RU2619770C1 - Composition for body mass control and human body functional state maintenance - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: proposed composition is made in a solid dosage form in the form of capsules. At that, the amount of ingredients in one 500 mg capsule is, mg: green coffee extract - 100.0, brown algae extract as a source of fucoxanthin - 75.0, extract of African mango seeds - 31.25, extract of rhizome root - 75.0, L-carnitine α - 125.0, lipoic acid - 15.0, coenzyme Q10 - 12.5, lactose - 51.25, talc - 5.0, calcium stearate - 5.0, silica - 5.0.

EFFECT: invention allows to create a balanced polycomponent complex that provides an effective complex effect on the body, which consists in body weight reduction and maintaining of the body functional state with excessive body weight and alimentary obesity.

7 dwg, 25 tbl, 4 ex

Description

The invention relates to medicine, relates to a composition for controlling body weight and maintaining the functional state of the body of people with excess body weight and alimentary obesity.

The problem of prevention and treatment of overweight and, especially, obesity has gained unprecedented relevance and its importance is growing. The World Health Organization (WHO) has declared the disease "an epidemic of the 21st century." According to WHO, overweight and obesity are defined as abnormal and excess body fat that can be detrimental to health. There is a well-proven relationship between overweight and obesity and a number of diseases. Overweight and obesity are among the five main risk factors for death. A huge number of cases of early disability and premature death is associated with the presence of this condition. According to the Parliamentary Hearings of the State Duma of the Russian Federation (November 2012), more than 50% of Russian citizens over 30 suffer from this disease and, as a result, the incidence of diabetes, cardiovascular and endocrine systems (including metabolic syndrome), musculoskeletal system apparatus, oncological diseases.

It is believed that excessive accumulation of adipose tissue is associated either with improper eating behavior, or with a genetic predisposition, or endocrine disorders, or disorders of the central nervous system, and physical inactivity, stress and poor ecology only exacerbate the situation. However, these factors are quite heterogeneous and have very little in common. There are cases of obesity that cannot be explained by the above reasons. Often, excess fat accumulation occurs due to a violation of the energy balance in the body, as a result of which part of the energy received from food, instead of being converted into the active form (heat and / or work), is stored as a passive energy reserve in fat cells.

Alimentary obesity is most common, usually in individuals with a hereditary predisposition to overweight. This option of obesity develops in cases where the calorie content of food exceeds the energy consumption of the body. Alimentary obesity is characterized by a gradual increase in body weight. Subcutaneous adipose tissue is distributed evenly, sometimes to a greater extent accumulates in the abdomen and thighs. There are no signs of endocrine gland damage. This type of obesity often affects middle-aged and elderly women, leading a sedentary lifestyle. When collecting an anamnesis with a detailed clarification of the daily diet, it is usually established that patients systematically overeat.

Body mass index (BMI), which is the ratio of body weight to height, is often used to classify obesity and overweight. The index is calculated as the ratio of body weight in kilograms to the square of growth in meters (kg / m ² ). According to the WHO definition, if the BMI is greater than or equal to 25, the patient has overweight. If the BMI is greater than or equal to 30 - obesity. In clinical practice, the main diagnostic diagnostic criterion for obesity is the determination of excess total body weight in relation to the norm established statistically. However, to determine the severity of the disease, it is important not so much an excess of the total body weight as an excess of adipose tissue mass, which can differ significantly even in individuals with the same age, height and body weight. In this regard, the most relevant for the diagnosis and assessment of the effectiveness of the treatment of overweight and obesity is the determination of body composition and it is fat mass.

In connection with the high significance of this problem, the need for finding new approaches to the prevention and treatment of this pathology is growing.

Currently, a wide variety of methods are used to treat overweight and obesity. These are various systems of physical exertion, muscle electrical stimulation, surgical plastics. With BMI ≥ 30, as well as BMI ≥ 27 and the presence of pathological conditions associated with obesity, pharmacotherapy of excess body weight should be carried out. In a separate row is diet therapy (including treatment with hunger), as well as psychotherapeutic methods of treatment aimed at correcting the person [1-6].

The generally accepted strategy for helping patients with overweight and obesity is to use a non-drug therapy program for all patients, which, if necessary, can be supplemented by the methods of medical and (or) surgical treatment of obesity. Non-drug methods of treating obesity, which with a certain degree of probability can provide a gradual continuous decrease in body weight, are based on lifestyle changes, dietary modifications, decreased alcohol consumption, increased physical activity. It has now been established that adult obese patients can weekly lose about 0.5 kg of body weight while reducing daily food intake by 500-1000 kcal from the baseline. A more serious restriction of nutrition with the use of low-calorie diets allows you to accelerate weight loss, but it does not practically affect the long-term results of diet therapy. The combination of restrictive diets with increased physical activity makes maintaining weight loss over a longer period more likely. The combination of diet with loads for six months is able to provide a decrease in body weight with obesity by 5-10% [7].

Nevertheless, despite the proven effectiveness of combining diet therapy with increased physical activity, only 20% of patients seeking to reduce body weight successfully combine these therapeutic approaches. Practical experience indicates that the reduction in body weight achieved using non-drug methods requires the patient to constantly observe certain conditions: constant diet, maintaining physical activity at an achieved level, and so on. Obese patients, as a rule, are quite difficult to constantly adhere to restrictive recommendations, including due to behavior patterns, and their body weight gradually returns to its original level or even begins to exceed it.

Non-drug treatment of obesity cannot be successful without adequate behavioral therapy. This area of non-drug treatment involves creating a patient’s motivation for weight loss, focusing on a lifelong program to combat obesity, self-monitoring with a diary of body weight, nutrition and physical activity, limiting the intake of drugs that promote weight gain, treatment of sexual dysfunction and depressive disorders, combating stress, a "sedimentary" lifestyle, adhering to the rules of eating and other activities.

Since obesity is a chronic pathological condition, proceeding to its treatment - non-drug or pharmacotherapy, it should be expected that it will be quite long. Numerous clinical studies indicate that after discontinuation of drugs that reduce body weight, its increase almost inevitably occurs, often to a level exceeding the original. The choice of this or that drug is empirical and is based on a consideration of the general condition of the patient, underlying obesity diseases, existing contraindications for use, concomitant therapy (risk of interactions), the need to monitor the cost of treatment and, finally, the preferences of the patient himself.

Currently, the pharmaceutical market has a number of phytopreparations and biologically active food additives (BAA), offered by their manufacturers to reduce body weight and / or prevent obesity, which can be used in overweight people at the stage of non-drug treatment as dietary supplements to the diet used. Most often, green coffee, dry green tea extract, chitosan, cinnamon, turmeric, ginger, guarana, garcinia, chromium picolinate, L-carnitine, certain fatty acids, ephedra alkaloids, including ephedrine, bollards and stigmas of corn are used as components of such additives and others [8-13].

When considering the problem of correction of body weight, one should also consider such a thing as metabolic syndrome. It includes five indicators: abdominal obesity, high blood pressure, increased fasting blood glucose, high blood triglycerides and low high density lipoproteins. Moreover, the appearance of one of these factors indicates an increased risk of development of all the others.

Unfortunately, official medicine, judging by the materials of the last conference on the metabolic syndrome (November 2014), uses an extremely limited range of natural components to combat this multifactorial pathological condition of the body. Evidence of the effectiveness of such funds for weight loss and obesity treatment, consistent with evidence-based medicine, is extremely insufficient. Therefore, the search for formulations based on natural compounds to reduce body fat mass, their comprehensive study and development of recommendations for use in practice are very relevant.

Among the means for correcting body weight, the dietary supplement Reduksin®-Light Strengthened Formula is quite well known (LLC Polaris, Murmansk) [14]. Currently, this dietary supplement in the practice of weight loss and treatment of obesity is most widely used by various groups of the population, by the principle of action is close to the claimed composition, and therefore adopted as a composition of the prototype.

