BG66783B1 - Total cholesterol level prevention and regulation agent - Google Patents

Abstract

The agent for the prevention and regulation of the total cholesterol level in the blood is based on natural ingredients and provides greater efficiency in achieving normal concentrations of LDL cholesterol in the blood serum, establishing a healthy balance between LDL and HDL, a significant decrease the risk of side effects and safety in prolonged use. The agent contains a dry extract of red yeast rice and a dry grape seed extract, as well as according to the invention further comprising a dry extract of Lespedeza capitata L. at the following ratio of components (wt.%) : dry red yeast rice extract from 35 to 55, dry grape seed extract from 15 to 25 and dry extract of Lespedeza capitata L. from 25 to 40.

Description

Field of technology

The invention relates to a means for the prevention and regulation of the level of total cholesterol in the blood on the basis of natural ingredients.

BACKGROUND OF THE INVENTION

It is known that one third of ischemic heart disease (CHD) is associated with high levels of cholesterol and triglycerides. It has been found that a 10% reduction in serum cholesterol in men around the age of 40 leads to a 50% reduction in cardiovascular disease within 5 years. The same reduction in serum cholesterol in men over the age of 70 leads to an approximately 20% reduction in the incidence of ischemic heart disease over the next 5 years.

In 2008, there was a worldwide increase in total cholesterol levels (> 5.0 mmol / l) in 39% of the adult population (37% for men and 40% for women).

The use of statins for lowering cholesterol levels by inhibiting 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase is known. Statins control the level of lipids circulating in the blood - a major modifiable risk factor for atherosclerosis. Their effect on overall mortality is compared with that of antibiotics. Significant reductions in cholesterol levels are achieved in patients who have high baseline cholesterol levels. However, statins significantly increase the risk of side effects, including an increased risk of diabetes and abnormal liver enzyme tests, as well as less frequent but severe side effects, especially with muscle damage. The most common side effects are elevated liver enzymes and muscle problems. In randomized trials, statins increased the risk of adverse effects by 39% compared with placebo (odds ratio 1.4); two-thirds of them are myalgia or elevated liver enzymes with serious side effects.

U.S. Pat. No. 6,818,233 B2 discloses a dietary supplement composition comprising grape seed extract, grape skin extract (extract extracted from grape skins) and an enzyme. The food supplement may additionally contain ginkgo biloba extract, blueberry extract and quercetin.

Patent publication CN 101731599 A describes a composition for regulating blood lipids and treating cardiovascular diseases, which contains: red rice yeast from 2 to 96 parts, glycosides from gynostema pentafilum from 0.5 to 20.0 parts, flavonoids from kudzu vine from 0.1 to 10 parts, black mushroom extract from 1 to 30 parts, selenium from 0.0001 to 0.01 parts and proanthocyanidins from grape seed from 0.2 to 20 parts.

These known compositions have a relatively low efficacy in achieving normal concentrations of LDL cholesterol in the blood serum.

Technical essence of the invention

The subject of the invention is the creation of a means for prevention and regulation of the level of total cholesterol in the blood, which provides greater efficiency in achieving normal concentrations of LDL cholesterol in the blood serum, establishing a healthy balance between LDL and HDL, significantly reducing the risk from side effects and safety with prolonged use.

The agent for prevention and regulation of the level of total cholesterol in the blood contains dry extract of red rice yeast and dry extract of grape seed, and according to the invention additionally contains dry extract of Lespedeza capitata L. in the following ratio of components (in % by weight):

dry extract of red rice yeast from 35 to 55, dry extract of grape seed from 15 to 25 and dry extract of Lespedeza capitata L. from 25 to 40.

The synergistic combination of dry extracts of red rice yeast, grape seed and lespedeza kapita provides higher efficiency of the agent according to the invention by simultaneously

Descriptions of issued patents for inventions № 12.2 / 31.12.2018 creation of several levels of inhibition of the metabolic pathway during the biosynthesis of cholesterol and cholesterol esters, which is the main, different from the known products, pathway of action of the agent. As a result of the synergistic action of the active ingredients of the drug, normal concentrations of LDL cholesterol in the blood serum are achieved, a healthy balance between LDL and HDL and a reduction of high triglyceride levels. The product is a natural product, which prevents the risk of side effects, ensures safety with prolonged use and allows its inclusion in various treatment regimens. The active ingredients of the phytopreparation potentiate their effect by simultaneously reducing endogenous cholesterol production and the absorption of exogenous cholesterol, while having an anti-atherosclerotic effect by modulating the gene expression of proteins. The simultaneous action of the three main components in three directions achieves a significant increase in the effectiveness of the drug compared to the effect of each of them, taken separately.

