RU2699669C1 - Novel compositions of n-carbamoylmethyl-4-phenyl-2-pyrrolidone - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to a formulation having nootropic activity, a pharmaceutical composition and a medicinal agent. Disclosed composition containing N-carbamoylmethyl-4-phenyl-2-pyrrolidone and at least one additional compound selected from group comprising 4-phenylpyrrolidone-2,2-(2-oxo-4-phenylpyrrolidin-1-yl)acetic acid, ethyl-2-(2-oxo-4-phenylpyrrolidin-1-yl)acetate and optical isomers thereof.

EFFECT: claimed formulation is characterized by that it is less hygroscopic and more stable than the known substance of Fonturacetam.

13 cl, 12 tbl, 12 ex

Description

The invention relates to the field of medicine, pharmacology and the pharmaceutical industry, in particular to new compositions containing N-carbamoylmethyl-4-phenyl-2-pyrrolidone (phenylpiracetam) 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, a pharmaceutical composition based on said formulations and a drug based on said th pharmaceutical composition.

Nootropics, or neurometabolic stimulants, are drugs designed to provide a specific effect on the higher mental functions of the brain. Nootropics are believed to be able to stimulate mental activity, activate cognitive functions, improve memory and increase learning ability. Nootropics are thought to increase brain resistance to a variety of harmful effects, such as excessive stress or hypoxia.

A new generation of nootropic drugs includes the drug with INN phoneturatetam (N-carbamoyl-methyl-4-phenyl-2-pyrrolidone), which was registered and approved for industrial production by the Russian Ministry of Health in 2003. Unlike other nootropic drugs, it has the most a wide range of pharmacological activity [RF Patent No. 2539375, publ. 01/20/2015].

Phenylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) has long and firmly established itself as an effective drug for the treatment of central nervous system diseases of various origins, especially associated with vascular diseases and metabolic disorders in the brain, intoxication (in particular, in post-traumatic conditions and phenomena of chronic cerebrovascular insufficiency), accompanied by a deterioration in intellectual-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 psycho-organic syndromes, manifested by intellectual-mnestic disorders and apathetic-abulic phenomena, as well as sluggish apathic states in schizophrenia; treatment of convulsive conditions; treatment of obesity (alimentary-constitutional origin); prevention of hypoxia, increase 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 and mnestic disorders) [Phenotropil article, Drug Directory, Rlsnet.ru Website of the Russian Drug Register, https://www.rlsnet.ru / tn_index_id_27152. htm].

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

Phenylpiracetam has a pronounced anti-amnestic effect, has a direct activating effect on the integrative activity of the brain, promotes memory consolidation, improves concentration and mental activity, facilitates the learning process, increases the speed of information transfer between the cerebral hemispheres and the resistance of brain tissue to hypoxia and toxic effects, has anticonvulsant action and anxiolytic activity [RF Patent No. 2050851, publ. 12/27/1995]; has a positive effect on metabolic processes and blood circulation of the brain, stimulates redox processes, increases the energy potential of the body due to the utilization of glucose, improves regional blood flow in ischemic areas of the brain [RF Patent No. 2183117, publ. 06/10/2002]; increases the content of norepinephrine, 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, increased physical performance, pronounced antagonism to the cataleptic effect of antipsychotics, as well as weakening the severity of hypnotic effects of ethanol and hexobarbital; exhibits adaptogenic effect in increasing the body's resistance to stress in conditions of excessive mental and physical stress, fatigue, hypokinesia and immobilization, at low temperatures; stimulates the production of antibodies in response to the introduction of antigen, which indicates immunostimulating properties, but at the same time does not contribute to the development of immediate hypersensitivity and does not alter the allergic inflammatory reaction of the skin caused by the introduction of a foreign protein; does not have teratogenic, mutagenic, carcinogenic and embryotoxic properties; has low toxicity.

