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

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, dietary supplement, or food for special medical purposes, which can positively influence metabolic syndrome as well as general aging symptoms or age-related diseases. Furthermore, the oral active ingredient combination can be used as a nutritional additive in animal feed or as a veterinary medicinal product.

[0002] With increased life expectancy, health impairments that usually only become noticeable after the age of 40 are increasingly coming into focus. These include, in particular, cardiovascular disease, type 2 diabetes, and symptoms associated with declining sex hormone levels. In many cases, these impairments are caused by the so-called metabolic syndrome. This develops unnoticed over many years and manifests itself in the following symptoms: - high blood pressure - elevated blood lipids, especially hypertriglyceridemia - decreasing muscle absorption capacity for sugar (peripheral insulin resistance, impaired glucose tolerance) - increasing overweight, 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, particularly hypercaloric diet, lack of physical exercise, oxidative stress, and smoking. This leads to obesity, which subsequently leads to insulin resistance. A significant influence on the development of metabolic syndrome is Visceral fat. This tissue, rich in fat cells, is located between the organs of the abdominal cavity. These fat cells are hormonally active and promote, among other things, insulin resistance. In parallel, altered blood lipid levels (high concentrations of triglycerides and small, dense LDL particles) often occur. A diet high in acellular flour, sugar, and other refined industrial foods, which may promote an inflammatory microbiome in the gut, is considered a contributing factor. Put simply, metabolic syndrome is the price of inactivity, (too) much food, nicotine, stress, and other lifestyle factors that determine the lifestyle 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. Since this is usually either insufficient or not successful at all, there is no shortage of suggestions to at least compensate for malnutrition with nutritional supplements or foods for special medical purposes. When 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 especially triglycerides to reduce the risk of heart attacks and strokes. Long-term therapy with, for example,Statins frequently result in clinically relevant side effects such as increased blood pressure, muscle pain, cramps, weight gain, elevated blood sugar and liver function tests, gastrointestinal complaints, chronic fatigue, itching, or headaches. These secondary conditions are often treated with additional medications. This means that a larger number of different medications are usually prescribed and taken. In addition, the expected or necessary effect is not achieved in individual cases. Even food supplements or foods for special medical purposes can occasionally have undesirable side effects. Often, These lack sufficient efficacy. Therefore, the problem remains of finding effective agents that are as free from adverse effects as possible for treating the signs of aging and metabolic syndrome. The objective 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 therapy for age- or lifestyle-related metabolic syndrome within the framework of dietary 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, after a time delay following intake of the co-factor boron and possibly other co-factors such as other minerals and vitamins, 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.

[0005] The above-mentioned task 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, whereby L-arginine, L-citrulline and the selenium compound are dosed 2 to 4 hours after the boron for absorption from the diet. The latter is achieved either by a delayed administration of a separately packaged dose of boron 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) in 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 primarily produced by extraction from duck feathers. This results in an acidic L-arginine HCl, which exhibits reduced bioavailability and is not vegan. Alternatively, vegan L-arginine is obtained by fermenting sugar cane or grain as 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 exhibits high bioavailability and a neutral taste. Other physiologically acceptable and readily water-soluble L-arginine salts, such as citrates or malates, are also possible.

[0007] The positive effect of L-arginine-containing compositions on cardiovascular diseases has 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, Multicenter Nutrition 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), which is located in the blood vessels.

[0008] However, a combination with L-citrulline and a selenium compound such as selenite, as well as with boron as a cofactor, was not considered in published studies. Nor was there any evidence that delayed dosing of L-arginine, L-citrulline, and a selenium compound after the intake of the cofactor boron and possibly other cofactors could be beneficial. 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.

[0010] 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.

[0011] The third component is a water-soluble selenium compound, especially selenite, preferably an alkali salt of selenious acid. Sodium selenite, selenomethionine, and selenocysteine ​​are particularly preferred.

[0012] Well-known dietary supplements that contain selenium in combination with L-arginine and / or L-citrulline, and in some cases, other components, include Dorecfil (www.exvital.de), Arteries and Vessels 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.

[0013] 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. A water-soluble boron salt is preferably used, particularly preferably an inorganic borate, especially sodium tetraborate. Boric acid can also be used.

