BG112473A - Food supplement for maintenance and recovery of the normal function and architectonics of the liver - Google Patents

Abstract

The invention relates to a synergetic nutritional supplement for maintenance and recovery of normal liver function and architectonics, including a dry extract of Sylibum marianum and one or more components selected from choline citrate, DL-alpha-tocopheryl acetate, uridine monophosphate , folic acid, Vitamin B12, Vitamin A, beta-carotene, Vitamin D, Vitamin E, Vitamin K, Vitamin B1, Vitamin B2 (riboflavin), Niacin as nicotinic acid, Niacin as nicotinamide, pantothenic acid, Vitamin B6, folic acid, biotin, Vitamin C, calcium, magnesium, iron, copper, iodine, zinc, manganese, selenium, chromium (trivalent), molybdenum, phosphocholine citrate, DL-alpha-tocopheryl acetate, uridine monophosphate, folic acid and Vitamin B12 and carriers and excipients. Preferably, the nutritional supplement includes choline citrate in an amount of 237.14 mg, dry extract of Sylibum marianum in an amount of 22.2 mg, DL-alpha-tocopheryl acetate in an amount of 100 mg, uridine monophosphate in an amount of 50 mg, folic acid in an amount of 400 µg and Vitamin B12 in an amount of 6 µg. The nutritional supplement, through its ingredients according to the utility model, acts synergistically as an antioxidant, reduces inflammation in the liver, reduces the accumulation of fat in the liver, normalizes liver transaminase levels and reduces viremia in hepatitis, inhibits the transformation of liver stellate cells in activated myofibroblasts, reduces plasma levels of homocysteine, stabilizes the hepatocyte cell membranes, improves mitochondrial function of the liver cells, increases synthesis of nucleic acids and phospholipids in the liver cells, stimulates the beginning of tissue regeneration and furthers the recovery of normal architectonics of the liver.

Description

NUTRITIONAL SUPPLEMENT FOR MAINTENANCE AND RESTORATION OF THE NORMAL FUNCTION AND ARCHITECTONICS OF THE LIVER

DESCRIPTION

FIELD OF THE INVENTION

The present invention relates to the field of food supplements and in particular to a food supplement for the restoration of normal function and the architecture of the liver.

BACKGROUND OF THE INVENTION

International Patent Application WO2013124700, published August 29, 2013, discloses a pharmaceutical composition comprising oil isolated from Silybum marianum seeds as the sole active ingredient and pharmaceutically acceptable carriers and excipients. The composition according to WO2013124700 has hepatoprotective properties provided by an oil extract of Silybum marianum. WO2013124700 neither mentions nor aims to provide a synergistic combined effect on the restoration of normal liver function and architecture.

SUMMARY OF THE INVENTION

The object of the invention is to provide a food supplement which has at the same time a stimulating effect on the restoration of the normal function and the architonics of the liver. For this purpose, a food supplement was created containing a dry extract of Sylibum marianum (milk thistle) and at least one or more of the following components: choline citrate, DL-alpha-cocopheryl acetate, uridine monophosphate, folic acid and Vitamin B12, and optionally including one or more of the following Vitamin A, beta-carotene, Vitamin D, Vitamin E, Vitamin K, Vitamin B1, Vitamin B2 (riboflavin), Niacin as nicotinic acid, Niacin as nicotinamide, pantothenic acid, Vitamin B6, folic acid, Vitamin B12, Biotin, Vitamin C, calcium, magnesium, iron, copper, iodine, zinc, manganese, selenium, chromium (trivalent), molybdenum, phosphorus,

Choline citrate was included in the preparation because it was found that the intake of low levels of choline with food leads to the development of liver damage, and the spectrum of this damage varies from steatosis to hepatocellular carcinoma (HCC). Choline is an important part of the mitochondrial membrane, and mitochondrial dysfunction plays a central role in the pathogenesis of liver disease. Choline together with folic acid are involved in the conversion of homocysteine to methionine. Studies with healthy volunteers have found that consuming adequate amounts of folic acid and methionine, but reduced choline intake, can lead to fat accumulation in the liver and muscle damage that recovers after taking extra choline.

Silymarin is a natural product found in the species Silybum marianum, known as milk thistle. The plant contains seven flavolignans and the flavonoid taxifoline. The dry extract of Sylibum marianum is obtained from seeds which undergo a technological process including, for example, solvent extraction, supercritical extraction, cold pressing, hot pressing and similar pressing processes.

