RU2732245C1 - Novel compositions of n-carbamoylmethyl-4-phenyl-2-pyrrolidone for treating and preventing obesity - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: first object is the use of a composition comprising N-carbamoylmethyl-4-phenyl-2-pyrrolidone (fonturacetam) and at least one additional compound selected from a group, including 4-phenylpyrrolidone-2, 2-(2-oxo-4-phenylpyrrolidin-1-yl)acetic acid, ethyl-2-(2-oxo-4-phenylpyrrolidin-1-yl)acetate, optical isomers thereof and pharmaceutically acceptable salts, for treating and/or preventing obesity or overweight. Second object is using a pharmaceutical composition, a drug or a ready dosage form containing the composition in a therapeutically effective amount.EFFECT: technical result consists in improvement of stability (storage time) of composition, high rate of dissolution, reduced hygroscopicity of composition compared to prototype; expanding the range of products possessing anorexigenic activity for treating and preventing obesity or overweight; high activity of the disclosed composition compared to the prototype.16 cl, 17 tbl, 12 ex

Description

The invention relates to the field of medicine, pharmacology and the chemical-pharmaceutical industry, namely to new compositions for the treatment and / or prevention of obesity, containing N-carbamoylmethyl-4-phenyl-2-pyrrolidone (phonylpiracetam) and at least one additional compound selected from the group consisting of 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate and their optical isomers and pharmaceutically acceptable salts, pharmaceutical compositions based on said compositions, medicinal product based on said compositions or said pharmaceutical composition, and finished dosage form based on said compositions, said pharmaceutical composition or said medicinal product.

Obesity is one of the most pressing and widespread chronic diseases in the world today. The sharp increase in the number of obese people is associated with a number of reasons, which include a decrease in the proportion of physical labor, as well as physical activity in general (up to walking), a change in the diet to richer in fats and carbohydrates, the popularity of high-calorie drinks and fast foods. food, an increase in the level of stress and nervous disorders, computerization of leisure [1].

According to the World Health Organization (WHO) for 2016, more than 1.9 billion people over 18 years of age and more than 340 million children and adolescents (of which about 41 million are children under 5 years of age) are obese or overweight in the world body (according to the Quetelet index above 25 kg / m ² ), and the severity of the course and the presence of severe concomitant pathology is observed in the majority (89%) of patients. In terms of the number of people who are obese or overweight, and the rate of spread, obesity is considered a non-infectious epidemic. With the continued rate of obesity spread, according to WHO experts, these figures will double by 2025. The most common comorbidities are type 2 diabetes mellitus, arterial hypertension, atherosclerosis of the vessels of the lower extremities, ischemic heart disease, impaired reproductive and sexual function, and some forms of oncopathology. Obesity leads to shortened life expectancy and poor quality of life. Epidemiological studies indicate that obesity leads to a reduction in life expectancy by 8-10 years, contributes to the development of concomitant diseases and leads to such psychological consequences as low self-esteem, depression, anxiety, decreased psychological adaptation, and others [2, 3, 4] ...

The main regulator of human eating behavior is the central nervous system, first of all, the hypothalamus, which performs the function of a higher vegetative center that regulates metabolism, thermoregulation, the activity of blood vessels and internal organs, eating, sexual behavior, and mental functions. The hypothalamus receives signals from various organs and systems of the body, unites and acts on the body through various descending paths in order to maintain energy balance. In the case of the regulation of eating behavior and metabolism, such signals can be hormones of the digestive tract, such as ghrelin, YY peptide, cholecystokinin, as well as insulin and adipose tissue hormones, primarily leptin and adiponectin. Failures in the regulatory function of the hypothalamus can lead to the development of obesity, but most often they are caused precisely by incorrect signals received and processed by the hypothalamus. Thus, the development of obesity is often associated with the adipose tissue hormone leptin, which is produced in response to food intake. Leptin stimulates POMC neurons in the hypothalamus, thereby causing a feeling of fullness and a decrease in the amount of food consumed, and inhibits the work of AgRP / NPY neurons in the hypothalamus, the excitation of which causes hunger. Fasting leads to a decrease in serum leptin levels as well as activation of the hypothalamic-pituitary-adrenal axis, inhibition of growth hormone, thyroid function, and reproductive function, which can lead to obesity. Mutations in the leptin gene or mutations in leptin receptors (genetic obesity associated with leptin), or an excess of leptin (leading to the development of leptin resistance of hypothalamic receptors) also cause the development of morbid obesity, accompanied by many neuroendocrine abnormalities [18-22].

Thus, obesity or overweight can be due to a number of reasons, moreover, most often there is a combination of them. Thus, according to the International Classification of Diseases (ICD-10), obesity belongs to the class of diseases of the endocrine system, nutritional disorders and metabolic disorders, which includes the following groups: thyroid diseases (congenital iodine deficiency syndrome, including endemic conditions associated with iodine deficiency, and conditions resulting from inadequate secretion of thyroid hormones in the developing fetus, as well as those associated with natural goitrogenic factors; thyroid diseases associated with iodine deficiency, and similar conditions such as acquired hypothyroidism due to iodine deficiency; subclinical hypothyroidism due to iodine insufficiency; other forms of hypothyroidism; other forms of non-toxic goiter; thyrotoxicosis (hyperthyroidism); thyroiditis; other diseases of the thyroid gland), diabetes mellitus (type I diabetes mellitus, including labile, with onset at a young age, with a tendency to ketosis; diabetes mellitus Type II, including early diabetes scrap in adulthood, with onset in adulthood, without a tendency to ketosis, stable, as well as non-insulin dependent diabetes mellitus of young people; diabetes mellitus (both type I and II) associated with malnutrition; other specified forms of diabetes mellitus; diabetes mellitus, unspecified), other disorders of glucose regulation and internal secretion of the pancreas, disorders of other endocrine glands (hypoparathyroidism; hyperparathyroidism and other disorders of the parathyroid (parathyroid) gland; hyperfunction of the pituitary gland; hypofunction and other disorders of the pituitary gland; Itsenko-Cushing's syndrome; adrenogenitalysmal dysfunctions ; other disorders of the adrenal glands; ovarian dysfunction; testicular dysfunction; disorders of puberty, not elsewhere classified; polyglandular dysfunction; diseases of the thymus gland; other endocrine disorders, including in other diseases); malnutrition; other types of malnutrition; obesity and other types of excess nutrition (localized fat deposition; obesity due to excess energy supply; obesity due to drug intake; extreme obesity accompanied by alveolar hypoventilation; other forms of obesity, including morbid obesity, and unspecified obesity; and other types of excess nutrition, such as hypervitaminosis A, hypercarotenemia, vitamin B6 megadose syndrome, hypervitaminosis D and others; as well as the consequences of excess nutrition); metabolic disorders (metabolic disorders of aromatic amino acids; metabolic disorders of branched-chain amino acids and fatty acid metabolism; other metabolic disorders of amino acids; lactose intolerance; other metabolic disorders of carbohydrates; metabolic disorders of sphingolipids and other lipid accumulation diseases; metabolic disorders of glucosaminoglycans; metabolic disorders of glycoproteins; metabolic disorders of lipoproteins and other lipidemias; metabolic disorders of purines and pyrimidines; metabolic disorders of porphyrin and bilirubin, including defects in catalase and peroxidase; mineral metabolism disorders; cystic fibrosis; amyloidosis; decreased fluid volume, including dehydration, decreased plasma or extracellular fluids, hypovolemia; other disorders of water-salt metabolism or acid-base balance; other metabolic disorders, including those caused by taking medications, and, including Lonois-Bansod adenolipomatosis, trimethylaminuria; endocrine and metabolic disorders iya arising after medical procedures; eating disorders and metabolic disorders in other diseases). In addition, obesity can be one of the consequences of various mental and behavioral disorders (grade 5 according to ICD-10), including chromosomal pathologies that belong to the category of mental retardation (in particular, Berjeson-Forsmann-Lehmann syndrome, Alstrom syndrome, syndrome Proteus (Cohen's syndrome), Bork's X-linked mental retardation syndrome (MENMO syndrome), Prader-Willi syndrome (including those associated with a 6q16 deletion), Sotos syndrome, Weaver cider (Weaver-Smith syndrome), Shereshevsky-Turner syndrome , Wilson-Turner syndrome (WTS), X-linked mental retardation syndrome 6 (MRXS6, with gynecomastia and obesity), Beckwith-Wiedemann syndrome). From the point of view of genetics, the following forms of obesity can be distinguished: monogenic obesity, genetic syndromes associated with obesity, and simple obesity, characterized by polygenic inheritance. From the point of view of etiopathogenetic classification, obesity is subdivided into exogenous-constitutional obesity (primary, alimentary-constitutional), gynoid and android type; and symptomatic (secondary) obesity, which in turn is subdivided into symptomatic obesity with an established genetic defect (including as part of known genetic syndromes with multiple organ damage), cerebral symptomatic obesity, endocrine symptomatic obesity, and iatrogenic symptomatic obesity (caused by the use of a number of medicinal preparations) [18-22].