The moderate psychostimulating effect of the drug is combined with anxiolytic activity, it improves mood, has some analgesic effect, increasing the threshold of pain sensitivity. While taking the drug, there was an improvement in vision, which manifests itself in an increase in visual acuity, brightness and fields of vision [Article “Phenotropil”, Drug Directory, Internet site “Register of Russian Medicines” Rlsnet.ru, https://www.rlsnet.ru /tn_index_id_27152.htm].

The prior art pharmaceutical composition having nootropic activity, including N-carbamoyl-methyl-4-phenyl-2-pyrrolidone as the active substance [RF Patent No. 2240783, publ. November 27, 2004].

The prior art pharmaceutical composition having a nootropic effect, in the form of a solution for injection, containing phenylpiracetam and water for injection, characterized in that it additionally contains 2-hydroxypropyl-β-cyclodextrin [RF Patent No. 2414898, publ. 03/27/2011].

The pharmaceutical composition in the form of a solution for injection with nootropic activity is known, characterized in that it includes N-carbamoylmethyl-4-phenyl-2-pyrrolidone as an active principle, 200 / 0.5 hydroxyethyl starch and water for injection as excipients [RF patent No. 2524651, publ. 07/27/2014].

The prior art pharmaceutical composition in the form of tablets containing N-carbamoyl-methyl-4-phenyl-2-pyrrolidone and auxiliary components, characterized in that it contains as auxiliary components lactose monohydrate, carboxymethyl cellulose, polyvinylpyrrolidone and a stearic acid salt [Patent RF number 2560691, publ. 08/20/2015].

The prior art also knows the composition of (RS) -2- (2-oxo-4-phenylpyrrolidin-1-yl) acetamide having modulating activity with a commensurate effect, a method for producing a pharmaceutical substance, characterized in that the obtained raw material is subjected to purification, crystallization, stabilization by processing the composition with demineralized water and isothermal crystallization from propanol, followed by drying, which increases the efficiency, safety, stability and breadth of therapeutic use [RF Patent No. 2480214, publ. 04/27/2013].

At the same time, analogues of 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, are known [US4144246, publ. 03/13/1979].

The compound 4-phenylpyrrolidone-2 is also known, which is structurally related to phenylpiracetam, but its biological activity is not described.

The inventors of the present invention unexpectedly found that new formulations comprising phenylpiracetam (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 of fonthuracetam 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 beginning" (drug substance, medicinal substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture of a medicinal product (means )

“Medicinal product (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 formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.

"Pharmaceutical composition" means a composition comprising the new 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, excipients, dispensers, delivery vehicles such as preservatives, stabilizers, fillers, disintegrants, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, anti bacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and 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 achieved using a variety of antibacterial and antifungal agents, for example, benzyl alcohol, urotropin, ethylenediaminetetraacetic acid, benzoic acid, chlorobutanol, sorbic acid, parabens, alkylpyridinium, benzetonium and their pharmaceutically acceptable salts and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved with agents that slow down the absorption of the active principle, for example, such as hydrophilic polymer release retardants, for example, cellulose derivatives, polyethylene oxide, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, alginates, carbomers, hydrophobic release retardants, such as glyceryl, aluminum monostearate. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, buffers, and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, microcrystalline cellulose, sodium citrate, calcium carbonate, calcium phosphate and the like. Various organic and inorganic acids, such as malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, and sorbic acids, can be used to adjust the pH. 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. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, 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 the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds, or obtained on purpose. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained 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 (Detailed description of the properties of such salts is given in Berge SM, et al., “Pharmaceutical Salts” // J. Pharm. Sci. 1977, 66: 1-19 ) Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal 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 obtained are hydroxide, carbonate, sodium 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 sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should 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, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

It is an object of the present invention to provide a storage stable, non-hygroscopic, readily soluble, economically feasible, industrially feasible, preparative formulation of fonthuracetam (N-carbamoyl-methyl-4-phenyl-2-pyrrolidone).

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

Thus, the inventors unexpectedly 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 substance of fonthuracetam improves some properties of the substance of fonthuracetam.