Silymarin exerts a hepatoprotective effect through the following mechanisms ¹⁹ :

o Acts as an antioxidant against lipid peroxidation o Stabilizes cell membranes by regulating their permeability in the presence of xenobiotics and inhibits the absorption of toxins o Regulates gene expression. This effect is due to the structural similarity of the molecule with that of steroid hormones, and as a result tissue regeneration occurs.

o Reduces inflammation in the liver as a result of reduced cytokine secretion and reduced tissue damage o Inhibits the transformation of liver stellate cells into activated myofibroblasts, which are responsible for the deposition of collagen fibrils leading to cirrhosis

Silymarin has a healing effect in a number of liver diseases such as steatosis, cirrhosis, alcoholism, hemochromatosis, viral hepatitis. Normalization of serum levels of liver enzymes, viremia and improvement of clinical symptoms are achieved.

Silymarin was found to result in a significant 7% reduction in liver-related mortality (OR: 0.54, p <0.01).

DL-alpha-tocopheryl acetate Vitamin E is a fat-soluble vitamin that has excellent antioxidant properties. These properties are due to its chemical structure, which has a long 2nd position chain facilitating the incorporation of Vitamin E into biomembranes, so that the hydroxyl (OH) group on the cyclic structure becomes optimal for free radical scavenging and lipid peroxidation. Due to its structure, Vitamin E performs two important functions with respect to cell membranes ¹⁶ :

1) Protects polyunsaturated fatty acids from free radical damage - acts as an antioxidant

2) Protects phospholipids from damage - acts as a membrane stabilizing agent

There was a significant decrease in serum alanine aminotransferase and glutamyl transferase and a decrease in the oxidative stress markers thyrodoxin and thiobarbituric acid in patients with steatohepatitis. At the same time, histological improvement is observed, expressed in a decrease in necroinflammatory activity and fibrosis.

Uridine monophosphate is a nucleotide with the following chemical formula.

UMP performs a variety of effects, as it produces a number of other biologically active molecules ³⁰ · ³¹ :

> ► RNA - UMP is one of the four bases of RNA and participates in its synthesis> Other nucleodites - through the pyrimidine salvage pathway UMP can be stored in the form of uridine triphosphate (UTP) and cytidine triphosphate (CTP)

Glycogen - the combination of UTP with glucose-1-phosphate forms uridine diphosphate glucose (UDPG), which is the main building block for glycogen biosynthesis> - Glycoproteins - the combination of UTP with N-acetylglucosamine (GIcNAc, which forms UNAcNAcIcNAc) substrate for protein glycosylation> Phospholipids - the combination of CTP with phosphocholine forms cytidine diphosphocholine (CDPC), which is an essential molecule for membrane phospholipid biosynthesis

Disruption of uridine homeostasis leads to disruption of pyrimidine synthesis in the liver. There is evidence that low levels of pyrimidines can trigger cell arrest and apoptosis and, consequently, fat accumulation. UMP inhibits the accumulation of fat in the liver by modeling the acetylation of proteins by the liver. This means that uridine alters the activation of enzymes involved in metabolism, redox and antioxidant processes, and in particular the NAD + / NADH ratio.

The therapeutic potential of uridine for the prevention of drug-induced steatosis has been demonstrated with fenofibrate and tamoxifen, which are known to lead to fatty acid buildup in the liver. The effect on induced steatosis is explained by pyrimidine synthesis, which accelerates the biosynthesis of membrane phospholipids.

UMP improves mitochondrial function in HIV patients as assessed by the 13C-methionine test and results in an increase in subcutaneous adipose tissue in lipoatrophic HIV patients without an increase in liver fat. Oral administration of UMP is thought to prevent uridine depletion at the cellular level because the key enzyme for endogenous pyrimidine synthesis is encoded by mitochondrial DNA and may therefore be affected by mitochondrial damage and mitochondrial DNA depletion.

Folic acid, also called vitamin B9, is one of the most important for health. Folic acid deficiency in the body causes disorders of cell division. Many of its derivatives with similar biological activity, called folates, are involved in a number of enzymes involved in the synthesis of a large number of amino acids and nucleotides, and hence play a key role in the synthesis of DNA and RNA that determine cell division.