The available scientific evidence suggests that the goal of obesity treatment is a moderate decrease in body weight with an obligatory decrease in the risk of developing concomitant diseases, stabilization of the achieved body weight, and improvement in the quality and duration of life. According to WHO recommendations, the basis of a comprehensive program for controlling body weight is non-drug methods of therapy: rational hypocaloric nutrition, increased physical activity, and lifestyle changes. In medicine, methods of treating obese patients with the use of apparatus physiotherapy and balneotherapy methods are widely used [5, 6]. Surgical treatment of obesity is very common, such as the use of an intragastric balloon, adjustable gastric banding (GVB), longitudinal gastric resection (LRG) or sleeve, vertical, SLIV resection, gastric bypass surgery (GG), biliopancreatic shunting (BPS). However, surgical treatment often has a number of serious side effects such as heaviness in the stomach, dull epigastric pain, nausea and vomiting, gastric perforation or intestinal obstruction, ulceration, gastrointestinal bleeding, dumping syndrome, metabolic complications associated with inadequate protein intake , minerals and vitamins, cholelithiasis, as well as the development of reflux esophagitis, bleeding from the hilum of the spleen or the suture line, the eruption of the staple suture, which can lead to serious health consequences requiring surgery, anastomoses incompetence, and, in addition, death is possible (for example, with biliopancreatic shunting, the percentage of deaths can be about 8%) [7]. Thus, despite the numerous types of surgical operations developed for obesity, almost all operations have significant disadvantages and side effects of varying severity, there are also a number of individual contraindications for such operations. The main reason for obese people turning to surgical methods of treatment is that the majority (up to 95%) of patients cannot achieve and then maintain a clinically significant decrease in body weight, and in severe obesity, the effectiveness of conservative therapy does not exceed 5-10%. The most common reasons that prevent people from achieving significant weight loss are the wrong, independent choice of a diet that does not provide the body with the necessary amount of nutrients, which leads to difficulties in adherence and the presence of stressful situations in which most people eat high-calorie foods and drinks, and may abuse alcohol. The preparation of a diet for the treatment of obesity and overweight should be done together with specialists - an endocrinologist, nutritionist, physiotherapist and psychologist, since it must be complete, balanced and contain all the components necessary for the body (proteins, carbohydrates, fats, trace elements and vitamins ), and it is also necessary to take into account the individual characteristics of the organism, including hormonal imbalance. A psychologist's consultation is carried out in order to create the patient's correct psychological mood to change his lifestyle (proper nutrition, which must be observed throughout the patient's life, and physical activity necessary to maintain the body in a healthy state). To facilitate the patient's adaptation to a new lifestyle, it is possible to prescribe nootropic drugs, which is especially important if the patient is exposed to numerous stressful situations and abuses alcohol. Also, in combination with a diet, for the treatment of obesity and overweight, experts prescribe biologically active additives and drugs that reduce appetite (anorexigenic drugs) [8, 9].

Thus, a comprehensive and effective treatment for obesity should include correct, balanced nutrition, physical activity, and at the initial stage of treatment and, if necessary (for example, if the patient starts to eat and gain weight again, or in case of alcohol abuse ) - the appointment of anorexigenic and nootropic drugs, and the most preferable is the combination of nootropic and anorexigenic activity in one drug.

Phenylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) has long and firmly established itself as an effective drug for the treatment of diseases of the central nervous system of various origins, especially those associated with intoxication, accompanied by a deterioration in intellectual and mnestic functions, a decrease in motor activity; treatment of neurotic conditions, manifested by lethargy, increased exhaustion, decreased psychomotor activity, impaired attention, memory impairment; treatment of learning disorders; treatment of psychoorganic syndromes, manifested by intellectual-mnestic disorders and apathic-abulic phenomena, as well as sluggish conditions in schizophrenia; treatment of convulsive conditions; treatment of obesity of alimentary-constitutional genesis; prevention of hypoxia, increasing resistance to stress; correction of the functional state of the body in extreme conditions of professional activity in order to prevent the development of fatigue and to increase mental and physical performance; correction of daily biorhythm, with inversion of the sleep-wake cycle; for the treatment of chronic alcoholism (in order to reduce the phenomena of asthenia, depression, intellectual-mnestic disorders, relief of the "withdrawal symptom") [10].

N-carbamoylmethyl-4-phenyl-2-pyrrolidone (fonturacetam)

Phenylpiracetam increases the resistance of brain tissue to hypoxia and toxic effects, has anxiolytic activity [11]; has a positive effect on metabolic processes, stimulates redox processes, increases the energy potential of the body due to the utilization of glucose [12]; increases the content of noradrenaline, dopamine and serotonin in the brain, does not affect the level of GABA, does not bind to GABA _A and GABA _B receptors, does not significantly affect the spontaneous bioelectric activity of the brain; exhibits a moderately pronounced stimulating effect, manifested in relation to motor reactions, an increase in physical performance, a pronounced antagonism to the cataleptic action of neuroleptics, as well as a weakening of the severity of the hypnotic effect of ethanol and hexobarbital; shows an adaptogenic effect in increasing the body's resistance to stress under conditions of excessive mental and physical stress, with fatigue, hypokinesia and immobilization, at low temperatures; stimulates the production of antibodies in response to the introduction of an antigen, which indicates immunostimulating properties, but at the same time does not contribute to the development of immediate hypersensitivity and does not change the allergic inflammatory response of the skin caused by the introduction of a foreign protein; does not possess teratogenic, mutagenic, carcinogenic and embryotoxic properties; has low toxicity [10].

The nootropic effect of the drug is combined with anxiolytic activity, it has some analgesic effect, increasing the threshold of pain sensitivity. While taking the drug, an improvement in vision was also noted, which manifests itself in an increase in acuity, brightness and fields of vision [10].

When used as a course, phenylpiracetam has a pronounced anorexigenic effect [10]. At the same time, the nootropic effects of phonylpiracetam make it possible to create a favorable psychological climate in the patient, facilitating the adaptation of the patient to a healthy lifestyle, increase the patient's resistance to stress in conditions of excessive mental and physical stress, with fatigue, hypokinesia and immobilization, which reduces the likelihood of relapses, expressed in the use of high-calorie and fatty foods and drinks, alcohol abuse and the possible minimization of physical activity. In this connection, it is obvious to the person skilled in the art that phenylpiracetam can be used as an adjunct to a balanced diet and physical activity for long-term use in order to correct body weight for the treatment of obesity or overweight caused by diseases of the endocrine system, nutritional disorders, metabolic disorders substances, mental disorders and / or conduct disorders.

Known analogues of fonturacetam 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid and ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, which are activators of cognitive functions [13].

Also known is the compound 4-phenylpyrrolidone-2, which is structurally related to fonturacetam, but its biological activity has not been described.

The inventors of the present invention have surprisingly discovered that novel formulations comprising phonylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and at least one additional compound selected from the group consisting of 4-phenylpyrrolidone-2, 2- (2 -oxo-4-phenylpyrrolidin-1-yl) acetic acid and ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, have better properties than the substance-powder fonturacetam currently used in the pharmaceutical industry , and selected by the authors of the present invention as a prototype.

2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid

ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate

4-phenylpyrrolidone-2

The following are definitions of terms that are used in the description of the present invention.

"Medicinal principle" (drug substance, drug substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, which has pharmacological activity and is the active principle of a pharmaceutical composition used for the production and manufacture of a drug (means ).

"Drug (preparation)" - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other ready-made forms, intended for the restoration, correction or change of physiological functions in humans and animals, as well as for treatment and disease prevention, diagnostics, anesthesia, contraception, cosmetology and others.

