RU2831146C1 - Phyto-regulator of lipid metabolism - Google Patents

Abstract

FIELD: chemistry; pharmaceutics; food industry.

SUBSTANCE: composition of the phyto-regulator of lipid metabolism in the form of a tablet is characterized by the fact that the active ingredients include red yeast rice (Monascus purpureus) extract with monacolin K content of 5 wt.% of extract weight, extract of pomegranate flowers (Punica granatum L.), extract of artichoke leaves (Cynara Scolymus), extract of Amur cork tree bark (Phellodendron amurense Rupr.) with berberine content of 85-88 wt.% of the total weight of the extract, nicotinic acid or niocine, coenzyme Q10 (ubiquinone), as auxiliary substances – microcrystalline cellulose and amorphous silicon dioxide with the following content of components, mg: extract of red yeast rice 180.0-220.0; extract of pomegranate flowers 72.0-88.0; artichoke leaf extract 63.0-77.0; Amur cork tree bark extract 52.0-62.0; nicotinic acid or niocine 36.0-44.0; coenzyme q10 (ubiquinone) 1.8-2.2; microcrystalline cellulose 390.8-470.2; amorphous silicon dioxide 16.0-20.0.

EFFECT: invention allows normalizing energy metabolism in the body, reducing the level of low-density lipoproteins, maintaining the level of total cholesterol in blood.

1 cl, 1 tbl, 2 ex

Description

The invention relates to the chemical-pharmaceutical and food industries and concerns new biologically active compounds based on plant-based products that regulate and normalize lipid metabolism.

Lipid metabolism, or lipid metabolism, is a complex biochemical and physiological process that occurs in the cells of living organisms.

The importance of lipids in the body is great: they form the basis of the central nervous system, form the lipid matrix of cell membranes and cell organelles, and play a major role in energy metabolism. That is, without normal lipid metabolism, the full functioning of the body is impossible.

However, their excessive intake into the body, especially combined with insufficient physical activity, can cause lipid metabolism disorders. According to some data, characteristic manifestations of this disorder are found in more than 10% of children and 60% of the adult population of economically developed countries.

Indicators of impaired lipid transport in lipoproteins are elevated levels of total cholesterol (TC), TC in low-density lipoproteins (LDL), triglycerides (TG), and reduced levels of TC in high-density lipoproteins (HDL) [Preventive Medicine. 2016; 19(1): 15-23].

An imbalance of lipoproteins and triglycerides can lead to the development of a number of diseases. In particular, lipid metabolism disorders cause an increased risk of developing dyslipidemia, insulin resistance, cardiovascular diseases such as atherosclerosis, hypertension, coronary heart disease (CHD) and heart failure, diabetes, obesity, and therefore require timely correction.

Currently, there are five main classes of drugs used, depending on their mechanism of action for a particular type of dyslipidemia:

- statins;

- nicotinic acid and its derivatives;

- fibrates;

- bile acid sequestrants;

- antioxidants.

However, a reliable effect on mortality from cardiovascular diseases and the risk of developing cardiovascular complications has been proven only for drugs from the statin group. The action of these drugs is based on the inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-co-A) reductase. By inhibiting the biosynthesis of cholesterol in the liver and intestines, statins reduce intracellular cholesterol stores. This causes the formation of an increased number of LDL receptors and accelerates their removal from the plasma. The effect of statins is mainly aimed at reducing the level of LDL cholesterol and total cholesterol. Recent studies have shown that the use of high doses of statins can significantly reduce the level of triglycerides and compete with the effect of fibrates. However, despite the positive effects, statins can cause side effects, the most common of which include myopathy, type II diabetes, as well as the effect of drugs on the state of the central nervous system and cognitive functions [J Am Coll Cardiol. 2016 May 24; 67(20): 2395-2410].

Thus, although statins are effective treatments, there is a need for alternative products that could combine a safer tolerability profile with efficacy.

