EA020673B1 - Pharmaceutical composition having neuroprotective, antiamnesic, antioxidant, antihypoxic, neurometabolic and anti-ischemic activity (variants) - Google Patents

Abstract

The invention relates to the field of the pharmaceutical industry and medicine. The aim of the present invention is to create an effective pharmaceutical composition having neuroprotective, antiamnesic, antioxidant, antihypoxic and anti-ischemic activity. This aim is achieved in that the pharmaceutical composition contains 2-ethyl-6-methyl-3-hydroxypyridine succinate and the peptide Met-Glu-His-Phe-Pro-Gly-Pro and differs from the prototype in that it additionally contains the following minerals: potassium, magnesium and manganese. Furthermore, a portion of theC carbon isotopes in the pharmaceutical composition is substituted byC carbon isotopes. The technical results of the invention are the more rapid onset of a therapeutic effect, an enhanced therapeutic effect with no increase in the concentration of 2-ethyl-6-methyl-3-hydroxypyridine succinate and the peptide Met-Glu-His-Phe-Pro-Gly-Pro, and improved stability during the shelf life.

Description

FIELD OF THE INVENTION

The invention relates to the pharmaceutical industry and medicine and can be used in the manufacture and use of pharmaceutical compositions with a polypeptide sequence Me1-C1i-H18-Pb-Rgo-C1u-Rgo, which have neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, anti-ischemic activity.

State of the art

An important problem of modern medicine is the creation of new drugs that can effectively protect and also treat brain diseases.

An effective area of research in this area is the creation of new drugs based on methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (hereinafter, semax) and ethylmethylhydroxypyridine succinate (hereinafter, mexidol) preparations.

Semax is a drug that effectively affects the processes associated with the formation of memory and learning, improves mnemonic functions, improves the adaptation of the human body to hypoxia, cerebral ischemia, anesthesia and other damaging effects. In other words, semax improves the energy processes of the brain, increasing its resistance to stress damage, hypoxia. Semax is a good nootropic, neurometabolic stimulant.

In turn, Mexidol has a mechanism of action, the fundamental difference from the mechanism of action of traditional neuro-psychotropic drugs is its lack of specific binding to known receptors (Scientific Research Institute of Pharmacology RAMS, Voronina T.A. Mexidol. Main effects, mechanism of action, application (1 Шр : // \ y \ y \ u.ooey.gi / te \ 1Yo1.1Ts) Mexidol is an inhibitor of free radical processes, lipid peroxidation, it activates superoxide dismutase, has an effect on the physicochemical properties of membranes wounds, increases the content of polar lipid fractions (phosphotidylserine and phosphotidylinositol, etc.) in the membrane, reduces the ratio of cholesterol / phospholipids, reduces the viscosity of the lipid layer and increases the fluidity of the membrane, activates the energy-synthesizing functions of mitochondria and improves energy metabolism in the cell and, thus, protects the apparatus cells and the structure of their membranes.

The change in the functional activity of the biological membrane caused by mexidol leads to conformational changes in protein macromolecules of synaptic membranes, as a result of which mexidol exerts a modulating effect on the activity of membrane-bound enzymes, ion channels and receptor complexes, in particular benzodiazepine, G AMA, acetylcholine, enhancing their ability to bind to ligands, increasing the activity of neurotransmitters and activation of synaptic processes. Along with this, Mexidol has a pronounced lipid-lowering effect, reduces the level of total cholesterol and low density lipoproteins and increases high density lipoproteins.

Thus, the mechanism of action of mexidol is determined primarily by its antioxidant properties, the ability to stabilize cell biomembranes, activate the energy synthesizing functions of mitochondria, modulate the functioning of receptor complexes and the passage of ion currents, enhance the binding of endogenous substances, improve synaptic transmission and the relationship of brain structures. Thanks to this mechanism of action, Mexidol exerts influence on key basic links in the pathogenesis of various diseases, has a wide range of effects, extremely small side effects and low toxicity, and has the ability to potentiate the action of other central active substances, especially those that realize their action as direct receptor agonists.

The application claims two variants of the pharmaceutical composition. Each of the claimed pharmaceutical compositions has, as active substances, a polypeptide sequence of Me1-C1i-HkPbie-Progo-C1u-Progo and 2-ethyl-6-methyl-3-hydroxypyridine succinate.

Below are analogues that describe the polypeptide sequence of Me1-C1i-H18-PbErgo-C1u-Prgo and 2-ethyl-6-methyl-3-hydroxypyridine succinate.

An analogue to each variant of the pharmaceutical composition is a pharmaceutical composition for the treatment of ischemic stroke, containing the polypeptide sequence Me1-C1i-Hk-P11eRgo-C1u-Rgo (RF patent 2251429, publ. July 27, 2004).

The disadvantage of the analogue is the relatively low speed of the onset of the therapeutic effect.

In addition, there is an analogue - RF patent 2156087, publ. 09/20/2000. The patent describes a biologically active food supplement (BAA), including potassium, manganese, zinc, iron and an additional 29 different substances. The patent claims that the dietary supplement has antihypoxic and antioxidant properties.

The disadvantage of the analogue is the impossibility of its use for medicinal purposes.

It is known the use of Semax as a neuroprotector (patent for the invention of the Russian Federation 2394816, publ. 20.07.2010). In the patent of the Russian Federation 2394816 in the table. Figure 7 shows the change in neurological deficit in rats after bilateral ligation of the common carotid arteries under the influence of Semax, Mexidol and Amtizol preparations. The patent concludes that Mexidol is more preferable than Semax because of the insufficient effectiveness of the latter and the impossibility of increasing its concentration in solution.

Known analogue (patent for the invention of the Russian Federation 2425670, publ. 08/10/2011). In the analogue, ce 1 020673 max and choline alfoscerate are used. The drug choline alfoscerat increases the effectiveness of Semax.

It is known to use the semax peptide of the formula Me! -C1i-H18-Pb-Pe-Cl-Si-Prgo as an antithrombotic, anticoagulant, fibrin-depolymerization and fibrinolytic agent (RF patent 2290194, publ. 27.12.2006).

The disadvantage of the analogue is its relatively low effectiveness of the therapeutic effect.

It is known to use the Me! -C1i-H18-Pb-Pe-C1u-Prgo polypeptide sequence as a memory stimulant (USSR copyright certificate 939440, publ. 06/30/1982), which is the basis of a nootropic drug and a pharmaceutical composition of nootropic action (RF patent No. 2045958 C 16 A61K 38/08, 1994).

The disadvantage of the analogue is the relatively low speed of the onset of the therapeutic effect.

Known patent application 2006146529, publ. 07/20/2008. The application describes a pharmaceutical composition having neurotropic, antiamnestic, antihypoxic and antiischemic activity. The composition as active ingredients contains semax and mexidol or their pharmaceutically acceptable salts in therapeutically effective amounts. Here, the effectiveness of Semax is enhanced by the use of Mexidol.

Also known patent EAPO 008591, publ. 06/29/2007. The patent proposes the use of derivatives of 3- (3,5-dioxo-4,5-dihydro-3H- (1,2,4) triazin-2-yl) benzamide as P2X ₇ inhibitors for the treatment of various diseases, including ischemia with a stroke or heart attack. The patent provides for the use of isotopes ¹³ C, ¹⁵ Ν, etc. for making isotopic labels in a drug. The isotopes determine the dynamics of the distribution of the drug in the tissues of the body.

Another analogue to the pharmaceutical composition variants is an agent containing mexidol and excipients: potato starch, polyvinylpyrrolidone, stearic acid magnesium, microcrystalline cellulose, milk sugar (RF patent 2145855, publ. 26.05.1999). The drug is intended for the treatment of impaired brain functions, in particular acute and chronic cerebrovascular disorders.

The disadvantage of this analogue is the low stability of the pharmaceutical product over the expiration date.

Also analogous to all variants of the pharmaceutical composition is a stable pharmaceutical composition for injection containing Mexidol, succinic acid, Trilon B and water for injection (RF patent 2205640, publ. 09.04.2002). The drug is prescribed intravenously and intramuscularly.

The disadvantage of this analogue is the low stability of the pharmaceutical composition over the expiration date.

In addition, there is an analogue - RF patent 2156087, publ. 09/20/2000. The patent describes a biologically active food supplement, including potassium (4-380 mg / l), magnesium (1-510 mg / l), iron (1-2100 mg / l), zinc (1-1240 mg / l), Mexidol (1-200 mg / L) and an additional 29 different substances. The patent claims that the dietary supplement has antihypoxic and antioxidant properties.

The disadvantage of the analogue is the impossibility of its use as a composition for injection. Another disadvantage is the low content of mexidol in a liter. About three orders of magnitude less than what is required for the injection solution.

The prototype of the two variants of the invention is the pharmaceutical composition (application for the invention of the Russian Federation 2006146529/15, publ. 20.07.2008), with neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity, containing 2-ethyl-6-methyl-3-hydroxypyridine succinate as well as the polypeptide methionine-glutamine-histidine-phenylalanine-prolyl-glycine-proline (Me! -C1i-H18-Pb-Pe-Clo-Prgo).

The objective of the prototype was to expand the arsenal of drugs with pronounced neuroprotective activity, in combination with antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity.

Studies have shown that the prototype is not always effective in these pathologies. Another disadvantage of the prototype is the relatively low speed of the onset of the therapeutic effect.

Signs of the prototype Pharmaceutical composition with neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity, containing 2-ethyl-6-methyl-3-hydroxypyridine succinate, methionine-glutamistidine-phenylalanine-proline-glycine! -H18-Pb-Rgo-C1u-Rgo) coincide with the features of the claimed variants of the invention.

In the prototype, a pharmaceutically acceptable solvent is water (distilled water or water for injection). A pharmaceutically acceptable excipient in the pharmaceutical composition is ammonium acetate.

- 2,020,673

The structural formula of the methionine-glutamine-histidine-phenylalanine-prolyl-glycine proline polypeptide (Me1-C1i-H18-Pb-Rgo-C1u-Rgo)

The formula of 2-ethyl-6-methyl-3-hydroxypyridine succinate can be represented as follows:

The N + -4 bond is a covalent bond.

The above preparation contains a 2-ethyl-6-methyl-3-hydroxypyridine cation (2-ethyl-6-methyl-3hydroxypyridinium) and a pharmaceutically acceptable anion, namely C ₄ H ₆ O ₄ . The ionic bond between the cation and the anion is the bond between the negatively and positively charged particles in the preparation.

As the anion, not only succinate can be used, but also another substance, in particular chloride. Therefore, a wider formulation of features describing 2-ethyl-6-methyl-3-hydroxypyridinium may be as follows:

A pharmaceutical composition containing 2-ethyl-6-methyl-3-hydroxypyridinium and a pharmaceutically acceptable anion.

The disadvantages of the prototype are the relatively low speed of the onset of the therapeutic effect, not sufficiently large therapeutic effect of the pharmaceutical product, low stability of the pharmaceutical composition over the expiration date.

SUMMARY OF THE INVENTION

Let us define the terms.

Shelf life - the period during which the pharmaceutical composition retains its properties in a measure that ensures its intended use.

Neuroprotective activity of the pharmaceutical composition (drug) - stopping and limiting damage to brain tissue that develops as a result of acute ischemia (hypoxia).