"Pharmaceutical composition" means a composition comprising a novel composition of N-carbamoyl-methyl-4-phenyl-2-pyrrolidone and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, dispensing agents, delivery vehicles such as preservatives, stabilizers, fillers, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavorings, antibacterial agents, fungicides, lubricants, sustained delivery regulators, selection and the ratio of which depends on their nature, method of administration of the composition and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as other pharmaceutically acceptable surfactants, and mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents, such as benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, chlorobutanol, sorbic acid, parabens, alkyl pyridinium, benzethonium and their pharmaceutically acceptable salts and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided by agents that delay the absorption of the active principle, for example, such as hydrophilic polymer release agents, for example, cellulose derivatives, polyethylene oxide, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, alginates, carbomers, hydrophobic release retardants such as glycerolate, aluminum monostearate. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, buffers, as well as mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, microcrystalline cellulose, sodium citrate, calcium carbonate, calcium phosphate, and the like. For pH adjustment, various organic and inorganic acids can be used, such as malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids. Examples of dispersing agents and distributing agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, colloidal silicon dioxide, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical or rectal administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, as a mixture with traditional pharmaceutical carriers. Suitable unit forms of administration include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

"Pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of acids and bases as claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation, or purification of compounds, or they can be specially prepared. In particular, base salts can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of the salts obtained in this way are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like [14]. Salts of the claimed acids can also be specially prepared by reacting a purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metallic salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be derived are sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are basic enough to form a stable salt and are suitable for medical use (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane, and the like. In addition, tetraalkylammonium hydroxides such as choline, tetramethylammonium, tetraethylammonium, and the like can be used for salt formation. The basic amino acids, lysine, ornithine and arginine, can be used as amino acids.

The objective of the present invention is to develop a storage-stable, non-hygroscopic, readily soluble, economically feasible, commercially available, preparative composition of fonturacetam (N-carbamoyl-methyl-4-phenyl-2-pyrrolidone) for the treatment and / or prevention of obesity or overweight.

The stability in the solid state and the shelf life of the active ingredients are very important factors. The drug compound and compositions containing it must be able to be stored for significant periods of time without exhibiting a significant change in the physicochemical properties of the active component (for example, its chemical composition, density, hygroscopicity and solubility).

Thus, the inventors have surprisingly found that the presence of 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl ) acetate, or their optical isomers and pharmaceutically acceptable salts, in the fonpiracetam substance improves some properties of the fonpiracetam substance, such as stability, dissolution rate, and reduces hygroscopicity. In this case, the presence of 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, or their optical isomers and pharmaceutically acceptable salts in the composition according to the present invention not only does not lead to a decrease in the activity of fonturacetam (prototype), but, on the contrary, can increase the pharmaceutical activity of the fonturacetam substance. The new formulations containing phonylpiracetam according to the present invention do not lead to the development of immediate hypersensitivity and do not change the allergic inflammatory response of the skin caused by the introduction of a foreign protein; do not possess teratogenic, mutagenic, carcinogenic and embryotoxic properties; have low toxicity. In this connection, the new compositions containing phonylpiracetam according to the present invention can be used for the treatment and / or prevention of obesity, as an anorexigenic and nootropic agent, for the treatment and prevention of toxic and psychological effects caused by alcohol abuse (in order to reduce the phenomena of asthenia, intellectual and mnestic disorders, relief of the "withdrawal syndrome").

Technical results of the present invention:

- increased stability (storage time) of the composition according to the present invention in comparison with the prototype;

- increasing the rate of dissolution of the composition in comparison with the prototype;

- a decrease in the hygroscopicity of the composition in comparison with the prototype;

- expanding the arsenal of drugs with anorexigenic activity for the treatment and prevention of obesity or overweight;

- increasing the activity of the claimed composition in comparison with the prototype.

The problem is solved, and the technical result is achieved by creating a composition for the treatment and / or prevention of obesity with anorexigenic activity, including N-carbamoylmethyl-4-phenyl-2-pyrrolidone (phonylpiracetam) and at least one additional compound selected from the group including 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate and / or their optical isomers and / or their pharmaceutically acceptable salts, said composition comprising 4-phenylpyrrolidone-2 in an amount of 0.25% to 20.00%, and / or 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of not more than 20.00% wt and / or ethyl-2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of not more than 20.00% wt.

According to preferred embodiments, the specified technical result is also achieved in that:

- the additional compound is 4-phenylpyrrolidone-2 in an amount of 0.25 to 1.00 wt%;

- the above composition contains 4-phenylpyrrolidone-2 in an amount from 0.30 to 0.60% by weight;

- the above composition contains 4-phenylpyrrolidone-2 in an amount from 0.50 to 0.60% by weight;

- the additional compound is 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of 0.01 to 1.00 wt%;

- the above composition contains 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount from 0.10 to 0.50 wt%;

- the above composition contains 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount from 0.10 to 0.20 wt%;

- the additional compound is ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of 0.01 to 1.00% by weight;

- said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of 0.10 to 0.50% by weight;

- the above composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount from 0.10 to 0.20% wt.

The stated task is also achieved, and the technical result is achieved by creating a pharmaceutical composition for the treatment and / or prevention of obesity, and the said composition contains in a therapeutically effective amount any of the above composition and at least one pharmaceutically acceptable carrier.

The task is also achieved, and the technical result is achieved by creating a medicament for the treatment and / or prevention of obesity, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, and the said agent contains in a therapeutically effective amount any of the above composition or the above pharmaceutical composition.

The subject of the present invention is a composition for the treatment and / or prevention of obesity or overweight, comprising N-carbamoylmethyl-4-phenyl-2-pyrrolidone (fonturacetam) and at least one additional compound selected from the group consisting of 4-phenylpyrrolidone-2 , 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate and / or their optical isomers and / or their pharmaceutically acceptable salts , wherein said composition contains 4-phenylpyrrolidone-2 in an amount of 0.25% to 20.00%, and / or 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of not more than 20.00 % wt and / or ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of not more than 20.00% wt.

More preferred is a composition characterized in that the additional compound is 4-phenylpyrrolidone-2 in an amount of 0.25 to 1.00% by weight.

More preferred is a composition characterized in that said composition contains 4-phenylpyrrolidone-2 in an amount of 0.30 to 0.60% by weight.

More preferred is a composition characterized in that said composition contains 4-phenylpyrrolidone-2 in an amount of 0.50 to 0.60% by weight.

More preferred is a composition characterized in that the additional compound is 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of 0.01 to 1.00 wt%.

More preferred is a composition characterized in that said composition contains 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount from 0.10 to 0.50 wt%.

More preferred is a composition characterized in that said composition contains 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount from 0.10 to 0.20 wt%.

More preferred is a composition characterized in that said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of 0.01 to 1.00 wt%.

More preferred is a composition characterized in that said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of 0.10 to 0.50 wt%.

More preferred is a composition characterized in that said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of 0.10 to 0.20 wt%.

More preferred is a composition characterized in that said composition contains phonylpiracetam in an amount of more than 96.00% by weight.

More preferred is a formulation wherein the obesity or overweight is primary obesity or overweight.

More preferable is a composition characterized in that obesity or overweight is obesity or overweight of alimentary-constitutional origin.

More preferred is a composition characterized in that it is intended for the treatment of obesity or overweight caused by diseases of the endocrine system, nutritional disorders and / or metabolic disorders.

More preferred is a composition characterized in that it is intended for the treatment of obesity or overweight caused by at least one disease selected from the group consisting of thyroid diseases, diabetes mellitus, glucose regulation disorders, endocrine gland endocrine disorders, malnutrition , overnutrition, metabolic disorders, mental and behavioral disorders, obesity or overweight caused by medication.

It is also a subject of the present invention to provide a pharmaceutical composition for the treatment and / or prevention of obesity or overweight, which contains a therapeutically effective amount of said composition comprising fonpiracetam and at least one additional compound selected from the group comprising 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate and their optical isomers and pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients is meant diluents, auxiliary agents and / or carriers used in the pharmaceutical field. A pharmaceutical composition along with a composition comprising phonylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and at least one additional compound selected from the group consisting of 4-phenylpyrrolidone-2, 2- (2-oxo-4 -phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate and their optical isomers and pharmaceutically acceptable salts, according to the present invention may include other active substances, including are active, provided that they do not cause undesirable effects.

If necessary, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with conventional pharmaceutical carriers.

The carriers used in the pharmaceutical compositions of the present invention are those used in the pharmaceutical field to produce common forms, in particular, in oral forms binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, flavoring agents are used. ; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

The subject of the present invention is also a medicament for the treatment and / or prevention of obesity or overweight, in the form of tablets, capsules or solution for injection, placed in a pharmaceutically acceptable package, containing in a therapeutically effective amount a composition comprising phonylpiracetam and at least one additional compound selected from the group consisting of 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate and optical isomers and pharmaceutically acceptable salts thereof; or the pharmaceutical composition of the present invention.