According to many researchers, such means could be natural preparations that are less toxic and have a milder effect. It is known that one of the principles of phytotherapy is a systemic and comprehensive approach. This provision is met by the use of multicomponent herbal preparations in pharmacotherapy, which have a number of advantages over monopreparations. In particular, due to the complex chemical composition and rational combination of biologically active substances, they have a multifaceted effect on the body: they act, on the one hand, directly on the lesion, on the other hand, they provide pharmacological correction of various functional systems, and also increase the resistance of the body as a whole.

For this reason, phytonutraceuticals with lipid-lowering properties have been studied as a promising alternative to conventional therapy for patients with lipid metabolism disorders, hypercholesterolemia, with the aim of reducing the main risk factors for atherosclerosis and improving cardiovascular health.

To improve the plasma lipid profile in patients with dyslipidemia, many modern guidelines recommend using a phytoregulator such as red yeast rice.

Compositions containing red yeast rice extracts that contain more than 5% by weight of monacolin K are known, which are useful for reducing cholesterol and/or triglyceride levels in a subject (US 20120196928 A1 - 2012.08.02).

Red yeast rice (RYR)-based drugs may be considered for use in patients with low and moderate cardiovascular risk who have not achieved the target LDL-C level and who have no indications for statin therapy. However, monacolin, being a natural structural analogue of lovastatin, has a similar side effect profile and, accordingly, is relatively safe for some patients, while for others it is not indicated for use.

A drug for oral use, in the form of tablets or powder for extemporaneous use, is known, which is capable of exerting a beneficial effect on the cardiovascular system and has hypolipidemic activity, hypocholesterolemic and triglyceride-lowering activity, antioxidant activity and a protective effect on the vascular endothelium, containing berberine in combination with policosanol and/or red yeast and an antioxidant such as astaxanthin and/or folic acid [US 9623108 B2 - 2017.04.18].

A combination of berberine and silymarin or Beriberis aristata extract containing berberine and Silybum marianum extract containing silymarin is known for the treatment of hyperglycemia and lipid imbalance [EP 2149377 B1 - 2016.09.14].

Known formulations containing berberine may cause side effects such as nausea and stomach pain.

A number of commercially available drugs are produced based on red yeast rice, such as ArmoLIPID [Instructions for the ArmoLIPID dietary supplement, Vidal Handbook, https://www.vidal.ru/drugs/armolipid], which can be indicated as the closest analogue (prototype).

ArmoLIPID is available in the form of an 800 mg tablet containing the following active ingredients:

Policosanols - 10 mg,

red fermented Monascus purpureus (yeast) rice - 200 mg,

monacolin content - 3 mg,

folic acid - 0.2 mg,

ubidecarenone (coenzyme Q10) - 2 mg,

astaxanthin – 0.5 mg.

As auxiliary substances, the tablet contains stabilizers: dibasic calcium phosphate (E341ii), microcrystalline cellulose (E460i); emulsifiers: magnesium stearate (E470b), mono- and diglycerides of fatty acids (E471), silicon dioxide (E551).

The drug is a source of folic acid and can be used to improve the lipid profile of blood plasma in dyslipidemia.

However, this composition improves, but does not normalize lipid metabolism. In addition, it is not recommended to use it in combination with other hypolipidemic drugs, that is, it cannot be prescribed to groups of patients taking statins for vital indications.

The objective of the present invention is to eliminate the disadvantages of the prior art.

The problem is solved by the developed composition of a phyto-regulator of lipid metabolism in the form of a tablet with an improved profile of tolerability, bioavailability, pharmacokinetics, containing the following components, mg:

Red yeast rice extract (Monascus purpureus) containing monacolin K 5 wt.% of the extract weight - 180.0-220.0;

Pomegranate flower extract (Punica granatum L.) - 72.0-88.0;

Artichoke leaf extract (Cynara Scolymus) - 63.0-77.0;

Extract of Amur cork tree bark (Phellodendron amurense Rupr.) with a berberine content of 85-88 wt.% of the total mass of the extract - 52.0-62.0;

Nicotinic acid or niacin - 36.0-44.0;

Coenzyme Q10 (ubiquinone) - 1.8-2.2;

Microcrystalline cellulose - 390.8-470.2;

Amorphous silicon dioxide - 16.0-20.0.