[0014] Delayed dosing can be achieved, on the one hand, through separate dosage forms, which can be the same or different. Suitable forms include capsules, coated tablets, tablets, juice, drops, syrup, powder, or granules. It is advisable to provide each of the two delayed doses in a single dosage form, preferably in one or more capsules, tablets, coated tablets, or a sachet containing powder and / or granules for stirring into liquid.

[0015] 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 one daily dose or half a daily dose or a quarter of a daily dose.

[0016] 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. Here, the components L-arginine, L-citrulline, and selenium compound are used in a sustained-release form with a delayed active ingredient release. Galenic forms with delayed active ingredient release are known for pharmaceuticals. They serve to release an active ingredient at a later time after ingestion or over a longer period. According to the invention, delayed release is used, but not over a longer period. The selected, special sustained-release form ensures a delayed release of the components L-arginine, L-citrulline, and selenium compound only approximately 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.

[0017] A suitable 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 higher pH, typically > pH 7, and release the enclosed active ingredients. These conditions are met, for example, by shellac-coated microgranules and ethylcellulose- or alginate-based micro- or nanoparticles. Alternatively, starch-coated microgranules or nanoparticles can be used, 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, particularly during passage through the stomach, with rapid bioavailability of the boron and, if applicable, of the other cofactors contained in water-soluble form.Approximately 2 to 4 hours later, the coated components are released and rapidly absorbed in the small intestine, e.g., through pH-activated or alpha-amylase-induced release. Rapid bioavailability of the delayed-release components is preferably ensured by using appropriate, highly water-soluble derivatives such as inorganic or organic salts or, for example, esters.

[0018] The active ingredient combination in one dosage form preferably comprises a water-soluble boron salt or boric acid powder, optionally with other readily water-soluble cofactors, and the components L-arginine, L-citrulline, and selenium compound in water-soluble form as shellac-coated microgranules in a sachet. For oral administration, the contents of the sachet are stirred into water to prepare a drinking solution.

[0019] A suitable daily dose is usually divided into 1 to 3 single doses, preferably into 1 to 2 single doses and most preferably as 1 single dose taken in the morning.

[0020] 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 of L-arginine, from 1.0 to 10.0 g of L-citrulline and from 10 to 150 pg of selenium compound. Preference is given to 1.0 to 3.0 g of L-arginine, from 2.0 to 8.0 g of L-citrulline and from 20 to 100 pg of selenium compound, particularly preferably from 1.5 to 2.5 g of L-arginine, from 3.0 to 4.0 g of L-citrulline and from 35 to 70 pg of selenium compound. The amounts stated refer to the amounts calculated as free amino acid or selenium; accordingly, more of the preferred compounds is used. 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 includes a separate or non-delayed release, i.e.A non-delayed daily dose of boron containing 1 to 9 mg, preferably 2 to 5 mg, particularly preferably about 3 mg 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 kg to 100 kg or up to 120 kg. For very high body weights, from approximately 110 kg or 120 kg, considering taking two doses calculated for a body weight of 80 kg. This is preferred for body weights of approximately 140 or 150 kg or more.

[0021] 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 proanthocyanidins), 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 wholly or partially in another dosage form, for example in another capsule, tablet, or sachet. Preferably, the additional co-factor(s) is / are used in a readily water-soluble form.

[0022] A first preferred additional cofactor 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 preferred, with magnesium bisglycinate being particularly preferred.

[0023] A second preferred cofactor is zinc. A suitable dose is 10 to 25 mg of zinc per daily dose, preferably about 15 mg. Zinc is often used as zinc oxide, but preferably in the form of a highly water-soluble salt, particularly as zinc glycinate, zinc citrate, zinc gluconate, and most preferably as zinc glycinate.

[0024] A third preferred cofactor is manganese. A daily dose of manganese is typically 0.5 to 5 mg, preferably about 3 mg. Manganese is preferably used in the form of a water-soluble salt, in particular as manganese glycinate or manganese gluconate.

[0025] A fourth preferred additional cofactor 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 preferred water-soluble form is methyltetrahydrofolate.

[0026] A fifth preferred 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.

[0027] A sixth preferred additional cofactor is vitamin B2. Preferably, 1 to 5 mg of vitamin B2 is used per daily dose, with approximately 3 to 5 mg being particularly preferred.

[0028] A seventh preferred additional cofactor is vitamin B6. A daily dose of 1 to 20 mg of vitamin B6 is preferred, especially about 5 mg.