Technical results of the present invention:

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

- increasing the dissolution rate of the composition compared to the prototype;

- a decrease in the hygroscopicity of the composition compared to the prototype;

- expansion of the arsenal of funds with nootropic activity;

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

The problem is solved, and the technical result is achieved by the creation of a composition having nootropic activity, including N-carbamoylmethyl-4-phenyl-2-pyrrolidone (phenylpiracetam) 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 / or their optical isomers and / or their pharmaceutically acceptable salts moreover, said composition contains 4-phenylpyrrolidone-2 in an amount of from 0.25% to 20.00%, and / or 2- (2-oxo-4-fe nylpyrrolidin-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 by the fact that:

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

- said composition contains 4-phenylpyrrolidone-2 in an amount of from 0.30 to 0.60% by weight .;

- said composition contains 4-phenylpyrrolidone-2 in an amount of 0.50 to 0.60% by weight;

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

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

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

- an additional compound is ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of from 0.01 to 1.00% wt .;

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

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

The task is also carried out, and the technical result is achieved by creating a pharmaceutical composition having nootropic activity, and said composition contains in a therapeutically effective amount any of the aforementioned composition and at least one pharmaceutically acceptable carrier.

The task is also carried out, and the technical result is achieved by the creation of a drug having nootropic activity in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, said agent containing in a therapeutically effective amount any of the aforementioned composition or the aforementioned pharmaceutical composition.

The subject of this invention is also a new pharmaceutical composition having nootropic activity, which contains a therapeutically effective amount of said composition, including phenylpiracetam 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, and at least one pharmaceutically acceptable carrier.

Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with a composition comprising phenylpiracetam (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, the present invention may include other active substances, including possessing activity, provided that they do not cause unwanted effects.

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

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

The subject of this invention is also a medicament having nootropic activity in the form of tablets, capsules or an injection solution, placed in a pharmaceutically acceptable package containing a therapeutically effective amount of a composition comprising phenylacetam and at least one additional compound selected from the group including 4-phenylpyrrolidon-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 or a pharmaceutical composition of the present invention.

Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of an agent containing the new N-carbamoylmethyl-4-phenyl-2-pyrrolidone composition of the present invention in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion, as well as depending 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, when obtaining the pharmaceutical composition of the present invention in the form of dosage units, the above effective dosage must be taken into account, with each dosage unit containing 10-500 mg of the new N-carbamoylmethyl-4-phenyl-2-pyrrolidone composition of the present invention preferably 50-300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

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

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

The synthesis of the target product is carried out according to the method [Vorona M., Weinberg G., Vikainis S., Kuznetsov E., Lebedev A., Ponomarev Yu., Chernobrovy A., Zveinets L., Dambrova M. New synthesis methods 2 - [(4 -R) -2-oxo-4-phenylpyrrolidin-1-yl] acetamide ((R) -phenotropyl). HCG. 2012. T. 48. No. 5. P. 775 - 778], in which the ability of N-alkylated 4-aminobutyric acid esters 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 was added 19.07 g (82.8 mmol) K ₃ PO ₄ · H ₂ O and 10 g of molecular sieves 4Å. The resulting suspension was stirred at room temperature for 24 hours, filtered, the filtrate was evaporated to dryness in vacuo.

To carry out cyclization, the 4-carbamoylmethylamino-3-phenylbutyric acid n-butyl ester obtained in the residue is dissolved in 150 ml of toluene, 2 g (8.68 mmol) of K ₃ PO ₄ · H ₂ O and 0.05 g (0) are added to the solution 15 mmol) Bu ₄ NBr. The suspension is refluxed for 2 hours, cooled, filtered, the filtrate is evaporated to dryness, the precipitate is washed with demineralized water, cooled to a temperature from 0 to 5 ° C. Wet N-carbamoylmethyl-4-phenyl-2-pyrrolidone is dried at a temperature of from 60 to 65 ° C until the mass loss upon drying is not more than 0.5%. The final product is purified from impurities by column chromatography. Yield 3.55 g (63%). T. pl. for 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 fonthuracetam