Red yeast rice extract is obtained from rice by fermentation with the so-called red yeast (Monascus purpureus). It contains monacolins, which structurally compete at the level of HMGCoA reductase with HMGCoA, the precursor of mevalonate, thereby reducing the level of cholesterol in the plasma. The monacolin K contained in red yeast rice in the stated amount ensures the maintenance of normal LDL concentrations in the blood.

Another component of the composition, the Amur cork tree bark extract (CAS Number 164288-52-2), is related to traditional Asian medicine. Amur cork tree (Amur cork tree, lat. Phellodendron amurense) is a tree of the Rutaceae family. In the present invention, it is a source of berberine, which is contained in the bark, is an organic compound of plant origin, a natural alkaloid. Berberine has a hypocholesterolemic effect by reducing the level of LDL cholesterol and inhibiting the biosynthesis of triglycerides (TG) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) and activating 5'AMP. The extract in the form of powder can be obtained by extracting dry Amur cork tree bark with a water-alcohol solution (ethanol 70%), followed by concentrating the resulting extract and drying.

Artichoke leaf extract Cynara scolymus has lipid-lowering properties due to indirect modulation of HMG-CoA reductase activity and increased excretion of C and neutral bile acids and sterols. Artichoke leaf extract (LP-006846) is a dry official extract (https://www.rlsnet.ru/active-substance/artisoka-listev-ekstrakt-1072).

Nicotinic acid (Niacin, also known as vitamin B3, PP) is a water-soluble vitamin that gives rise to the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Nicotinic acid reduces the level of total cholesterol, apolipoprotein A, triglycerides.

Pomegranate flower extract Punica granatum L. (registration certificate RU.77.99.11.003.E.000218.01.11 dated 14.01.2011) has significant antioxidant activity, which is explained by its polyphenols, including ellagic acid and punicalagin. The commercial extract is produced as a dry powder obtained by spraying the ethanol extract. The dried pomegranate flowers are extracted using 70% ethanol for 20 hours at 95°C. The resulting extract is filtered, concentrated under vacuum at 60°C and sent for drying.

Coenzyme Q10 (ubiquinone) has a pronounced lipid-lowering, anti-asthenic, anti-inflammatory effect and can be successfully used in the treatment of asthenic conditions, cardiovascular pathology (including hyperlipidemia and myopathy caused by statins), and carbohydrate metabolism disorders (insulin resistance).

Thanks to the developed qualitative and quantitative composition of the phyto-regulator, normalization of energy metabolism in the body is ensured, the level of low-density lipoproteins ("bad" cholesterol) is reduced, the level of total cholesterol in the blood is maintained, the normal functional state of the cardiovascular system is maintained, and in the case of combination with statins, their effectiveness increases, which allows their dosages to be reduced.

The proposed composition protects the liver, practically does not cause side effects inherent in individual components, and is also not addictive.

The invention can be illustrated by the following examples.

Example 1

Microcrystalline cellulose - 433.0 mg;

Red yeast rice extract (Monascus purpureus) (monacolin K content 10.0 mg) - 200.0 mg;

Pomegranate flower extract (Punica granatum L.) - 80.0 mg;

Artichoke leaf extract (Cynara Scolymus) - 70.0 mg;

Amur cork tree bark extract (Phellodendron amurense Rupr.) containing berberine 50.0 mg - 57.0 mg;

Nicotinic acid - 40.0;

Amorphous silicon dioxide - 18.0;

Coenzyme Q10 (ubiquinone) - 2.0;

Total tablet weight: 900 mg.