Medicines can be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally, or topically). The clinical dosage of the agent containing the new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone according to the present invention in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, the rate of their metabolism and excretion from the body, as well as depending on on the age, sex and stage of the patient's disease, while the daily dose in adults is usually 10-500 mg, preferably 50-300 mg. Therefore, during the preparation of the drug of the present invention from the pharmaceutical composition in the form of dosage units, it is necessary to take into account the above effective dosage, while each dosage unit of the drug should contain 10-500 mg of the new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone according to the present invention preferably 50-300 mg. As directed by your doctor or pharmacist, these drugs can be taken several times over specific periods of time (preferably one to six times).

The subject of the present invention is also a finished dosage form for the treatment and / or prevention of obesity or overweight, in the form of tablets, capsules or solution for injection, placed in a pharmaceutically acceptable package, containing in a therapeutically effective amount a composition comprising phonylpiracetam and at least , one additional compound selected from the group consisting of 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl ) acetate and their optical isomers and pharmaceutically acceptable salts, the pharmaceutical composition of the present invention or the medicament of the present invention.

The subject of the present invention is also the use of the composition according to the present invention for the treatment and / or prevention of obesity or overweight.

The subject of the present invention is also the use of a pharmaceutical composition according to the present invention, a medicament according to the present invention or a finished dosage form according to the present invention for the treatment and / or prevention of obesity or overweight.

The subject of the present invention is also a method for the treatment and / or prevention of obesity or overweight, comprising administering to a patient having said obesity or overweight a pharmaceutical composition of the present invention, a medicament of the present invention, or a finished dosage form of the present invention.

The following examples of implementation of the inventions illustrate, but do not limit the claimed group of inventions.

Example 1. Obtaining fonturacetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone).

The synthesis of the target product was carried out according to the method [15], in which the ability of N-alkylated esters of 4-aminobutyric acid to cyclize to N-alkylpyrrolidin-2-ones was used.

To a solution of 7.50 g (27.6 mmol) of 4-amino-3-phenylbutyric acid n-butyl ester hydrochloride and 5.61 g (30.3 mmol) of iodoacetamide in 150 ml of DMF were added 19.07 g (82.8 mmol) K ₃ PO ₄ · H ₂ O and 10 g of molecular sieves ₄ Å. The resulting suspension was stirred at room temperature for 24 h, filtered, the filtrate was evaporated to dryness in a vacuum.

To carry out cyclization, the n-butyl ester of 4-carbamoylmethylamino-3-phenylbutyric acid obtained in the residue was dissolved in 150 ml of toluene, 2 g (8.68 mmol) of K ₃ PO ₄ H ₂ O and 0.05 g (0 , 15 mmol) Bu ₄ NBr. The suspension was boiled for 2 hours under reflux, cooled, filtered, the filtrate was evaporated to dryness, the precipitate was washed with desalted water cooled to a temperature of 0 to 5 ° C. Next, wet N-carbamoylmethyl-4-phenyl-2-pyrrolidone was dried at a temperature of 60 to 65 ° C until the loss in weight on drying was no more than 0.5%. The final product was purified from impurities by column chromatography. Yield 3.55 g (63%). T. pl. for the racemic product 129–130 ° C.

Example 2. Determination of the content of 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid and ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in the composition of fonturacetam ...

The composition of fonturacetam was investigated for the content of 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid and ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate by HPLC with using standards.

Mobile phase (PF) A. 1.0 ml of trifluoroacetic acid was placed in a volumetric flask with a capacity of 1000 ml, 500 ml of water for chromatography was added and stirred, then the volume of the solution was brought to the mark with water for chromatography and degassed in any convenient way.

The shelf life of the solution is 1 month.

Mobile phase (PF) B. Acetonitrile for chromatography.

Test solution. About 750 mg (accurately weighed) of the powder of the fonturacetam substance was placed in a volumetric flask with a capacity of 250 ml, dissolved in 150 ml of water for chromatography, placed in an ultrasonic bath and kept for 5 min. Then, after cooling to room temperature, the volume of the solution was brought to the mark with water for chromatography and stirred. The resulting solution was filtered through a membrane filter with a pore diameter of 0.45 μm, discarding the first 2 ml of filtrate.

Standard solution (a). About 25 mg (accurately weighed) of a standard sample of fonturacetam was placed in a 25 ml volumetric flask and dissolved in 15 ml of water for chromatography, the volume of the solution was brought to the mark with the same solvent and mixed.

Standard solution (b). 1.0 ml of the standard solution (a) was placed in a 25 ml volumetric flask, the volume of the solution was brought up to the mark with water for chromatography and stirred. Then 1.0 ml of the resulting solution was placed in a volumetric flask with a capacity of 20 ml, the volume of the solution was brought to the mark with water for chromatography and stirred.

Table 1. Chromatographic conditions

Column 75 × 4.6 mm, filled with С ₁₈ sorbent, 2.6 μm (Kinetex 2.6u C18 110A, Phenomenex, USA) Flow rate 1.2 ml / min Column temperature 30 ° C Detector spectrophotometric, 260 nm Injected sample volume 50 μl

Elution was carried out in a gradient mode in accordance with Table 1.

Table 2. Elution conditions

Time (min) PF A (v / v%) PF B (v / v%) 0 - 1 90 ten 18 90 → 10 10 → 90 8 - 11 ten 90 11 - 12 10 → 90 90 → 10 12 - 15 90 ten

The standard solution (b) was chromatographed at least 5 times. The chromatogram registration time is 8 min. All peaks were clearly visible. The retention time of the peak of fonturacetam is about 4.0 minutes. The retention time of the 4-phenylpyrrolidone-2 peak relative to the fonturacetam peak is about 1.9, the 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid peak is about 1.6 and the ethyl-2- (2-oxo -4-phenylpyrrolidin-1-yl) acetate - about 2.4.

The test solution and the standard solution were chromatographed to obtain at least 3 chromatograms. In this case, the peaks whose areas were less than 30% of the peak area of fonturacetam in the chromatogram of the standard solution (b) were not taken into account.

Example 3. Obtaining samples of phonylpiracetam containing additional compounds.

Samples of the composition of fonturacetam containing 4-phenylpyrrolidone-2 0.25%, 0.3%, 0.5%, 0.6%, 1.0% and 20.0% wt. were obtained from the sample obtained in example 1 by adding to the sample the calculated amount of 4-phenylpyrrolidone-2 and thoroughly mixing the resulting composition.

Samples of the composition of fonturacetam containing 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid 0.01%, 0.6%, 1.0% and 20.0% wt. were obtained from the sample obtained in example 1 by adding to the sample the calculated amount of 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid and thoroughly mixing the resulting composition.

Samples of the composition of fonturacetam containing ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate 0.01%, 0.6%, 1.0% and 20.0% wt. were obtained from the sample obtained in example 1 by adding to the sample the calculated amount of ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate and thoroughly mixing the resulting composition.

Example 4. Determination of the kinetics of dissolution of new formulations, including fonpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 4-phenylpyrrolidone-2, fonturacetam and 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid , and fonturacetam and ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate.

The dissolution kinetics of the new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, obtained in example 3, was evaluated by the content of the substance N-carbamoylmethyl-4-phenyl-2-pyrrolidone and compared with the dissolution kinetics of the prototype. The instrument for determining the rate of dissolution was a three-necked vessel with a capacity of 1 liter. A thermometer was inserted into one of the tubes, a glass tube for taking samples and their integration into the other, and into the third - the main part of the device - a cylindrical basket 3.6 cm high and 2.5 cm in diameter, made of stainless steel in the form of a mesh with holes 40 mesh diameter (about 0.351 mm). The basket was mounted on the motor shaft.

A dissolving medium (1000 ml) was poured into the vessel, which in this experiment was an alkaline solution of pancreatin, which corresponds to the human saliva medium and is important for determining the solubility of sublingual (orodisperse) dosage forms. The test sample was placed in a cylindrical basket, which was placed at a distance of 2 cm from the bottom of the vessel.

The temperature of the dissolving medium during the experiment was kept constant (37 ± 0.5 ° C). The speed of rotation of the basket in the medium was controlled with an accuracy of ± 5%; it was 200 rpm. At set time intervals, samples of 1-2 ml were taken for analysis to determine the content of the solute. The taken volume of the solvent was immediately replaced with a new one. Dissolution was monitored for the selected component, N-carbamoylmethyl-4-phenyl-2-pyrrolidone.

For Comparative Samples 1-4, 200 mg of a new formulation was used, including phonylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 0.25%, 0.6%, 1.0% and 20.0% by weight. 4-phenylpyrrolidone-2, respectively, and for comparative sample 5 - 200 mg of the prototype.