The composition of the phenylpiracetam was studied 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 is placed in a 1000 ml volumetric flask, 500 ml of chromatography water are added and stirred, then the volume of the solution is chromatographed 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 substance fonthuracetam is 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 incubated for 5 minutes. Then, after cooling to room temperature, bring the volume of the solution with water for chromatography to the mark and mix. The resulting solution was filtered through a membrane filter with a pore diameter of 0.45 μm, discarding the first 2 ml of the filtrate.

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

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

Table 1. Chromatographic conditions

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

Elution is carried out in a gradient mode in accordance with table 1.

Table 2. Elution Conditions

Time (min) PF A (vol./about.%) PF V (vol./about.%) 0 - 1 90 ten eighteen 90 → 10 10 → 90 8 - 11 ten 90 11 - 12 10 → 90 90 → 10 12 - 15 90 ten

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

The test solution and standard solution are chromatographed to obtain at least 3 chromatograms. Not take into account peaks, the area of which is less than 30% of the peak area of fonturatsetam in the chromatogram of a standard solution (b).

Example 3. Obtaining samples of phenylpiracetam containing additional compounds

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

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

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

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

The dissolution kinetics of the new N-carbamoylmethyl-4-phenyl-2-pyrrolidone composition obtained in Example 3 is evaluated by the substance content of N-carbamoylmethyl-4-phenyl-2-pyrrolidone and compared with the dissolution kinetics of the prototype. The device for determining the dissolution rate is a three-necked vessel with a capacity of 1 liter. A thermometer is introduced into one of the tubes, a glass tube for sampling and their integration in the other, and the main part of the device is 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 is mounted on the axis of the motor.

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

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

For comparative samples 1-4, 200 mg of a new composition is used, including phenylpiracetam (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 composition is used, including phenylpiracetam (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 composition is used, including phenylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 0.01%, 0.6%, 1.0% and 20.0% by weight. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, respectively.

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

The results obtained as a percentage of the dissolved active substance of 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

Concentration in solution,% of maximum theoretical concentration Time, sec 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 98.5 100 100 75,4 900 97.4 100 100 100 89.2 1200 100 100 100 100 100.0

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

Concentration in solution,% of maximum theoretical concentration Time, sec 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 99.9 100 100 75,4 900 98.7 100 100 100 89.2 1200 100 100 100 100 100.0

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

Concentration in solution,% of maximum theoretical concentration Time, sec 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 98.9 100 100 75,4 900 98.2 100 100 100 89.2 1200 100 100 100 100 100.0

The results demonstrate that the dissolution rate of new compositions 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 takes place is statistically significantly less than for the comparative prototype sample, which can be especially useful for preparing tablets in orodispersed form.

Example 5. The 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 is evaluated by the content of the substance, and compared with the stability of the prototype by accelerated aging.

All samples were stored in glass bottles sealed with rubber stoppers with aluminum caps in a climate chamber under accelerated testing conditions. The content of the active substance is determined by HPLC using standards.

The method of "accelerated aging" is to withstand the test drug at temperatures and humidity exceeding the temperature and humidity of its storage during handling. At elevated temperatures, as a rule, physicochemical processes occurring in medicines are accelerated, leading to undesirable quality changes over time. Thus, at elevated temperatures, the period of time during which controlled quality indicators of the drug are kept within acceptable limits (experimental shelf life) is artificially reduced in comparison with the shelf life at storage temperature. This can significantly reduce the time required to establish the 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 that provides any specified shelf life.

Shelf life (C) at storage temperature (t _xp ) is associated with the experimental shelf life (C _E ) at elevated experimental storage temperature (t _e ) with the following relationship:

,

,

.where is the compliance coefficient

.

The temperature coefficient of the chemical reaction rate (A) is taken to be 2.5. The given dependence is based on the Vant-Hoff rule about a 2-4-fold increase in the rates of chemical reactions with an increase in temperature by 10 ° С.