[0029] An eighth preferred additional cofactor is vitamin B12. Preferably, 1 to 50 pg of vitamin B12 is used per daily dose, particularly preferably about 25 pg.

[0030] In a preferred embodiment, several of the preferred further co-factors are contained in the oral active ingredient combination according to the invention, for example two, three or even more. Particularly preferably, all eight preferred further co-factors are contained. Likewise particularly preferably, vitamin C, folic acid, manganese, zinc, and magnesium are contained as further co-factors, in particular in an intestinally tolerated form with high bioavailability (e.g. as calcium ascorbate, methyl tetrahydrofolate and the minerals as glycinate or citrate). The preferred further co-factor(s) are contained in particular in the stated amounts and / or in the form of the stated compounds. According to the invention, the further co-factors are preferably combined with boron in one dosage form. It is also possible to combine individual further co-factors with the components L-arginine, L-citrulline and selenium compound.For example, magnesium can be partially combined with the components L-arginine, L-citrulline, and the selenium compound. A separate dosage form of the other cofactor(s) is also possible, but not preferred.

[0031] The dosage form of the oral active ingredient combination is manufactured in a conventional manner. Excipients are often used for this purpose. These are usually inert and are used to improve shelf life, stability, for shaping, to adjust weight and consistency, for taste and appearance. In addition, excipients can be important for promoting release, absorption and bioavailability, for adjusting pH and osmolarity, for protection and for the manufacturing process. Typical excipients include antioxidants, flavorings, binders, fragrances, emulsifiers, colors, film formers, fillers, gelling agents, taste correctors, complexing agents, preservatives, solvents, solubilizers, buffers, ointment bases, acidulants, acidity regulators, acids and bases, lubricants, sweeteners, glazing agents, thickeners and disintegrants.

[0032] With the oral active ingredient combination according to the invention, all relevant symptoms and disorders of the metabolic syndrome could be surprisingly positively influenced when administered at staggered intervals. In particular, the active ingredient combination supports the reduction of LDL cholesterol and especially triglycerides. It also improves blood pressure, testosterone levels, and liver function, as well as liver metabolism, expressed by an unexpectedly high reduction in the liver markers gamma-GT and GPT. The treatment showed no side effects, and no additive oxidative stress (radical exposure) occurred during the study period. In addition to its use in humans, its applications also include its use as a nutritional additive for animal feed and as a veterinary medicinal product for mammals, particularly horses, dogs, and cats.

[0033] The invention will be explained with reference to the following examples, without, however, being limited to the specifically described embodiment. The invention also relates to all combinations of preferred Forms of implementation, provided they are not mutually exclusive. The terms "approximately" or "approx." in conjunction with a numerical value 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.

[0034] Examples For an application study, one 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 capsule form, and a second dosage form containing L-arginine, L-citrulline, and selenium compound was provided in powder form for dissolving in sachets. The two capsules, as a daily dose for morning intake, together contained: 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 flavoring and erythritol.

[0035] 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: hypertension, lipid metabolism disorders, type 2 diabetes, overweight / obesity, libido and potency disorders, menopausal symptoms. Subjects ranged in age from 40 to 85 years. None of the subjects met any of the following exclusion criteria: systemic active autoimmune disease (including rheumatoid arthritis, Crohn's disease), active malignant tumor disease, active infectious disease, pregnancy, or post-myocardial infarction.

[0036] The subjects were divided into two groups, A and B. Group B received the inventive oral drug combination, with the co-factors administered in the morning and the components L-arginine, L-citrulline, and selenium compound administered approximately 2 to 4 hours later. For comparison, Group A administered all components simultaneously in the morning.

[0037] At the beginning of the study, weight and blood counts were measured. After the end of the eight-week study period, weight and blood counts were measured again, and the subjects were interviewed in a final interview about a range of health issues, such as fatigue, physical fitness, and mental stability / stress resistance. Four women and six men were recruited into Group B. During the course of the study, 1 subject in group A discontinued participation; of the remaining subjects, 6 were men and 3 were women in group A. The blood values ​​determined were: HbA1c, total bilirubin, 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 drug testosterone replacement), SHBG, CRP, IL6, IP 10, Lp-PLA2, MDA-LDL, nitrotyrosine, AGE, Lp-PLA 2.Significant differences between groups A and B were found for HbA1c, LDL cholesterol, triglycerides, GPT, gamma GT, testosterone (men) and nitrotyrosine.