> Folic acid deficiency leads to decreased de novo synthesis of phosphatidylcholine, which is clinically manifested in the accumulation of triglycerides in patients with non-alcoholic steatosis> Folic acid deficiency increases oxidative stress in the liver and alters methionine metabolism, which is associated with increased hepatocellular apoptosis.

> Intake of folic acid effectively inhibits MAO (P) N-oxidase-mediated production of superoxide anion, which leads to reduced lipid peroxidation in the liver and hepatoprotective effect> - Folic acid regulates * levels of homocysteine * which is associated with liver and cardiovascular damage. It has been found that the intake of dietary supplements containing folic acid leads to an effective reduction in the concentration of homocysteine.

> The combined intake of Vitamin B12 and Folic acid significantly reduced plasma homocysteine levels more than the effect of folic acid alone. These results show that the two vitamins act synergistically and have a hepatoprotective effect.

A prospective cohort study of 415 patients with hepatitis B followed over a 4-year period found that higher folic acid levels were associated with lower ALT levels, liver damage, and the risk of developing hepatocellular carcinoma.

Vitamin B12 contains a cobalt complex and is therefore known as cobalamin. Its molecular weight is the largest of all other vitamins and is known to accumulate in the liver, which serves as a reservoir. When the liver is damaged, the stored Vitamin B12 is excreted in the blood, which leads to an acute deficiency of Vitamin B12 and as a result metabolic dysfunction occurs. A diet low in Vitamin B12 leads to liver damage and even to the spontaneous development of hepatocellular carcinoma.

Statistics show that between 5% and 20% of the adult population is deficient in Vitamin B12, and up to 40% have low plasma levels of Vitamin B12, which is why daily intake is important.

> There is evidence of a protective effect of Vitamin B12 against acute liver damage> - Impaired mitochondrial integrity due to depleted levels of Vitamin B12 and glutathione in the liver contributes to increased glycolytic activity and acute decrease in hepatic glycogen reserves in liver

Vitamin B12 significantly reduces the activity of stellate cells and increases the hydrolysis of deposited collagen, which supports the regeneration of hepatocytes. Vitamin B12 therapy restores biomarkers of liver function, glycogen content and hepatic reserves of Vitamin B12.

Vitamin B12 helps to restore the normal architecture of the liver in experimental models. For this reason, the authors recommend that Vitamin B12 be included in the treatment of liver fibrosis

In addition to reducing liver enzyme levels, Vitamin B12 inhibits the accumulation of collagen fibrils. Reverse transcriptase chain reaction (RT-PCR) has shown that the gene expression of both fibrosis markers (smooth muscle actin and heat shock protein 47) is suppressed by Vitamin B12. The cobalt complex of Vitamin B12 is thought to play a role in inhibiting liver inflammation and fibrogenesis. These data indicate that Vitamin B12 is a hepatoprotective agent

In addition, it has been found that Vitamin B12 (in the form of cyanocobalamin or methylcobaltamine when present is present in an amount of up to 300 uq. Similarly, when folic acid is present, in the form of folic acid or a salt of folic acid i.e. folate is present in an amount to tocopheryl acetate or succinate or D-alpha-tocopheryl acetate or succinate is present in an amount up to 500 mg, choline, in the form of citrate or other salt is present in an amount up to 1000 mg, uridine, in the form of uridine or uridine

In addition, the food supplement according to the invention contains suitably selected pharmaceutically acceptable carriers and / or excipients. The carriers and excipients may be selected from the group of sweeteners, colorants, moisture retainers, emulsifiers. Examples without limitation for clarification include the following maltodextrin (charge agent), microcrystalline cellulose (charge agent), magnesium stearate (anti-agglomerating agent), white gelatin capsules n ° 00 (colorant E-171 titanium dioxide). The food supplement according to the utility model can be formulated in any dosage form according to the mode of administration chosen. The preferred form of administration is a solid dosage form, in particular encapsulated, for which purpose both gelatin and non-gelatin capsules are suitable. The food supplement according to the utility model is prepared by conventional procedures, mainly by pre-mixing the components. Pharmaceutically acceptable carriers and excipients suitable for the composition of the food supplement of the utility model are known from the manuals available to those skilled in the art (eg Revesz Piroska, Gyogyszertechnologia, Theory Book, Edition 1, JATE Press, Szeged, Hungary, 2009, Paal Tamas ( Editor Board of Hungarian Pharmacopoeia, National Institute of Pharmacy), 2006. Magyar Gyogyszerkonyv - Pharmacopoea Hungarica. Medicina Konyvkiado Zrt. Budapest, Hungary, European Directory of Quality of Medicines (EDQM), 2005, European Pharmacopoeia, published EDQM, Strasbourg, P. France).