In accordance with the general pharmacopoeial article OFS.1.1.0009.15, the value of the compliance coefficient (K), depending on the selected temperature range (t _e -t _xp ), equal to 30 ° C, is 15.6. The experimental storage period for a selected shelf life of 3 years is 71 days.

Statistical processing of parameters and presentation of the results of the study are 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% by weight. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid (samples 6-9, respectively), and 0.01%, 0.6%, 1.0% and 20.0% by weight. 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 presented below in tables 6-8.

It was found that after 71 days of storage under the accelerated aging method, the new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone of the present invention have a statistically significantly increased stability. The substance of the prototype 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 of the present invention are significantly more stable during storage compared to the prototype.

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

storage time at (t _e -t _xp ) = 30 ^о С, day The amount of active ingredient detected by HPLC in% of theoretical content Sample 1 Sample 2 Sample 3 Sample 4 Prototype 0 100 100 100 100 100 ten 99.9 100 100 100 99.9 20 99.8 99.9 100 100 99.5 thirty 99.7 99.9 100 100 99,2 40 99.6 99.9 99.9 99.9 98.7 fifty 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. Assessment of the stability of the composition with 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid by accelerated aging in comparison with the prototype

storage time at (t _e -t _xp ) = 30 ^о С, day The amount of active ingredient detected by HPLC in% of theoretical content Sample 6 Sample 7 Sample 8 Sample 9 Prototype 0 100 100 100 100 100 ten 99.9 100 100 100 99.9 20 99.8 99.9 100 100 99.5 thirty 99.7 99.9 100 100 99,2 40 99.6 99.9 99.9 99.9 98.7 fifty 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 accelerated aging in comparison with the prototype

storage time at (t _e -t _xp ) = 30 ^о С, day The amount of active ingredient detected by HPLC in% of theoretical content Sample 10 Sample 11 Sample 12 Sample 13 Prototype 0 100 100 100 100 100 ten 99.9 100 100 100 99.9 20 99.8 99.9 100 100 99.5 thirty 99.7 99.9 100 100 99,2 40 99.5 99.8 99.9 99.9 98.7 fifty 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

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.

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% by weight. 4-phenylpyrrolidone-2 (samples 1-4, respectively), 0.01%, 0.6%, 1.0% and 20.0% by weight. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid (samples 6-9, respectively), and 0.01%, 0.6%, 1.0% and 20.0% by weight. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate (samples 10-13, respectively) and the prototype at room temperature showed that the prototype is hygroscopic and exhibits a large increase in humidity, starting from 60% relative humidity. The new formulations of N-carbamoylmethyl-4-phenyl-2-pyrrolidone do not show any significant increase in humidity except for storage at a relative humidity above 90%. The results are presented below in tables 9-11.

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

Relative humidity% Humidity increase,% 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 12.1 100 9.0 5,6 5.1 4.9 16.5

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

Relative humidity% Humidity increase,% 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 12.1 100 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% Humidity increase,% 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 12.1 100 9.2 5.9 5.5 5,0 16.5

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

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

Acute toxicity study:

Materials and methods:

The study of acute toxicity of the claimed composition containing phenylpiracetam and 20.00% wt. 4-phenylpyrrolidone-2, with a single intragastric administration was carried out on 20 white non-linear male mice weighing 18-20 g, contained in standard vivarium conditions with free access to water and feed. Doses of 180, 250, 320, and 390 mg (according to phonetracetam) / kg body weight were tested. For 14 days, the general condition of the animals was evaluated. 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.

Acute toxicity parameters yielded the following results:

DL ₅₀ = 418 mg / kg, DL ₁₆ = 334 mg / kg, DL ₈₄ = 581 mg / kg.