For Comparative Samples 6-9, 200 mg of a new formulation was used, including phonylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 0.01%, 0.6%, 1.0% and 20.0% by weight. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, respectively.

For comparative samples 10-13, 200 mg of a new formulation was used, including fontyracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 0.01%, 0.6%, 1.0% and 20.0% wt. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, respectively.

The temperature of the dissolving medium during the experiment was kept constant (37 ± 0.5 ° C). The speed of rotation of the basket in the medium was controlled with an accuracy of ± 5%; it was 200 rpm. At set time intervals, samples of 1–2 ml were taken for analysis to determine the drug substance content. The taken volume of the solvent was immediately replaced with a new one.

The results obtained as a percentage of the dissolved active substance from the maximum concentration are shown in tables 3-5.

Table 3. Kinetics of dissolution of N-carbamoylmethyl-4-phenyl-2-pyrrolidone with 4-phenylpyrrolidone-2

Time, sec Concentration in solution, in% of the maximum theoretical concentration Sample 1,% Sample 2,% Sample 3,% Sample 4,% Sample 5,%
(prototype) 0 0 0 0 0 0 ten 18.0 17.9 18,7 19.9 18.0 thirty 30.1 34.9 36.1 38.2 28.8 60 39.9 41.2 43.0 45.1 35.6 300 60.8 67.3 72.1 77.5 53.0 600 87.4 98.5 100.0 100.0 75.4 900 97.4 100.0 100.0 100.0 89.2 1200 100.0 100.0 100.0 100.0 100.0

Table 4. Kinetics of dissolution of N-carbamoylmethyl-4-phenyl-2-pyrrolidone with 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid

Time, sec Concentration in solution, in% of the maximum theoretical concentration Sample 6,% Sample 7,% Sample 8,% Sample 9,% Sample 5,%
(prototype) 0 0 0 0 0 0 ten 19.5 20.5 21.8 20.9 18.0 thirty 32.0 37.9 38.1 39.2 28.8 60 44.5 43.2 45.0 47.1 35.6 300 63.6 71.3 77.2 79.7 53.0 600 89.8 99.9 100.0 100.0 75.4 900 98.7 100.0 100.0 100.0 89.2 1200 100.0 100.0 100.0 100.0 100.0

Table 5. Kinetics of dissolution of N-carbamoylmethyl-4-phenyl-2-pyrrolidone with ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate

Time, sec Concentration in solution, in% of the maximum theoretical concentration Sample 10,% Sample 11,% Sample 12,% Sample 13,% Sample 5,%
(prototype) 0 0 0 0 0 0 ten 19.0 19.9 19.7 20.5 18.0 thirty 31.5 35.9 37.1 40.2 28.8 60 40.7 42.2 46.0 49.5 35.6 300 61.9 68.3 78.1 80.0 53.0 600 88.5 98.9 100.0 100.0 75.4 900 98.2 100.0 100.0 100.0 89.2 1200 100.0 100.0 100.0 100.0 100.0

The results indicate that the dissolution rate of the new formulations of N-carbamoylmethyl-4-phenyl-2-pyrrolidone is higher than the dissolution rate of the prototype. In particular, the time during which 50% dissolution of the new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone occurs is statistically significantly shorter than for the comparative prototype sample, which can be especially useful for obtaining tablets in orodisperse form.

Example 5. Study of stability during storage of a new composition.

The stability of the new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, obtained in example 3, was evaluated by the content of the substance and compared with the stability of the prototype by the accelerated aging method.

All samples were stored in glass vials, sealed with rubber stoppers with aluminum caps, in a climatic chamber under accelerated testing conditions. The active substance content was determined by HPLC using standards.

The "accelerated aging" method consists in keeping the tested medicinal product at temperatures and humidity higher than the temperature and humidity of its storage during circulation. At elevated temperatures, as a rule, physical and chemical processes occurring in drugs are accelerated, leading over time to undesirable changes in quality. Thus, at an elevated temperature, the period of time during which the controlled quality parameters of the medicinal product remain within acceptable limits (experimental shelf life) is artificially reduced in comparison with the shelf life at the storage temperature. This significantly reduces the time required to establish an expiration date.

According to the results obtained in the process of "accelerated aging" of the drug, it is also possible to solve the inverse problem, i.e. set the storage temperature to a specified shelf life.

The shelf life (C) at storage temperature (tx) is related to the experimental shelf life (SE) at an elevated experimental storage temperature (te) by the following relationship:

,

,

.where the match factor

...

The temperature coefficient of the rate of chemical reaction (A) is assumed to be 2.5. The given dependence is based on the Van't Hoff rule about a 2-4-fold increase in the rates of chemical reactions with an increase in temperature by 10 ° C.

), равного 30℃, составляет 15,6. Срок экспериментального хранения при выбранном сроке годности 3 года составляет 71 сутки.In accordance with the general pharmacopoeial monograph of the General Pharmacopoeia Monograph 1.1.0009.15, the value of the conformity coefficient (K) depending on the selected temperature range (

) equal to 30 ℃ is 15.6. The experimental storage period for a selected shelf life of 3 years is 71 days.

Statistical processing of the parameters and presentation of the study results were carried out in accordance with the Rules of Good Clinical Practice of the Eurasian Economic Union using the statistical package SPSS Statistics 19.0.

It is shown that the new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone according to the invention, namely: 0.25%, 0.6%, 1.0% and 20.0% wt. 4-phenylpyrrolidone-2 (samples 1-4, respectively), 0.01%, 0.6%, 1.0% and 20.0% wt. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid (samples 6-9, respectively), and 0.01%, 0.6%, 1.0% and 20.0% wt. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate (samples 10-13, respectively), have a statistically significantly increased storage stability compared to the prototype. The results are shown below in Tables 6-8.

It was found that after 71 days of storage under the conditions of the accelerated aging method, the new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone according to the present invention have a statistically significantly increased stability. The prototype substance remains stable for less than 10 days, then the content of N-carbamoylmethyl-4-phenyl-2-pyrrolidone decreases by more than 4%. That is, the new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone according to the present invention are significantly more stable during storage compared to the prior art.

Table 6. Evaluation of the stability of the composition with 4-phenylpyrrolidone-2 by the method of accelerated aging in comparison with the prototype

Storage time at (t _e -t _xp ) = 30 ^о С, day The amount of active ingredient found by HPLC data in% of theoretical content Sample 1 Sample 2 Sample 3 Sample 4 Prototype 0 100.0 100.0 100.0 100.0 100.0 ten 99.9 100.0 100.0 100.0 99.9 20 99.8 99.9 100.0 100.0 99.5 thirty 99.7 99.9 100.0 100.0 99.2 40 99.6 99.9 99.9 99.9 98.7 50 99.4 99.8 99.9 99.9 98.2 60 99.2 99.7 99.7 99.7 97.5 71 99.0 99.5 99.6 99.7 95.9

Table 7. Evaluation of the stability of the composition with 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid by the method of accelerated aging in comparison with the prototype

Storage time at (t _e -t _xp ) = 30 ^о С, day The amount of active ingredient found by HPLC data in% of theoretical content Sample 6 Sample 7 Sample 8 Sample 9 Prototype 0 100.0 100.0 100.0 100.0 100.0 ten 99.9 100.0 100.0 100.0 99.9 20 99.8 99.9 100.0 100.0 99.5 thirty 99.7 99.9 100.0 100.0 99.2 40 99.6 99.9 99.9 99.9 98.7 50 99.4 99.8 99.9 99.9 98.2 60 99.2 99.7 99.8 99.8 97.5 71 99.1 99.6 99.7 99.8 95.9

Table 8. Evaluation of the stability of the composition with ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate by the method of accelerated aging in comparison with the prototype.

Storage time at (t _e -t _xp ) = 30 ^о С, day The amount of active ingredient found by HPLC data in% of theoretical content Sample 10 Sample 11 Sample 12 Sample 13 Prototype 0 100.0 100.0 100.0 100.0 100.0 ten 99.9 100.0 100.0 100.0 99.9 20 99.8 99.9 100.0 100.0 99.5 thirty 99.7 99.9 100.0 100.0 99.2 40 99.5 99.8 99.9 99.9 98.7 50 99.3 99.7 99.8 99.8 98.2 60 99.2 99.5 99.6 99.7 97.5 71 99.1 99.3 99.5 99.6 95.9

Example 6. Determination of hygroscopicity.

The reduced hygroscopicity is a great advantage of the new formulations of N-carbamoylmethyl-4-phenyl-2-pyrrolidone in the preparation and storage of the substance.