The composition of the prototype composition, made in solid dosage form for oral use in the form of 650 mg capsules, includes four safe natural components, the sources of which are plants:

5-hydroxytryptophan derived from griffonia seeds 50 mg conjugated linoleic acid 500 mg Chinese yam root shredded 70 mg extract from wild yam extract 30 mg

The main action of the prototype composition is carried out in two directions: appetite control and acceleration of satiety, as well as modeling a toned and attractive silhouette due to the impact on the "problem areas".

The prototype composition contributes to the effective reduction of body weight, eliminates the risks of obesity and return to harmony by:

- Decrease in body fat mass (fat deposits both in the subcutaneous tissue and around the internal organs (visceral fat));

- increase muscle mass and the formation of a "healthy" contour of the figure;

- Correction of “problem areas” (waist, hips, abdomen) using a combined effect on muscle and fat tissue;

- decrease in appetite;

- Improving the emotional background, which facilitates dieting and motivates further weight loss.

The components included in the composition of the prototype components affect the main components of effective weight loss and restoration of normal physique.

Appetite control is ensured by the presence of 5-hydroxytryptophan, an important amino acid for the human body in the composition of the prototype composition, to produce the hormone “joy” of serotonin. Serotonin helps to reduce appetite, accelerates the onset of satiety, improves mood and normalizes sleep in dieters, making the process of losing weight much easier.

“Conjugated linoleic acid (CLA)” is a generalized term used to refer to a mixture of positional isomers and geometric isomers of an essential fatty acid — linoleic acid [15]. As part of the prototype composition of CLA in combination with chopped Chinese yam root and extract from wild yam extract, working in synergy affect fat and muscle tissue, helping to burn existing fat reserves, preventing the formation of new fat deposits, as well as toning muscle tissue. In addition, their action enhances the beta-oxidation of fatty acids and the formation of the optimal ratio of adipose and muscle tissue. Due to this, the silhouette becomes fit and attractive.

CLA in synergy with Chinese yam root chopped and extract from wild yam extract helps reduce fat accumulation by adipocytes (adipose tissue cells), accelerates fat mass reduction and volume reduction in “problem areas” - waist, abdomen, hips.

In addition to subcutaneous fat, there is also a decrease in visceral fat (fat around the internal organs), due to this the waist becomes thinner, and the stomach is smaller. Hips become already due to the work of the femoral muscles, which burn fat most intensively with the assistance of the components that make up the prototype composition.

KLK also helps to increase muscle mass, especially when combining its intake with physical exercises.

Thus, CLA has a "modeling" effect on the silhouette of the body due to the simultaneous effect on the reduction of fat mass, as well as the growth and strengthening of muscle mass. At the same time, fat begins to leave the places of its greatest accumulation - waist, hips, stomach.

Shredded root of Chinese yams reduces the desire for fat intake, increases the excretion of cholesterol with bile. Saponins extracts from wild yam extract serve as a source of dehydroepiandrosterone (DHEA), which inhibits the formation of visceral fat. This improves the function of vital organs and prevents complications of obesity.

To reduce body fat mass and the formation of a toned silhouette, it is recommended to take the prototype composition 1 capsule 2 times a day with meals or immediately after meals for 1 month. As a rule, there is a need to repeat course administration 3-4 times a year. It’s absolutely easy to get a prototype composition.

Along with the noted advantages for the composition of the prototype is characterized by a number of disadvantages:

- insufficient daily dosage of CLA to ensure the required effectiveness of the composition of the prototype;

- there is no convincing data on the clinical efficacy of CLA according to meta-analysis [16];

- the high cost of monthly admission (3000-3500 rubles), which makes the prototype composition unavailable for many population groups;

- weight loss and a decrease in the risk of obesity, a marked decrease in volumes in the “problem areas” are guaranteed only if the combination of the prototype composition with physical activity is combined.

For a set of biologically active substances included in it, the prototype composition cannot fully provide an effective influence on the development of the pathology under consideration and prevent its complications.

The multifactorial nature of the formation of excess body weight and, especially, obesity, requires the development and practical use of multicomponent formulations based on safe natural compounds that affect various aspects of pathology.

In this regard, the aim of the invention was to expand the range of means for controlling body weight by creating a balanced multicomponent complex based on safe natural compounds, the sources of which are plants, providing an effective complex effect on the body, which consists in reducing body weight and maintaining the functional state of the body, whose indicators are reduced during the development of this pathology, which does not contain substances hazardous to health, non-toxic, and does not have the NOSTA to cumulation sensitizing action and long-term negative consequences, storage stable.

Achieving this goal is possible by creating a balanced multicomponent complex, the composition of which is represented by safe natural compounds, the sources of which are plants, as well as mitochondrial metabolites and corresponds to the main pathogenetic mechanisms of obesity and its complications, which allows controlling body weight due to a complex effect on the mechanisms development of obesity and maintain the functional state of the body.

The complex effect of the claimed composition on the control mechanisms of body weight is:

- reducing the absorption of carbohydrates from food;

- switching to using fats instead of carbohydrates as an energy source;

- strengthening the processes of splitting of adipose tissue;

- increase utilization of visceral fat;

- activation of fat burning processes in cellular mitochondria;

- remodeling of the human body by increasing lean body mass;

- decreased appetite;

- additional intake of micronutrients into the body;

- antidepressant action.

To implement the specified complex effects in the multicomponent composition of the claimed composition includes:

- green coffee extract;

- brown algae extract - a source of fucoxanthin;

- extract of seeds of African mango;

- ginger rhizome extract;

- L-carnitine;

- coenzyme Q ₁₀ ;

- α-lipoic acid.

A distinctive feature of the claimed composition, first of all, is that in its composition there are factors that determine the utilization of glucose and fats.

Among the factors determining glucose utilization, green coffee extract, standardized by the total content and profile of chlorogenic acids (CGA), primarily the high content of ellagic and other phenolic acids, was used as the main active ingredient. Due to this, green coffee extract helps to suppress the activity of digestive enzymes that break down food starch and reduce the breakdown of glycogen in the liver (due to inhibition of glucose-6-phosphatase). Under the influence of green coffee extract, there is a decrease in blood glucose intake and its concentration in blood plasma, modulation of the synthesis of intestinal incretin hormones - glucose-dependent insulinotropic polypeptide (HIP) and glucone-like peptide-1 (GLP-1), which affects postprandial insulin secretion and thereby inhibits glucose production and promotes its absorption by tissues. As a result, the risk of developing obesity, hyperglycemia, and diabetes is reduced.

Green coffee extract increases the body's ability to burn fat and has a unique ability to prevent the excess intake of carbohydrates in the blood plasma (prevents the breakdown of glycogen in the liver and the absorption of glucose in the intestine).

In addition to the green coffee extract, the composition of the claimed composition includes active ingredients that enhance the main effect of the claimed composition:

- carotenoid from brown algae - fucoxanthin - affects visceral fat;

- African mango seed extract reduces insulin resistance and reduces the formation of fatty acids in adipose tissue;

- Ginger rhizome extract normalizes the functions of the digestive system, helps to normalize the lipid profile, activates metabolic processes.

To activate energy metabolism at the cellular level and, due to this, burning fats and carbohydrates in the cells, a metabolite complex consisting of L-carnitine, α-lipoic acid, coenzyme Q ₁₀ mitochondrial metabolites is additionally introduced into the composition of the claimed composition.

