EA022859B1 - Pharmaceutical composition for injections having neuroprotector, antiamnesic, antioxidant, antihypoxic and antiischaemic activity (embodiments) - Google Patents

Abstract

The invention relates to the field of the pharmaceutical industry and medicine. The problem of the invention consists in producing an effective pharmaceutical composition having neuroprotector, antiamnesic, antioxidant, antihypoxic and antiischaemic activity. The problem is solved in that the pharmaceutical composition for injections comprises 2-ethyl-6-methyl-3-hydroxypyridine succinate, and differs from the prototype by that it additionally comprises the following mineral substances: potassium, magnesium, iron, manganese. Moreover, in the pharmaceutical composition, some of theC carbon isotopes are substituted byC carbon isotopes. The technical results of the invention consist in increasing the rate at which a therapeutic effect is achieved, increasing the therapeutic effect without increasing the concentration of the preparation 2-ethyl-6-methyl-3-hydroxypyridine succinate, and increasing the stability over the shelf life.

Description

The invention relates to the field of pharmaceutical industry and medicine and can be used in the creation and use of pharmaceutical compositions with neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity.

The level of technology.

An important problem of modern medicine is the creation of new drugs that can effectively protect and also treat brain diseases. For the treatment of acute cerebrovascular accidents, dyscirculatory encephalopathy, vegetative-vascular dystonia, atherosclerotic dysfunctions of the brain, neurotic and neurosis-like disorders with anxiety, for the relief of withdrawal symptoms in alcoholism, modern Russian drugs are used to treat acute intoxication with antipsychotics and a number of other diseases.

6-methyl-2-ethyl-3-hydroxypyridine succinate, in particular Mexidol (Instructions for use of the drug Mexidol. Registration number P No. 002161/01).

Mexidol has a mechanism of action, the fundamental difference from the mechanism of action of traditional neuropsychotropic drugs is its lack of specific binding to known receptors (Scientific Research Institute of Pharmacology RAMS, T.A. Voronin. Mexidol. Main effects, mechanism of action, application (L11p: // No. No. uueb.gi / teh1bo1.b1t). Mexidol is an inhibitor of free radical processes, lipid peroxidation, it activates superoxide dismutase, affects the physicochemical properties of the membrane, increases the content of polar lipid fractions (phosphotidylserine and phosphotidylinositol, etc.) in the membrane, reduces the cholesterol / phospholipid ratio, 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 cell apparatus and structure their membranes.

The change in the functional activity of the biological membrane caused by mexidol leads to conformational changes in the protein macromolecules of synaptic membranes, as a result of which mexidol has 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 the ligand 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. Due to this mechanism of action, Mexidol affects the 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 centrally acting substances, especially those that realize their action as direct receptor agonists.

The invention claimed two variants of the pharmaceutical composition.

An analogue to each variant of the pharmaceutical composition is a pharmaceutical composition having neurotropic, antiamnestic activity, containing Mexidol and Semax (application for invention of the Russian Federation 2006146529, published on December 27, 2006).

The disadvantage of this analogue is the low stability of the pharmaceutical composition over the shelf life (in particular, within 3 years).

Another analogue of the pharmaceutical composition variants is an agent containing mexidol and excipients: potato starch, polyvinylpyrrolidone, magnesium stearic acid, microcrystalline cellulose, milk sugar (RF patent 2145855, published May 26, 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, published 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, published on 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.

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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 1 liter, about three orders of magnitude less than that required for the injection solution.

Also known patent EAPO 008591, published 29.06.2007. 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. This patent may be an analogue for 4-7 variants of the invention.

The prototype of the two variants of the invention is a pharmaceutical composition for injection (Instructions for use of the drug Mexidol. Registration number P No. 002161/01) containing 2-ethyl-6-methyl-3-hydroxypyridine succinate.

In the prototype as anion used With ₄ H ₆ About ₄ (succinate). Succinate is an anion of succinic acid or a salt of this acid.

In the prototype, the amount of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate is 50 g / L.

The drug is used for acute and chronic cerebrovascular insufficiency and related diseases, including stroke and its consequences. Studies have shown that the prototype is not always effective in these pathologies.

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

The Ν + -Η 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.

The characteristics of the prototype pharmaceutical composition for injection contains 2-ethyl-6-methyl-3-hydroxypyridine succinate coincide with the characteristics of the claimed variants of the invention.