The hygroscopicity was evaluated by storing the solid compound in chambers with constant relative humidity at room temperature for 96 hours. Comparison of anhydrous new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone with a content of 0.25%, 0.6%, 1.0% and 20.0% wt. 4-phenylpyrrolidone-2 (samples 1-4, respectively), 0.01%, 0.6%, 1.0% and 20.0% wt. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid (samples 6-9, respectively), and 0.01%, 0.6%, 1.0% and 20.0% wt. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate (Samples 10-13, respectively) and the prototype at room temperature showed that the prototype was hygroscopic and showed a large increase in humidity starting at 60% RH. The new formulations of N-carbamoylmethyl-4-phenyl-2-pyrrolidone did not show any significant increase in humidity except when stored at a relative humidity above 90%. The results are shown in Tables 9-11 below.

Table 9. Evaluation of hygroscopicity at room temperature (96 hours) of the composition with 4-phenylpyrrolidone-2 in comparison with the prototype

Relative humidity,% Moisture gain,% Sample 1 Sample 2 Sample 3 Sample 4 Prototype 0 0.0 0.0 0.0 0.0 0.0 15 0.0 0.0 0.0 0.0 0.0 thirty 0.1 0.0 0.0 0.0 0.2 45 0.1 0.1 0.0 0.0 0,4 60 1.3 0,4 0.1 0.1 2.0 75 2.9 0.9 0,4 0.3 5.5 90 6.9 3.7 2.8 2.6 12.1 one hundred 9.0 5.6 5.1 4.9 16.5

Table 10. Evaluation of hygroscopicity at room temperature (96 hours) of the composition with 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in comparison with the prototype

Relative humidity,% Moisture gain,% Sample 6 Sample 7 Sample 8 Sample 9 Prototype 0 0.0 0.0 0.0 0.0 0.0 15 0.0 0.0 0.0 0.0 0.0 thirty 0.1 0.0 0.0 0.0 0.2 45 0.3 0.2 0.0 0.0 0,4 60 1.5 1.4 0.5 0,4 2.0 75 3.9 2.0 0.6 0.5 5.5 90 7.5 4.5 3.8 3.5 12.1 one hundred 9.5 6.5 5.7 5.5 16.5

Table 11. Evaluation of hygroscopicity at room temperature (96 h) of the composition with ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in comparison with the prototype

Relative humidity,% Moisture gain,% Sample 10 Sample 11 Sample 12 Sample 13 Prototype 0 0.0 0.0 0.0 0.0 0.0 15 0.0 0.0 0.0 0.0 0.0 thirty 0.1 0.0 0.0 0.0 0.2 45 0.2 0.1 0.0 0.0 0,4 60 1.4 1,2 0.3 0.2 2.0 75 3.3 2.5 0.7 0.5 5.5 90 7.2 4,3 3.7 3.5 12.1 one hundred 9.2 5.9 5.5 5.0 16.5

Example 7. Investigation of the general toxic effect of new compositions, including phonylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 20.0% wt. 4-phenylpyrrolidone-2, phonylpiracetam and 20.0% wt. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, and phonylpiracetam and 20.0% wt. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate.

Objective of the study: determination of tolerable, toxic and lethal doses and causes of death of animals, assessment of the degree of damaging effect of the drug during its long-term administration on small laboratory animals, identification of the most sensitive organs and body systems and study of the degree of reversibility of the caused damage

Acute toxicity study:

Materials and methods:

Study of acute toxicity of the claimed composition containing phonylpiracetam and 20.00% wt. 4-phenylpyrrolidone-2, with a single intragastric administration, was carried out on 20 white nonlinear male mice weighing 18-20 g, kept under standard vivarium conditions with free access to water and food. The doses of the drug were tested at 180, 250, 320 and 390 mg (according to fonturacetam) / kg of body weight. The general condition of the animals was assessed for 14 days. The toxicity of the drugs was judged by the death of animals and the general picture of intoxication. Statistical analysis was performed using Statistica 6.0 software.

The acute toxicity parameters gave the following results:

DL50 = 418 mg / kg, DL16 = 334 mg / kg, DL84 = 581 mg / kg.

Thus, according to the parameters of acute toxicity according to the classification of Hodge and Sterner (1943), the investigated drug can be classified as moderately toxic compounds.

Subchronic toxicity of the preparation was studied on 25 white nonlinear male rats weighing 168-229 g kept under standard vivarium conditions with free access to water and food. For 30 days, the study drug was administered intragastrically to the animals of the experimental groups for 30 days, once a day at doses of 6 and 60 mg (according to phonylpiracetam) / kg of body weight in the form of a suspension in 2% starch gel, which, respectively, is equal and 10 times higher than the therapeutic the dose for a person, taking into account the interspecies conversion. After the end of the experiment, all animals were sacrificed for further pathomorphological examination of internal organs and tissues.

The local irritant effect was assessed by macroscopic and microscopic examination of the injection sites - the gastrointestinal tract.

Statistical comparison of the experimental and control groups was carried out according to the Student's t-test.

Results.

In the groups of animals that received intragastrically suspensions of the study drug at a dose of 60 mg / kg, there was a tendency to a decrease in the rate of weight gain. The studied drug at doses of 6 and 60 mg / kg did not cause deviations in biochemical and hematological parameters. There was no change in daily urine output for the groups of animals that received the experimental drug in relation to the group of control animals that received intragastrically 2% starch gel in the same volume.

Pathomorphological and microscopic examination of the internal organs indicated the absence in the tested doses of pronounced signs of the toxic effect of the drug on the internal organs, but indicated a possible manifestation of its local irritating effect on the gastric mucosa after 30 days of intragastric administration at a dose 10 times higher than the therapeutic dose, taking into account the interspecific conversion doses.

Compositions including fonturacetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 20.0% wt. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, and phonylpiracetam and 20.0% wt. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate.

In the course of the study, it was found that new formulations according to the present invention, including fonpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 4-phenylpyrrolidone-2, fonturacetam and 2- (2-oxo-4-phenylpyrrolidine-1- yl) acetic acid, and fonturacetam and ethyl-2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, do not show mutagenic properties in experiments on fruit flies, do not have allergenicity, do not have reproductive toxicity.

Example 8. Obtaining a medicinal product in the form of tablets.

1600 mg of starch, 1600 mg of chopped lactose, 400 mg of talc and 1000 mg of the fonturacetam formulation according to the present invention containing 0.6 wt% 4-phenylpyrrolidone-2 were mixed and compressed into a bar. The resulting bar was crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The resulting granules were tableted into a suitable tablet form, each weighing 560 mg.

Example 9. Obtaining a medicinal product in the form of sustained-release tablets.

In the unit for granulation and drying by fluidization technology was loaded sieved low viscosity hydroxypropyl methylcellulose and the fonpiracetam composition according to the present invention, containing 0.1 wt.% 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid and 0.1 wt. % ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate and started the granulation process using water as a humidifier. The drying process was continued until reaching the "loss in weight on drying" value of 2.0 ± 0.5%.

At the end of the granulation process, the resulting dry granulate was calibrated through a metal sieve with a hole diameter of 0.8 mm.

A drum mixer was charged with screened microcrystalline cellulose, calibrated granulate and screened lactose. Stirred for 2-4 minutes. Then loaded sifted talc, colloidal silicon dioxide, mixed for 2-3 minutes, then loaded sifted magnesium stearate, high viscosity hydroxypropyl methylcellulose, and mixed for 1-2 minutes.

The tablet mass was compressed on a rotary press using round punches (deep sphere) with a diameter of 8.0 ± 0.2 mm.

Example 10. Obtaining a medicinal product in the form of capsules.

Thoroughly mixed the composition of fonturacetam according to the present invention, containing 20% wt.% Ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, with lactose powder in a ratio of 2 to 1. The resulting powder mixture was packed in 300 mg gelatin capsules of a suitable size.

Example 11. Obtaining a medicinal product in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection.

Mixed 500 mg of the composition of fonturacetam according to the present invention, containing 0.5 wt.% 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid and 0.1 wt.% Ethyl-2- (2-oxo-4 -phenylpyrrolidin-1-yl) acetate, with 300 mg of chlorobutanol, 2 ml of propylene glycol, 4 ml of surfactant Tween-80 and 100 ml of injection water. The resulting solution was filtered and placed in 1 ml ampoules, which were sealed.

Example 12. Study of the anorexigenic effect of new formulations containing phonylpiracetam according to the present invention.

