a lower reaction of blood sugar and hemoglobin is achieved during the lifespan of the erythrocytes. It can therefore be assumed that the positive effect shown would be further increased if the study duration was sufficiently long. [00047] With regard to liver function, there was a smaller difference between groups A and B for the bilirubin value. In group B, the value was reduced between -0.05 and -0.33 mg/dl in 5/10 (50%) of the subjects and between -0.02 and -0.29 mg/dl in 6/9 (67%) of the comparison group A. The liver enzyme GPT improved significantly more in group B than in the comparison group A. In group B, 8/10 (80%) of the subjects showed an improvement with a reduction between -1 and -39 U/l. In the comparison group A, only 4/9 (44%) of the subjects showed a reduction between -2 and -7 U/l. In comparison group A, the liver enzyme gamma-GT showed an effect in more subjects, but on average it was less effective than in group B. In group B, 5/10 (50%) showed an improvement of between -4 and -89 U/l. In comparison group A, 7/9 (78%) of the subjects showed a reduction in the gamma-GT value of between -1 and -14 U/l. In group B, there was an improvement of GPT into the normal range in 2 subjects (from 60 U/l to 21 U/l and from 53 U/l to 31 U/l), and of Gamma GT in one subject (108 U/l to 19 U/l). In comparison group A, no subject was able to achieve an improvement in the liver enzyme values into the normal range; on the contrary, in one subject the GPT value deteriorated beyond the normal range (from 21 U/l to 36 U/l).

[00048] The relevant blood lipid values were consistently improved more in group B than in the comparison group A. For LDL cholesterol, 7/10 (70%) of the subjects in group B improved with a reduction between -2.00 mg/dl and -34 mg/dl. In the comparison group A, 4/9 (44%) between -4.00 mg/dl and -19.00 mg/dl. Triglycerides are considered to be the strongest risk parameter among blood lipids with regard to the development and progression of metabolic syndrome and its secondary diseases. Triglycerides were reduced between -25.60 mg/dl and -204.00 mg/dl in 8/10 (80%) of the subjects in group B, and between -0.70 mg/dl and -42.00 mg/dl in 5/9 (56%) of the subjects in the comparison group A. In group B, 5 Subjects showed an improvement into the normal range (from 360 mg/dl to 156 mg/dl, from 214 mg/dl to 134 mg/dl, from 251 mg/dl to 136 mg/dl, from 206 mg/dl to 132 mg/dl, and from 150 mg/dl (normal limit) to 75.5 mg/dl). No subject in group A was able to achieve an improvement into the normal range, but 3 subjects in group A showed a significant deterioration beyond the normal range (from 133 mg/dl to 278 mg/dl, from 109 mg/dl to 198 mg/dl, and from 127 mg/dl to 199 mg/dl).

[00049] In terms of testosterone levels, an improvement was achieved in 80% of the male subjects in both groups. The testosterone levels were not determined in 2 subjects who had undergone testosterone replacement therapy. In group B, the increase was more pronounced, with an increase of between +0.20 nmol/l and +3.40 nmol/l, while in the comparison group A, an increase of only between +0.20 nmol/l and +1.80 nmol/l was achieved.

[00050] Example 4: General well-being

On average, the subjects lost 2.4 kg of body weight over the course of the study and reported a reduction in their feeling of hunger. The subjects were questioned in intensive individual interviews about a variety of specific symptoms. The results are summarized in Table 3. The subjects were also questioned about their general condition. The results are summarized in Table 4.

[00051] Table 3: Number of patients with slight or significant improvement of the respective symptoms

[00052] Table 4: general constitution

[00053] The subjects in group B and the comparison group A were asked about existing complaints or symptoms and their improvement during the 8-week intake of the study medication. The subjects indicated whether there was a slight improvement or a significant improvement in the respective complaints/symptoms. Table 3 contains a summary of all reported complaints/symptoms and their improvement over the course of taking the study medication for both group B and comparison group A. In summary, it was shown that in group B the proportion of significant improvements with 43 of the total 80 complaints mentioned (corresponding to 53.5%) clearly exceeds the proportion of significant improvements in group A. In comparison group A, only 14 significant improvements were reported out of a total of 40 complaints mentioned. (corresponding to 35.0%). The symptom "tiredness" was mentioned before the start of the study by 6 of the 10 subjects in group B and by 4 of the 9 subjects in comparison group A. Surprisingly, 4 of the 6 affected subjects in group B reported a significant improvement compared to only 2 of the 4 affected subjects in comparison group A. Other examples are "cramps" and "muscle tension", which were significantly improved in the 2 and 3 affected subjects in group B, respectively, compared to only a slight improvement in the 3 subjects with cramps and 2 subjects with muscle tension in comparison group A. A similar picture can be seen with "joint pain" with a significant improvement in 3 of 4 subjects in group B, compared to only a slight improvement in the 3 subjects in comparison group A. Another example can be found with psychological-mental symptoms such as "wet hands" with a significant improvement in 3 of 4 subjects in group B. Furthermore, a significant improvement was seen in "easy fatigue" in the 2 affected subjects in group B, and also in "itching" with a significant improvement in all 3 affected subjects in group B. A surprising treatment success was seen in one subject in Group B had a "tinnitus" that disappeared completely during the 8-week study medication and, surprisingly, returned after the study medication had been stopped. A total of 4 test subjects reported postmenopausal symptoms before the start of the study, which were significantly alleviated in 2 of the 3 affected women in group B, compared to only a slight improvement in one test subject in comparison group A.