As the anion, not only succinate can be used, but also another substance, in particular chloride. Therefore, a wider formulation of features consistent with the invention may be as follows:

A pharmaceutical composition for injection 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, the insufficiently large therapeutic effect of the pharmaceutical agent, the low stability of the pharmaceutical composition over the expiration date.

SUMMARY OF THE INVENTION

Let us define the terms.

Injection - the introduction of a medicinal solution (composition) directly under the skin, into a muscle, into a vein.

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

The present invention is the creation of an effective pharmaceutical composition with neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity.

The problem is solved due to the fact that the pharmaceutical composition for injection, with neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity, containing 2-ethyl-6-methyl-3-hydroxypyridine succinate, differs from the prototype in that it contains mineral substances in the following ratio components, mg / l:

2-ethyl-6-methyl-3-hydroxypyridine succinate - 1 · 10 ³ -300-10 ³ ;

potassium - 0.020-27.7;

magnesium - 0.065-70.3;

iron - 0.027-24.5;

Manganese - 0.006-7.5.

The problem is also solved due to the fact that the pharmaceutical composition for injection, with antiamnestic, antioxidant, antihypoxic, antiischemic activity, containing 2-ethyl-6-methyl-3-hydroxypyridine succinate, characterized by the prototype, which contains minerals in the following ratio of components, mg / l:

2-ethyl-6-methyl-3-hydroxypyridine succinate - 1 -10 ³ -300-10 ³ ;

potassium - 0.020-27.7;

magnesium - 0.065-70.3;

iron - 0.027-24.5;

manganese is 0.006-7.5, and the pharmaceutical composition contains carbon isotopes ¹³ C, the ratio pC = + ³ 'C / W.'.

where pS is the ratio of the amount of carbon isotopes ¹³ C to the total amount of carbon in the pharmaceutical composition;

Ν ^{Ι3 ί} '.' - the number of carbon isotopes ¹³ C in the pharmaceutical composition;

NС - the total amount of carbon isotopes in the pharmaceutical composition is from 0.005 to 0.75.

Additionally, each of the above pharmaceutical compositions for injection can be made in such a way that the pH value is from 4 to 7.

The claimed compositions use a pharmaceutically acceptable solvent, in particular water for injection or another solvent.

Technical results of the invention:

an increase in the onset of the onset of the therapeutic effect (a decrease in the onset of the therapeutic effect) while maintaining the duration of action without increasing the concentration of the pharmaceutical composition 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 in the activity of the endogenous system and a decrease in the intensity of free radical processes;

an increase in the therapeutic effect without increasing the concentration of the pharmaceutical composition 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 in the activity of the endogenous system and a decrease in the intensity of free radicals processes

increasing the stability of the pharmaceutical composition with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate over the expiration date.

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

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

Known injection solution (RF application No. 94015245, published December 27, 1995), in which a 5-10% solution of hyaluronic acid is used as a regulator of the rate of exposure.

Known pacemaker drug (RF patent No. 2068697, published 10.11.1996), containing green toad poison, chlorobutanodihydrate, 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 (AS USSR No. 1683190, published on 04/20/1995). 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 the pharmaceutical agent by introducing mineral substances into the composition of the agent. A description of the effects of the claimed pharmaceutical formulations will be given below.

Below is a summary of minerals.

Minerals are subdivided into macro- and microelements.

Macronutrients include calcium, phosphorus, magnesium, potassium, sodium, chlorine and sulfur.

Trace elements: iron, copper, manganese, zinc, cobalt, iodine, fluorine, chromium, molybdenum, vanadium, nickel, strontium, silicon, selenium are recognized as essential for human and animal life.

Macronutrients regulate water-salt metabolism, maintain the osmotic pressure in cells and intercellular fluids, which is necessary for the movement of nutrients and drugs between them. Blood formation processes occur with the participation of iron, copper, manganese, calcium and other mineral substances (elements). Minerals (trace elements) activate the action of enzymes, hormones, participate in all types of metabolism.

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Mineral substances (Fe, Cu, Ζη, etc.) in solution (in particular, in the pharmaceutical composition for injection) are contained in pharmaceutically acceptable salts, for example succinates, chlorides, carbonates or sulfates, as well as in various pharmaceutically acceptable complex compounds.

Minerals, metal salts have an antimicrobial effect, inactivating the enzymes necessary for the life of microorganisms. Enzyme inactivation occurs through the interaction of metal ions with sulfhydryl groups of enzymes.