Anorexigenic effect of new compositions for the treatment and prevention of obesity, including phonylpiracetam with a content of 0.25%, 0.6%, 1.0% and 20.0% wt. 4-phenylpyrrolidone-2 (samples 1, 2, 3, 4, respectively), 0.01%, 0.6%, 1.0% and 20.0% wt. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid (samples 6, 7, 8, 9, respectively), and 0.01%, 0.6%, 1.0% and 20.0% wt. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate (samples 10, 11, 12, 13, respectively) was studied on a model of obesity of alimentary-constitutional genesis [16]. Sample 5 contained a prototype (containing fonturacetam, but not containing analogs and compounds closely related to fonturacetam - 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid and ethyl-2- (2-oxo 4-phenylpyrrolidin-1-yl) acetate).

In the study, 175 male Wistar rats were used, which received a diet containing about 70% lard and beef lard, fish, meat, carbohydrates ad libitum. Changes in body weight were recorded every 7-10 days. The rats were housed in five rats in temperature-controlled boxes (with an average temperature of 21 ° C) with a 12-hour day and night cycle and with round-the-clock access to water and food. Fattening of animals began at the age of one month, after their body weight exceeded 50 g [17]. After 3.5-4 months, the body weight of the animals in the experimental groups and the control group exceeded the normal body weight of rats fed with a laboratory diet by more than 25%. It is this form of obesity that is most often found in the population of industrialized countries and is caused by malnutrition against the background of physical inactivity. All animals showed a decrease in motor activity, especially pronounced after a meal. Then the rats were divided into 35 groups (34 experimental groups and a control group), in each group, 5 animals: samples 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, which received 100 mg / day of the corresponding composition containing phonylpiracetam, calculated per person, samples 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, receiving 200 mg / day of the corresponding composition containing phonylpiracetam , per person, samples 2, 5, 7, 11, receiving 50 mg / day of the corresponding composition containing phonylpiracetam, calculated per person, samples 2, 5, 7, 11, receiving 250 mg / day of the corresponding composition, containing phonylpiracetam, calculated per person, as well as the control group receiving placebo. The division of rats into groups was carried out in such a way that the body weight of the rats within the group did not differ by more than 5%. Treatment of obesity in rats was carried out for 45 days by daily oral gavage of formulations containing fonturacetam in a dosage corresponding to the experimental group. The animals of the control group were administered orally using a placebo probe. The rats of the experimental and control groups continued to receive the above high-calorie diet. To determine the effectiveness of the treatment of obesity, the animals continued to be weighed every 7 days, their activity was assessed in the open field test, the amount of food consumed was measured, and biochemical blood tests were performed. From the prior art, indicators of body weight and biochemical parameters of blood are known in Wistar rats in normal conditions and in obesity of alimentary-constitutional genesis (Tables 12-13) [17].

Table 12. Protein composition of blood serum in alimentary-constitutional obesity in rats, M ± m

Indicators Rats fed a laboratory diet Rats fed a diet containing about 70% pork and beef lard, fish, meat, carbohydrates ad libitum Total protein, mg / ml 64.8 ± 2.81 62.4 ± 3.11 Protein spectrum,% Albumin 38.2 ± 1.31 28.7 ± 0.57

-глобулины

-globulins 20.5 ± 1.92 20.7 ± 1.16

-globulins 14.0 ± 0.50 18.1 ± 0.44 c - globulins 11.6 ± 0.58 25.0 ± 0.70 d - globulins 18.8 ± 1.45 11.0 ± 0.21

Table 13. Indicators of lipid metabolism in blood serum with alimentary-constitutional obesity in rats, M ± m

Indicators Rats fed a laboratory diet Rats fed a diet containing about 70% pork and beef lard, fish, meat, carbohydrates ad libitum VLDL + LDL, mg% 47.0 ± 4.4 49.0 ± 2.8 Cholesterol, mmol / l 2.1 ± 0.14 2.5 ± 0.12 Triglycerides, mmol / l 1.1 ± 0.19 1.2 ± 0.15 Lipoprotein spectrum,% VLDL 8.2 ± 0.61 16.4 ± 0.85 LDL 15.9 ± 2.51 18.5 ± 1.86

LPV

31.5 ± 3.60 23.4 ± 0.65 LPV

44.4 ± 2.75 42.7 ± 1.19

Thus, from the literature data presented in tables 12-13, biochemical blood parameters were identified, which significantly differ in Wistar rats in normal conditions and in obesity of alimentary-constitutional genesis, namely, the number of albumin, α2-globulins, β-globulins, γ - globulins, very low density lipoproteins (VLDL), high density lipoproteins (HDL2). The anorexigenic activity of the formulations containing phonylpiracetam according to the present invention was assessed by measuring the above biochemical parameters in the blood of animals in comparison with the similar activity in the treatment of the prototype (Tables 14, 15, 16, 17).

Table 14. Biochemical parameters of blood in rats with alimentary-constitutional obesity treated with formulations containing phonylpiracetam according to the present invention at a dosage of 100 mg / day per person (compared to the prototype).

A drug Serum protein composition and lipid metabolism parameters in rat blood serum Albumin α2 - globulins β - globulins γ - globulins VLDL HDL2 Sample 1 30.9 ± 0.7 17.3 ± 0.5 21.2 ± 0.8 13.0 ± 0.3 14.2 ± 0.8 25.6 ± 0.6 Sample 2 31.1 ± 0.6 17.2 ± 0.3 21.1 ± 0.6 13.1 ± 0.4 14.3 ± 0.7 25.7 ± 0.7 Sample 3 31.3 ± 0.7 17.1 ± 0.4 21.0 ± 0.7 13.2 ± 0.4 14.1 ± 0.6 25.7 ± 0.6 Sample 4 30.1 ± 0.7 17.5 ± 0.3 21.5 ± 0.6 12.8 ± 0.3 14.6 ± 0.6 25.3 ± 0.6 Sample 5 (prototype) 28.7 ± 0.6 18.2 ± 0.3 22.9 ± 0.6 12.1 ± 0.3 15.9 ± 0.6 23.9 ± 0.7 Sample 6 31.1 ± 0.6 17.3 ± 0.4 21.1 ± 0.6 13.1 ± 0.3 14.1 ± 0.6 25.7 ± 0.6 Sample 7 31.2 ± 0.7 17.1 ± 0.5 20.9 ± 0.5 13.2 ± 0.2 14.1 ± 0.7 25.8 ± 0.7 Sample 8 31.4 ± 0.7 17.0 ± 0.4 20.8 ± 0.6 13.3 ± 0.3 13.9 ± 0.6 25.8 ± 0.6 Sample 9 30.2 ± 0.8 17.5 ± 0.3 21.5 ± 0.7 12.9 ± 0.4 14.5 ± 0.7 25.4 ± 0.6 Sample 10 31.1 ± 0.7 17.3 ± 0.4 21.1 ± 0.7 13.1 ± 0.3 14.2 ± 0.6 25.6 ± 0.8 Sample 11 31.3 ± 0.7 17.1 ± 0.3 21.1 ± 0.6 13.3 ± 0.4 14.1 ± 0.8 25.7 ± 0.7 Sample 12 31.3 ± 0.6 17.1 ± 0.4 20.9 ± 0.7 13.4 ± 0.3 14.1 ± 0.7 25.8 ± 0.6 Sample 13 30.4 ± 0.8 17.4 ± 0.4 21.4 ± 0.8 12.9 ± 0.4 14.6 ± 0.6 25.5 ± 0.7 Control group 27.1 ± 0.6 19.1 ± 0.4 26.2 ± 0.7 10.4 ± 0.4 17.8 ± 0.6 22.1 ± 0.7

Table 15. Biochemical parameters of blood in rats with alimentary-constitutional obesity treated with formulations containing phonylpiracetam, according to the present invention at a dosage of 200 mg / day per person (compared to the prototype).