The medicine activates metabolic processes in the brain, protects nerve cells from attacks of free radicals and toxins, as well as from other harmful effects.

Antiamnestic activity of the drug is a counteraction to amnesia.

Amnesia is a general or partial inability to recall recent or distant events.

The antioxidant activity of the drug is the ability to slow the oxidation of organic compounds.

Antihypoxic activity of the drug - improves utilization of oxygen circulating in the body and increases the body's resistance to hypoxia (oxygen deficiency). Hypoxia is a state of oxygen starvation due to impaired external and internal (tissue, cellular) respiration.

Neurometabolic activity - stimulates the synthesis and utilization of oxygen and glucose, increases ATP synthesis under conditions of ischemia and hypoxia by more than an order of magnitude.

Anti-ischemic activity of the drug - prevents local anemia, often due to a vascular factor (narrowing or complete obstruction of the lumen of the artery), leading to temporary dysfunction or permanent damage to the tissue or organ.

Ischemia is local anemia, often caused by a vascular factor (narrowing or complete obstruction of the lumen of the artery), leading to temporary dysfunction or permanent damage to the tissue or organ. The consequences of ischemia depend on the degree and rate of decrease in blood flow parameters, the duration of ischemia, tissue sensitivity to hypoxia, and the general condition of the body. The organs of the central nervous system and myocardium are the most sensitive to ischemia.

Ischemia has a number of significant differences from hypoxia.

Ischemia is characterized by relative or absolute insufficiency of blood supply, which is manifested not only by local tissue hypoxia, but also by other metabolic disorders due to insufficient intake of nutrients.

Ischemia is a dynamic and, as a rule, potentially reversible process. The likelihood of ischemic necrosis (heart attack) of the tissue directly depends on the duration and degree of decrease in local blood flow.

- 3,020,673

The myocardium is the muscle layer of the heart, which makes up its main mass. Built from a special striated muscle tissue, which is a tight connection of muscle cells. A functional feature of the myocardium is rhythmic automatic contractions, alternating with relaxation, occur continuously throughout the life of the body.

The objective of the present invention is to provide an effective pharmaceutical composition with neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity.

The problem is solved due to the fact that the pharmaceutical composition possessing neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity contains 2-ethyl-6-methyl-3-hydroxypyridine succinate, methionine-glutamistidine-phenylalanine-prolyl polypeptide (Me1-O1i-NT8-Pb-Rgo-O1u-Rgo) and differs from the prototype in that it additionally contains mineral substances in the following ratio of components in mg / l:

2-ethyl-b-methyl-3-hydroxypyridine succinate - 0.4 10 ³ - 300 10 ³ ; methionine-glutamine-histidine-phenyl alanine-prolyl-glycine proline polypeptide - 0.1-30;

potassium - 0.001 - 158.0; magnesium - 0.0001 - 70.3; Manganese - 0.001 - 7.5.

The problem is also solved due to the fact that the pharmaceutical composition having neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity contains 2-ethyl-6-methyl-3-hydroxypyridine succinate, methioninglutamine-histidine-phenylalanine-prolyl polypeptide Proline (Me1-Cl1-H18-Pb-Pro-Cl-Cl-Pro) and differs from the prototype in that it additionally contains mineral substances in the following ratio of components in mg / l:

2-ethyl-b-methyl-3-hydroxypyridine succinate - 0.4 10 ³ - 300 '10 ³ ; the methionine-glutamine-histidine-phenylalanine-prolyl-glycine proline-0.1-30 polypeptide;

potassium - 0.001 - 158.0;

magnesium - 0.0001 - 70.3; manganese is 0.001 - 7.5, and the pharmaceutical composition is designed in such a way that it contains ¹³ C carbon isotopes, and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the pharmaceutical composition is from 0.005 to 0.75.

The active ingredients in the pharmaceutical solution are the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and the methionine-glutamine-histidine-phenylalanine-prolyl-glycine proline polypeptide (Me1-C1i-H18-Pb-Rgo-C1u-Rgo).

The pharmaceutical composition is in the form of a solution, for example, in the form of a solution for injection. The pharmaceutical composition has a pH value of from 4 to 7.

The kinematic viscosity of the pharmaceutical composition, made in the form of a solution, from 1.01 to 1.23 mm ² / s The kinematic viscosity of the pharmaceutical composition is determined using a capillary viscometer.

Also, the pharmaceutical composition can be made in the form of nasal drops or a solution for oral administration (in particular, syrup, dietary supplement).

In the pharmaceutical composition, in addition to the active substances of the polypeptide, methionine-gluthingistidine-phenylalanine-prolyl-glycine-proline (or its pharmaceutically acceptable salt), the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate (or its pharmaceutically acceptable salt) and mineral substances can Use a pharmaceutically acceptable solvent. In addition to the solvent, a pharmaceutically acceptable excipient or pharmaceutically acceptable excipients may be used in the pharmaceutical composition.

As a pharmaceutically acceptable solvent, water (distilled water) as well as another solvent may be used.

Ammonium acetate, sodium disulfate (sodium metabisulfate) or another pharmaceutically acceptable substance may be used as a pharmaceutically acceptable excipient.

In other words, the basis of the pharmaceutical composition are the active substances: the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the methionine-glutamine-histidine-phenylalanine-prolyl-glycine-proline polypeptide (Me1-C1i-H18-Pb-Rgo-C1u-Rgo) and minerals in a pharmaceutically acceptable solvent, in particular in water.

In the pharmaceutical composition, the active substances and minerals are selected from the above ranges, and the rest is up to a liter of solvent.

The technical results of the invention are to increase the rate of occurrence of the therapeutic effect (decrease the time of the onset of the therapeutic effect) while maintaining the duration of action without increasing the concentration of the methionine-glutamine-histidine-phenylalanine-prolyl-glycine-proline polypeptide (Me1-O1i-NT8-Pbie-Rgo-O1u Рgo) and the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate in the treatment of disorders of the nervous system, ischemia and hypoxia of the central nervous system and myocardium, amnesia, as well as with an increase in the activity of the endogenous system and the mind nshenii intensity of free radical processes;

an increase in the therapeutic effect without an increase in the concentration of the methionine-gluthingistidine-phenylalanine-prolyl-glycine-proline polypeptide (Me1-S1c-H18-Pb-Pro-C1u-Progo) and the 2-ethyl-6-methyl-3-hydroxypyridine succinate preparation in the treatment of a nervous system disorder , ischemia and hypoxia of the central nervous system and myocardium, amnesia, as well as with an increase in the activity of the endogenous system and a decrease in the intensity of free radical processes;

increasing the stability of the pharmaceutical composition with the methionine-glutamine-histidine phenylalanine-prolyl-glycine-proline polypeptide (Me1-S1c-H18-Pb-Pro-C1u-Pro) and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate over the shelf life.

The lower limit of the content in the pharmaceutical composition of the methioninglutamine-histidine-phenylalanine-prolyl-glycine-proline polypeptide and the lower limit of the content in the pharmaceutical composition of 2-ethyl-6-methyl-3-hydroxypyridine succinate can be used to treat children and pregnant women, as well as as a part of dietary supplement.

The upper limit of the pharmaceutical composition of the polypeptide methioninglutamine-histidine-phenylalanine-prolyl-glycine-proline and the upper limit of the pharmaceutical composition of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate can be used to treat adults with severe stroke.

Pharmaceutical formulations with upper bounds for the methionine-glutamingistidine-phenylalanine-prolyl-glycine-proline polypeptide and the 2-ethyl-6-methyl-3-hydroxypyridine succinate preparation are concentrated formulations and may be diluted with a pharmaceutically acceptable solvent. Concentrated execution of pharmaceutical formulations is convenient during transportation and storage.

Currently, increasing the speed of the onset of the therapeutic effect with the introduction of drugs into the body provides the dosage of the drug and the time of its exposure;

introducing into the solution an auxiliary ingredient - an accelerator of the speed of exposure (a special case of a regulator of the speed of exposure).

Here are some examples.

A known solution (RF application No. 94015245, publ. 12/27/1995), in which a 5-10% solution of hyaluronic acid is used as a regulator of the speed of exposure.

Known pacemaker drug (RF patent No. 2068697, publ. 10.11.1996) containing green toad venom, chlorobutane dihydrate, sodium chloride and water. To increase the onset of the pacemaker effect (while maintaining the duration of action) provided by the specified poison, up to 95% ethyl alcohol is introduced into the drug. Alcohol due to osmotic phenomena causes pain and local negative reaction, which accelerates the effect of the drug.

Biologically active additives are known which, when introduced together with the active principle, increase the pharmacological activity of therapeutic drugs by optimizing the rate of assimilation of the active principle. So, polyvinylpyrrolidone and sorbic acid are additionally introduced into the antitumor agent (USSR author's certificate 1683190, publ. 20.04.1995). These components increase the antitumor activity of the active principle.

In the invention, an increase in the speed of the onset of the therapeutic effect is achieved while maintaining the duration of action without increasing the concentration of active substances in the pharmaceutical agent by introducing mineral substances into the pharmaceutical composition.

Studies have shown that the mineral substances that make up the preparations enhance their therapeutic effect. This is ensured, mainly due to a pronounced irritating effect on body tissues, as well as by exposure to the enzymatic system of the body.

For all options considered in the invention of pharmaceutical compositions, the rational ranges of the values of the content of mineral substances are as follows:

potassium - 0.001-158.0; magnesium - 0.0001 - 70.3; Manganese - 0.001 - 7.5,

These ranges partially overlap with the ranges of mineral values in dietary supplements

- 5,020,673 (see RF patent 2156087). The novelty of the invention is ensured by the use in the pharmaceutical composition of the polypeptide methionine-glutamine-histidine-phenylalanine-prolyl-glycine-proline (Me1-C1iH18-Pb-Rgo-C1u-Rgo).

When developing the invention it was found that an increase in the speed of the onset of the therapeutic effect, an increase in the therapeutic effect without increasing the concentration of the peptide Me1-C1i-H18-Pb-Pe-C1u-Prgo and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the pharmaceutical composition, increasing the stability of the pharmaceutical composition with the peptide Me1-C1i-H18-Pb-Pe-C1u-Rgo and the preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate over the shelf life is provided by the introduction of certain minerals into the pharmaceutical composition (a certain combination of mineral o) in a quantity strictly defined for each mineral. As a result of the studies, a weight range in the pharmaceutical composition was established for each mineral. The use of less than indicated in the range, the amount of mineral substance does not lead to the achievement of technical results. The use of a larger amount of a mineral substance than indicated in the range not only does not lead to the achievement of technical results, but worsens the therapeutic effect of the action of the peptide Me1-C1i-H18Pb-Rgo-C1u-Rgo and the preparation 2-ethyl-6-methyl-3- hydroxypyridine succinate. It was found that with an increase in the concentration of minerals in the pharmaceutical composition (above the stated ranges), they suppress the action of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate and the peptide Me1-C1i-H18Pbie-Rgo-C1u-Rgo, the therapeutic effect of the drug disappears.