Metals have a pronounced local effect on the mucous membranes. At the concentrations of mineral substances considered in the patent, the local action of these substances may be astringent or irritating.

The mechanism of local action of metals is due to their ability to react with tissue proteins. As a result of this interaction, proteins coagulate and form albuminates with metal ions. Moreover, if partial coagulation of proteins occurs only in the surface layers of tissues, an astringent or irritating effect is observed that is reversible.

Studies have shown that the mineral substances that make up the drug 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 - 0.020-27.70; magnesium - 0.065-70.30; iron - 0.027-24.50; Manganese - 0.006-7.5.

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 drug 2-ethyl-6-methyl-3-hydroxypyridine succinate in the pharmaceutical composition, an increase in the stability of the pharmaceutical composition with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate during the expiration date is provided by the introduction in the pharmaceutical composition of certain minerals (a certain combination of minerals) in a strictly defined quantity 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 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 drug 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 effect of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate, the therapeutic effect of the drug disappears. A strong irritating effect from the action of large concentrations of mineral substances appears.

An additional increase in the speed of the onset of the therapeutic effect, an increase in the therapeutic effect without increasing the concentration of the pharmaceutical composition and the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the pharmaceutical composition, an increase in the stability of the pharmaceutical composition with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate the expiration date is ensured by the partial replacement in the pharmaceutical composition of carbon isotopes ¹² C with carbon isotopes ¹³ C.

List of drawings

In FIG. 1 shows the UV spectrum of the claimed pharmaceutical composition for injection and mexidol.

In FIG. 2 presents a chromatogram of a sample of the claimed pharmaceutical composition.

In FIG. 3-6 presents chromatograms of a sample of the claimed pharmaceutical composition milking injection.

In FIG. 7-9 show chromatograms of a sample of the claimed pharmaceutical composition for injection on a chiral column.

In FIG. 10 shows a chromatogram of a sample of the claimed pharmaceutical composition for injection.

In FIG. 11 represents ΜδΜδ of ion 438.7.

In FIG. 12 represents ΜδΜδ of ion 138.

In FIG. 13 presents the determination of the mass fraction of components of a sample of the claimed pharmaceutical composition.

In FIG. 14 shows the 'H NMR spectrum of a sample of the claimed pharmaceutical composition in I ₂ O.

In FIG. 15 presents ¹ H NMR spectrum of a sample of the claimed pharmaceutical composition in ΌΜδΌΜ.

In FIG. 16-18 presents ¹³ C NMR spectra of a sample of the claimed pharmaceutical composition with and without suppression.

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In FIG. 19 shows the 'H NMR spectrum of a sample of the claimed pharmaceutical composition.

In FIG. 20, 21 are high resolution mass spectra of a mixture of derivatives of the claimed pharmaceutical composition.

In FIG. 22 is a diagram of a cavitation reactor for isotope enrichment of various mixtures.

In FIG. 23 is a cross-sectional view of a cavitation reactor.

In FIG. 24 is a diagram of an isotope enrichment plant.

Information confirming the possibility of carrying out the invention

In FIG. 1-10 presents chromatograms of samples of the pharmaceutical composition for injection with minerals.

Chromatograms of samples of the pharmaceutical composition for injection with a different composition of minerals are similar (the differences are small and are comparable with the thick line in the graphs).

Split options

The composition of the mobile phase:

A - water with the addition of 113 μl trifluoroacetic acid per 1 liter;

B - acetonitrile with the addition of 113 μl trifluoroacetic acid per 1 liter.

Standard gradient from 5% B to 100% B in 20 min.

Column size 250x4.6 mm sorbent KergokP-Rig ΘΌ8.

UV detection 220 nm.

Adiep Chromatographic System! 1200 5sps5.

Mass Detector Adyep! 6310 1op Tgar bsm8.

In FIG. 1 shows the UV spectrum (upper curve) of the claimed pharmaceutical composition for injection containing the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals. The lower curve on the graph is Mexidol.

The abscissa axis is the wavelength, the ordinate axis is the optical density.

In FIG. 2 presents a chromatogram of a sample of the claimed pharmaceutical composition for injection. Registration at a wavelength of 220 nm.

The abscissa is time; the ordinate is absorption at a wavelength of 220 nm.

In FIG. 3 presents a chromatogram of a sample of the claimed pharmaceutical composition for injection with mass-selective detection of the 1st peak.

On the upper graph, the abscissa shows time, the ordinate shows intensity.