[00054] From the tables it can be seen that the active ingredient combination according to the invention was able to increase endurance, general well-being, physical condition and mental fitness in both groups, as far as complaints in this regard were present. In group B, however, an improvement occurred more frequently overall than in the comparison group A. Almost all Subjects reported feeling less "stressed", "overworked" and "weak" during the study - with only minor differences reported between group B and comparison group A.

[00055] The increase in effectiveness on blood pressure, lipid metabolism, liver function and sex hormones found clearly exceeds the expectations of an L-arginine or L-arginine/L-citrulline preparation based on published data. A reduction in triglyceride levels of 17.7% compared to 31.4% reduction with the active ingredient combination according to the invention was only described for one L-arginine commercial product, TELCOR Arginin plus, in D. Menzel et al., doi.org/10.1007/s00394-016-1342-6. TELCOR Arginin plus is a food for special medical purposes (daily dose: 2,400 mg L-arginine, 400 pg folic acid, 4 mg Vit. B6, 8 pg Vit. B12). Arginine products are generally known to reduce systolic and diastolic peripheral blood pressure. The TELCOR-Arginine plus study cited also explicitly refers to the reduction in blood pressure at night. The study results reported were that systolic blood pressure fell by 16.5% and diastolic by 14.7% the night before the start of the study. At the end of the 6-month study, the nighttime reduction in diastolic blood pressure increased by 2.9% to 17.9% and systolic by 3.2% to 19.4%. According to the German Hypertension League, these reductions are within the range of fluctuations in the circadian rhythm. Another aspect to be taken into account when interpreting the study is that no study participants with existing drug therapy for hypertension were included in the TELCOR-Arginine plus study. The surprisingly significant reduction in blood pressure after taking the active ingredient combination according to the invention was even achieved in the test subjects on top of the continuation of the respective medicinal anti-hypertensive therapy.

[00056] A reduction in liver enzymes or an increase in testosterone blood levels has not been reported for any available product. Other reports on The L-arginine and L-arginine/L-citrulline products introduced in 2014 only demonstrate a clinical effect as dietary supplements or foods for special medical purposes, namely a reduction in systolic and diastolic blood pressure with an improvement in blood circulation and a reduction in homocysteine levels. A reduction in the risk factor homocysteine by taking folic acid and vitamin B6 is a well-known medical standard.

[00057] The increased effectiveness and improved safety of use of the active ingredient combination according to the invention when taken at different times could be due to effective conditioning (stabilization and activation) of the eNOS enzyme complex. The interaction with the co-factor boron appears to cause conditioning of the eNOS enzyme before the staggered intake of the components L-arginine, L-citrulline and selenium compound provides sufficient NO quantities for arterial vascular regulation and other effects with high safety of use. The high level of safety of use and effectiveness is therefore based on the selection and dosage of the co-factor coupled with the staggered intake of L-arginine, L-citrulline and selenium. The formulation according to the invention differs significantly from all other known L-arginine products in this respect.

[00058] In the comparison group A, when the co-factor and the components L-arginine, L-citrulline and selenium compound were taken together, an effectiveness was observed that was significantly lower than the effectiveness when taken at different times (group B), but was still higher and broader (lipids, liver values and testosterone) than with known products, e.g. compared with the published results of the TELCOR-arginine plus studies.

[00059] Based on the effectiveness found, the use of the oral active ingredient combination as a drug for the treatment of one or more of the diseases/symptoms of the metabolic syndrome - i.e. peripheral insulin resistance/diabetes type II, obesity, hypertension, lipid metabolism disorders as well as erectile dysfunction, libido disorders and menopausal complaints - promising. Therapeutic use to improve liver dysfunction is also possible. In addition, the combination of active ingredients is ideally suited to be used as a dietary supplement or food for special medical purposes for preventive purposes and as an adjunct to therapy from the age of 40.