[0038] Example 1: Blood pressure All study patients with elevated blood pressure (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 medications throughout 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 ​​taken into account were from the 3rd day after the start and end of the study, respectively. The other subjects in Groups A and B who did not regularly check their blood pressure also reported that their elevated blood pressure decreased during the study.

[0039] Table 1

[0040] The table values ​​show that the oral drug combination, in addition to existing drug therapy, reduced blood pressure by an average of 15% for systolic and 10% for diastolic blood pressure in both groups B and A. After the end of the study, blood pressure returned to the mean pre-study values.

[0041] As a result, the oral active ingredient combination according to the invention is therefore very well suited to support hypertension 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. For blood pressure values ​​in the upper normal range or with slight elevation, taking the oral drug combination may be sufficient to prevent or delay the development of overt hypertension.

[0042] Example 2: Application security The safety of use was tested by measuring nitrotyrosine blood levels. The laboratory parameter nitrotyrosine indicates nitrosative stress. It is known that in the context of inflammatory diseases, particularly 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 exacerbate inflammatory processes. Inflammatory vascular wall reactions are crucial for the development or exacerbation of atherosclerotic vascular changes and their subsequent diseases. Therefore, sufficient stabilization and activation of the vascular wall-regulating enzyme eNOS is very important for sufficient and regulated NO supply throughout the day.

[0043] In Group B, no new elevation of nitrotyrosine levels above the threshold was observed during the 8-week study period. In contrast, in Group A, nitrosative stress was measured in two subjects that had not been present before the start of the study. This represents a significant advantage in terms of high application safety when administering cofactor(s) and substrates at different times.

[0044] Example 3: Diabetes, liver function, lipid metabolism, sex hormones. The blood values ​​for blood lipids, liver function, glucose, 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 the study medication is given.

[0045] Table 2

[0046] Table 2 shows that an improvement was achieved with regard to HbA1c as a long-term blood glucose value. In group B, 5 / 10 (50%) subjects achieved a reduction in HbA1c 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 delayed dosing according to the invention in group B was thus somewhat more effective. This positive effect is surprising, since the measured HbA1c value corresponds to the reaction of blood sugar with the hemoglobin of the erythrocytes. The average lifespan of 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 demonstrated positive effect would be further enhanced with a sufficiently long study duration.

[0047] In terms of liver function, there was a smaller difference in the bilirubin level between groups A and B. In group B, the value decreased 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 control group A. The liver enzyme GPT improved significantly more in group B than in control group A. In group B, 8 / 10 (80%) of the subjects showed an improvement with a reduction between -1 and -39 U / l. In control group A, only 4 / 9 (44%) of the subjects showed a reduction between -2 and -7 U / l. For the liver enzyme gamma-GT, an effect was observed in more subjects in comparison group A, although on average, the effect was less than in group B. In group B, 5 / 10 (50%) subjects showed an improvement between -4 and -89 U / l. In comparison group A, 7 / 9 (78%) of the subjects showed a reduction in the gamma-GT value between -1 and -14 U / l.In Group B, two subjects showed an improvement in GPT values ​​into the normal range (from 60 U / L to 21 U / L and from 53 U / L to 31 U / L), and one subject showed an improvement in Gamma GT values ​​(from 108 U / L to 19 U / L). In Group A, no subjects achieved an improvement in liver enzyme values ​​into the normal range; on the contrary, one subject's GPT value deteriorated beyond the normal range (from 21 U / L to 36 U / L).

[0048] 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%) improved between -4.00 mg / dl and -19.00 mg / dl. Triglycerides are considered the most significant 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. This resulted in 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 achieved an improvement into the normal range, but three 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).

[0049] With regard to testosterone levels, an improvement was achieved in 80% of the male subjects in both groups. Testosterone levels were not measured in two subjects undergoing testosterone replacement therapy. In group B, the increase was more pronounced, ranging 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.

[0050] 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 feelings of hunger. The subjects were interviewed in intensive individual sessions about a variety of specific symptoms. The results are summarized in Table 3. The subjects were also asked about their general health. The results are summarized in Table 4.