An additional increase in the speed of the onset of the therapeutic effect, an increase in the therapeutic effect without an increase in the concentration of the Me1-C1i-H18-Pbe-Rgo-C1u-Rgo peptide and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the pharmaceutical composition, increase in the stability of the pharmaceutical composition with the Me1 peptide -C1i-H18-Pb-Rgo-C1u-Rgo and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate during the shelf life is provided by the partial replacement in the pharmaceutical composition of carbon isotopes ¹² With carbon isotopes ¹³ C.

List of drawings

In FIG. Figure 1 shows a chromatogram of a pharmaceutical composition with the Me1-C1i-H | 5-RieRgo-C1u-Rgo peptide with a UV detector (210 nm). Sorbent C18.

In FIG. Figure 2 shows a chromatogram of a pharmaceutical composition with the peptide Me1-C1i-H | 5-RieRgo-C1u-Rgo with an MS detector. A peak with a retention time of 4.096 minutes is highlighted.

In FIG. 3 shows a chromatogram of a pharmaceutical composition with the peptide Me1-C1i-H | 5-RieRgo-C1u-Rgo with an MS detector. A peak with a retention time of 4.664 minutes is highlighted.

In FIG. Figure 4 shows a chromatogram of a pharmaceutical composition with the peptide Me1-C1i-H | 5-RieRgo-C1u-Rgo with an MS detector. A peak with a retention time of 5.282 minutes is highlighted.

In FIG. Figure 5 shows a chromatogram of a pharmaceutical composition with the peptide Me1-C1i-H | 5-RieRgo-C1u-Rgo with an MS detector. A peak with a retention time of 12.163 minutes is highlighted.

In FIG. Figure 6 shows the chromatogram (left side) of the pharmaceutical composition with the Me1C1i-H18-Pbe-Prgo-C1u-Prgo peptide on a column with a chiral sorbent and with a UV detector (220 nm).

In FIG. Figure 7 shows the chromatogram (right side) of the pharmaceutical composition with the Me1C1i-H18-Pbe-Prgo-C1u-Prgo peptide on a column with a chiral sorbent and with a UV detector (220 nm). A peak with a retention time of 5.274 is highlighted.

In FIG. Figure 8 shows a chromatogram of a pharmaceutical composition with the Me1-C1i-H | 5-RieRgo-C1u-Rgo peptide on a column with a chiral sorbent and with an MS detector (220 nm). A peak with a retention time of 5.274 is highlighted.

In FIG. Figure 9 shows a chromatogram of a pharmaceutical composition with the Me1-C1i-H | 5-RieRgo-C1u-Rgo peptide on a column with a chiral sorbent and with an MS detector (220 nm). A peak with a retention time of 6.366 is highlighted.

In FIG. 10 shows a chromatogram of a pharmaceutical composition with the peptide Me1-C1i-H | 5-RieRgo-C1u-Rgo on a column with a chiral sorbent and with an MS detector (220 nm). A peak with a retention time of 7.263 is highlighted.

In FIG. 11 shows a chromatogram (left side) of the pharmaceutical composition on a column with a chiral sorbent and with a MS detector (220 nm). A peak with a retention time of 14.648 is highlighted.

In FIG. Figure 12 shows the chromatogram (right side) of the pharmaceutical composition with the Me1C1i-H18-Pbe-Prgo-C1u-Prgo peptide on a column with a chiral sorbent and with an MS detector (220 nm). A peak with a retention time of 14.648 is highlighted.

In FIG. 13 shows the MgM spectrum of the peptide Me1-C1i-H18-Pbe-Prgo-C1u-Prgo (left side) of the molecular ion with a value of Ζ = 153.5.

In FIG. Figure 14 shows the Mg Mg spectrum of the peptide Me1-C1i-H18-Pbe-Prgo-C1u-Prgo (right side) of the molecular ion with a value of Ζ = 153.5.

In FIG. 15 shows a high-resolution mass spectrum of a pharmaceutical composition with the Me1-C1i-H18-Pb-Pe-Pro-C1u-Pro peptide.

In FIG. 16 shows a chromatogram of a sample of a pharmaceutical composition with a preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate.

- 6,020,673

In FIG. 17-20 show chromatograms of a sample of a pharmaceutical composition with 2ethyl-6-methyl-3-hydroxypyridine succinate.

In FIG. 21-23 are chromatograms of a sample of a pharmaceutical composition with a preparation of 2ethyl-6-methyl-3-hydroxypyridine succinate on a chiral column.

In FIG. 24 shows a chromatogram of a sample of a pharmaceutical composition with a preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate.

In FIG. 25 represents ΜδΜδ of ion 438.7.

In FIG. 26 represents ΜδΜδ of ion 138.

In FIG. 27 presents the determination of the mass fraction of components of a sample of a pharmaceutical composition with a preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate.

In FIG. 28 shows a ¹ H-NMR spectrum of a sample of a pharmaceutical composition with a preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate in Ό2Θ.

In FIG. Figure 29 shows the ¹ H-NMR spectrum of a sample of pharmaceutical composition with a preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate in ΌΜδΘ.

In FIG. 30-32, ¹³ C-NMR spectra of a sample of a pharmaceutical composition with a preparation of 2ethyl-6-methyl-3-hydroxypyridine succinate with and without suppression are presented.

In FIG. 33 shows a ¹ H-NMR spectrum of a sample of a pharmaceutical composition with a preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate.

In FIG. 34 and 35 show high resolution mass spectra of a mixture of derivatives of a pharmaceutical composition with a preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate.

In FIG. 36 is a diagram of a cavitation reactor for isotope enrichment of various mixtures.

In FIG. 37 is a cross-sectional view of a cavitation reactor.

In FIG. 38 is a diagram of an isotope enrichment plant.

Information confirming the possibility of carrying out the invention

The invention is illustrated by the examples below.

Example 1 - a method of introducing minerals into water.

Example 2 - a method of obtaining pharmaceutical compositions and verification of stability.

Example 3 - tests for general toxicity.

Examples 4-8 illustrate the effectiveness of the claimed pharmaceutical compositions with neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity. The studies were carried out using materials published in sources (1-5). In the application, for clarity, presents a comparison of the effects of the claimed pharmaceutical formulations with the action of the drug Mexidol.

The concentrations of the ΜοΙ-ΟΙιι-Ηίδ-ΡΙιο-ΡΐΌ-ΟΙν-пепти peptide and the 2-ethyl-6-methyl-3-hydroxypyridine succinate preparation were selected so that the results could be compared with the results of using only the 2-ethyl-6-methyl-3 preparation -hydroxypyridine succinate.

Example 1. The introduction of mineral substances in solution (in water) was carried out according to the method (6). There are other ways to introduce minerals into the solution. Solutions were prepared from pure metals using pharmaceutically acceptable solvents to ensure storage stability of the solutions.

To conduct in-depth studies, when developing an application for an invention, the concentration of metals in solutions was provided in the following ranges, mg / l:

potassium - 0.001 - 158.0; magnesium - 0.0001 - 70.3; Manganese - 0.001 - 7.5.

The concentration of metals in solutions was controlled by the atomic absorption method for determining the contents of sodium, potassium, calcium, magnesium, iron, manganese, copper, zinc, lead, cadmium, cobolt, nickel, and chromium. A.1.3.2.1 source (6).

Example 2. For example, we describe the receipt of one pharmaceutical composition with potassium, magnesium, iron of a certain concentration.

4 l of water for injection is poured into a stirred reactor (5 l). Then, the peptide ΜοΙ-ΟΙιι-Ηίδ-ΡΙιο-ΡΐΌ-ΟΙν-ΡΐΌ - 0.1 mg is loaded into the reactor and the solutions are filled with mineral substances with constant stirring.

In another reactor with a stirrer (5 L volume), 4 L of water for injection is poured. Then, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate - 10,000 mg is loaded into this reactor and the solutions with mineral substances are poured with constant stirring.

Then the resulting solutions are poured into the reactor with a stirrer, the pH of the solution is adjusted to a value of 4.5. The resulting solution was adjusted to a volume of 10 l with water for injection and passed through a filter. If necessary, in order to increase or decrease the concentration of active substances, the pharmaceutical composition may be lyophilized. Reduce peptide concentration if necessary.

- 7,020,673

Me! -C1i-H18-Pb-Rgo-C1u-Rgo, a preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and mineral substances, for example, twice, 10 l of water was added to the resulting solution. The solution was mixed with water in a reactor with a stirrer with a volume of more than 22 l. Thus, all the compositions indicated in the table were obtained. 1-24.

The control showed the qualitative performance of the pharmaceutical composition.

Laboratory studies of the claimed pharmaceutical formulations have been performed.

In the application of FIG. Figures 1-35 illustrate studies of a separate solution with a preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate (Fig. 1-15) and with the peptide Me1-C1i-H18-Rie-Rgo-C1u-Rgo (Fig. 16-35) before mixing them in a 12 liter reactor.

In FIG. Figures 1-12 show chromatograms of the studied sample of the pharmaceutical composition with the peptide Me1-C1i-H18-Rie-Rgo-C1u-Rgo and minerals.

In FIG. Figures 13 and 14 show the MgM spectra of the pharmaceutical composition with the peptide Me1-O1i-H18Rie-Pro-ClO-Pro.

And in FIG. 15 shows a high-resolution mass spectrum of a pharmaceutical composition with the peptide Me1-O1i-H18-Rie-Rgo-C1u-Rgo.

In FIG. 16-24 show chromatograms of a sample of a pharmaceutical composition with 2ethyl-6-methyl-3-hydroxypyridine succinate.

In FIG. 25 and 26 represent MgM ion 438.7 and ion 138.

In FIG. 27 presents the determination of the mass fraction of components of a sample of a pharmaceutical composition with a preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate.

In FIG. 28-33 show the 'H-NMR and ¹³ C-NMR spectra of a sample of pharmaceutical composition with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate in Ό2Θ.

In FIG. 34 and 35 show high resolution mass spectra of a mixture of derivatives of a pharmaceutical composition with a preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate.

The remaining pharmaceutical compositions claimed and described in the application were also subjected to laboratory tests. Chromatograms of samples of pharmaceutical compositions with a different composition of mineral substances are similar (the differences are small and are comparable with the thick line in the graphs).

Example 3. Tests for general toxicity were carried out by intraperitoneal administration of pharmaceutical compositions based on the peptide Me1-O1i-H18-Rie-Rgo-O1u-Rgo, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals in rats.

For studies of the concentration of components in the solutions selected, mg / l 2-ethyl-b-methyl-3-hydroxypyridine succinate -300 * 10 ³ ; polypeptide methionine-glutamine-histidine-phenylalanine-prolyl-glycine proline - 30;

potassium 275.0; magnesium 105.0; Manganese - 25.5.

Lp ₅₀ is up to 1000 mg / kg when administered intraperitoneally.

With intramuscular administration, Lp ₅₀ is up to 3000 mg / kg, which allows the claimed compounds to be classified as non-toxic substances.

With prolonged use of pharmaceutical compositions based on the peptide Me1-O1i-H18-Rye-Rgo-O1uRgo, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine, succinates and minerals in rats did not reveal changes in the organs and tissues of the body (there were minor )

Example 4. The antioxidant activity of pharmaceutical compositions based on the peptide Me1-O1i-H18Rie-Rgo-01u-Rgo, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and containing ¹³ C isotopes was compared with the antioxidant activity of the drug mexidol chemiluminescent method (1).