Α-Lipoic acid is important for stimulating glucose metabolism. It is a necessary component of the energetically important, aerobic pathway of glucose conversion, which determines its transformation through anaerobically formed pyruvate into a key component of the Krebs energy cycle — acetyl coenzyme A. α-lipoic acid helps to reduce glucose concentration in blood plasma and the accumulation of glycogen in the liver, is involved in the regulation of carbohydrate and lipid metabolism, stimulates the exchange of cholesterol, increases the content of glutathione, which in combination with the antioxidant effect of reduced s α-lipoic acid contributes significantly to the antioxidant activity of the claimed composition. Due to its participation in fat metabolism, α-lipoic acid increases the biosynthesis of phospholipids, in particular phosphoinositol, which helps to stabilize cell membranes that are often damaged in obesity.

To provide an energy-efficient aerobic pathway for the utilization of glucose with the participation of α-lipoic acid, the composition of the claimed composition includes coenzyme Q ₁₀ (KoQ ₁₀ ), since the biochemical mechanism of the formation of adenosine triphosphate (ATP) along this path is the electron transport chains of mitochondria, in the functioning of which coenzyme plays an important role Q ₁₀ .

Factors that determine the utilization of fats are extracts of seeds of African mango and ginger rhizomes, which normalize lipid metabolism and help optimize the lipid profile while enhancing metabolism. It is worth emphasizing the uniqueness of the action of the components of the seeds of African mango, which consists in enhancing the breakdown of fats by increasing the sensitivity of adipose tissue to leptin, a peptide hormone produced by the adipose tissue cells itself, which leads to suppression of the secretion of neuropeptide Y. As is known, an increase in the production of this hypothalamic mediator leads to stimulation of appetite and increased food intake. At the same time, under the influence of leptin, the production of lipolytic factors of the hypothalamus increases, the inhibition of hunger centers and a decrease in food intake, as well as the activation of the sympathetic nervous system, which leads to increased lipolysis and a decrease in fat mass. In addition, the components of African mango increase tissue sensitivity to insulin by enhancing the release of another adipose tissue peptide - adiponectin. The latter prevents the inflammatory processes in the endothelium of the vascular wall. These properties of African mango have a beneficial effect on blood sugar and prevent atherosclerotic vascular damage, which is a common occurrence in individuals with increased body weight, and even more so with obesity and metabolic syndrome.

The next important component of the claimed composition, actively affecting fat metabolism, is L-carnitine in combination with KoQ ₁₀ . L-carnitine is a molecular transporter of long-chain fatty acids of fats (including food) to mitochondria, where ATP synthesis is carried out with the participation of KoQ _{10 of the} respiratory mitochondrial chain, which helps to reduce the level of fats in the body. It is to ensure the necessary conditions for the effectiveness of the oxidation of fatty acids in the composition of the claimed composition provides for the combination of L-carnitine with KoQ ₁₀ .

An important intensifier of oxidation and “combustion” of both carbohydrates and fats in the mitochondria of cells is a brown alga carotenoid - fucoxanthin. Fucoxanthin induces the expression of UCP-1 protein, which uncouples electron transfer in the electron transport chain of mitochondria and oxidative phosphorylation with the formation of ATP. The consequence of this process is the intensification of the oxidation of fats and carbohydrates to cover the energy deficit that occurs in cells. It is especially important that this process takes place in visceral adipose tissue, which not only helps to reduce body fat around the waist, but, most importantly, reduces visceral-abdominal obesity (one of the indicators of the metabolic syndrome). Moreover, in terms of preventing complications of obesity, primarily of the visceral-abdominal type, the property of fucoxanthin to stimulate liver biosynthesis of docosahexaenoic acid from precursors (α-linolenic and eicosapentaenoic acids), not only contributing to a decrease in atherogenic cholesterol in blood plasma and risk the development of atherosclerosis (especially pronounced in individuals with overweight and, especially, metabolic syndrome), but also helps to resolve inflammation of the vascular endothelium.

Of the other important properties of the components that make up the claimed composition, one should point out the antioxidant effect (ellagic and other phenolic acids and green coffee polyphenols, brown algae fucoxanthin, ginger rhizome polyphenols, α-lipoic acid, coenzyme Q ₁₀ , etc.) , prophylactic anticarcinogenic effect (especially fucoxanthin), hepatoprotective activity (ginger rhizome, African mango, coenzyme Q ₁₀ ), which are important factors in the prevention of dangerous complications in overweight individuals and all the more obese.

In addition, the claimed composition is characterized by the presence of a number of additional positive effects in relation to the human body, which is especially important for those who seek not only to lose weight, but also to maintain the functional state of their body. The inventive composition has a positive effect on carbohydrate metabolism (improved glucose tolerance test indicators), on fat metabolism (improved lipid profile of blood plasma), contributes to a gentle decrease in blood pressure, increase physical performance and endurance, resistance to hypoxia and other adverse factors, improve mental performance by improving the mnestic functions of the central nervous system (memory and learning ability).

It should also be noted that when taking the claimed composition does not require a change in the usual way of life. The inventive composition can be taken in addition to food, without changing the diet and / or physical activity during the day, which is important for people with overweight and obesity.

The inventive composition has a complex multicomponent composition, and its effectiveness in reducing body weight exceeds the efficiency of its constituent components, which is achieved due to the effective integrated recovery of metabolic processes in the cell, which are usually impaired in obesity.

In general, the components of the claimed composition are selected in such a way that its qualitative and quantitative composition is aimed at inhibiting the absorption and biosynthesis of the main energy components of food (carbohydrates and fats) and the intensification of their aerobic catabolism.

To improve the manufacturability of the process of obtaining the claimed composition, auxiliary technological additives are introduced into its composition, which are used as lactose, talc, calcium stearate, silicon dioxide.

Thus, in the composition of the claimed composition, the ingredients are selected so that the claimed composition is a balanced complex, and the number of them in one capsule weighing 500 mg is, mg:

green coffee extract 100.0 brown algae extract - source of fucoxanthin 75.0 african mango seed extract 31.25 ginger rhizome extract 75.0 L-carnitine 125.0 coenzyme Q ₁₀ 12.5 α-lipoic acid 15.0 lactose 51.25 talc 5,0 calcium stearate 5,0 silica 5,0

The ability to achieve the objectives of the invention is confirmed by the results of the studies presented in the following examples.

Example 1. Obtaining the inventive composition in an encapsulated solid dosage form for oral administration

The inventive composition is made in an encapsulated solid dosage form, which not only greatly simplifies its use when taken orally, but also provides reliable protection of its constituent components from the effects of factors causing their degradation.

The process of obtaining the inventive composition in an encapsulated solid dosage form provided for the following steps:

- preparation of raw materials (screening of substances through an SGS-30 vibrating screen with a mesh size of 1 mm, grinding screening at a hammer mill MM-10 and re-screening);

- preparing a mixture for granulation (dosing of the components of the claimed composition in the following order: first, the main components of the composition are sequentially dosed, including extracts of green coffee, brown algae, African mango seeds, ginger rhizomes, L-carnitine, coenzyme Q ₁₀ , α-lipoic acid then auxiliary components are subsequently dosed, including lactose, talc, calcium stearate, silicon dioxide);

- obtaining a mixture for encapsulation by mixing in a mixer V-shaped S-300 (mixing time at the rate of 100 kg - 1 hour);

- quality control of the mixture for encapsulation;

- encapsulation using a capsule machine (machine) ZANASI 40E;

- during encapsulation, strict periodic control of the appearance and average weight of the capsules;

- dust removal of finished capsules using a deduster.

For the introduction of the main components of the claimed composition the following were used: green coffee extract (NATUREX, France), brown algae extract containing 10% fucoxanthin (A AND Z FOOD ADDITIVES Co., LTD, China), African mango seed extract (NATUREX, France), extract ginger rhizomes (NATUREX, France), L-carnitine (LONZA, Switzerland), coenzyme Q ₁₀ (QINGDAO SAMIN CHEMICAL CO., Ltd, China), α-lipoic acid (SABINSA CORPORATION, India).