In the lower graph along the abscissa, the value of t / ζ, where t is the mass of the ion; ζ is the ion charge, along the ordinate axis is the intensity.

In FIG. 4 shows a chromatogram of a sample of the claimed pharmaceutical composition for injection with mass-selective detection of the 2nd peak.

On the upper graph, the abscissa shows time, the ordinate shows intensity.

In the lower graph along the abscissa, the value of t / ζ, where t is the mass of the ion; ζ is the ion charge, along the ordinate axis is the intensity.

In FIG. 5 shows a chromatogram of a sample of the claimed pharmaceutical composition for injection with mass-selective detection of the 3rd peak.

On the upper graph, the abscissa shows time, the ordinate shows intensity.

In the lower graph along the abscissa, the value of t / ζ, where t is the mass of the ion; ζ is the ion charge, along the ordinate axis is the intensity.

In FIG. 6 shows a chromatogram of a sample of the claimed pharmaceutical composition for injection with mass-selective detection of the 4th peak.

On the upper graph, the abscissa shows time, the ordinate shows intensity.

In the lower graph along the abscissa, the value of t / ζ, where t is the mass of the ion; ζ is the ion charge, along the ordinate axis is the intensity.

In FIG. 7 shows a chromatogram of a sample of the claimed pharmaceutical composition for injection on a chiral column, registration at a wavelength of 220 nm.

The abscissa axis is time, the ordinate axis is the absorption intensity at a wavelength of 220 nm.

In FIG. 8 shows a chromatogram of a sample of the claimed pharmaceutical composition for injection on a chiral column (UMS CH1CAL ΝΕΑ (K) 250x4.6 mm, 8 = 5 μm, 30 nm) with mass-selective detection.

On the upper graph, the abscissa shows time, the ordinate shows intensity.

In the lower graph along the abscissa, the value of t / ζ, where t is the mass of the ion; ζ is the ion charge, along the ordinate axis is the intensity.

In FIG. 9 shows a chromatogram of a sample of the claimed pharmaceutical composition for injection on a chiral column (UMS CH1CAL ΝΕΑ (K) 250x4.6 mm, 8 = 5 μm, 30 nm) with mass-selective detection.

On the upper graph, the abscissa shows time, the ordinate shows intensity.

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In the lower graph along the abscissa, the value of t / ζ, where t is the mass of the ion; ζ is the ion charge, along the ordinate axis is the intensity.

In FIG. 10 shows a chromatogram of a sample of the claimed pharmaceutical composition for injection. Registration at a wavelength of 220 nm.

The abscissa is time, the ordinate is intensity.

In FIG. 11 presents M8M8 ion 438.7.

On the upper graph, the abscissa shows time, the ordinate shows intensity.

In the lower graph along the abscissa, the value of t / ζ, where t is the mass of the ion; ζ is the ion charge, along the ordinate axis is the intensity.

In FIG. 12 presents M8M8 of ion 138.

On the upper graph, the abscissa shows time, the ordinate shows intensity.

In the lower graph along the abscissa, the value of t / ζ, where t is the mass of the ion; ζ is the ion charge, along the ordinate axis is the intensity.

In FIG. 13 presents the determination of the mass fraction of the components of a sample of the claimed pharmaceutical composition for injection by the EZI method. (equipment ЕЗИ - 8бех 75 temperature 40 ° С).

The abscissa is time, the ordinate is intensity.

In FIG. 14- shows the 'H NMR spectrum of a sample of the claimed pharmaceutical composition in Ό ₂ Θ.

In FIG. 15 presents the ‘H NMR spectrum of a sample of the claimed pharmaceutical composition in IM8O.

In FIG. 16 shows the ¹³ C NMR spectrum of a sample of the claimed pharmaceutical composition with suppression.

In FIG. 17 presents ¹³ C NMR spectra of a sample of the claimed pharmaceutical composition without suppression.

In FIG. 18 shows ¹³ C NMR spectra of a sample of the claimed pharmaceutical composition without suppression.

In FIG. 19 shows the ‘H NMR spectrum of a sample of the claimed pharmaceutical composition.

The structure of 2-ethyl-6-methyl-3-hydroxypyridine (2-ethyl-6-methyl-3-hydroxypyridinium) cation was determined from the totality of NMR spectra.

The invention is illustrated by the examples below.

Example 1. The method of introducing minerals into water for injection.

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, antiischemic activity. The studies were carried out using materials published in the sources [1-5].