Examples of the invention

The invention is illustrated by the following example, which does not limit it.

Example. Means for prevention and normalization of cholesterol, LDL and HDL levels, with composition (in% by weight): dry extract of red rice yeast - 47,223, dry extract of grape seed - 19,444 with a content of proanthocyanidins 95% and dry extract of Lespedeza capitata L. - 33,333.

The dry extracts of the above active substances are mixed in a stainless reactor in the above ratio, excipients are added and the resulting mixture is homogenized to give a homogeneous product which is packaged in tablets. Each tablet contains the following biologically active substances: dry extract of red rice yeast - 340 mg, dry extract of grape seed - 140 mg and dry extract of Lespedeza capitata L. - 240 mg.

The daily intake is 1-2 tablets before meals.

The dry yeast extract of red rice is obtained by fermentation of rice with red yeast (Monascus purperus). It contains monacolin K (3.12%), mevinolinic acid and lovastatin, which have a direct effect on cholesterol metabolism.

Monacolin K is one of the main therapeutic components for lipid regulation. It contains several types of monacolins that competitively inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA-reductase) in the liver. HMG-CoA reductase converts 3-hydroxy3-methylglutaryl-coenzyme A to mevalonate. The result is a reduction in cholesterol production.

Monacolins do not completely block the production of the basic structures necessary for cholesterol synthesis, but only reduce it. Therefore, they are also referred to as competitive HMG-CoA reductase inhibitors. Their action is reversible and decreases over time. The half-life is about 1.5-2 hours, and their action begins after about 30-60 minutes.

Lovastatin is a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase. In the body, lovastatin is hydrolysed to an active metabolite, β-hydroxy acid. Orally administered, 10% is eliminated in the urine and 83% in the faeces. Much of lovastatin and its metabolite (> 95%) are bound to plasma proteins. Lovastatin is widely used in hypercholesterolaemia (type 2A) and hypercholesterolaemia accompanied by hypertriglyceridaemia (type 2B).

Among the various monacolins, mevinolinic acid (also known as lovastatin hydroxy acid, mevinolinic acid, monacolin K hydroxy acid) dominates together with the corresponding lactone lovastatin (monacolin K, alpha-6-methylcompactin) with a total share of 85-90%.

Because mevinolinic acid is the dominant monacolin, it also accounts for most of the pharmacological effects. The difference between mevinolinic acid and lovastatin is an additional H ₂ O-molecule in mevinolinic acid, which leads to significant differences in action. In the aqueous-acidic environment, lovastatin is primarily converted to the hydroxy acid

Descriptions of issued patents for inventions № 12.2 / 31.12.2018 form, resp. the dynamic equilibrium between mevinolinic acid and lovastatin is significantly shifted in favor of mevinolinic acid. The reason for this is that the lactonization of mevinolinic acid in lovastatin requires energy (4.93 kcal / Mol), while the reverse process (hydrolysis of mevinolinic acid in lovastatin) releases 2.42 kcal / Mol.

When the lactone lovastatin is placed in an aqueous acidic medium (eg gastric juice), it hydrolyzes itself, without the presence of enzymes, to a certain percentage in mevinolinic acid, but in these circumstances mevinolinic acid can be converted back to the lactonic form. Therefore, after oral administration, the lovastatin component in the stomach is already available in the form of mevinolinic acid.

Mevinolinic acid dissolves easily in water but hardly in fat. The lactone lovastatin is difficult to dissolve in water and easily in fat. These solubility properties determine the open (mevinolinic acid) or closed (lovastatin) lactone ring. Mevinolinic acid is absorbed from the digestive tract up to 83-100%, and the lactone lovastatin - only up to 30%. The different fat solubility makes it almost impossible (after the passage of the two lactones in the serum of mevinolinic acid) to cross the cell membrane.

The significant difference between mevinolinic acid and lovastatin is in the pharmacological action. Lovastatin is inactive and only after its conversion to mevinolinic acid does it become an active active form. Mevinolinic acid is an open lactone ring, which makes it an active ingredient. Mevinolinic acid directly inhibits HMG-CoA reductase in the liver. Lovastatin is activated extremely slowly. Initially taken, one part of it is broken down non-enzymatically in the stomach, and another part of it is enzymatically converted to mevinolinic acid. The remaining lovastatin only works when it is chemically activated in the liver by the enzyme CYP3A4 from the cytochrome P450 enzyme system. Three different hydroxy acid and lactone forms of lovastin then arise, namely those of the substances 6 'beta-hydroxylovastatin, 3' -hydroxy-lovastatin and 6 '-exomethylene lovastatin. While natural mevinolinic acid acts directly, lovastatin must first be converted to a minimum of seven structures in order to work.