As you can see, the process of obtaining the inventive composition in an encapsulated solid dosage form for oral administration is simple, and the ingredients used are available under industrial conditions and are available.

Example 2. Safety assessment of the claimed composition

The safety of the claimed composition was evaluated by the results of sanitary-chemical analysis, microbiological studies, determination of toxicological characteristics, including acute toxicity during intragastric administration, chronic toxicity, as well as determining the ability to cumulate, sensitizing effect, the development of possible long-term effects.

Sanitary chemical analysis

Sample preparation was carried out according to GOST 26929-94 “Raw materials and food products. Sample preparation. Mineralization to identify toxic elements. Interstate standard. " Lead and cadmium were determined according to GOST 30178-96 “Raw materials and food products. Atomic absorption method for the determination of toxic elements. Interstate standard. " Arsenic was determined according to GOST 26930-86 “Raw materials and food products. Method for the determination of arsenic. " Mercury was determined according to the "Guidelines for the detection and determination of total mercury in food products by flameless atomic absorption" (No. 5178-90).

The content of organochlorine pesticides (toxicants) was determined according to the "Methodological guidelines for the determination of residues of organochlorine pesticides" (No. 1766-77) and official methods of analysis of AOAC ("Official methods of analysis of the AOAC", 1984, 14th ed., Chapter 29, P . 537-538).

The studies were carried out using laboratory scales VLR-500, gas-liquid chromatograph "Carlo Erba" (model HRGC 5700), exchange cells of the Italian company "Texnoplast".

The results of the measurements are presented in table 1 and indicate that in the claimed composition the content of toxicants (organochlorine pesticides HCTs and DCT) and hazardous substances (lead, cadmium, mercury, arsenic) does not exceed the allowable levels established by the Technical Regulation of the Customs Union TP ТС 021 / 2011 “On the safety of food products” (Appendix 3, Section 10) [17]. The same pesticides as aldrin and heptachlor in the claimed composition were not found.

Microbiological research

Microbiological studies were carried out in accordance with the requirements of the guidelines MUK 4.2.577-96 "Methods of microbiological control of baby food, therapeutic nutrition and their components" and MUK 2.3.2.721-98 "Determining the safety and effectiveness of biologically active food additives", GOST R 52814 -2007 “Food products. Method for the identification of bacteria of the genus Salmonella ", GOST R 52816-2007" Food products. A method for identifying and determining the number of bacteria of the group of Escherichia coli (coliform bacteria) ", GOST 10444.12-88" Food. Method for determination of yeast and mold fungi ”, GOST 30726-2001“ Food products. Methods for the identification and quantification of bacteria of the species Escherichia coli. "

It has been experimentally established that, according to microbiological safety indicators, the claimed composition meets the requirements established by the Technical Regulation of the Customs Union TP TS 021/2011 "On Food Safety" (Annexes 1 and 2, Section 1.9) (table 2)].

Acute toxicity study.

To determine the indicators of acute toxicity, the claimed composition was vyulyat healthy outbred white rats of both sexes weighing 130-150 g and 180-200 g intragastrically in the form of water-starch suspensions. The introduction was carried out through a metal atraumatic probe in increasing doses using the Litchfield-Wilcoxon probit analysis modified by Z. Roth [18].

During the experiment, to study the effects of the claimed composition, experimental groups of 6 animals of the same sex in each were formed. In addition, there were similar in number groups of control animals of each sex, to which equivalent volumes of solvent were introduced along the same route — 1% starch suspension. Animals were randomly assigned to groups using randomization. The criteria for the acceptability of randomization were considered to be the absence of external signs of diseases and the homogeneity of groups by body weight (± 10%).

Experimental animals were monitored for 14 days with registration of indicators: mortality, time of death of animals, symptoms of poisoning, results of daily monitoring of general condition and behavior, weighing, results of monitoring feed and water consumption, results of autopsy and macroscopic description of dead and surviving animals at the end studies (euthanasia was carried out by an overdose of ether), the results of determining the mass coefficients (MK) of internal organs.

The introduction of the claimed composition in the maximum tolerated doses (20 g / kg for rats and 25 g / kg for mice) did not cause the death of experimental animals. Not noted any other signs of negative effects of the claimed composition. In the first day, lethargy, lethargy, decreased feed and water intake, and diarrhea were noted. On the remaining days, the general condition and behavior of the animals of the experimental groups did not differ from the animals of the control group. In particular, no dyspeptic symptoms were noted. At autopsy - without features. There were no gender differences during intoxication.

At autopsy one day after acute administration, it was revealed that pleura and chest organs were not changed. Light pale pink, airy, without seals to the touch. The size of the heart is within normal limits. In the cavities of the heart contains a small amount of liquid blood. The heart muscle is dense, brown in color. The stomach is filled with a small amount of solid food. The mucous membrane is shiny, folded, slightly pinkish in color.

The mucosa of the small intestine is shiny, smooth, pinkish in color. The size and shape of the liver do not differ from the control. The surface of the liver is smooth. The capsule is thin, transparent. The liver pattern in the section is not changed. Liver tissue is moderately full-blooded. The kidneys are of normal size and shape, brownish in color, dense, with a distinct cortical and medullary substance in the section. The thyroid gland, adrenal glands and pancreas do not differ in appearance from the control.

The results of studying the dynamics of changes in body weight, water and feed consumption of experimental animals, as well as the dynamics of changes in body weight of surviving white mice receiving the inventive composition within 14 days of observation, they practically did not differ (tables 3-6).

Analysis of the MK values of the organs of surviving white rats and mice revealed that the acute administration of the claimed composition in the maximum tolerated dose did not cause any significant differences compared with the control group of animals receiving 1% starch suspension (tables 7 and 8).

The condition of the animals that survived acute intoxication indicates good tolerance and harmlessness of the claimed composition when it is administered in the maximum tolerated doses.

Thus, the results of toxicometry, necropsy data and observation of experimental animals within 14 days after acute administration allow us to classify the claimed composition as non-toxic (relatively harmless according to S.D. Zagolnikov) and low-hazard (hazard class IV according to GOST 12.1.007) substances .

The study of the ability to cumulate

Studies of the ability to cumulate were carried out on white non-linear male rats weighing 180-200 g with the introduction of the inventive composition intragastrically through an atraumatic metal probe for 30 days at a daily dose of 1.5 g / kg. Animals of the control group received 1% starch suspension in the same volume.

Monitoring of basic physiological parameters was carried out after 30 days of chronic daily administration of the claimed composition.

No lethal effects were observed throughout the observation period. The general condition and behavior of the experimental animals remained normal and did not differ from the parameters of the control group throughout the experiment.

The autopsy of rats euthanized the day after the last injection of the claimed composition showed that the size, shape and color of their internal organs did not have macroscopic changes compared with the control group. The mucous membranes of the stomach and small intestine were shiny, pale pink, with no signs of irritation or inflammation.

During histological examination of preparations of the lungs, myocardium, liver, kidneys and gastric mucosa of experimental animals receiving the claimed composition, dystrophic, inflammatory or necrobiotic changes in organs were not detected.

Therefore, chronic intragastric administration of the claimed composition into experimental animals did not cause dystrophic or destructive changes in parenchymal organs and was not accompanied by irritation of the mucous membranes of the gastrointestinal tract (GIT). Thus, according to the integral indicator of cumulation, the claimed composition does not have the ability to cumulate.