Claims

patent claims 1. Oral active ingredient combination as a nutritional additive for animal feed, medicinal products, food supplements or foods for special medical purposes, which comprises L-arginine, L-citrulline and a selenium compound, each in water-soluble form, characterized in that water-soluble boron is contained and wherein L-arginine, L-citrulline and selenium compound are formulated for intake at an interval of 2 to 4 hours after the boron. 2. Active ingredient combination according to claim 1, characterized in that L-arginine, L-citrulline and selenium compound are formulated in a dosage form separate from the dosage form of the boron. 3. Active ingredient combination according to claim 2, characterized in that it is available as a kit of - Capsules, tablets or dragees containing the water-soluble boron and - Sachets comprising the components L-arginine, L-citrulline and selenium compound in powder form and/or as microgranules for dissolving. 4. Active ingredient combination according to claim 1, characterized in that L-arginine, L-citrulline and selenium compound are formulated in a sustained-release form for time-delayed release in a dosage form together with the non-sustained-release boron. 5. Active ingredient combination according to claim 4, characterized in that the components L-arginine, L-citrulline and selenium compound are provided together as shellac-coated microgranules together with the uncoated boron as powder in sachets with a single dose. 6. Active ingredient combination according to one of claims 1 to 5, characterized in that L-arginine is contained as L-arginine base or L-arginine HCl or as L-arginine alpha-ketoglutarate, citrate or malate, in particular as alpha-ketoglutarate, and/or L-citrulline is contained as L-citrulline or in particular L-citru hin malate and/or the selenium compound is contained as selenite, preferably as an alkali salt of selenious acid, in particular as sodium selenite, and/or the boron is a tetraborate or boric acid, in particular sodium tetraborate. 7. Active ingredient combination according to one of claims 1 to 6, characterized in that a dosage form of the components L-arginine, L-citrulline and selenium compound comprises: 0.5 to 10.0 g L-arginine, preferably 1.0 to 3.0 g or 1.5 to 2.5 g 1.0 to 10.0 g L-citrulline, preferably 2.0 to 8.0 g or 3.0 to 4.0 g 10 to 150 pg selenium compound, preferably 20 to 100 pg or 35 to 70 pg, wherein the amount of L-citrulline is preferably 1.5 to 3 times the amount of L-arginine. 8. Active ingredient combination according to one of claims 1 to 7, characterized in that a dosage form comprises from 1 to 9 mg, preferably from 2 to 5 mg, particularly preferably about 3 mg of boron. 9. Active ingredient combination according to one of claims 1 to 8, characterized in that one or more vitamins and/or minerals are included as further co-factors, in particular magnesium, manganese, zinc, folic acid, vitamin C, vitamin B2, vitamin B6, vitamin B12, and two or more thereof. 10. Active ingredient combination according to claim 9, characterized in that from 100 to 1000 mg magnesium, preferably from 120 to 150 mg, preferably as magnesium bisglycinate, magnesium citrate, magnesium gluconate or magnesium L-threonate, in particular as magnesium glycinate, and/or from 10 to 25 mg zinc, preferably about 15 mg, preferably as zinc glycinate, zinc citrate or zinc gluconate, in particular as zinc glycinate, and/or from 0.5 to 5 mg manganese, preferably about 3 mg, preferably as manganese glycinate or manganese gluconate, in particular as manganese glycinate, and/or from 200 to 1000 pg folic acid, preferably from 400 to 600 pg, preferably as methyl tetrahydrofolate, and/or from 200 to 1000 mg vitamin C, preferably from 200 to 300 mg, preferably as calcium ascorbate or Vitamin C ester or vitamin C complex consisting of calcium ascorbate and L-threonate, in particular as calcium ascorbate, and/or from 1 to 5 mg of vitamin B2, preferably from 3 to 5 mg, and/or 1 to 20 mg of vitamin B6, preferably about 5 mg, and/or from 1 to 50 pg of vitamin B12, preferably about 25 pg are contained in the dosage form of the boron salt and/or the components L-arginine, L-citrulline and selenium compound or are provided as a kit in the form of an additional dosage form with the oral active ingredient composition. 11. Active ingredient combination according to claim 9 or 10, characterized in that manganese, zinc, magnesium, vitamin C and folic acid are included as further co-factors, or magnesium, manganese, zinc, folic acid, vitamin C, vitamin B2, vitamin B6 and vitamin B12. 12. Active ingredient combination according to one of claims 1 to 11, characterized in that one or more further amino acids are included. 13. Use of an oral active ingredient combination according to one of claims 1 to 12 as a nutritional additive for animal feed, Food supplements or foods for special medical purposes. 14. Use according to claim 13 for the treatment or support of the treatment or prevention of one or more of the following diseases: diabetes type II, obesity, hypertension, lipid metabolism disorders, Liver dysfunction, erectile dysfunction and libido disorders. 15. Oral active ingredient combination according to one of claims 1 to 12 for use as a medicament or veterinary medicament. 16. Use according to claim 15 for the treatment or aiding the treatment or prevention of one or more of the diseases: Type II diabetes, obesity, hypertension, lipid metabolism disorders, liver dysfunction, erectile dysfunction and libido disorders.