Example 1

The introduction of mineral substances into the solution (into water for injection) was carried out according to the procedure [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 the invention, the concentration of metals in solutions was provided in the following ranges, mg / l:

potassium - 0.01-27.7; magnesium - 0.03-70.3; iron - 0.01-24.5; Manganese - 0.006-7.5.

In addition, studies have been conducted on the extremely high content of minerals in the compositions. These studies will be written below.

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, cobalt, nickel, and chromium. A.1.3.2.1 source [6].

Example 2

For an example, we describe the preparation of one pharmaceutical composition with potassium, magnesium, manganese, and iron of a certain concentration.

8 l of water for injection is poured into a stirred reactor. After that, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate - 10 g was loaded into the reactor, a solution with potassium (total potassium content 0.22 mg) was poured, a solution with magnesium (total magnesium content 0.7 mg) was poured, and the solution was filled with iron (total iron content 0.25 mg), pour solution with manganese (total manganese content 0.06 mg), with constant stirring. Then adjust the pH of the solution to 4.5. The resulting solution was adjusted to a volume of 10 l with water for injection and passed through a filter.

During control found:

‘H NMR spectrum in IM8O:

'H NMR (600 MHz, PM8O-a ₆ ): 12.1-9.9 (m, 2.75H); 7.020 (d, 1 _AB = 8.4 Hz, 1H); 6.840 (d, 1 _AB = 8.4 Hz, 1H);

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2.671 (q, 1 = 9.6 Hz, 2.05H); 2.502 (s, 0.25H); 2.429 (s, 4.12H); 2.303 (s, 3.08H); 1.130 (t, 1 = 7.5 Hz, 3.07 N).

¹³ C NMR Spectrum:

^! H NMR (400.4 MHz, Ό ₂ Θ): 7.720 (d, 1 _AB = 8.8 Hz, 0.92H); 7.402 (d, 1 _AB = 8.8 Hz, 0.92H); 4.090 (s, 58.4H); 2.894 (q, 1 = 7.6 Hz, 2H); 2.547 (s, 2.98H); 2.492 (s, 3.97H); 1.450 (t, 1 = 9 Hz, 3.03 H).

¹ H NMR spectrum in Ό ₂ Θ:

^! H NMR (400.4 MHz, Ό ₂ Θ): 7.720 (d, 1 _AB = 8.8 Hz, 0.92H); 7.402 (d, 1 _AB = 8.8 Hz, 0.92H); 4.090 (s, 58.4H); 2.894 (q, 1 = 7.6 Hz, 2H); 2.547 (s, 2.98H); 2.492 (s, 3.97H); 1.450 (t, 1 = 9 Hz, 3.03 H).

¹³ C NMR spectra:

¹³ C NMR (600 MHz, ΌΜ8Θ-ά ₆ ): 174.18 (m); 149.90 (m); 149.15 (m); 147.02 (m); 122.72 (dd, f = 6 Hz, 1 ₂ = 636 Hz); 121.48 (dk, f = 18 Hz, 1 ₂ = 636 Hz); 29.38 (tm, φ = 20.4 Hz, 1 ₂ = 510 Hz); 25.33 (tk, f = 18 Hz, 1 ₂ = 510 Hz); 23.13 (cd, f = 9 Hz, 1 ₂ = 504 Hz); 12.98 (ct, f = 21 Hz, 1 ₂ = 504 Hz).

The control showed the qualitative performance of the pharmaceutical composition.

Similarly, other claimed pharmaceutical formulations with minerals and a 2-ethyl-6-methyl-3-hydroxypyridine succinate preparation were obtained and controlled.

Laboratory studies of the claimed pharmaceutical formulations have been performed. In FIG. 1-19 illustrates studies of only one pharmaceutical composition, mg / l:

2-ethyl-6-methyl-3-hydroxypyridine succinate - 10-10 ³ ;

potassium - 0.220;

magnesium - 0.70;

iron - 0.25;

Manganese - 0.06.

The remaining pharmaceutical compositions claimed and described in the invention were also subjected to laboratory tests.

It was found that ¹ H NMR spectra and ¹³ C NMR spectra are not sensitive to a slight change in the amount and concentration of minerals in the pharmaceutical composition.

Another example. In FIG. 1 shows a UV spectrum of a pharmaceutical composition. The concentration of the preparation 2-ethyl-6-methyl-3-hydroxypyridine succinate 0.054 g / ml was determined by UV spectrophotometry. According to ND N002161 / 01-140308, 1 ml of the drug should contain from 0.045 to 0.055 g. The lower curve in the graph is the standard sample of 2-ethyl-6-methyl-3-hydroxypyridine succinate (Mexidol preparation), the upper one is the claimed pharmaceutical composition.