From the above it can be concluded that in comparison with the finished dosage form of lovastatin red rice yeast acts pharmacologically much more optimally.

The dry grape seed extract contains gallic acid, catechin, epicatechin, which have a cholesterol-lowering effect. Gallic acid, catechin and epicatechin significantly inhibit pancreatic cholesterol ester depending on their concentration. Moreover, they bind to taurocholic acid, taurodoxoxycholic acid and glycodexycholic acid at levels ranging from 38.6% to 28.2%. The three main polyphenolic compounds contained in grape seed have a cholesterol-lowering effect by inhibiting pancreatic cholesterol ester, binding to bile acids and reducing cholesterol micelles, which leads to a reduction in cholesterol absorption.

Gallic acid, catechin and epicatechin inhibit cholesterol esterase depending on the concentration. However, these compounds (IC50> 100 ug / ml) are less effective than simvastatin, which is used as an inhibitor of pancreatic cholesterol esterase. In general, pancreatic cholesterol esterase plays an important role in hydrolyzing cholesterol esters (through food), which release free cholesterol in the intestinal lumen. It also improves the incorporation of cholesterol into mixed micelles and the transport of free cholesterol to enterocytes.

Inhibition of cholesterol esterase leads to a restriction of the absorption of cholesterol ingested with food, which in turn has the effect of reducing total cholesterol in the blood serum.

These three polyphenols inhibit pancreatic cholesterol esterase, leading to increased control of dietary cholesterol derivatives and restriction of free cholesterol in the bloodstream.

Gallic acid, catechin and epicatechin are responsible for the inhibition of pancreatic cholesterol esterase. They also bind to bile acids, leading to a decrease in

Descriptions of issued patents for inventions № 12.2 / 31.12.2018 the solubility of cholesterol in micelles.

The dry extract of lespedeza capital contains kaempferol 3,7-dirhamnopyranoside, a yellow molecular weight compound (MW: 286.2 g / mol), a common natural flavonoid. This flavonoid is widely used in many plant-derived foods and traditional medicine. Kaempferol and its glycosides have many different pharmacological actions, such as antioxidant, anti-inflammatory, anti-cancer, antimicrobial, neuroprotective, antidiabetic and others. The efficacy of kaempferol on inflammatory molecules such as E-selectin (E-sel), intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesionmolecule-1 (VCAM-1) and monopithetic chemotactic protein 1 (MCP-1) in induced high cholesterol atherosclerosis. Kaempferol 3,7-dirhamnoside has anti-atherosclerotic activity by modulating protein gene expression.

The dry extract of lespedeza capital, in addition to kaempferol, also contains the active ingredients Quercetin and Lespecapitoside 1.1%.

Based on the above, it can be concluded that a phytopreparation with natural components and derivatives has been created, which affect many stages of cholesterol metabolism at endogenous and exogenous levels. In this way the drug achieves high efficiency while significantly reducing the risk factor from the appearance of contraindications in patients forced to take cholesterol-lowering products for a long (permanent) time.

The agent according to the invention provides several levels of inhibition of the metabolic pathway during the biosynthesis of cholesterol and cholesterol esters, which is the main, other than known products, route of action of the agent. Lovastatin, contained in the dry extract of red rice yeast, is used in hypercholesterolaemia (type 2A) and hypercholesterolaemia accompanied by hypertriglyceridemia (type 2B). Lovastatin is inactive and only after its conversion to mevinolinic acid does it become an active active form. Mevinolinic acid is an open lactone ring, which makes it an active ingredient. It directly inhibits 3-hydroxy3-methyl-glutaryl-coenzyme A reductase (HMG-CoA-reductase) in the liver. The inhibitors (gallic acid, catechin, epicatechin) of pancreatic cholesterol esterase contained in the dry grape seed extract have the potential to alter cholesterol metabolism in many directions. Cholesterol esterase is thought to contribute to the presence of free cholesterol by catalyzing the hydrolysis of cholesterol esters and contributing to the formation of lysolecithin-containing micelles, which are agents for efficient cholesterol uptake by catalyzing the hydrolysis of lecithin. Kaempferol 3,7-dirhamnoside, contained in the extract of the lespedes capital, has an antiatherosclerotic effect by modulating the gene expression of a protein.

Claims (1)

Patent claims 1. Means for the prevention and regulation of the level of total cholesterol in the blood, containing dry extract of red rice yeast and dry extract of grape seed, characterized in that it contains additionally dry extract of Lespedeza capitata L. in the following ratio of components (in% by weight): dry yeast extract from red rice from 35 to 55, dry grape seed extract from 15 to 25 and dry extract from Lespedeza capitata L. from 25 to 40.