Sensitizing study

The study of the sensitizing effect of the claimed composition was carried out on guinea pigs. To do this, 0.02 ml of water dilution of the claimed composition at a dose of 10 mg / kg was injected once into the skin of the outer surface of the animal’s ear with a tuberculin syringe, and after 10 days, the claimed composition was applied to the pre-cut sections of the skin of the lateral back surface of 2 × 2 cm powder form at the rate of 20 mg / cm ² . Blood sampling in experimental animals was carried out 3 hours after the staging of skin samples.

The results of evaluating the effect of the claimed composition on the sensitizing effect are presented in table 9 and indicate the absence of signs of sensitization in the peripheral blood - eosinophilia or an increase in the level of lysis in the reaction of specific leukocyte lysis (RSLL) compared with the control. Examination of the back skin of experimental animals showed no signs of irritation. Therefore, the claimed composition upon epicutaneous contact does not have a sensitizing effect, that is, it does not provoke the development of allergies.

Study of the development of possible long-term effects

The study of a possible gonadotoxic effect was carried out in accordance with methodological recommendations for indicators required in the initial assessment of chemicals [19, 20]. The study of mutagenic activity was carried out according to the frequency of micronuclei formation in polychromatophilic bone marrow erythrocytes (from the femur) of white mice in accordance with the methodological recommendations [21, 22].

The results of a study of the possible gonadotoxic and mutagenic effects of the claimed composition when administered for 10 days at a dose of 1 g / kg, carried out 15 days after the end of its administration, indicate the absence of significantly significant changes in gonadotoxicity and mutagenicity indicators (table 10). Inhibition of spermatogenesis or an increase in the frequency of mutations was also not observed.

Therefore, the claimed composition does not have a toxic effect on reproductive function and does not have a mutagenic effect. This indicates its safety in terms of the development of long-term negative consequences in humans.

Example 3. Evaluation of the stability of the claimed composition during storage

We investigated the possibility of maintaining the activity and safety of the claimed composition, made in solid form in the form of a powder, and established a guaranteed shelf life in case of storage at different temperatures and without the use of special equipment.

During the experiment, the powder was placed in 120 consumer packages in the form of double plastic bags and stored for 3.0 years at temperatures of 5 ± 2 ° С, 10 ± 3 ° С, 25 ± 5 ° С, 35 ± 6 ° С (according to 25 packs for each temperature storage mode). Every 6 months of storage, 5 packages were selected from the corresponding temperature regime and powder characteristics were determined: organoleptic characteristics (appearance, color, smell), physicochemical parameters (polyphenol content in terms of tannin, hydroxycinnamic acids in terms of chlorogenic acid, fucoxanthin , L-carnitine, α-lipoic acid, coenzyme Q ₁₀ , mass fraction of moisture, disintegration, average weight of the contents of the capsule), microbiological purity. To assess possible changes in these characteristics during storage, their values were determined at the beginning of the study.

The data presented in table 11 indicate that at normal storage temperature (25 ± 5 ° C) organoleptic and physico-chemical parameters, as well as microbiological purity of the claimed composition, made in solid form in the form of a powder, practically do not change during 3.0 years.

Thus, the guaranteed shelf life of the claimed composition is at least 3.0 years, subject to the safety of packaging. Special temperature storage conditions or the use of special equipment is not required.

Example 4. Assessment of the biological activity of the claimed composition

The biological activity of the claimed composition was evaluated on the basis of studying its ability to normalize fat metabolism and, due to this, cause body weight correction in experimental animals, as well as maintain the functional state of the body and, above all, adaptive capabilities, reduced, as a rule, in the presence of excess body weight and obesity .

The study of the characteristics of the biological activity of the claimed composition was performed in comparison with the indicators of the most widely used dietary supplement Reduxin®-Light Amplified Formula (prototype composition).

The experiments to assess these characteristics were performed on white non-linear male rats with a standard weight of 150-160 g, received from the Rappolovo RAMS nursery in the Leningrad Region, in which experimental obesity was modeled.

In modeling experimental obesity in rats, a diet saturated with fats was used as a model for inducing hyperlipidemia and obesity [23]. For this, experimental animals consumed a homogeneous feed of the following composition:

- casein - 5%;

- sunflower oil mixed with pork fat - 40%;

- glucose - 43%;

- agar - 2%;

- salts, vitamins - 4%;

- cholic acid - 1%;

- thiouracil - 1%;

- cholesterol - 4%.

In addition, the rats were additionally intragastrically injected with a 10% oil emulsion of pork fat at a dose of 100 mg / kg.

The inventive composition was administered at a dose of 150 mg / kg (approximate "therapeutic and prophylactic" dose for rats, taking into account the interspecific dose transfer ratio of 5.9 for humans with an average weight of 70 kg, based on 4 capsules per day).

The prototype composition was administered at a dose of 120 mg / kg (approximate "therapeutic and preventive" dose for rats, taking into account the interspecific dose transfer ratio of 5.9 for humans with an average weight of 60-70 kg, based on 2 capsules per day of 650 mg (LLC Polaris, Murmansk).

The claimed composition and the prototype composition were administered intragastrically through an atraumatic probe one hour before the administration of pork fat for 1.5 months against the background of the above diet.

The intact group of rats received the usual vivar diet.

All animals received ad libitum water.

All tests and subsequent blood sampling was carried out at the end of the study 18 hours after the last injection of the claimed composition and the prototype composition. During this period, experimental animals were deprived of food.

Statistical processing of the experimental results was performed according to Student-Fisher.

The study of the ability to correct body weight of experimental animals due to the normalization of fat metabolism.

During the experiment, we studied the effect of the claimed composition and the composition of the prototype on the indicators of fat metabolism and body weight. All laboratory tests were performed according to standard methods [24, 25]. Serum β-lipoproteins (β-LPs) were determined by the turbodimetric method, free (non-esterified) fatty acids (NEFA) - titrometrically, total bilirubin (OB) - spectrophotometrically, phospholipids (PL) - by the content of total phosphorus.

The dynamics of rat body weight was studied using VLR-500 weights.

Also, at the end of the experiment, experimental animals were individually planted in metabolic cages of the Italian company Tecniplast Gazzada for 24 hours to collect excrement (feces). Then, in the feces, the amount of neutral fat, the presence of fatty acids and soap were determined by conventional methods [26].

The experimental results presented in tables 12 and 13 confirmed the adequacy of the obesity model used: in the control group (without prophylaxis), the content of total lipids, low-density lipoproteins, triglycerides, cholesterol in the blood significantly increased, and the serum phospholipids, on the contrary, decreased, increased atherogenic coefficient. The body weight of the experimental animals increased significantly.

In the experimental groups receiving the claimed composition and the composition of the prototype, normalization of lipid metabolism was observed. Animals in the experimental groups were more active, without signs of obesity. Moreover, the claimed composition reduced body weight by 21% more (p <0.05) than in the case of the use of the composition of the prototype.

Thus, it was experimentally established that the claimed composition exhibits a lipid-lowering effect and effectively reduces the body weight of experimental animals.

This is also evidenced by the normalization of the coprogram for the prophylactic use of the claimed composition and the composition of the prototype.

Effect on high temperature resistance of rats

The adaptogenic properties of the claimed composition were evaluated by the effect of the temperature factor on experimental animals, which allows a comprehensive assessment of the effect of the claimed composition on metabolic systems, the stability of which in conditions of hyperthermia determines the survival of individuals.

To assess the stability of rats under hyperthermia, the experimental and control groups of 6 animals in a cage were placed in a ventilated thermostat and kept at a temperature of 60 ° C. The device of the heat chamber made it possible to provide adequate gas exchange, sufficient to prevent oxygen deficiency, and made it possible to observe the animals through a glazed inspection hole. During the observation, the development of symptoms of the lesion was recorded and the time of manifestation of the convulsive syndrome and death of individuals was noted.