[0051] Table 3: Number of patients with slight or significant improvement in the respective symptoms

[0052] Table 4: general constitution

[0053] Subjects in Group B and the comparison group A were asked about existing complaints or symptoms, as well as their improvement during the 8-week treatment with the study medication. Subjects indicated whether they experienced 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 during the course of treatment with the study medication for both Group B and the comparison group A. In summary, it was shown that in Group B, the proportion of significant improvements, with 43 of the 80 complaints reported (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. (corresponding to 35.0%). The symptom "fatigue" 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 emerges for "joint pain," with significant improvement in 3 of the 4 subjects in Group B, compared to only a slight improvement in the 3 subjects in comparison Group A.Another example is found in psychological and mental symptoms such as "clammy palms," with significant improvement in 3 of 4 subjects in Group B. Furthermore, a significant improvement was observed in "mild fatigue" in the 2 affected subjects in Group B, as well as in "itching," with significant improvement in all 3 affected subjects in Group B. A surprising treatment success was seen in one subject in Group B with "tinnitus," which completely disappeared during the 8-week study medication and, surprisingly, recurred after discontinuation of the study medication. A total of 4 subjects reported postmenopausal symptoms before the start of the study, which were significantly alleviated in 2 of 3 affected women in Group B, compared to only a slight improvement in one subject in the comparison group A.

[0054] The tables show that the active ingredient combination according to the invention was able to improve endurance, general well-being, physical condition, and mental fitness in both groups, as far as complaints in these areas were present. However, in group B, an improvement was observed 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.

[0055] The observed increase in effectiveness on blood pressure, lipid metabolism, liver function, and sex hormones significantly exceeds expectations for 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% with the active ingredient combination according to the invention was only described for one commercial L-arginine 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 vitamin B6, 8 pg vitamin B12). Arginine products are generally known to reduce systolic and diastolic peripheral blood pressure. The cited TELCOR-Arginine plus study also explicitly mentions the reduction in blood pressure at night.The study results reported a 16.5% drop in systolic blood pressure and a 14.7% drop in diastolic blood pressure 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 in systolic blood pressure by 3.2% to 19.4%. According to the German Hypertension League, these reductions are within the range of circadian rhythm fluctuations. Another aspect to consider when interpreting the study is that the TELCOR-Arginine plus study did not include any participants already receiving drug therapy for hypertension. The surprisingly significant reduction in blood pressure after taking the active ingredient combination according to the invention was even achieved in the subjects on top of their continued drug anti-hypertensive therapy.

[0056] 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 as dietary supplements or foods for special medical purposes demonstrate only a reduction in systolic and diastolic blood pressure with improved blood flow and a reduction in homocysteine ​​levels. Reducing the risk factor homocysteine ​​through the intake of folic acid and vitamin B6 is a well-established medical standard.

[0057] The increased efficacy and improved safety of use of the active ingredient combination according to the invention when administered at different times could be attributed to effective conditioning (stabilization and activation) of the eNOS enzyme complex. The interaction with the cofactor boron appears to effect conditioning of the eNOS enzyme before the delayed administration of the components L-arginine, L-citrulline, and selenium compound provides sufficient NO levels for arterial vascular regulation and other effects with high levels of safety. The high levels of safety and efficacy are thus based on the selection and dosage of the cofactor coupled with the delayed administration 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.

[0058] In comparison group A, when the co-factor and the components L-arginine, L-citrulline and selenium compound were taken together, an efficacy was observed that was significantly lower than the efficacy when taken at a later time (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.

[0059] Based on the efficacy found, the use of the oral drug combination as a drug for the treatment of one or more of the diseases / symptoms of the metabolic syndrome - i.e. Peripheral insulin resistance / type 2 diabetes, obesity, hypertension, lipid metabolism disorders, erectile dysfunction, libido disorders, and menopausal symptoms – promising. Furthermore, therapeutic use to improve liver dysfunction is possible. Furthermore, the combination of active ingredients is ideally suited for use as a dietary supplement or food for special medical purposes for people over the age of 40, both preventatively and as an adjunct to therapy.

Claims

Patent claims 1 . An oral active ingredient combination as a nutritional additive for animal feed, medicinal products, food supplements or food for special medical purposes, comprising L-arginine, L-citrulline and a selenium compound, each in water-soluble form, characterized in that water-soluble boron is included 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 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 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 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 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 any 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 any one of claims 1 to 12 for use as a medicament or veterinary medicament.

16. Use according to claim 15 for the treatment or support of the treatment or prevention of one or more of the following diseases: Type II diabetes, obesity, hypertension, lipid metabolism disorders, liver dysfunction, erectile dysfunction and libido disorders.

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