In the pharmaceutical formulations, the content of the peptide Me1-O1i-H18-Pbe-Prgo-O1u-Prgo is 0.5 mg / l, the content of the preparation 2-ethyl-6-methyl-3-hydroxypyridine succinate is 50,000 mg / l. The preparation Mexidol contained the peptide Me1-O1i-H18-Rie-Pro-O1u-Pro - 50,000 g / l. The serial numbers of the pharmaceutical formulations 4956 (see table. 7).

The effect of Mexidol was also compared with pharmaceutical compositions based on the Me1-O1i-H18-Rie-Rgo-O1u-Rgo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and with a carbon content of ¹³ C equal to 0.5 and 75% of the total carbon in the pharmaceutical composition (see tables. 8 and 9).

The results of the comparison of pharmaceutical formulations with Mexidol are given in table. 25.

According to antioxidant activity (AOA), pharmaceutical formulations based on the Me1-O1i-Ht8-Pbe-Rgo-O1u-Rgo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals were found to be superior to mexidol by the amount of up to 24%.

- 8,020,673

It was also found that, according to their antioxidant activity, pharmaceutical compositions based on the Me1-O1i-H18-Pbe-Pro-O1u-Progo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and with a carbon isotope content of ¹³ C to 75% of the total carbon in the pharmaceutical composition was generally superior to mexidol by up to 29%.

Pharmaceutical formulations with serial numbers 49, 57 and 65 did not exceed Mexidol.

Pharmaceutical formulations with serial numbers 55 and 56 by AOA practically did not exceed the pharmaceutical composition with serial number 54.

Pharmaceutical formulations with serial numbers 63 and 64 by AOA did not exceed the pharmaceutical composition with serial number 62.

Pharmaceutical formulations with serial numbers 71 and 72 in terms of AOA did not exceed the pharmaceutical composition with serial numbers 70. Formulations 71 and 72 showed a slight decrease in AOA.

Therefore, pharmaceutical formulations with serial numbers 55 and 56, 63 and 64, 71 and 72 to use as an antioxidant agent is not economically feasible (costly). In addition, for AOA, compositions with serial numbers 56, 64, and 72 were somewhat inferior to Mexidol. AOA of pharmaceutical formulations with serial numbers 169-192 was also investigated.

It was found that in terms of antioxidant activity, these pharmaceutical formulations generally exceeded Mexidol by up to 5%.

Studies on the antioxidant activity of pharmaceutical compositions were also carried out according to the methodology (8). The results are similar to the above.

Example 5. Antihypoxic and neurometabolic activity of pharmaceutical compositions based on the peptide Me1-C1i-H | 5-RNe-Rgo-C1u-Rgo. the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes containing ¹³ C were compared with the activity of the drug mexidol.

Comparisons were made on nonlinear white mice (males) weighing 25-27 g for acute hypoxia (9,

10).

Acute hypoxia (normobaric hypoxic hypoxia) was modeled by placing mice in a 250 cm ³ heat chamber.

In the experiments, the lifespan of animals was recorded after the cessation of air access to the heat chamber. Animals were placed in a heat chamber individually.

Mexidol was administered once intraperitoneally 30, 60 and 90 minutes before placing the mice in the heat chamber and stopping air from entering the heat chamber.

The time from the moment of drug administration to the placement of mice in a heat chamber and cessation of air access in the table is indicated by TV in minutes.

Each of the pharmaceutical compositions based on the peptide Me1-O1i-H18-Pb-Prgo-O1u-Prgo, the preparation of 2ethyl-6-methyl-3-hydroxypyridine, succinates and minerals was administered once intraperitoneally also 30, 60 and 90 min before placing the mice in thermal chamber and the termination of access of air to the thermal chamber.

After placing the mice in a heat chamber, as oxygen was consumed, its concentration in the air and in the body of the mice decreased, and the amount of carbon dioxide increased. As a result, animals developed acute hypoxic hypoxia. Life expectancy (until breathing stopped) was recorded using a stopwatch, and the effectiveness of the tested drugs was judged by its increase.

Comparison results of the antihypoxic and neurometabolic activity of pharmaceutical formulations based on the Me1-O1i-H18-Pbie-Rgo-O1u-Rgo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and ¹³ C carbon isotopes containing the antihypoxic activity of the drug are given in table. 26-29.

Using a model of acute normobaric hypoxic hypoxia (in a heat chamber), it was found that most pharmaceutical formulations based on the Me1-O1i-H18-Pbie-Prgo-O1u-Rgo peptide, the 2ethyl-6-methyl-3-hydroxypyridine succinate and mineral substances increased the duration mice up to 16% compared with mexidol.

An increase in the speed of the onset of the therapeutic effect was established while maintaining the duration of action without increasing the concentration of the pharmaceutical agent. This is clearly seen in the table. 29. The claimed drugs increase the onset of the therapeutic effect, which brings together the values of life expectancy at Tv = 30 min and Tv = 60 and 90 min.

An increase in the therapeutic effect was achieved without increasing the concentration and amount of the Me1-C1i-H | 5-RNe-Rgo-C1u-Rgo peptide and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate.

Comparisons were also made on models of acute hypobaric hypoxia in an exhaust pressure chamber with imitation of raising animals at a speed of 50 m / s to a height of 11,000 m; acute hemic hypoxia and acute histotoxic hypoxia.

The results of these comparisons are similar to those obtained in the acute normobaric hypoxic hypoxia model.

In addition, studies have been conducted to increase the concentration of the peptide Me1-C1i-H®-PH-9 020673

Рgo-С1у-Рго up to the value of 30 mg / l and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate up to the value of 300 g / l. An increase in the efficiency of action was observed compared with the best pharmaceutical compositions mentioned above based on the peptide Me1-O1i-H18-Pbe-Prgo-O1y-Prgo and the preparation 2-ethyl-6-methyl3-hydroxypyridine succinate. However, the increase in efficiency did not exceed 3-5%. An increase in the concentration of the Me1-O1i-H18-Pbe-Pro-O1u-Pro peptide of more than 30 mg / l, in particular up to 100 mg / l, did not lead to an increase in efficiency compared to the best pharmaceutical formulations.

Also, the effectiveness of Mexidol was compared with the effectiveness of the pharmaceutical compositions No. 1-48. It was found that compounds No. 1-24 exceeded the effect of Mexidol by about 3%. Compositions 25-48 in their effect exceed the effect of Mexidol by no more than 5%.

Example 6. The neuroprotective effect of pharmaceutical compositions based on the peptide Me1-O1i-H1krye-Rgo-01u-Rgo, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and containing ¹³ C carbon isotopes was compared with the neuroprotective effect of the drug mexidol .

When comparing the content of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate - 10 g / l, the peptide Me1-O1c-H15-Pb-Rgo-O1u-Rgo - 0.1 mg / l, Mexidol - 10 g / l (diluted with water 1: 5).

Comparative studies were performed on white non-linear male rats weighing 250-270 g, in which ischemic stroke and hemorrhagic stroke were simulated.

Ischemic stroke in rats was reproduced by bilateral ligation of the common carotid arteries. The experimental animals were injected intraperitoneally with Mexidol and the claimed pharmaceutical formulations with serial numbers from 25 to 48. The characteristics of these pharmaceutical formulations are given in table.

4-6.

Animals after surgery were observed for 2 weeks, taking into account the survival of rats. Neurological deficit in animals was determined every hour during the first 24 hours, and then 1 time per day. The severity of the condition was determined by the sum of the corresponding points.

The results of the study of the neuroprotective effects of drugs are presented in table. 30. An analysis of the results shown in the tables showed that in rats who received intraperitoneal injection of mexidol, the neurological deficit was most pronounced (5.3 ± 0.1 points) 3, 4, and 5 days after bilateral ligation of the common carotid arteries. The number of rats in the experiment is 12. Of these, 2 animals died (16.67%).

In experiments, it was found that the compositions based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1i-H15-Pbie-Prgo-O1u-Prgo, mineral substances and carbon isotopes ¹³ C in doses of 20 mg per day on the rat have a pronounced neuroprotective effect, generally superior in severity to the action against neurological deficiency of mexidol.

Twenty four experiments were performed with rats that received an intraperitoneal pharmaceutical composition based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-C1i-H | 5-RNe-Rgo-C1u-Rgo. mineral substances and carbon isotopes ¹³ C. The number of rats in each experiment is 12. In the experiments 10-15% of animals died.

Pharmaceutical formulations with serial numbers 25, 33 and 41, as well as 31, 32, 39, 40, 47, 48 do not exceed Mexidol in the neuroprotective effect (see Table 30). The neuroprotective effects of the remaining compounds are superior to the neuroprotective effect of Mexidol.

The most pronounced neuroprotective effect in pharmaceutical formulations with serial numbers 29, 30, 37, 38, 45, 46.

However, the following should be considered. The pharmaceutical composition 30 in its neuroprotective effect does not exceed the composition 29. Therefore, the composition 30 is not advisable to use.

The pharmaceutical composition 38 in its neuroprotective effect does not exceed the composition 39. Therefore, the composition 38 is not advisable to use.

Pharmaceutical composition 46 in its neuroprotective effect does not exceed composition 45. Therefore, composition 46 is not advisable to use.

Hemorrhagic stroke (GI) in rats was reproduced by modeling local hemorrhage in the brain (creating GI with cerebral ischemia), was performed according to the method (11). In accordance with the method, rat craniotomy and brain tissue destruction were performed in the area of the internal capsule with the subsequent injection of the same rat into the site of blood damage (0.03 ml of blood). Thus, a stroke was achieved in the area of the internal capsule with virtually no damage to neighboring brain tissues.

The pharmaceutical composition based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1i-H18-Pbe-Pro-O1u-Pro, mineral substances and carbon isotopes ¹³ C was administered to animals intraperitoneally at a dose of 20 mg per day a rat. Mexidol was also administered intraperitoneally to animals at a dose of 20 mg per day in rats. The administration schedule was as follows: the first injection was carried out 2 hours after the operation, then 3 injections after 4 hours. Then the pharmaceutical composition based on the preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate, the peptide Me1-O1i-H18-Pb-Prgo-O1u -Rgo and minerals, as well as Mexidol was administered daily once a day for 14 days.

Within 14 days after the operation, coordination of movements on a rotating rod for 2 min and the ability of the drugs to increase the survival of animals were evaluated (see table. 31).

It has been established that pharmaceutical formulations with serial numbers 25, 33 and 41, 31, 32, 39, 40, 47,

- 10 020673 in coordination of movement on a rotating rod practically do not surpass Mexidol. The neuroprotective effects of the remaining compounds are superior to the neuroprotective effect of the drug mexidol.

The coordination of rat movement increases markedly when using formulations with serial numbers 28-30 (see the characteristics of the compositions in Table 4), 36-48 (see the characteristics of the compositions in Table 5), 44-46 (see the characteristics of the compositions in Table. 6). However, the following should be considered.

The pharmaceutical composition 30 in its neuroprotective effect does not exceed the composition 29. Therefore, the composition 30 is not practical to use.

The pharmaceutical composition 38 in its neuroprotective effect does not exceed the composition 37. Therefore, the composition 38 is not practical to use.