The kinematic viscosity of the pharmaceutical composition is 1.180 mm / s (from a range of 1.01 to 1.23 mm ² / s). Determined using a capillary viscometer.

Studies of stability (shelf life) showed that the pharmaceutical compositions thus obtained are stable and retain their initial values for 3.5 years. UV spectrophotometry and other of the above studies were carried out every six months for 3.5 years. An increase in the stability of the claimed pharmaceutical formulations over 3.5 years has been established compared with Mexidol. Mexidol showed stable properties for 3 years. In mexidol, sodium metabisulfite stabilizer provides stability.

Example 3

Tests for general toxicity were performed by intraperitoneal administration of pharmaceutical formulations based on 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals in rats.

For studies of the concentration of mineral substances in solutions selected, mg / l:

potassium - 30,000;

magnesium - 80,000;

iron - 30,000;

Manganese - 10,000.

EO. ranges from 950 to 1000 mg / kg with intraperitoneal administration.

When administered intramuscularly, EP ₅₀ is up to 3000 mg / kg, which allows the claimed compounds to be classified as non-toxic substances.

With long-term use of pharmaceutical compositions based on 2-ethyl-6-methyl-3-hydroxypyridine, succinates and minerals in rats did not reveal changes in organs and tissues of the body (were insignificant).

Example 4

The antioxidant activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals was compared with the antioxidant activity of the drug mexidol chemiluminescent method [7].

Mexidol containing 2-ethyl-6-methyl-3-hydroxypyridine succinate 50 g / l, sodium metabisulfate 1 g / l were compared with pharmaceutical formulations based on 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals ( serial numbers of pharmaceutical formulations 49-56).

Mexidol containing 2-ethyl-6-methyl-3-hydroxypyridine succinate — 50 g / l, sodium metabisulfate — 1 g / l, was also compared with pharmaceutical formulations based on the preparation 2-ethyl-6-methyl-3-7 022859 hydroxypyridine succinate, minerals and with a carbon content of ¹³ C equal to 0.5 and 75% of the total carbon in the pharmaceutical composition (serial numbers of pharmaceutical formulations 5772).

It was found that in antioxidant activity (AOA), pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals mainly exceeded Mexidol by 10-20%.

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 compositions with serial numbers 55 and 56, 63 and 64, 71 and 72 to use as an antioxidant agent is not economically feasible (costly).

Studies on the antioxidant activity of pharmaceutical formulations were also carried out according to the method [8]. The results are basically the same as above.

Example 5

The antihypoxic activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl3-hydroxypyridine succinate, minerals and ¹³ C carbon isotopes was compared with the antihypoxic activity of mexidol.

Comparisons were made on nonlinear white mice (males) weighing 23-27 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 tables is indicated by Tv in minutes.

Each of the pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals was administered once intraperitoneally also 30, 60 and 90 minutes before placing the mice in the heat chamber and stopping the air from entering the heat chamber.

After placing 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.

The results of comparing the antihypoxic activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and containing ¹³ C carbon isotopes with the antihypoxic activity of the drug mexidol are given in table. 13-16.

On the model of acute normobaric hypoxic hypoxia (in a heat chamber) it was found that most of the pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals increased the life expectancy of mice by an average of more than 5% 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. 16. The claimed drugs increase the speed of 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 drug 2-ethyl-6-methyl-3-hydroxypyridine succinate.

Comparisons were also made on the following models: acute hypobaric hypoxia in an exhaust pressure chamber with imitation of raising animals at a speed of 50 m / s to a height of 11000 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.

Example 6

The neuroprotective effect of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes containing ¹³ C was compared with the neuroprotective effect of the drug mexidol (with a concentration of 2-ethyl-6-methyl-3-hydroxypyridine succinate - 10 g / l).

- 8 022859

Comparative studies were performed on white non-linear male rats weighing 220-250 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 for 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. 17. An analysis of the results shown in the table showed that in rats who received intraperitoneal injection of mexidol, the neurological deficit was most pronounced (5.4 ± 0.1 points) 3 and 4 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, minerals and carbon isotopes ¹³ C at doses of 20 mg per day on the rat exerted a pronounced neuroprotective effect, generally superior in severity to against neurological deficiency 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, minerals and carbon isotopes ¹³ C. The number of rats in each experiment was 12. In the experiments, 8-14% died animals.