Hereinafter, the invention will be further disclosed with the present specific embodiment, which example, however, should in no way be construed as limiting the scope of protection defined by the claims.

EXAMPLE

In one embodiment, the food supplement of the invention comprises in a capsule with a capacity of 755 mg ± 5%. the following components:

Choline citrate (with a content of * Choline * 83'td) - "£ 37.14 td

Silymarin (dry extract of milk thistle (Sylibum marianum) -22.2 mg

DL-alpha-tocopheryl acetate (containing Vitamin E - 50 mg), antioxidant 100 mg

Uridine monophosphate 50 mg

Folic acid 400 pg

Vitamin B12 (cyanocobalamin) 6 pg

In addition to said composition, carriers and excipients such as sweeteners, colorants, moisture retainers, emulsifiers are included. By way of clarification, maltodextrin, microcrystalline cellulose, magnesium stearate are included as such, and the capsules are white gelatin capsules n ° 00 (colorant E-171 titanium dioxide). The total amount of carriers and excipients included is until the total quantitative mass for the capacity of the selected capsule is reached.

In order to obtain the composition thus presented, a preliminary weighing of the presented components of a calibrated analytical balance is provided. Mixing and homogenization are then carried out in a mixer and the mixing is continued until a completely homogeneous mixture is achieved, which is subsequently filled into pre-provided capsules. The capsules may be of the gelatin and non-gelatin type.

The invention shows that as a result of the synergistic action of the components, the food supplement acts as:

Antioxidant by capturing free radicals and increasing the content of cellular glutathione (natural antioxidant)

Reduces inflammation in the liver as a result of reduced cytokine secretion and reduced tissue damage

Reduces the accumulation of fat in the liver as a result of inhibition of lipid peroxidation • · · · · · · ··

Normalizes the level ** of liver transaminases and reduces viremia in hepatitis

Inhibits the transformation of liver stellate cells into activated myofibroblasts, which are responsible for the deposition of collagen fibrils leading to cirrhosis

Reduces plasma levels of homocysteine, which is associated with liver damage

Stabilizes hepatocyte cell membranes by regulating their permeability in the presence of xenobiotics and inhibits the absorption of toxins

Improves mitochondrial function of liver cells

Increases the synthesis of nucleic acids and phospholipids in liver cells

Stimulates the onset of tissue regeneration and helps to restore the normal architecture of the liver.

Claims (4)

CLAIMS ·· A food supplement for maintaining and restoring the normal function and architecture of the liver, comprising a dry extract of Sylibum marianum and carriers and excipients, characterized in that it also contains one or more components selected from choline citrate, DL-alpha-tocopheryl acetate, uridine monophosphate, folic acid, Vitamin B12, Vitamin A, beta-carotene, Vitamin D, Vitamin E, Vitamin K, Vitamin B1, Vitamin B2 (riboflavin), Niacin as nicotinic acid, Niacin as nicotinamide, Pantothenic acid , folic acid, biotin, Vitamin C, calcium, magnesium, iron, copper, iodine, zinc, manganese, selenium, chromium (trivalent), molybdenum, phosphorcholine citrate, DL-alpha-tocopheryl acetate, uridine monophosphate, folic acid12 and Vitamin B . Food supplement according to claim 1, characterized in that it contains choline citrate in an amount of 237.14 mg, dry extract of Sylibum marianum in an amount of 22.2 mg, DL-alpha-tocopheryl acetate in an amount of 100 mg, uridine monophosphate in 50 mg, folic acid 400 pg and Vitamin B12 6 pg. Food supplement according to any one of claims 1 and 2, characterized in that the carriers and excipients are selected from the group of sweeteners, colorants, moisture retainers, emulsifiers. Food supplement according to claim 3, characterized in that the carriers and excipients are selected from maltodextrin, microcrystalline cellulose, magnesium stearate, titanium dioxide.