Pharmaceutical composition 46 in its neuroprotective effect does not exceed composition 45. Therefore, composition 46 is not practical to use.

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1i-NT8-Pbe-Prgo-O1y-Prgo, mineral substances and carbon isotopes ¹³ C increase (compared with mexidol) rat survival after operations.

In addition, studies have been conducted to increase the concentration of the drug 2-ethyl-6-methyl3-hydroxypyridine succinate to 300 g / l and above, the peptide Me1-O1i-H18-Pb-Rgo-O1u-Rgo to a value of 30 mg / l and above . There was an increase in the effectiveness of the compositions with increased concentrations compared to the best pharmaceutical compositions mentioned above based on the preparation of 2ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1c-H18-Pb-Rgo-O1u-Rgo (see table. 30) . Effectiveness increased by 3-5%. A further increase in the concentration of the preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate and the Me1-O1c-H18-Pbe-Pro-O1u-Pro peptide led to a decrease in efficiency compared to the best pharmaceutical formulations mentioned above.

Also, the effectiveness of Mexidol was compared with the effectiveness of the pharmaceutical compositions No. 1-48, 169-192. It was found that compounds No. 1-24, 169-192 exceeded the effect of Mexidol by about 3%. Compositions 25-48 in their effect exceed the effect of Mexidol by no more than 5%.

Example 7. Antiamnestic effect of pharmaceutical formulations based on the preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate, the peptide Me1-C1i-H | 5-RNe-Rgo-C1u-Rgo. mineral substances and carbon isotopes ¹³ C were compared with the anti-amnestic effect of the drug mexidol.

Comparisons were made on white non-linear mice (males) weighing 25-27 g.

The effect of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1c-H18-Pbe-Pro-O1u-Pro, mineral substances and carbon isotopes ¹³ C and the drug mexidol on amnesia (learning processes and memory) in mice was investigated using a conditioned reaction of passive avoidance of electrodermal irritation. Mice were exposed to electroconvulsive shock (current of 30 mA for 0.3-0.5 s to the auricles) immediately after learning the conditioned passive avoidance reaction (model of amnesia caused by electroconvulsive shock) (10, 12).

The effect of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1c-H18-Pbe-Pro-O1u-Pro, mineral substances and carbon isotopes ¹³ C and the drug mexidol on amnesia was also evaluated on the model scopolamine amnesia after learning a conditioned passive avoidance reaction (10).

The drugs were administered once intraperitoneally 30, 60 and 90 minutes before the training of mice. The safety of the conditioned reaction of passive avoidance was checked 24 hours after the amnesiac effect.

On the model of amnesia caused by electroconvulsive shock, it was found that in mice pharmaceutical compositions based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-C1iH18-Pb-Rgo-O1u-Rgo, minerals and carbon isotopes ¹³ C, as well as the drug Mexidol actively prevent the development of amnesia of the conditioned reaction of passive avoidance (see table. 32).

Table analysis 32 shows that pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-O1i-H18-Pbe-Prgo-O1u-Prgo peptide, mineral substances and ¹³ C carbon isotopes increase the onset of the therapeutic effect while maintaining the duration actions without increasing the concentration of active substances in a pharmaceutical agent.

The above effects can be achieved through the use of Mexidol by increasing the dose of Mexidol or its concentration in the dose. In the experiments (see table. 32), the amount of Mexidol was increased from 20 to 40 mg per mouse.

On the model of scopolamine amnesia, it was found that in mice pharmaceutical compositions based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1i-H18-Pbe-Prgo-O1u-Rgo, mineral substances and carbon isotopes ¹³ C , as well as the drug Mexidol also prevent the development of amnesia of the conditioned reaction of passive avoidance (see table. 33).

Pharmaceutical formulations based on the peptide of the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, Me1-O1i-H18-Pbe-Prgo-O1u-Prgo, mineral substances and carbon isotopes ¹³ C increase the onset of the therapeutic effect while maintaining the duration of action without increasing the concentration of the pharmaceutical.

- 11,020,673

An increase in the speed of the onset of the therapeutic effect and an increase in the therapeutic effect due to the use of Mexidol can be achieved by increasing its amount in the injection.

Example 8. The anti-ischemic effect of pharmaceutical compositions based on the peptide Mc1-C1i-NkRie-Rgo-01u-Rgo, minerals and carbon isotopes ¹³ C was compared with the anti-ischemic effect of the drug mexidol. The comparison results are presented in table. 34 and 35.

Studies were conducted on white non-linear mice (males) weighing 35-37 g.

Brain ischemia was reproduced by ligation of both common carotid arteries. Animals after surgery were observed for 7 days. Pharmaceutical formulations based on the preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate, the Me1-O1i-H18-Rye-Prgo-O1u-Prgo peptide and minerals, and the preparation Mexidol were administered intraperitoneally for 7 days. On the first day, drugs were administered twice: immediately after surgery and 3 hours after surgery. In the second, third, etc. until the seventh day, the drugs were administered once a day.

After bilateral ligation of the common carotid arteries (and not using the above drugs), more than 90% of the mice died during the observed days.

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-S1c-H18-Rie-Pro-S1u-Pro, mineral substances and carbon isotopes ¹³ C, as well as the drug mexidol significantly increased the survival of mice in observation period. The concentration of the peptide Me1-O1i-H18-Rye-Pro-Og-Og-Rgo ranged from 0.1 to 30 mg / L. The concentration of the preparation 2-ethyl-6methyl-3-hydroxypyridine succinate was 1 and 300 g / l. From the table. 34 and 35 it can be seen that the survival rate of mice when using the majority of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1i-H18-Rie-Rgo-O1u-Rgo, mineral substances and carbon isotopes ¹³ C higher than the survival of mice when using Mexidol.

At present, ¹³ C carbon isotopes in the world are widely used in biochemistry and medicine for diagnostics. The application presents the results of our own studies on the effect of ¹³ C carbon isotopes on the stability and effectiveness of drug formulations based on the Me1-C1nH18-Rie-Rgo-C1u-Rgo peptide and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate.

It was found that increasing the stability of the claimed pharmaceutical composition over the expiration date can be achieved by replacing (from 0.5 to 75%) carbon isotopes of ¹² C with carbon isotopes of ¹³ C. It has been established that carbon isotopes of ¹³ C in the molecules of the Me1-O1i peptide -H18-Rye-Rgo-O1y-Rgo and 2-ethyl-6-methyl-3-hydroxypyridine succinate molecules slow down the chemical reactions occurring in the molecules, form stronger covalent bonds than carbon isotopes ¹² C.

Carbon isotopes ¹³ C increase the resistance of molecules to the oxidative effects of radicals.

Carbon isotopes ¹³ C are not toxic. The experiments show that feeding mice and rats with foods enriched with 75% ¹³ C carbon does not lead to side effects and poor health.

In the process of experimental verification of the claimed pharmaceutical compositions enriched in ¹³ C carbon isotopes, it was found that these compositions have increased stability, they are non-toxic and, in addition, have increased neuroprotective, antiamnestic, antioxidant, antihypoxic, anti-ischemic activity compared to the pharmaceutical composition, in which isotopes of carbon ¹³ C.

Methods for the production of stable highly enriched non-radioactive carbon isotope ¹³ C are widely used in Russian and world industry. Well developed methods for producing carbon isotope ¹³ C by gas diffusion through the porous walls, the diffusion in a vapor stream, thermal and distillation method, an isotope exchange, centrifugation, electrolysis, genetic engineering and others. A brief description of these techniques is provided in the source (13).

At the Moscow State Academy of Fine Chemical Technology. Lomonosova M.V. They are working out modern nanotechnologies for producing and incorporating atoms of stable carbon ¹³ C isotopes into molecules of various structures. At the academy, molecules of isotopically labeled compounds with various levels of isotope enrichment are obtained - from fractions of a percent to one hundred percent of isotopes in a substance. The work is in the interests of medical diagnosis. The source (14) contains 165 references to foreign sources of information on the isotope enrichment of various substances.

In turn, the authors actively participated in the work on the isotopic enrichment of hydrocarbons, as well as reagents for the production of various drugs. The reagents were enriched with ¹³ C carbon isotopes (replacing ¹² C carbon isotopes with ¹³ C carbon isotopes) in a cavitation reactor designed by Professor V. I. Kormilitsyn. (Moscow Energy Institute Technical University).

The reactor was manufactured according to the procedure given in the source (15). The flow velocity in the reactor, along the length of the channel, varied from 10 to 50 m / s.

In FIG. 36 is a diagram of a cavitation reactor for isotope enrichment of various mixtures, in particular hydrocarbon reagents for the preparation of the peptide Me1-O1i-H18-Rie-Rgo-O1u-Rgo and 2ethyl-6-methyl-3-hydroxypyridine succinate enriched in ¹³ C. carbon isotopes located

- 12 020673 in the installation, which contains the pump 6NK-6x1, providing a maximum flow rate of 90 m ³ / h, a pressure of 125 m with an electric motor power of 75 kW, a rotational speed of the electric motor rotor and pump wheel 2950 rpm. Additionally, the installation contains tanks for reagents and measuring instruments.

The enrichment of 2-ethyl-6-methyl-3-hydroxypyridine succinate with ¹³ C isotopes of carbon is carried out similarly.

The installation diagram is shown in FIG. 38.

The cavitation reactor 1 (see Fig. 36) is made in the form of a flat Laval nozzle with cavitation bodies 2-9 in the channel 10.

In FIG. 37 is a cross-sectional view of a cavitation reactor. The reactor channel in the area of cavitation bodies is divided into several channels. For example, cavitation bodies 5 and 6 divide the channel into smaller channels 13, 14 and 15. Outside, the channel is limited by walls 16 and 17, as well as two covers 11 and 12.

In FIG. 16, arrows 18 show the direction of movement of the reagent at the inlet to the reactor, arrow 19 shows the direction of movement of the reagent at the outlet of the reactor.

In the wall 16, channels 24 and 25 are made for supplying carbon dioxide and nitrogen to the cavitation zones.

Installation works as follows. The hydrocarbon reagent from the tank 28 is pumped through the reactor 27 through the pump 27 and enters the tank 28. The pressure drop in the reactor is controlled by pressure gauges 29 and 30. The temperature of the reactant is monitored by thermometer 31. The reagent is heated in the tank by a heater 32.

When the reactor is operating, the hydrocarbon reagent moves along the cavitator channel in direction 18. When flowing around cavitation bodies, the stream is divided into several streams. Beyond the cavitation bodies, cavitation areas arise. In particular, behind the bodies (if you look in the direction of movement of the reagent) cavitation 2, 3, and 4 are cavitation zones 20, 21, 22, and 23. Upon entering the cavitation region, the reagent boils, cavitation bubbles appear, and cavitation bubbles collapse when leaving the cavitation region . Moreover, in the area (in the place) of the collapse of the cavitation bubble, an increase in pressure is observed to several thousand atmospheres and an increase in temperature to a thousand or more degrees Celsius. Through channels 24 and 25, carbon dioxide is supplied to the stream so that the gas enters the cavitation zone.

The gas-vapor mixture obtained in the reactor, together with the liquid reagent, enters the vessel 28. Next, the gas-vapor mixture is passed through a pipe 33 to a separator with a porous partition, where the gas-vapor mixtures with ¹³ C and ¹² C are separated.