Pharmaceutical formulations with serial numbers 25, 33 and 41 in terms of neuroprotective action practically do not exceed Mexidol. 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 26 - 32, 34-40, 42-48.

However, the following should be considered. Pharmaceutical formulations 31, 32 in their neuroprotective effect do not exceed composition 30. Therefore, these formulations are not practical. Pharmaceutical formulations 39, 40 in their neuroprotective effect do not exceed composition 38. Therefore, these formulations are not practical. Pharmaceutical formulations 47, 48 in their neuroprotective effect do not exceed composition 46. Therefore, these formulations are not practical.

Hemorrhagic stroke (GI) in rats was reproduced by modeling local hemorrhage in the brain (creating GI with cerebral ischemia) according to the method [11]. In accordance with the technique, rat skull trepanation 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 of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and carbon ¹³ C isotopes was administered to animals intraperitoneally at a dose of 20 mg per day in rats. Mexidol was administered to animals intraperitoneally at a dose of 20 mg per day in a rat. 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 of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals, as well as mexidol, were 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. 18).

It was found that pharmaceutical compositions with serial numbers 25, 33 and 41 in coordination of movement on a rotating rod practically do not exceed Mexidol. The neuroprotective effects of the remaining compounds are superior to the neuroprotective effect of Mexidol.

The coordination of rat movement increases markedly when using formulations with serial numbers 26-32 (see the characteristics of the compositions in Table 4), 34-40 (see the characteristics of the compositions in Table 5), 42-48 (see the characteristics of the compositions in Table. 6). However, the following should be considered.

Pharmaceutical formulations 31, 32 in their neuroprotective effect do not exceed composition 30. The same values are indicated by the signs - // -. Therefore, these compositions are not practical to use.

Pharmaceutical formulations 39, 40 in their neuroprotective effect do not exceed composition 38. Identical values are indicated by the signs - // -. Therefore, these compositions are not practical to use.

Pharmaceutical formulations 47.48 in their neuroprotective effect do not exceed composition 46. The same values are indicated by the signs - // -. Therefore, these compositions are not practical to use.

Pharmaceutical formulations based on 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, and ¹³ C carbon isotopes increase (compared to Mexidol) rat survival after surgery.

- 9 022859

Example 7

The anti-amnestic effect of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and carbon ¹³ C isotopes was compared with the anti-amnestic effect of the drug mexidol.

Comparisons were made on white non-linear mice (males) weighing 23-27 g.

The effect of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and carbon isotopes ¹³ C and the preparation mexidol on amnesia (learning and memory processes) in mice was studied using the conditioned reaction of passive avoidance of electrodermal irritation. The mice were exposed to electroconvulsive shock (current 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, minerals and carbon isotopes ¹³ C and the preparation mexidol on amnesia was also evaluated using the scopolamine amnesia model after learning the 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 formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and carbon isotopes ¹³ C, as well as the drug mexidol actively prevent the development of amnesia of the conditioned reaction passive avoidance (see table. 19). The number of mice trained in the conditioned passive avoidance reaction ranged from 91 to 95%. Moreover, almost all pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals, as well as formulations containing ¹³ C carbon isotopes, provide the lower range value. Mexidol provides the lower range value.

Table analysis 19 shows that pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, and ¹³ C carbon isotopes increase the rate of onset of the therapeutic effect while maintaining the duration of action without increasing the concentration of the pharmaceutical agent. There is also an increase in the therapeutic effect without increasing the concentration of the 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. 19), the amount of Mexidol was increased from 20 to 40 mg per mouse.

On the scopolamine amnesia model, it was found that in mice pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes ¹³ C, as well as the preparation mexidol also prevent the development of amnesia of the conditioned passive avoidance reaction (see Table 20).

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals 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 agent. There is also an increase in the therapeutic effect without increasing the concentration of the pharmaceutical agent.

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 formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon ¹³ C isotopes was compared with the anti-ischemic effect of the drug mexidol. The comparison results are presented in table. 21.

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 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, minerals and carbon isotopes ¹³ C, as well as the preparation Mexidol significantly increased the survival of mice during the observation period. The concentration of the drug 2-ethyl-6-methyl-3hydroxypyridine succinate was 1 g / L. An increase in the concentration of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the formulations up to 50-300 g / l led to a further increase in the survival of mice.