Experimental data indicate that a four-week administration of the claimed composition contributes to a positive effect on the resistance of rats to hyperthermia (table 14). The rate of development of the convulsive syndrome in rats receiving the claimed composition has a distinct tendency to decrease, and their lifespan in conditions of hyperthermia is significantly higher. Thus, the claimed composition has an adaptogenic effect and, when applied on a course, can increase resistance to extreme factors.

Impact on cognitive function

Animal experiments were carried out in accordance with the “Methodological recommendations for preclinical study of drugs with a nootropic type of action” [27].

The basic model for assessing the effect of substances on the formation and reproduction of a commemorative trace in normal conditions and in the conditions of its experimental violation is the technique of the conditioned passive avoidance reflex (passive avoidance reaction) [28]. The main advantages of this method are the speed of reflex production (learning from one sample) and the possibility of differentiated effects on different phases of memory. The method is based on the inhibition of congenital activity or acquired skills, leading to negative consequences for the body. In conditions of passive avoidance, the animal learns to avoid harmful factors by suppressing certain forms of behavior, in this study - to avoid the preferred dark space. There are several variants of the passive avoidance reaction method developed in one combination. The most commonly used form of passive avoidance reaction was used in this study.

The experimental animals were divided into 4 groups: the control and three experimental animals, 10 animals each. Before developing passive avoidance reaction, experimental animals of the first and second experimental groups were administered intragastrically for 10 days, respectively, of the claimed composition and the prototype composition at a dose of 100 mg / kg each. The animals of the third experimental group were also injected intragastrically for 10 days with the comparison drug Noopept ^® 10 mg tablets (CJSC Master Clone, Moscow) in the form of an aqueous suspension at a dose of 5 mg / kg (the maximum therapeutic dose adapted for rodents in humans was per active component). Animals of the control group were injected with 1% starch suspension in a volume of 0.2 ml.

The installation for generating a passive avoidance reflex is a plywood box - a compartment that consists of an illuminated part with a 40 W incandescent lamp mounted and darkened with 2 mm diameter copper rods on the floor. To the rods through the lather and the closing key, current is supplied from the network. Between themselves, the parts are separated by a partition with an opening that overlaps the shutter.

On the 11th day of the study, the passive avoidance reaction was performed in rats in an installation, the triggering stimulus of which was the animal in a brightly lit space. The rat was placed in the bright part of the compartment. After the rat transitioned to the dark part, fatal pain was immediately applied with 5 consecutive stimuli of alternating current (1 mA, each lasting 1 s with an interval of 2 s).

During testing (repeated placement in the illuminated part of the compartment after 24 h in order to determine the preservation of passive avoidance reaction), each animal was observed for 180 s. In this case, the latent period of the rat’s transition to the dark part of the compartment, the time spent in the light and dark parts of the compartment, and the number of animals that did not enter the dark part of the compartment (number of trained animals) were recorded.

The results presented in table 15 indicate that the claimed composition, the prototype composition and the preparation “Noopept ^® tablets 10 mg”, if used prophylactically, improve the mnestic functions of the central nervous system of experimental animals: the time spent in the light chamber was increased, the latent period was extended, reduced time spent in a dark chamber, where animals experienced pain. Consequently, experimental animals improved memory and learning ability. Moreover, it was experimentally established that the claimed composition is superior in effectiveness to the prototype composition and is not inferior to the well-known and widely used nootropic drug “Noopept ^® tablets 10 mg”.

Effect on the resistance of rats to the effects of hypoxia

When evaluating the adaptogenic and cytoprotective effects of the claimed composition, hypoxia was simulated in a closed volume ("can hypoxia") [29].

Respiration from a confined space - re-respiration - is a fairly adequate and simple model of acute hypoxia [7, 26]. The animal, absorbing oxygen from an enclosed space due to breathing, causes the development of its deficiency - hypoxic hypoxia, which makes it possible to evaluate the studied drug by the integrated mortality rates for a certain observation time and resistance to oxygen deficiency (maximum life expectancy).

The animals were placed in a 2 L jar tightly closed with a glass lid lubricated with sealant. The maximum lifespan and symptoms of thanatogenesis were recorded using a stopwatch. Cans with animals during the study were in the air conditioner, ensuring the constancy of the experimental conditions (temperature + 20 ° C, humidity - 65-70%, atmospheric pressure).

Before the experiment, the animals of the experimental groups were injected intragastrically for four weeks with the claimed composition and the prototype composition at a dose of 150 mg / kg each. Animals of the control group were injected with 1% starch suspension in a volume of 0.2 ml.

It was experimentally established that the claimed composition contributes to a significant increase in the resistance of animals to the effects of adverse factors modeling the conditions of enclosed spaces, a smoky environment and underground transport, that is, it exhibits a cytoprotective effect (table 16). The inventive composition significantly increases the life time of rats and by this indicator significantly exceeds the composition of the prototype.

Impact on motor and research activity

Overweight helps reduce physical activity and emotionality. In this regard, the effect on the indicated indicators of the claimed composition and the prototype composition was studied in the case of their prophylactic use.

Movement activity was studied using the automatic activity registration system “Activity Cell” (Ugo Basile, Italy). The experimental animals were divided into three groups: control and two experimental animals with 10 animals each.

During the experiment, to assess spontaneous motor activity (SDA), the rat was placed for 3 min in the chamber.

The results of evaluating the impact of the claimed composition and the prototype composition on rats SDA are presented in table 17 and indicate that the prophylactic use of the claimed composition helps to increase the overall motor activity of rats, surpassing the prototype composition in this indicator.

Research activity was studied using a round plastic arena with a diameter of 100 cm with sides along the perimeter. The arena floor is raised and divided into 9 squares with holes for recording research activity. A light source is placed above the camera. The nature and number of movements are noted by the registrar. Six components of the behavior of experimental animals were recorded during 5 min of observation: the latent period of exit, vertical and horizontal activity, the number of peeps in minks, grooming and boluses. To determine the severity of the effect, the ratio of the number of movements in the experiment and control was used.

From the data presented in table 18, a decrease in the activity of experimental animals of the control group is seen. Obese rats showed a decrease in research activity (the total number of uprights, peeping in the mink), as well as an increase in anxiety (the number of bowel movements and grooming).

The prophylactic use of the claimed composition contributed to an increase in the research activity of animals, superior to the action of the prototype composition.

Effect on physical performance and muscle strength

Physical performance and muscle strength are important indicators of animal activity. The biological activity of the claimed composition was evaluated by the duration of swimming and muscle strength of experimental animals.

The effect on the duration of swimming mice

Swimming is a heavy physical dynamic load and allows you to evaluate the effectiveness of adaptogens and the activity of redox processes in the muscles of mice. During the experiment, swimming was carried out at a water temperature of 37 ° C and was carried out with a load, which is a lead tube on a rubber ring attached to the root of the tail of the mouse and comprising 10% of body weight. At the same time, 5 animals from the control and two experimental groups swam in a large bath. The animals of the first and second experimental groups were administered intragastrically daily, respectively, of the claimed composition and the prototype composition at a dose of 150 mg / kg each. Mice in the control group received daily intragastric 1% starch suspension in a volume of 0.2 ml.

The criterion of fatigue and cessation of swimming was considered the first "diving" of the mouse with the immersion of the nasal passages in water. The duration of the swimming of mice was recorded from the moment they were placed in the bath until the moment of the first “diving”. The results of testing conducted 14 days after daily administration of the claimed composition indicate that daily prophylactic administration to rats of the claimed composition has a protective effect and reduces fatigue (table 19), increases their endurance in the swimming test by approximately 93%, that is, significantly increases adaptive abilities organism. The prototype composition increases rat endurance by approximately 40%. Thus, in the test, the claimed composition is more effective than the prototype composition by more than 2 times.