In the experiments, the reactor worked from several hours to several days. A direct dependence of the degree of enrichment of the vapor-gas mixture and the reagent with the ¹³ C isotope ^{on the} operating time of the cavitation reactor is established.

The amount of ¹³ C carbon isotopes was controlled by high resolution mass spectroscopy.

As a result of the experiments, the reagent was enriched with the ¹³ C carbon isotope to 75%.

Thus, pharmaceutical compositions were obtained containing the peptide Me1-O1i-HT8-PbErgo-O1y-Prgo with a carbon isotope content of ¹³ C from 0.5 to 75% of the total carbon in the pharmaceutical composition.

The enrichment of 2-ethyl-6-methyl-3-hydroxypyridine succinate with ¹³ C isotopes of carbon is carried out similarly.

Thus, the implementation of the claimed pharmaceutical compositions provides an increase in the speed of the onset of the therapeutic effect (decrease in the time of the onset of the therapeutic effect) while maintaining the duration of action without increasing the concentration of the methionine-glutamine-histidine-phenylalanine-prolyl-glycine-proline polypeptide (Me1-O1i-H18-Pb -Rgo-O1u-Rgo) and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the treatment of disorders of the nervous system, ischemia and hypoxia of the central nervous system and myocardium, amnesia, as well as with an increase ktivnosti endogenous system and amelioration of free radical processes;

an increase in the therapeutic effect without increasing the concentration of the methionine-gluthingistidine-phenylalanine-prolyl-glycine-proline polypeptide (Me1-O1i-H18-Pb-Pro-O1y-Progo) and the preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate in the treatment of nervous system disorders , ischemia and hypoxia of the central nervous system and myocardium, amnesia, as well as with an increase in the activity of the endogenous system and a decrease in the intensity of free radical processes;

increasing the stability of the pharmaceutical composition with the methionine-glutamististidine-phenylalanine-prolyl-glycine-proline polypeptide (Me1-O1i-H18-Pbie-Prgo-O1y-Progo) and 2-ethyl-6methyl-3-hydroxypyridine succinate over the expiration date.

- 13,020,673

Table 1. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-S1c-H18-Pb-Pe-Pro-S1u-Progo peptide and minerals

Mineral substance The serial number of the pharmaceutical composition with 1 gram of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligram of the peptide Me1-O1i-H15-P11e-Rgo-O1u-Rgo in liter Τ ' 2 3 4 5 6 7 8 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

*) the numbering of pharmaceutical formulations is through

Table 2. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 0.5 % of total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 1 gram preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligram of the peptide Me1-01i-H1z-Pb-Rgo-01u-Rgo in liter nine 10 eleven 12 thirteen 14 fifteen sixteen Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 3. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-C1i-H18-Pbie-Prgo-C1u-Prgo, minerals and with a carbon content of ¹³ C equal to 75% of total carbon in pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 1 gram preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligram peptide Me1-O1i-H15-Pb-Pe-Prg-O1u-Prgo in liter 17 eighteen nineteen twenty 21 22 23 24 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.0! 7.5 25.5 55.0 99.0

Table 4. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-S1c-H18-Pb-Pe-Pro-S1u-Progo peptide and minerals

Mineral substance The serial number of the pharmaceutical composition with 10 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligrams of the Me1-C1i-H1z-Pb-Pe-Prgo-C1u peptide RGO in liter 25 26 27 28 29th thirty 31 32 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 5. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 0.5 % of total carbon in the pharmaceutical composition

Mineral substance The serial number of the pharmaceutical composition with 10 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligram peptide Me1-O1i-H15-RNe-Progo-O1- RGO in liter 33 34 35 36 37 38 39 40 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200,0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

- 14,020,673

Table 6. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 75% of total carbon in pharmaceutical composition

Mineral substance The serial number of the pharmaceutical composition with 10 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligrams of the peptide Me1-O1i-H15-Pb-Pro-O1- RGO in liter 41 42 43 44 45 46 47 48 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 7. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-C1i-H18-Pbie-Prgo-C1u-Prgo and minerals

Mineral substance Serial number of pharmaceutical composition with 50 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.5 milligrams of the peptide Me1-O1i-H18-Pb-Pro-O1- RGO in liter 49 fifty 51 52 53 54 55 56 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 8. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 0.5 % of total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 50 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.5 milligrams of the peptide Me1-O1i-H1z-Pbe-Prgo-O1u RGO in liter 57 58 59 60 61 62 63 64 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 9. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 75% of total carbon in pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 50 grams of 2-ethyl-6-megyl-3-hydroxypyridine succinate and 0.5 milligrams of the peptide Me1-O1i-H15-Pb-Prgo-O1- RGO in liter 65 66 67 68 69 70 71 72 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

- 15,020,673

Table 10. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me!

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 3 milligrams of the peptide Me1-01i-H13-Pb-Rgo-01- RGO in liter 73 74 75 76 77 78 79 80 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 11. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me! -C1i-H18-Pbe-Prgo-C1u-Prgo, mineral substances and with a carbon content of ¹³ C equal to 0, 5% of all carbon in pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 3 milligrams of the peptide Me1-O1i-Ng5-Pb-Prgo-O1- RGO in liter 81 82 83 84 85 86 87 88 Potassium, mg / L 0.0001 0.001 0.1 1,63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 12. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me! -C1i-H18-Pbe-Prgo-C1u-Prgo, mineral substances and with a carbon content of ¹³ C equal to 75% total carbon in pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 3 milligrams of the Me1-O1i-H1z-RNe-Progo-C1u peptide RGO in liter 89 90 91 92 93 94 95 96 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 13. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me! -C1i-H18-Pbie-Progo-C1u-Progo and minerals

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-megyl-3-hydroxypyridine succinate and 10 milligrams of the peptide Me1-C1i-H1z-Pb-Rgo-O1- RGO in liter 97 98 99 one hundred 101 102 103 104 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

- 16,020,673

Table 14. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-C1i-H18-Pbie-Prgo-C1u-Prgo, minerals and with a carbon content of ¹³ C equal to 0.5 % of total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-b-methyl-3-hydroxypyridine succinate and 10 milligrams of the peptide Me1-O1i-H15-Pb-Prgo-C1u RGO in liter 105 106 107 108 109 110 W 112 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 15. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 75% of total carbon in pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-b-methyl-3-hydroxypyridine succinate and 10 milligrams of the peptide Me1-01i-Sh5-Pb-Rgo-01- RGO in liter 113 114 115 116 117 118 119 120 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Mar ganets, mg / l 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 16. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-S1c-H18-Pb-Pe-Pro-S1u-Progo peptide and minerals

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-b-methyl-3-hydroxypyridine succinate and 30 milligrams of the peptide Me1-C1i-H15-Pb-Prgo-O1- RGO in liter 121 122 123 124 125 126 127 128 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 17. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 0.5 % of total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-b-megyl-3-hydroxypyridine succinate and 30 milligrams of the peptide Me1-O1i-H15-Pb-Prgo-O1- RGO in liter 129 130 131 132 133 134 135 136 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

- 17,020,673

Table 18. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 75% of total carbon in pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 30 milligrams of the Me peptide (-O1i-H13-Pb-Prgo-O1- RGO in liter 137 138 139 140 141 142 143 144 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 19. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-C1i-H18-Pbie-Prgo-C1u-Prgo and minerals

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligram of the peptide Me1-O1n-H15-Pb-Pro-O1- RGO in liter 145 146 147 148 149 150 | 151 152 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 20. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbie-Prgo-C1u-Prgo peptide, mineral substances and with a carbon content of ¹³ C equal to 0.5 % of total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligrams of the peptide MeRSNi-Sz-Pb-Pro-CHO- RGO in liter 153 154 155 156 157 158 159 160 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 21. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-C1i-H18-Pbie-Prgo-C1u-Prgo, minerals and with a carbon content of ¹³ C equal to 75% of total carbon in pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate and 0.1 milligrams of the peptide MeRO1i-H1z-Pb-Pe-O1- RGO in liter 161 162 163 164 165 166 167 168 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

- 18,020,673

Table 22. Pharmaceutical formulations based on 2-ethyl-6-methyl-3-hydroxypyridine succinate, ΜοΜ-ΟΙιι-Ηίδ-ΡΙιοΡΓΟ-ΟΙν-пепти peptide and minerals

Mineral substance Serial number of the pharmaceutical composition with 0.4 grams 2-ethyl-b-methyl-3-hydroxypyridine succinate and 0.1 milligram of the peptide Me1-O1i-H1z-Pb-Rgo-O1u-Prgo in liter 169 170 171 172 173 174 175 176 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 23. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, ΜοΙ-ΟΙιι-Ηίδ-ΡΙιο-ΡΐΌ-ΟΙν-пепти peptide. mineral substances and with a carbon isotope content of ¹³ C equal to 0.5% of the total carbon in the pharmaceutical composition

Mineral substance Serial number of the pharmaceutical composition with 0.4 grams 2-ethyl-b-methyl-3-hydroxypyridine succinate and 0.1 milligram of the peptide Me1-O1i-H1z-Pb-Rgo-O1u-Prgo in liter 177 178 179 180 181 182 183 184 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

Table 24. Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, Μβΐ-ΟΙυ-Ηίδ-ΡΗβ-ΡΓΟ-ΟΙγ-ΡΓΟ peptide, mineral substances and with a carbon content of ¹³ C equal to 75% of total carbon in pharmaceutical composition

Mineral substance Serial number of the pharmaceutical composition with 0.4 grams 2-ethyl-b-methyl-3-hydroxypyridine succinate and 0.1 milligram peptide Me1-O1i-H1z-Pbe-Pro-O1u-Pro in liter 185 186 187 188 189 190 191 192 Potassium, mg / L 0.0001 0.001 0.1 1.63 158.0 275.0 530.0 880.0 Magnesium, mg / L 0.00001 0.0001 0.001 0.28 70.3 105.0 200.0 330.0 Manganese, mg / L 0.0006 0.001 0.005 0.01 7.5 25.5 55.0 99.0

- 19 020673

Table 25. Comparison of the antioxidant activity of Mexidol containing 2-ethyl-6methyl-3-hydroxypyridine succinate 50 g / L with the antioxidant activity of pharmaceutical formulations based on 2-ethyl-6-methyl-3-hydroxypyridine succinate, Me1-O1 and peptide -Н18-Ре-Рго-О1у-Рго, mineral substances, as well as those containing ¹³ С carbon isotopes (serial numbers of pharmaceutical compositions 49-72)

Serial number pharmaceutical composition with 50 grams 2-ethyl-6- methyl 3- hydro ksipir idina succinate, 0.5 grams of peptide Me1-O1i-H1z-Pb-Rgo- O1u-Rgo in liter Antioxidant activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-O1i-H15-Pbie-Prgo- <31y-Prgo, mineral substances and carbon isotopes ^{| 3} C, Services Antioxidant Mexidol activity containing 2-ethyl-b- methyl 3- hydroxypyridine succinate - 50g / l, Service unit 49 3.51 3.50 fifty 3.88 51 3.97 52 4.25 53 4.38 54 4.38 55 3.55 56 3.49 57 3.51 58 3.89 59 3.99 60 4.28 61 4.41 62 4.41 63 3.51 64 3.48 65 3.51 66 3.91 67 4.05 68 4.35 69 4.53 70 4.53 71 3.50 72 3.49