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

Subchronic toxicity of the drug was studied on 25 non-linear white male rats weighing 168-229 g, contained in standard vivarium conditions with free access to water and food. The animals of the experimental groups were injected intragastrically at a dose of 6 and 60 mg (per phonetracetam) / kg body weight in the form of a suspension in 2% starch gel for 30 days daily, once a day, which is equal to and 10 times the therapeutic dose for a person taking into account interspecific conversion. After the experiment, all animals were euthanized for further pathomorphological examination of internal organs and tissues.

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

Statistical comparison of the experimental and control groups was carried out by t-student test.

results

In groups of animals that received intragastric suspensions of the studied drug at a dose of 60 mg / kg, there was a tendency to a decrease in the rate of increase in body weight, an insignificant but significant increase in the activity of blood transaminases, and a decrease in spontaneous motor activity of animals. The studied drug in doses of 6 and 60 mg / kg did not cause deviations of biochemical and hematological parameters. There was no change in daily diuresis for groups of animals treated with the experimental drug, relative to the group of control animals that received intragastrically 2% starch gel in the same volume.

Pathomorphological and microscopic examination of internal organs indicate the absence in the tested doses of pronounced signs of the toxic effect of the drug on the internal organs, but indicate 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 taking into account interspecific conversion doses.

Similarly, formulations are studied including phenylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 20.0% by weight. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, and phenylpiracetam and 20.0% by weight. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate.

The claimed new formulations, including phenylpiracetam (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) and 4-phenylpyrrolidone-2, phenylpiracetam and 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid, and phenylpiracetam and ethyl -2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, do not exhibit mutagenic properties in experiments on Drosophila, do not have allergenicity, and do not have reproductive toxicity.

Example 8. Obtaining a drug in the form of tablets

1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of the composition of the fonthuracetam according to the present invention, containing 0.6% by weight of 4-phenylpyrrolidone-2, are mixed and mixed into a bar. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each.

Example 9. Obtaining a drug in the form of sustained release tablets

Sifted low viscosity sieved hydroxypropylmethyl cellulose and the composition of phonetracetam 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 start the granulation process using water as a humidifier. The drying process is continued until the “mass loss on drying” indicator reaches 2.0 ± 0.5%.

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

Sifted microcrystalline cellulose, calibrated granulate and sifted lactose are loaded into a drum type mixer. Stirred for 2-4 minutes. Then sifted talcum powder is loaded, colloidal silicon dioxide is stirred for 2-3 minutes, then sifted magnesium stearate, high viscosity hydroxypropyl methylcellulose are loaded, and mixed for 1-2 minutes.

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

Example 10. Obtaining a drug in the form of capsules

Thoroughly mix the composition of the fonthuracetam according to the present invention, containing 20% by weight of ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate, with a lactose powder in a ratio of 2 to 1. The resulting powder mixture is packaged in 300 mg in suitable gelatin capsules.

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

500 mg of the composition of the phoneturatsetam 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 Tween-80 surfactant and 100 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.

Example 12. The study of antiamnestic activity

Antiamnestic activity of new compounds, including phenylpiracetam with a content of 0.25%, 1.0% and 20.0% wt. 4-phenylpyrrolidone-2 (samples 1, 3, 4, respectively), 0.01%, 1.0% and 20.0% by weight. 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid (samples 6, 8, 9, respectively), and 0.01%, 0.6%, 1.0% and 20.0% by weight. ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate (samples 10, 12, 13, respectively) are examined on the model of the conditioned passive avoidance reflex (passive avoidance reaction) in male Wistar rats weighing 180-250 g. For For this, the installation "Passive avoidence" of the company "Lafauette instrument company" (USA) is used, consisting of a chamber with an electrode floor, illuminated by a guillotine-closing opening with a brightly lit platform. To develop passive avoidance reaction, the rat is placed on the platform with its tail to the hole in the chamber with the electrode floor. For 180 s, the latent time of the first entry of the animal into the chamber is recorded. 3 minutes after placing the animal in the chamber at the moment when the animal was in it, and not on the platform, the hole is closed and irreparable electric pain irritation is applied through the floor (8 electrical pulses with an amplitude of 0.5 mA and a duration of 1 s each, the interval between pulses is 2 s ) After that, the animal is removed from the chamber. The safety of passive avoidance reaction is checked 24 hours after its production by placing the rat on the installation platform in the same manner as during training. For 180 s, the latent time of the first entry into the chamber is recorded. If the rat does not enter it, the latent time was considered equal to 180 s.