Effect on muscle strength in rats

Muscle strength was evaluated in white rats using a rat dynamometer. The results presented in table 20 indicate that according to the results of the test for muscle strength in the case of daily prophylactic use of the claimed composition, an increase of this indicator by 52% is observed compared to the control.

Using within 14 days of the composition of the prototype contributed to the fact that this indicator was approximately 15%.

Thus, in terms of influence on muscle strength, the claimed composition also exceeds the composition of the prototype.

Example 5. Evaluation of the effectiveness of the claimed composition.

In total, 30 male and female patients with nutritional obesity of the I-II degree, which were divided into two groups, were included in the study:

- 15 patients received the claimed composition for 90 days in a dosage of 2 capsules 2 times a day with meals (group 1). Patients underwent procedures to evaluate the effectiveness of the drug, clinical and biochemical blood tests and urinalysis 1 time in 30 days for 90 days.

- 15 patients received the claimed composition for 90 days in a dosage of 2 capsules 2 times a day with meals (group 2). Patients underwent procedures to evaluate the effectiveness of the drug 1 time in 30 days.

Patients included 10 men and 20 women aged 20 to 59 years. At the time of the start of the observation, the total number of patients was 30, there were no patients dropping out of the group during the observation, 30 patients completed all the studies.

The number of patients included middle-aged people without a pronounced concomitant pathology of organs and systems, the sample was representative, which provides a high degree of generalization of the research results.

The inventive composition was applied for 90 consecutive days. During the administration of the claimed composition, patients were advised not to change their eating habits (not to increase or decrease the amount of food consumed, not to use different diets (if the patient had not followed such diets), to avoid feast, to avoid drinking alcoholic beverages; not to quit smoking during research ) and change physical activity (do not start intensive sports and / or do not increase the intensity of walks or normal physical activity, do not reduce the intensity of the usual hedgehog daily exercise).

During the study, the following patient visits to the clinic were made: a screening visit (Visit 1) to include the patient in the study, a randomization visit and the start of taking the claimed composition (Visit 2), follow-up visits (Visit 3 and Visit 4) and a final visit three months after start receiving the claimed composition (Visit 5).

At a screening visit, a randomization visit, follow-up visits, a final visit, only patients in cohort 1 (n = 15) were assigned a clinical blood test, biochemical blood test, and urinalysis. All other visit procedures were the same for patients in both cohorts.

Visit 1 was carried out 7 ± 2 days before the first dose of the claimed composition. During Visit 1, a comprehensive clinical and laboratory examination was carried out: a standardized survey of the patient, a study of his medical history, physical examination and assessment of vital signs of the patient, assessment of clinical data, performance and evaluation of laboratory tests (clinical blood test, urinalysis, biochemical blood test pregnancy test for women of childbearing age), caliperometry and abdominal circumference measurements, bioimpedance composition of body weight using an analyzer bio-impedance composition of body weight “Diamant-AIST” (CJSC “Diamant”, St. Petersburg). The screening duration was 2-7 days.

After 7 ± 2 days from the start of Visit 1, after the completion of the clinical laboratory examination, on the day of Visit 2, adverse events and concomitant therapy were evaluated, eating behavior and psychological testing were evaluated, the patient was included in the study, and randomization was performed.

Visit 3 was carried out 30 ± 2 days after Visit 2 in order to assess the effectiveness and safety of receiving the claimed composition, as well as compliance. The patient’s diary and patient compliance with the diet and physical activity during the study, adverse events, concomitant therapy were evaluated, physical data, vital signs were evaluated, clinical and biochemical blood tests, urine tests were performed, caliperometry and measurement of the abdomen circumference, bioimpedance composition study body weight, assessment of eating behavior, compliance and tolerance of the claimed composition.

30 ± 2 days after Visit 3, Visit 4 was conducted to assess the efficacy and safety of receiving the claimed composition, as well as compliance. The patient’s diary and patient compliance with the diet and physical activity during the study, adverse events, concomitant therapy, vital signs were assessed, the patient underwent physical examination, clinical and biochemical blood tests, urinalysis were performed, and the compliance and tolerability of the drug were evaluated.

The study period for each individual patient was 104 days and consisted of a screening step for 3-7 days, an 8-week treatment step and subsequent follow-up for 2 weeks. The daily intake of the claimed composition is 2 capsules 2 times a day in the morning and evening with food. In total, each patient received 384 capsules (including 24 capsules for an emergency).

The effectiveness of the claimed composition was evaluated by its effect on:

- nutritional status of patients by studying the dynamics of body weight and BMI;

- the dynamics of the amount of adipose tissue in the body (body fat mass);

- the dynamics of the total thickness of the skin-fat folds;

- the dynamics of the waist circumference.

Effect on the nutritional status of patients.

It was experimentally established that after 1 month of taking the claimed composition, body weight and BMI decreased in 17 patients (57%), after 2 months in 25 patients (83%), and after 3 months in 28 (93%) patients.

During the 3-month follow-up period, a greater number of obese patients noted a positive effect - weight loss. By the end of the observation period, only in 2 (7%) patients body weight did not change; in all other patients, body weight decreased.

BMI of patients is a derivative of body weight, and, accordingly, in the process of observation, BMI underwent changes similar to the dynamics of body weight. The average BMI of patients at the time of the start of the observation was 32.2 kg / m ² , 1 month after the start of the drug administration it decreased to 32.0 kg / m ² , after 2 months - to 31.4 kg / m ² , and On the 3rd month of observation, the average BMI was 30.4 kg / m ² .

The results of a posteriori comparisons using the Bonferroni criterion are presented in table 21. As a result of pairwise comparisons of the patient’s body weight values, a statistically significant decrease in body weight was noted from the 2nd month of taking the claimed composition.

Over the course of the observation period (from the beginning of administration to the end of the 3-month period of administration of the claimed composition), a statistically significant linear trend in the decrease in body weight of patients was revealed. The dynamics of the average values of body weight and BMI while receiving the claimed composition and linear trends are presented in figures 1 and 2 (dashed lines indicate the trend lines). The average proportion of weight loss in successive periods of observation while taking the claimed composition is presented in figure 3.

Over the 3-month observation period, the average body weight of patients decreased from 91.3 kg to 86.1 kg and a decrease of 5.2 kg. In 14 (47%) patients, the decrease in body weight was more than 5 kg: in 3 (10%) patients, a significant decrease in body weight (more than 10 kg) was noted, in 11 (37%) patients, a decrease in body weight in the volume from 5 to 10 was noted kg In 14 (47%) patients, weight loss ranged from 3 to 5 kg.

Thus, a statistically significant sequential decrease in the patient’s body weight was observed experimentally while taking the claimed composition, which was reliably observed starting from the 2nd month from the start of the administration.

Effect on the dynamics of the amount of adipose tissue in the body (body fat mass).

The assessment of the dynamics of body fat mass was carried out based on the results of bio-impedance analysis of body composition. This method allows you to evaluate body fat mass - the total amount of adipose tissue in the body, including both visceral adipose tissue and subcutaneous fat. Over the 3-month follow-up period, the fat mass of patients decreased from 30.51 kg to 27.25 kg and amounted to 3.26 kg. The dynamics of the median fat mass while receiving the claimed composition is presented in figure 4.

Since the distribution of body fat mass was significantly different from normal, the Friedman criterion was used to analyze repeated measurements, which also showed the presence of statistically significant differences between the values of fat mass measured in successive observation periods.

To evaluate posterior comparisons, an adjusted level of statistical significance was calculated taking into account the effect of multiple comparisons. The results of posterior comparisons of fat mass values performed using the paired Wilcoxon test are presented in table 22.