Table 26. Results of checking the antihypoxic activity of the drug mexidol, dose) 100 mg (one ampoule containing the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate - 50 g / l)

Time from the moment of introduction preparation before placing mice into the heat chamber and termination air access (TV), min Life span, min thirty 33.7 *) **) 60 37.5 90 38.1

*) the dose of the drug per mouse **) the average time for the tested mice in the experiment

- 20,020,673

Table 27. The results of testing the antihypoxic activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the peptide Me1-C1i-H18-Pb-Rgo-C1u-Rgo and minerals. Dose 100 mg. Average life, min

Time Tv min Serial number of the pharmaceutical composition with 50 grams preparation of 2-ethyl-b-methyl-3-hydroxypyridine succinate and with 0.5 milligrams of the peptide Me1-C1i-H15-Rb-Rgo-C1u-Rgo in liter 49 fifty 51 52 53 54 55 56 thirty 33.6 36.5 37.5 38.1 38.7 38.7 38.7 33.1 60 37.4 37.8 38.5 39.1 43.1 43.1 43.1 37.0 90 38.0 39.5 41.5 42.3 43.8 43.8 43.8 38.0

Table 28. Results of testing the antihypoxic activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbe-Rgo-C1u-Rgo peptide, mineral substances and carbon isotopes ¹³ C. The dose of the drug 100 mg

Average life, min

Time Tv min Serial number of the pharmaceutical composition with 50 grams preparation of 2-ethyl-b-methyl-3-hydroxypyridine succinate and with 0.5 milligrams of the peptide Me1-01i-H15-Rb-Rgo-01u-Rgo in liter 57 58 59 60 61 62 63 64 thirty 33.6 36.5 37.6 38.3 38.9 38.9 33.6 33.1 60 37.4 37.8 38.6 39.3 43.3 43.3 37.5 37.0 90 38.0 39.5 41.6 42.5 43.8 43.8 38.1 38.0

Table 29. Results of testing the antihypoxic activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, the Me1-C1i-H18-Pbe-Rgo-C1u-Rgo peptide, mineral substances and carbon isotopes ¹³ C. The dose of the drug 100 mg

Average life, min

Time Tv min Serial number of the pharmaceutical composition with 50 grams preparation of 2-ethyl-b-methyl-3-hydroxypyridine succinate and with 0.5 milligrams of the peptide Me1-O1i-H18-P11e-Pro-O1u-Pro in liter 65 66 67 68 68 70 71 72 thirty 33.6 36.5 37.9 38.8 41.9 41.9 33.6 33.1 60 37.4 37.8 38.6 39.5 43.7 43.7 37.5 37.0 90 38.0 39.5 41.6 42.7 44.1 44.1 38.1 38.0

- 21 020673

Table 30. Results of testing the neuroprotective effect (on the model of ischemic stroke) of pharmaceutical formulations based on the Me! -O1i-H18-Pbie-Rgo-O1u-Rgo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes ¹³ C and the neuroprotective effect of the drug mexidol. Measurements in points, M ± t, where t = 0.1

A drug, ordinal number pharmaceutical composition, dose 20 mg per day for the rat Time after surgery, hour (day) 12 hour. 24 tea. 2 day 3 day 4 day 5 day 6 day 10 day 12 day 14 day Mexidol Mexidol, 20 mg 5.0 5.1 5.3 5.3 5.3 5.3 5.2 5.1 5.0 5.0 Pharmaceutical formulations based on the peptide Me1-O1i-H15-Pb-Rgo-O1u-Rgo, 2-ethyl-b-methyl-3-hydroxypyridine succinate and minerals Farm. composition No. 25 5.0 5.1 5.2 5.3 5.4 5.3 5.2 5.1 5.0 5.0 Farm. composition No. 26 4.7 4.7 4.7 4.7 4.7 4.6 4.5 4.4 4.4 4.3 Farm. composition No. 27 4.5 4.5 4.6 4.6 4.6 4.5 4.5 4.5 4.5 4.5 Farm. composition No. 28 4.3 4.4 4.6 4.6 4.6 4.5 4.4 4.4 4.4 4.4 Farm. composition No. 29 4.2 4.3 4.4 4.5 4.5 4.5 4.4 4.3 4.3 4.3 Farm. composition No. 30 4.2 4.3 4.4 4.5 4.5 4.5 4.4 4.3 4.3 4.3 Farm. composition No. 31 5,0 5.1 5.2 5.3 5.4 5.3 5.2 5.1 5,0 5.0 Farm. composition No. 32 5.1 5.1 5.2 5.4 5.4 5.4 5.3 5.2 5.1 5.0 Farm. composition No. 33 5.0 5.1 5.2 5.3 5.4 5.3 5.2 5.1 5,0 5.0 Farm. composition No. 34 4.7 4.7 4.7 4.7 4.7 4.6 4.5 4.4 4.4 4.3 Farm. composition X "35 4,5 4.5 4.6 4.6 4.6 4,5 4.5 4.5 4,5 4.5

Farm. composition No. 36 4.3 4.4 4.6 4.6 4.6 4.5 4.4 4.4 4.4 4.4 Farm. composition No. 37 4.2 4.2 4.3 4.4 4.5 4.5 4.4 4.3 4.3 4.3 Farm. composition No. 38 4.2 4.2 4.3 4.4 4.5 4.5 4.4 4.3 4.3 4.3 Farm. composition No. 39 5.0 5.1 5.2 5.3 5.4 5.3 5.2 5.1 5.0 5.0 Farm. composition No. 40 5.1 5.2 5.2 5.4 5.4 5.4 5.3 5.2 5.1 5.0 Farm. composition No. 41 5.0 5.1 5.2 5.3 5.4 5.3 5.2 5.1 5.0 5.0 Farm. composition No. 42 4.6 4.6 4.6 4.6 4.6 4.6 4.5 4.4 4.4 4.3 Farm. composition No. 43 4.5 4.5 4.5 4.5 4.6 4.5 4.5 4.5 4.5 4.5 Farm. composition No. 44 4.3 4.3 4.4 4.5 4.5 4.5 4.4 4.4 4.4 4.4 Farm. composition No. 45 4.2 4.2 4.3 4.4 4.4 4.4 4.4 4.3 4.3 4.3 Farm. composition No. 46 4.2 4.2 4.3 4.4 4.4 4.4 4.4 4.3 4.3 4.3 Farm. composition No. 47 5.0 5.1 5.2 5.3 5.4 5.3 5.2 5.1 5.0 5.0 Farm. composition No. 48 5.1 5.2 5.2 5.4 5.4 5.4 5.3 5.2 5.1 5.0

- 22 020673

Table 31. Results of testing the neuroprotective effect (on the model of hemorrhagic stroke) of pharmaceutical formulations based on Me peptide (-C1i-H18-Pb-Rgo-C1u-Rgo, preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals with carbon isotopes ¹³ C and the neuroprotective effect of Mexidol: The number of rats that did not stay on the rotating rod for 2 minutes (the number of surviving rats)

Drug serial number pharmaceutical composition dose of 20 mg per day per rat Time after surgery, days day 2 day 3 day 10 day 14 day Mexidol Mexidol, 20 mg 5 '(9) 4 (9) 3 (8) 1 (7) 0 (6) Pharmaceutical formulations based on the peptide Me1-O1i-H13-Rb-Rgo-C1u-Rgo, 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals Farm. composition No. 25 5 (9) 4 (9) 3 (8) 1 (7) 0 (6) Farm. composition No. 26 4 (10) 3 (9) 2 (9) 1 (8) 0 (8) Farm. composition No. 27 4 (10) 3 (U) 2 (9) 1 (8) 0 (8) Farm. composition No. 28 4 (10) 3 (U) 2 (9) 1 (8) 0 (8) Farm. composition No. 29 3 (U) 3 (U) 2 (9) 1 (9) 0 (8) Farm, composition No. 30 3 (U) 3 (U) 2 (9) 0 (9) 0 (9) Farm. composition No. 31 5 (9) 4 (9) 3 (8) 1 (7) 0 (6) Farm. composition No. 32 5 (9) 5 (8) 4 (8) 1 (6) 0 (6) Farm. composition No. 33 5 (9} 4 (9) 3 (8) 1 (7) 0 (6) Farm. composition No. 34 4 (U) 3 (9) 2 (9) 1 (8) 0 (8) Farm. composition No. 35 4 (U) 3 (10) 2 (9) 1 (8) 0 (8) Farm. composition No. 36 4 (10) 3 (U) 2 (9) 1 (8) 0 (8) Farm. composition No. 37 3 (U) 2 (U) 2 (9) 1 (9) 0 (9) Farm. composition No. 38 3 (10) 3 (U) 2 (9) 1 (9) 0 (9) Farm. composition No. 39 5 (9) 4 (9) 3 (8) 1 (7) 0 (6) Farm. composition No. 40 6 (9) 5 (8) 4 (8) 1 (6) 0 (6)

Farm. composition No. 41 5 (9) 4 (9) 3 (8) 1 (7) 0 (6) Farm. composition No. 42 4 (U) 3 (9) 2 (9) 1 (8) 0 (8) Farm. composition No. 43 4 (U) 3 (10) 2 (9) 1 (8) 0 (8) Farm. composition No. 44 4 (U) 3 (10) 2 (9) 1 (8) 0 (8) Farm. composition No. 45 3 (U) 2 (U) 2 (U) 1 (U) 0 (U) Farm, composition No. 46 3 (10) 3 (10) 2 (10) 1 (9) 0 (9) Farm. composition No. 47 5 (9) 4 (9) 3 (8) 1 (7) 0 (6) Farm. composition No. 48 6 (9) 6 (8) 5 (8) 1 (6) 0 (6)

*) the number of rats that did not stay on the rotating rod for 2 min **) the number of rats surviving at the time of control. 10 rats were provided for control

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Table 32. Results of checking the effect of pharmaceutical formulations based on the Me1-C1i-H18-PbErgo-O1u-Rgo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, ¹³ C minerals and carbon isotopes, and mexidol on amnesia in mice caused by electroconvulsive shock. The number of mice with amnesia of the conditioned passive avoidance reaction 24 hours after the amnesizing effect,% (values are rounded to the nearest whole number)

Drug serial number pharmaceutical composition dose of 20 mg per mouse The drug was administered once intraperitoneally per 15, 30, 60, 90 and 120 minutes before training mice fifteen thirty 60 90 120 Mexidol Mexidol, 20 mg 23 ’(21) 21 (20) 17 (15) 15 (13 ”) 15 (13 ”) Pharmaceutical formulations based on the peptide Me1-O1i-H1z-Pb-Rgo-C1u-Rgo, 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals Farm. composition No. 25 23 21 17 fifteen fifteen Farm. composition No. 26 22 twenty fifteen 14 14 Farm. composition No. 27 22 twenty sixteen fifteen 14 Farm, composition No. 28 22 twenty fifteen thirteen thirteen Farm. composition No. 29 17 fifteen 14 12 12 Farm. composition No. 30 17 fifteen 14 12 12 Farm, composition No. 31 23 21 17 fifteen fifteen Farm, composition No. 32 23 22 eighteen sixteen sixteen Farm. composition No. 41 23 21 17 fifteen fifteen Farm. composition No. 42 22 twenty fifteen 14 14 Farm. composition No. 43 22 twenty sixteen fifteen 14 Farm. composition No. 44 21 twenty fifteen thirteen thirteen Farm. composition No. 45 fifteen fifteen 14 12 eleven Farm. composition No. 46 fifteen fifteen 14 12 eleven Farm. composition No. 47 23 21 17 fifteen fifteen Farm. composition No. 48 23 22 eighteen sixteen sixteen