As amnestic factors, electroconvulsive shock (ESS 120 V, 300 ms) is applied, applied through the corneal electrodes immediately after the production of passive avoidance reaction, or scopolamine, administered subcutaneously at a dose of 1 mg / kg 60 minutes before the production of passive avoidance reaction.

The new composition of phenylpiracetam at a dose of 25, 50 and 100 mg / kg, the comparison drug piracetam at a dose of 100 and 300 mg / kg or 0.9% sodium chloride solution is administered intraperitoneally 45 minutes before training.

As follows from the data given in tables 12-14, the use of new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone reduces the severity of postconvulsive retrograde amnesia. The severity of the effect is directly dependent on the dose. Piracetam exhibits an antiamnestic effect in a dose of at least 300 mg / kg, exceeding the minimum detected antiamnestic dose of new N-carbamoylmethyl-4-phenyl-2-pyrrolidone formulations (25 mg / kg) by 12 times. In addition, new formulations of N-carbamoylmethyl-4-phenyl-2-pyrrolidone in doses of 25 to 100 mg / kg reduce the severity of amnesia caused by scopolamine. Moreover, in the indicated minimum doses, the new compositions of N-carbamoylmethyl-4-phenyl-2-pyrrolidone increase the latent period of entry into the “dangerous” chamber by 4.5 times compared with the latency of entry into it of amnesized ESH rats that were not injected, and isotonic sodium chloride solution. Consequently, the antiamnestic effect of the new formulations of phenylpiracetam is higher, and it is effective in lower doses than piracetam.

Table 12. The severity of postconvulsive retrograde amensia composition with 4-phenylpyrrolidone-2

A drug Latent time of the first entry into the camera, s Sample 1 (0.25%) Sample 3 (1.0%) Sample 4 (20.0%) Sodium chloride 55.2 55,2 55,2 Sodium chloride + ESH 6.9 6.9 6.9 Piracetam 100 mg / kg + ESH 59.2 59.2 59.2 Piracetam 300 mg / kg + ESH 129.5 * 129.5 * 129.5 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 25 mg / kg + ESH 30.1 30.5 33,4 The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 50 mg / kg + ESH 58.0 * 58.4 * 60.0 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 100 mg / kg + ESH 129.3 * 129.8 * 131.7 * Scopolamine 1 mg / kg 51,2 51,2 51,2 New N-carbamoylmethyl-4-phenyl-2-pyrrolidone formulation, 25 mg / kg + scopolamine 43.2 * 43.6 * 45.5 * New N-carbamoylmethyl-4-phenyl-2-pyrrolidone formulation, 50 mg / kg + scopolamine 64.4 * 64.7 * 66.5 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 100 mg / kg + scopolamine 94.0 * 94.2 * 98.0 *

* - p <0.05 compared with the group "Sodium chloride + ESH"

Table 13. The severity of postconvulsive retrograde amensia composition with 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid

A drug Latent time of the first entry into the camera, s Sample 6 (0.01%) Sample 8 (1.0%) Sample 9 (20.0%) Sodium chloride 55.2 55,2 55,2 Sodium chloride + ESH 6.9 6.9 6.9 Piracetam 100 mg / kg + ESH 59.2 59.2 59.2 Piracetam 300 mg / kg + ESH 129.5 * 129.5 * 129.5 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 25 mg / kg + ESH 33,2 33.5 35.5 The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 50 mg / kg + ESH 61.3 * 61.7 * 62.9 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 100 mg / kg + ESH 131.0 * 131.5 * 133.0 * Scopolamine 1 mg / kg 51,2 51,2 51,2 New N-carbamoylmethyl-4-phenyl-2-pyrrolidone formulation, 25 mg / kg + scopolamine 45.1 * 45.5 * 47.4 * New N-carbamoylmethyl-4-phenyl-2-pyrrolidone formulation, 50 mg / kg + scopolamine 67.2 * 67.5 * 68.8 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 100 mg / kg + scopolamine 97.0 * 97.4 * 98.5 *