A drug Serum protein composition and lipid metabolism parameters in rat blood serum Albumin α2 -globulins β - globulins γ - globulins VLDL HDL2 Sample 1 31.6 ± 0.6 17.1 ± 0.4 20.6 ± 0.7 13.6 ± 0.3 13.6 ± 0.6 26.2 ± 0.8 Sample 2 31.8 ± 0.7 17.0 ± 0.3 20.4 ± 0.6 13.6 ± 0.4 13.5 ± 0.7 26.2 ± 0.7 Sample 3 31.9 ± 0.5 16.8 ± 0.4 20.3 ± 0.7 13.8 ± 0.4 13.3 ± 0.7 26.4 ± 0.7 Sample 4 31.4 ± 0.8 17.2 ± 0.3 20.9 ± 0.6 13.3 ± 0.5 13.8 ± 0.6 25.9 ± 0.6 Sample 5 (prototype) 29.7 ± 0.7 17.9 ± 0.3 22.3 ± 0.6 12.4 ± 0.3 15.2 ± 0.7 24.6 ± 0.6 Sample 6 31.7 ± 0.7 16.9 ± 0.4 20.4 ± 0.7 13.7 ± 0.4 13.5 ± 0.6 26.3 ± 0.6 Sample 7 31.9 ± 0.6 16.8 ± 0.3 20.3 ± 0.6 13.8 ± 0.4 13.3 ± 0.7 26.4 ± 0.7 Sample 8 32.1 ± 0.6 16.7 ± 0.4 20.3 ± 0.6 13.9 ± 0.3 13.2 ± 0.6 26.6 ± 0.6 Sample 9 31.5 ± 0.7 17.1 ± 0.4 20.8 ± 0.8 13.4 ± 0.6 13.7 ± 0.7 26.1 ± 0.7 Sample 10 31.8 ± 0.8 16.9 ± 0.5 20.5 ± 0.7 13.6 ± 0.3 13.6 ± 0.6 26.2 ± 0.6 Sample 11 31.8 ± 0.6 16.9 ± 0.4 20.4 ± 0.7 13.7 ± 0.5 13.4 ± 0.7 26.4 ± 0.7 Sample 12 32.0 ± 0.7 16.8 ± 0.4 20.3 ± 0.6 13.9 ± 0.4 13.3 ± 0.7 26.5 ± 0.7 Sample 13 31.5 ± 0.8 17.1 ± 0.3 20.8 ± 0.8 13.2 ± 0.4 13.8 ± 0.5 26.0 ± 0.6 Control group 27.1 ± 0.6 19.1 ± 0.4 26.2 ± 0.7 10.4 ± 0.4 17.8 ± 0.6 22.1 ± 0.7

Table 16. Biochemical parameters of blood in rats with alimentary-constitutional obesity, treated with formulations containing phonylpiracetam, according to the present invention at a dosage of 50 mg / day per person (in comparison with the prototype).

A drug Serum protein composition and lipid metabolism parameters in rat blood serum Albumin α2 -globulins β - globulins γ - globulins VLDL HDL2 Sample 2 29.4 ± 0.5 17.7 ± 0.3 23.1 ± 0.6 12.2 ± 0.4 15.4 ± 0.6 24.3 ± 0.6 Sample 5 (prototype) 28.1 ± 0.6 18.6 ± 0.4 24.6 ± 0.6 11.3 ± 0.3 16.9 ± 0.7 22.9 ± 0.7 Sample 7 29.7 ± 0.6 17.6 ± 0.3 22.8 ± 0.6 12.4 ± 0.3 15.3 ± 0.6 24.6 ± 0.8 Sample 11 29.6 ± 0.7 17.7 ± 0.4 22.9 ± 0.7 12.3 ± 0.4 15.4 ± 0.7 24.4 ± 0.6 Control group 27.1 ± 0.6 19.1 ± 0.4 26.2 ± 0.7 10.4 ± 0.4 17.8 ± 0.6 22.1 ± 0.7

Table 17. Biochemical parameters of blood in rats with alimentary-constitutional obesity, treated with formulations containing phonylpiracetam, according to the present invention at a dosage of 250 mg / day per person (compared to the prototype).

A drug Serum protein composition and lipid metabolism parameters in rat blood serum Albumin α2 -globulins β - globulins γ - globulins VLDL HDL2 Sample 2 32.3 ± 0.6 16.8 ± 0.4 19.9 ± 0.6 14.2 ± 0.3 13.0 ± 0.6 26.6 ± 0.6 Sample 5 (prototype) 30.3 ± 0.7 17.7 ± 0.4 21.7 ± 0.7 12.9 ± 0.4 14.6 ± 0.7 25.1 ± 0.7 Sample 7 32.4 ± 0.6 16.6 ± 0.3 19.6 ± 0.6 14.3 ± 0.4 12.7 ± 0.6 26.8 ± 0.7 Sample 11 32.3 ± 0.7 16.7 ± 0.5 19.7 ± 0.7 14.2 ± 0.3 12.9 ± 0.7 26.7 ± 0.6 Control group 27.1 ± 0.6 19.1 ± 0.4 26.2 ± 0.7 10.4 ± 0.4 17.8 ± 0.6 22.1 ± 0.7

In the course of treatment in rats of the experimental groups receiving treatment with formulations containing fontyracetam, according to the present invention, a statistically significant decrease in appetite was observed (which was noted by a decrease in the amount of food consumed, data not shown), and, accordingly, body weight compared with rats of the control group ( in groups treated with new compositions according to the present invention at a dose of 50 mg / day in terms of a person, the decrease in body weight was about 17-20%, in groups treated at a dosage of 100 mg / day - about 23-27%, in groups , who received 200 mg / day - about 29-33%, and in the groups receiving 250 mg / day - about 35-38%) and a statistically significant increase in motor activity (in the "open field" test, data not shown).

The presented data are statistically significant (p <0.05) indicating that the new formulations containing phonylpiracetam according to the present invention have anorexigenic effect, and therefore can be used for the treatment and / or prevention of obesity or overweight. In addition, the new compositions according to the present invention have a higher anorexigenic activity, which is apparently due to the improvement in the physicochemical properties of the new compositions compared to the prototype (fonturacetam).

The invention can be used in medicine, chemistry, pharmacology and chemical-pharmaceutical industry.

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Claims (16)

1. The use of a composition comprising N-carbamoylmethyl-4-phenyl-2-pyrrolidone (fontyracetam) and at least one additional compound selected from the group consisting of 4-phenylpyrrolidone-2, 2- (2-oxo-4-phenylpyrrolidine- 1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, their optical isomers and their pharmaceutically acceptable salts, for the treatment and / or prevention of obesity or overweight, said composition contains from 0.25 to 1.00% wt. 4-phenylpyrrolidone-2, its optical isomer or its pharmaceutically acceptable salt and / or from 0.01 to 1.00% wt. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, its optical isomer or its pharmaceutically acceptable salt and / or from 0.01 to 1.00% wt. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, its optical isomer, or a pharmaceutically acceptable salt thereof. 2. The use according to claim 1, characterized in that the additional compound is 4-phenylpyrrolidone-2 in an amount of 0.25 to 1.00 wt%. 3. The use according to p. 1, characterized in that the said composition contains 4-phenylpyrrolidone-2 in an amount from 0.30 to 0.60% wt. 4. The use according to p. 1, characterized in that the said composition contains 4-phenylpyrrolidone-2 in an amount from 0.50 to 0.60% wt. 5. The use according to claim 1, characterized in that the additional compound is 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of 0.01 to 1.00 wt%. 6. The use according to p. 1, characterized in that said composition contains 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount from 0.10 to 0.50% wt. 7. The use according to claim 1, characterized in that said composition contains 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount from 0.10 to 0.20 wt%. 8. Use according to claim 1, characterized in that said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of 0.01 to 1.00 wt%. 9. The use according to p. 1, characterized in that said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount from 0.10 to 0.50% wt. 10. The use according to claim 1, characterized in that said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount from 0.10 to 0.20 wt%. 11. The use according to claim 1, characterized in that said composition contains phonylpiracetam in an amount of more than 96.00% wt. 12. Use according to claim 1, characterized in that the obesity or overweight is primary obesity or overweight. 13. Use according to claim 1, characterized in that obesity or overweight is obesity or overweight of alimentary-constitutional genesis. 14. The use according to any one of paragraphs. 1-13, characterized in that obesity or overweight are caused by diseases of the endocrine system, eating disorders and / or metabolic disorders. 15. The use according to any one of paragraphs. 1-14, characterized in that obesity or overweight is caused by at least one disease selected from the group consisting of thyroid diseases, diabetes mellitus, glucose regulation disorders, endocrine gland endocrine disorders, malnutrition, overnutrition, disorders metabolism, mental and behavioral disorders, obesity or overweight caused by medication. 16. The use of a pharmaceutical composition, medicament or finished dosage form containing (it) in a therapeutically effective amount, a composition comprising N-carbamoylmethyl-4-phenyl-2-pyrrolidone (fonpiracetam) and at least one additional compound selected from phenylpyrrolidone 2, 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, their optical isomers and their pharmaceutically acceptable salts, wherein said the composition contains from 0.25 to 1.00% wt. 4-phenylpyrrolidone-2, its optical isomer or its pharmaceutically acceptable salt and / or from 0.01 to 1.00% wt. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, its optical isomer or its pharmaceutically acceptable salt and / or from 0.01 to 1.00% wt. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, its optical isomer or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of obesity or overweight.