*) the number of mice in each experiment is 30 **) mexidol, a dose of 40 mg per mouse

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Table 33. Results of checking the effect of pharmaceutical formulations based on the Me1-O1i-H18-PbErgo-O1u-Rgo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, ¹³ C minerals and carbon isotopes, and mexidol on amnesia in mice caused by scopolamine. The number of mice with amnesia of the conditioned passive avoidance reaction 24 hours after the amnesizing effect,% (values are rounded to the nearest whole number)

Drug serial number pharmaceutical composition dose of 20 mg per mouse The drug was administered once intraperitoneally per 15.30, 60, 90 and 120 minutes before training mice fifteen 30 60 90 120 Mexidol Mexidol, 20 mg 23 '(21) 19 (15) 1501 ”) 13 (11) 13 (11) Pharmaceutical formulations based on the peptide Me1-O1i-H15-Pb-Rgo-O1u-Rgo, preparation 2 "ethyl-6-methyl-3-hydroxypyridine succinate and minerals Farm. composition No. 25 23 nineteen fifteen thirteen thirteen Farm. composition No. 26 22 eighteen 14 thirteen thirteen Farm. composition No. 27 21 17 thirteen thirteen 12 Farm. composition No. 28 21 fifteen eleven eleven eleven Farm. composition No. 29 17 thirteen 10 10 10 Farm. composition No. 30 17 thirteen 10 10 10 Farm. composition No. 31 23 nineteen fifteen thirteen thirteen Farm. composition No. 32 23 twenty sixteen thirteen thirteen Farm. composition No. 41 23 nineteen fifteen thirteen thirteen Farm. composition No. 42 22 eighteen 14 thirteen thirteen Farm. composition No. 43 21 17 thirteen thirteen 12 Farm. composition No. 44 21 fifteen eleven eleven eleven Farm. composition No. 45 sixteen thirteen 10 10 nine Farm, composition No. 46 sixteen thirteen 10 10 nine Farm. composition No. 47 23 nineteen fifteen thirteen thirteen Farm. composition No. 48 23 twenty sixteen thirteen thirteen

*) the number of mice in each experiment is 30 **) mexidol, a dose of 40 mg per mouse

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Table 34. Results of checking the effect of pharmaceutical compositions based on the Me1-C1i-H | 5-RNeRgo-O1u-Rgo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, ¹³ C carbon minerals and isotopes, as well as mexidol on the survival of mice on the 7th day after bilateral ligation of the common carotid arteries. The number of mice in each experiment is 30

Drug serial number pharmaceutical composition dose of 20 mg per mouse. The number of surviving mice per 7th day after bilateral dressing total carotid arteries,% (values are rounded to integer) Mexidol concentration 2-ethyl-b-methyl-3- hydroxypyridine succinate was 1 g / l (drug diluted with water 1: 50) 93 Pharmaceutical formulations based on the peptide Me1-C1i-H15-Pb- Rgo-C1u-Rgo, a preparation of 2-ethyl-b-methyl-3-hydroxypyridine succinate and minerals Pharmaceutical composition No. 1 93 Pharmaceutical composition No. 2 94 Pharmaceutical composition No. 3 94 Pharmaceutical composition No. 4 94 Pharmaceutical composition No. 5 95 Pharmaceutical composition No. 6 96 Pharmaceutical composition No. 7 96 Pharmaceutical composition No. 8 96 Pharmaceutical composition No. 9 93 Pharmaceutical composition No. 10 94

The pharmaceutical composition No. 11 94 Pharmaceutical composition No. 12 96 Pharmaceutical composition No. 13 97 Pharmaceutical composition No. 14 97 Pharmaceutical composition No. 15 97 Pharmaceutical composition No. 16 96 Pharmaceutical composition No. 17 93 The pharmaceutical composition No. 18 94 The pharmaceutical composition No. 19 96 Pharmaceutical composition No. 20 97 Pharmaceutical composition No. 21 97 The pharmaceutical composition No. 22 98 Pharmaceutical composition No. 23 98 The pharmaceutical composition No. 24 97

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Table 35. Results of checking the effect of pharmaceutical compositions based on the Me1-C1i-HK-P11eRgo-O1u-Rgo peptide, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes ¹³ C, as well as mexidol on survival mice on the 7th day after bilateral ligation of the common carotid arteries. The number of mice in each experiment is 30

Drug serial number pharmaceutical composition dose of 20 mg per mouse. The number of surviving mice per 7th day after bilateral dressing total carotid arteries,% (values are rounded to integer) Mexidol concentration 2-ethyl-6-methyl-3- hydroxypyridine succinate amounted to ZOOg / l 96 Pharmaceutical formulations based on the MeM31i-H18-Pb-peptide Рgo-О1у-Рго, a preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals Pharmaceutical composition No. 145 96 Pharmaceutical composition No. 146 96 Pharmaceutical composition No. 147 97 Pharmaceutical composition No. 148 97 The pharmaceutical composition No. 149 98 Pharmaceutical composition No. 150 98 The pharmaceutical composition No. 151 98 The pharmaceutical composition No. 152 98 The pharmaceutical composition No. 161 96 The pharmaceutical composition No. 162 96 The pharmaceutical composition No. 163 97

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The pharmaceutical composition No. 164 97 The pharmaceutical composition No. 165 98 The pharmaceutical composition No. 166 98 The pharmaceutical composition No. 167 98 The pharmaceutical composition No. 168 99 The pharmaceutical composition No. 89 96 Pharmaceutical composition No. 90 97 The pharmaceutical composition No. 91 97 The pharmaceutical composition No. 92 97 The pharmaceutical composition No. 93 98 The pharmaceutical composition No. 94 99 The pharmaceutical composition No. 95 99 Pharmaceutical composition No. 96 99 The pharmaceutical composition No. 97 97 The pharmaceutical composition No. 98 97 Pharmaceutical composition No. 99 97 Pharmaceutical composition No. 100 97 Pharmaceutical composition No. 101 99 The pharmaceutical composition No. 102 99 The pharmaceutical composition No. 103 99 The pharmaceutical composition No. 104 one hundred The pharmaceutical composition No. 105 97 The pharmaceutical composition No. 106 97 The pharmaceutical composition No. 107 97 The pharmaceutical composition No. 108 97 The pharmaceutical composition No. 109 99 Pharmaceutical composition No. 110 99 The pharmaceutical composition No. 111 one hundred

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The pharmaceutical composition No. 112 one hundred The pharmaceutical composition No. 113 97 The pharmaceutical composition No. 114 97 The pharmaceutical composition No. 115 97 Pharmaceutical composition No. 116 98 The pharmaceutical composition No. 117 99 The pharmaceutical composition No. 118 99 The pharmaceutical composition No. 119 one hundred The pharmaceutical composition No. 120 one hundred The pharmaceutical composition No. 121 97 The pharmaceutical composition No. 122 97 The pharmaceutical composition No. 123 98 The pharmaceutical composition No. 124 98 The pharmaceutical composition No. 125 99 The pharmaceutical composition No. 126 one hundred Pharmaceutical composition N "127 one hundred The pharmaceutical composition No. 128 one hundred Pharmaceutical composition No. 137 97 Pharmaceutical composition No. 138 97 Pharmaceutical composition No. 139 98 Pharmaceutical composition No. 140 99 The pharmaceutical composition No. 141 one hundred The pharmaceutical composition No. 142 one hundred The pharmaceutical composition No. 143 one hundred Pharmaceutical composition No. 144 one hundred

Literature

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2. Buresh Y., Bureshova O., Houston P.D. Methods and basic experiments on the study of the brain and behavior: Per. from English / Under. ed. Batueva A.S. - M .: Higher. school., 1991 .-- 399 p.

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4. Voronina T.A. Domestic drug of the new generation Mexidol: main effects, mechanism of action, application. - M., 2004 .-- 21 p.

5. Gusev E.I., Skvortsova V.I. Cerebral ischemia. - M .: Medicine, 2001.

6. Guidance on methods for monitoring the quality and safety of dietary supplements. - M .: Federal Center for Sanitary Inspection of the Ministry of Health of Russia, 2004, - 240 p.

7. Vladimirov Yu.A., Sherstnev M.P., Azimbaev T.K. Evaluation of antioxidant and antiradical activities of substances and biological objects using iron-initiated chemiluminescence // Biophysics. - 1992. - T.37, issue 6. - S.1041-1047.

8. Khavinson V.Kh., Morozov V.G., Anisimov V.N. The effect of epithalamin on free radical processes in humans and animals. Advances in Gerontology, 1999, Issue 3.

9. Guidelines for the experimental study of drugs proposed for clinical study as antihypoxic drugs. Edited by L. Lukyanova - M., 1990.

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12. Sitt K., Vapye E.R., Sat / and E., NaeGe1u U.E. EGGes! OG 1ke pooe1 sotropy apgase1at (Ko 135057) Europe iprahei 1agtpd apy tetogu sh goyep (5 // Rkusorbagtasok - 1982. - Wo1.78. - P. 104-111.

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Claims (3)

CLAIM 1. A pharmaceutical composition having neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity, containing 2-ethyl-6-methyl-3-hydroxypyridine succinate, methionine-glutamine-histidine-phenylalanine-proline-glycine-proline polypeptide ( δ-Ρйе-Ρ ^ о-Θ1у-Ρ ^ о), characterized in that it additionally contains mineral substances in the following ratio of components, mg / l: 2-ethyl-b-methyl-3-hydroxypyridine succinate 0.4 10 ³ - 300 polypeptide methionine-glutamine-histidine phenylalanine-prolyl-glycine-proline potassium magnesium 0.1-30; 0.001 - 158.0; 0.0001 -70.3; 0.001-7.5, manganese and the pharmaceutical composition is made in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the pharmaceutical composition is from 0.005 to 0.75. 2. A pharmaceutical composition possessing neuroprotective, antiamnestic, antioxidant, antihypoxic, neurometabolic, antiischemic activity, containing 2 ethyl-6-methyl-3-hydroxypyridine succinate, methionine-glutamine-histidine-phenylalanine-proline-glycine-proline polypeptide ( δ-Ρйе-Ρ ^ о-Θ1у-Ρ ^ о), characterized in that it additionally contains mineral substances in the following ratio of components, mg / l: 2-ethyl-b-methyl-3-hydroxypyridine succinate 0.4 10 ³ - 300 10 ³ ; polypeptide methionine-glutamine-histidine phenylalanine-prolyl-glycine-proline potassium magnesium 0.1-30; 0.001 - 158.0; 0.0001 -70.3; 0.001-7.5. manganese 3. The pharmaceutical composition according to any one of claims 1, 2, characterized in that the pH is 4-7.