Analysis of the dynamics of lean mass showed the absence of statistically significant dynamics of this indicator over the observation period (56.5 ± 9.2 kg initially, 55.1 ± 6.7 kg after 3 months), as well as the masses of the body's water sectors (42.8 ± 6 , 7 kg initially, 42.1 ± 5.0 kg after 3 months).

As a result of pairwise comparisons, it was found that 3 months after taking the claimed composition, a close to statistically significant decrease in fat mass was observed according to bioimpedance analysis of body composition.

Fluctuations in the fat mass of patients during the observation period may be associated with changes in the water sectors in the body, based on which the value of fat mass is calculated based on the results of bioimpedance analysis.

Influence on the dynamics of the total thickness of skin-fat folds.

The effectiveness of the claimed composition was also evaluated by its effect on the dynamics of the total thickness of the skin-fat folds (KZHS).

The total thickness of KZhS was calculated as the sum of the thickness of 4 skin-fat folds measured by a caliper. This indicator allows you to indirectly assess the volume of subcutaneous fatty tissue, isolated from visceral fatty tissue.

According to the results of a variance analysis of repeated measurements corrected by Greenhouse-Geisser, the total thickness of the QOL of patients at the start of observation and during subsequent visits was statistically significantly reduced. Over the 3-month observation period, a decrease in the total thickness of the QLC by 12.6 cm was noted. The results of pairwise comparisons indicate that a statistically significant decrease in the total thickness of the QLC was observed starting from the 1st month of taking the claimed composition (the results of pairwise a posteriori comparisons using Bonferroni criteria are presented in table 23).

The analysis revealed a statistically significant linear trend in reducing the thickness of the subcutaneous fatty tissue of patients over time observation. The dynamics of the average values of the total thickness of the KZhS against the background of taking the claimed composition and the existing linear trend of decline are presented in figure 5 (the dotted line indicates the trend line).

Influence on the dynamics of the waist circumference

The circumference of the waist allows you to indirectly assess the volume of visceral adipose tissue.

Over a 3-month follow-up period, patients taking the claimed composition showed a decrease in waist circumference of 3.2 cm. According to the results of the analysis of repeated measurements corrected by Greenhouse-Geisser, the waist circumference of patients at the time of observation and during subsequent visits was different. A statistically significant decrease in waist circumference was observed 2 months after the start of taking the claimed composition (the results of posterior comparisons using the Bonferroni criterion are presented in table 24).

A statistically significant linear trend of a decrease in the waist circumference over the course of the observation time while receiving the claimed composition is shown in Figure 6 (the dashed line indicates the trend line).

Thus, according to the results of a study of the effectiveness of the claimed composition in patients with obesity during the 3-month period of admission, a statistically confirmed significant improvement in somatometric indicators and indicators of the component composition of the body was noted: a decrease in the patient’s body mass and BMI, body fat mass, subcutaneous fat and circumference the waist. After a 3-month course of taking the claimed composition, therapeutic success was achieved in 93% of patients.

Against the background of taking the claimed composition, after 1 month from the start of administration, a significant decrease in the thickness of QOL was observed, after 2 months - a decrease in body weight / BMI and a decrease in waist circumference, after 3 months - a decrease in fat mass (figure 7).

Despite the fact that the body weight and BMI of patients remained high and corresponded to obesity, the main indicators of the nutritional status of patients significantly decreased, which is significant, taking into account the category of patients (obese patients) and the peculiarities of their eating behavior (the prevalence of external eating behavior) .

Assessment of tolerability and safety of the claimed composition

During the observation period for two months, none of the patients stopped taking the claimed composition. High adherence to the administration of the claimed composition was demonstrated by 100% of patients.

When assessing the safety of the course administration of the claimed composition, there were no significant changes in the indicators of vital functions and the appearance of significant clinical symptoms, no clinically significant changes in the clinical and biochemical parameters of blood, changes in the general analysis of urine, which could indicate a negative effect of the studied drug on the function of the corresponding organs and systems (laboratory indicators changed within the reference values and in the case when the changes in the indicators were statistically significant).

The results of the general analysis of urine corresponded to reference values both before and after the course of taking the claimed composition.

The dynamics of the main laboratory parameters in patients included in the safety assessment group are presented in table 25.

Thus, the studies showed that when exposed to the claimed composition, which is a balanced complex of safe natural compounds, the sources of which are plants, and mitochondrial metabolites:

- the body weight of obese patients is reduced, the composition of the body is improved: the mass of adipose tissue is reduced, the waist circumference and the volume of subcutaneous fat are reduced. After 3 months from the start of the drug, a decrease in body weight is achieved in almost all patients taking it. By the end of the observation period, 93% of patients receiving the claimed composition, noted a decrease in body weight, while in 50% of them, body weight decreases by more than 5 kg;

- against the background of course administration, a consistent significant decrease in somatometric indices is observed, which becomes more pronounced as the duration of drug administration increases. A significant decrease in the thickness of KZhS is observed after 1 month from the start of administration, a significant decrease in body weight / BMI and a decrease in waist circumference after 2 months, a significant decrease in fat mass after 3 months.

Reception of the claimed composition also provides additional positive effects, which is especially important for those who seek not only to lose weight, but also to maintain the functional state of their body. The inventive composition has a positive effect on carbohydrate-fat metabolism (improvement of biochemical parameters of blood plasma), increase physical performance and endurance, resistance to adverse factors, improve mental performance by improving mnemonic functions of the central nervous system (memory and learning ability).

In addition, the claimed composition is well tolerated by patients with obesity, is safe for this category of patients, since it does not contain toxic and hazardous components in quantities exceeding acceptable levels, is non-toxic, does not have the ability to cumulate, and does not have unwanted side effects.

The claimed invention meets the criterion of "novelty", since for the first time for the correction of body weight in obese patients it is proposed to use a composition that is a balanced complex of safe natural compounds, the sources of which are plants, and mitochondrial metabolites, the combined effect of which provides not only effective weight loss body and improving the composition of the body, but also maintaining the functional state of the body, performed in solid It encapsulates dosage form for oral administration.

The claimed invention meets the criterion of "inventive step", since the available information did not seem obvious the feasibility of combining in the composition of the claimed composition of natural compounds, the sources of which are plants, and mitochondrial metabolites, as well as the ability to maintain the functional state of the body.

The compliance of the claimed invention with the criterion of "suitability for use" is confirmed by the results of numerous studies that have shown a simple technology for the production of the claimed composition in a solid encapsulated dosage form for oral administration, the ingredients of which are manufactured under industrial conditions and are available, and the claimed composition has high storage stability, is safe, provides effective weight loss and improvement of the composition of the body, exists maintaining the functional state of the organism.

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28. Buresh Ya. Methods and basic experiments on the study of the brain and behavior. M .: Higher. school., 1991.399 s.

Claims (12)

Composition for controlling body weight and maintaining the functional state of the body of people with overweight and nutritional obesity, which includes safe natural compounds, the sources of which are plants, characterized in that it is a balanced complex, which also includes mitochondrial metabolites - L -carnitine, α-lipoic acid and coenzyme Q ₁₀ , as well as auxiliary technological additives, which are used as lactose, talc, calcium stearate and silicon dioxide, extracts of green coffee, brown algae as a source of fucoxanthin, African mango seeds and ginger rhizomes were used as safe natural compounds from plants, the composition was made in solid dosage form in the form of capsules and the number of ingredients in one capsule weighing 500 mg is, mg: green coffee extract - 100.0; brown algae extract - source of fucoxanthin - 75.0; African mango seed extract - 31.25; ginger rhizome extract - 75.0; L-carnitine - 125.0; coenzyme Q _{10 -} 12.5; α-lipoic acid - 15.0; lactose - 51.25; talc - 5.0; calcium stearate - 5.0; silicon dioxide - 5.0.

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