Method of obtaining

The components, raw materials and materials are added according to the recipe. The technological process of manufacturing the product includes the following stages:

All raw materials entering the production process are subject to control for compliance with the requirements of the normative and technical documentation in force for raw materials. The quality of each batch is determined by the company's employees in accordance with the acceptance rules and testing methods set out in the standards in force for them. Raw materials that do not meet the standards established by the technical documentation are not allowed into production. During the incoming inspection, the presence and content of the quality and safety certificate of the original products and packaging materials should be checked. All packaging materials must be accompanied by an analytical sheet, meet the requirements of TP TS 005/2011 and must be approved in the established manner for contact with food products.

The required amount of ingredients according to the recipe and depending on the specified batch volume are weighed and measured using electronic scales. If necessary, the raw materials are pre-dried, crushed and sifted. The crushed components used in the technological process are sifted and passed through a magnetic catcher.

The prepared ingredients according to the recipe are loaded into the mixer and thoroughly mixed for 15-20 minutes until the components are completely evenly distributed and a homogeneous mixture is obtained.

The finished mixture is fed to an automatic tablet press. Using a mechanism for sequential filling of the matrix with the help of punches, the mixture is pressed, and then the finished tablet is pushed out. Deviations in the weight of individual tablets from the nominal should not exceed 10%. Tablets that meet quality requirements are collected in receiving trays and transferred to the packaging section.

Directions for use: Adults: 1 tablet daily during meals. Duration of use: 1-2 months. If necessary, the dose can be repeated.

Example 2

The effect of phyto-regulator on lipid levels.

The study of the claimed composition (Example 1) and the prototype comparison drug (sold by Armolipid) involved 56 volunteers diagnosed with hypercholesterolemia and lyslipidemia. After 4 weeks of treatment with daily oral administration of 1 tablet of both the new composition and the comparison drug, a decrease in LDL, total cholesterol (TC) and triglyceride (TG) levels was noted.

However, in the group taking the claimed drug, clear advantages were noted, both in terms of bringing lipid metabolism indicators back to normal and in terms of safety (Table 1).

The new composition was also evaluated from the point of view of possible long-term use, and showed significant safety. When monitoring biochemical parameters, no liver or kidney dysfunctions were detected.

The drug has shown high bioavailability. It is quickly absorbed in the gastrointestinal tract. Protein binding is 95%. It is intensively metabolized by the first pass effect through the liver with the formation of active metabolites. It is excreted by 90% with feces and 10% with urine. T ¹ / ₂ is on average 3 hours.

The drug has a choleretic and antispasmodic effect, reduces the tone of the gallbladder muscles. When taking it, improved bile secretion, decreased its viscosity, and normalized the biochemical composition of bile were observed.

At the same time, patients note a significant improvement in their overall well-being.

The phyto-regulator can be used both independently and in addition to therapy or diets for hypercholesterolemia, dyslipidemia, digestive disorders, to prevent the risk of developing obesity, atherosclerosis and other cardiovascular diseases.

Claims (2)

The composition of the lipid metabolism phyto-regulator in the form of a tablet, characterized in that it includes as active components an extract of red yeast rice ( Monascus purpureus ) with a monacolin K content of 5 wt. % of the extract weight, an extract of pomegranate flowers ( Punica granatum L.), an extract of artichoke leaves ( Cynara Scolymus ), an extract of Amur cork tree bark ( Phellodendron amurense Rupr.) with a berberine content of 85-88 wt. % of the total extract weight, nicotinic acid or niocin, coenzyme Q10 (ubiquinone), as auxiliary substances - microcrystalline cellulose and amorphous silicon dioxide with the following content of components, mg: Red Yeast Rice Extract 180.0-220.0 Red Yeast Rice Extract 180.0-220.0 Pomegranate flower extract72.0-88.0 Pomegranate flower extract72.0-88.0 Artichoke Leaf Extract 63.0-77.0 Amur Cork Tree Bark Extract 52.0-62.0 Nicotinic acid or niocin 36.0-44.0 Coenzyme Q10 (ubiquinone) 1.8-2.2 10 (ubiquinone)1.8-2.2 Microcrystalline cellulose 390.8-470.2 Amorphous silicon dioxide 16.0-20.0 Amorphous silicon dioxide 16.0-20.0