* - p <0.05 compared with the group "Sodium chloride + ESH"

Table 14. The severity of the post-convulsive retrograde amines of the composition with ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate

A drug Latent time of the first entry into the camera, s Sample 10 (0.01%) Sample 12 (1.0%) Sample 13 (20.0%) Sodium chloride 55,2 55.2 55.2 Sodium chloride + ESH 6.9 6.9 6.9 Piracetam 100 mg / kg + ESH 59.2 59.2 59.2 Piracetam 300 mg / kg + ESH 129.5 * 129.5 * 129.5 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 25 mg / kg + ESH 31,0 31.3 33.1 The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 50 mg / kg + ESH 59.5 * 59.9 * 61.6 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 100 mg / kg + ESH 130.5 * 130.9 * 132.8 * Scopolamine 1 mg / kg 51,2 51,2 51,2 New N-carbamoylmethyl-4-phenyl-2-pyrrolidone formulation, 25 mg / kg + scopolamine 44.5 * 44.8 * 46.1 * New N-carbamoylmethyl-4-phenyl-2-pyrrolidone formulation, 50 mg / kg + scopolamine 65.8 * 66.1 * 67.9 * The new composition of N-carbamoylmethyl-4-phenyl-2-pyrrolidone, 100 mg / kg + scopolamine 95.4 * 95.8 * 97.5 *

* - p <0.05 compared with the group "Sodium chloride + ESH"

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

Claims (14)

1. A composition having nootropic activity, including N-carbamoylmethyl-4-phenyl-2-pyrrolidone (phenylpiracetam) 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, moreover, the composition contains 4-phenylpyrrolidone-2 in an amount of from 0.25% to 20.00% wt. or 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of not more than 20.00% by weight, or ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount no more than 20.00% wt. 2. The composition according to p. 1, characterized in that the additional compound is 4-phenylpyrrolidone-2 in an amount of from 0.25 to 1.00% wt. 3. The composition according to p. 2, characterized in that the said composition contains 4-phenylpyrrolidone-2 in an amount of from 0.30 to 0.60% wt. 4. The composition according to p. 3, characterized in that the said composition contains 4-phenylpyrrolidone-2 in an amount of from 0.50 to 0.60% wt. 5. The composition according to p. 1, characterized in that the additional compound is 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of from 0.01 to 1.00% wt. 6. The composition according to p. 5, characterized in that the said composition contains 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of from 0.10 to 0.50% wt. 7. The composition according to p. 6, characterized in that the said composition contains 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid in an amount of from 0.10 to 0.20% wt. 8. The composition according to p. 1, characterized in that the said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of from 0.01 to 1.00% wt. 9. The composition according to p. 8, characterized in that the said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of from 0.10 to 0.50% by weight. 10. The composition according to p. 9, characterized in that the said composition contains ethyl 2- (2-oxo-4-phenylpyrrolidin-1-yl) acetate in an amount of from 0.10 to 0.20% wt. 11. The composition according to p. 1, characterized in that the said composition contains phenylpiracetam in an amount of more than 96.00% wt. 12. A pharmaceutical composition having nootropic activity, said composition comprising in a therapeutically effective amount a composition according to any one of claims. 1-11 and at least one pharmaceutically acceptable carrier. 13. A medicament having nootropic activity in the form of tablets, capsules or injections in a pharmaceutically acceptable package, said medicament containing in a therapeutically effective amount, a composition according to any one of claims. 1-11 or the pharmaceutical composition according to p. 12.