- 10 022859

From the table. Figure 21 shows that the survival rate of mice using most pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and ¹³ C carbon isotopes is higher than the survival rate of mice using mexidol.

Pharmaceutical formulations No. 1, No. 9 and No. 17 are similar in action to Mexidol. With an increase in the amount of mineral substances in the compositions, their effect increases.

Pharmaceutical formulations No. 7, No. 8 in their effect do not exceed the effect of composition No. 6. Pharmaceutical formulations No. 15, No. 16 in their action do not exceed the effect of composition No. 14. Pharmaceutical formulations No. 23 and No. 24 in their action do not exceed the effect of composition No. 22 Therefore, to produce and apply them is impractical.

Thus, the application is described and the technical results of the claimed compositions are confirmed.

The composition of minerals in the above pharmaceutical formulations for injection was limited to the list of minerals (macrocells and microelements) in the Guide to 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. The Guide describes a method for introducing mineral substances into a solution, as well as methods for precisely controlling the amount of mineral substances in solutions.

In the above compositions, ranges of weight values (in mg / l) of the components of the compositions are given, which, in comparison with the prototype (mexidol) give an effect (by technical results) of more than 5%.

At present, ¹³ C carbon isotopes in the world are widely used in biochemistry and medicine for diagnostics. The description presents the results of our own studies on the effect of ¹³ C carbon isotopes on the stability and effectiveness of the action of drug formulations based on 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 2-ethyl-6 -methyl-3-hydroxypyridine succinate slows down the chemical reactions 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.

Investigations of pharmaceutical compositions for injections with ranges of pS values from 0.005 to 0.75, i.e. with a carbon isotope content of ¹³ C from 0.5 to 75% of the total carbon in the pharmaceutical composition.

Methods for the production of a stable highly enriched non-radioactive ¹³ C isotope are widely used in Russian and world industry. Methods for producing the ¹³ C isotope by gas diffusion through porous walls, diffusion in a steam stream, thermal diffusion, as well as by distillation, isotope exchange, centrifugation, electrolysis, genetic engineering, and others are well developed. A brief description of these methods is given in the source [13].

At the Moscow State Academy of Fine Chemical Technology. M.V. Lomonosov practiced modern nanotechnology for the production and incorporation of atoms of stable carbon isotopes ¹³ C 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 100% 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 isotopic 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 isotope (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. 22 is a diagram of a cavitation reactor for isotope enrichment of various mixtures, in particular hydrocarbon reagents, for the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate enriched in carbon isotope ¹² C. The reactor is located in the installation,

- 11 022859 which contains a 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 installation diagram is shown in FIG. 24.

The cavitation reactor 1 (see Fig. 22) is made in the form of a flat Laval nozzle with cavitation bodies 2-9 in the channel 10.

In FIG. 23 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. 22 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 1000 ° C. 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 tank 28. Next, the gas-vapor mixture is fed 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 for injection were prepared containing a preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate with a carbon content of ¹³ C from 0.5 to 75% of the total carbon in the pharmaceutical composition.

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 pharmaceutical composition 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 a decrease in the intensity of free cial processes;

an increase in the therapeutic effect without increasing the concentration of the pharmaceutical composition 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 in the activity of the endogenous system and a decrease in the intensity of free radicals processes

increasing the stability of the pharmaceutical composition with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate over the expiration date.

Table 1

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals

Mineral substance Serial number of pharmaceutical composition with 1 gram 2-ethyl-6-methyl-3-hydroxypyridine succinate per liter 1 ^ 2 3 4 5 6 7 8 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

*) The numbering of pharmaceutical formulations is through.

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table 2

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 0.5% of the total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 1 gram 2-ethyl-6-methyl-3-hydroxypyridine succinate per liter nine 10 eleven 12 thirteen 14 fifteen sixteen Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Table 3

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 75% of the total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 1 gram 2-ethyl-6-methyl-3-hydroxypyridine succinate per liter 17 eighteen nineteen twenty 21 22 23 24 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Mar ganets, mg / l 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Table 4

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals

Mineral substance The serial number of the pharmaceutical composition with 10 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate in liter 25 26 27 28 29th thirty 31 32 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Table 5

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 0.5% of the 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 in liter 33 34 35 36 37 38 39 40 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30,0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

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Table 6

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 75% of the total carbon in the pharmaceutical composition

Mineral substance The serial number of the pharmaceutical composition with 10 grams of 2-ethyl-b-methyl-3-hydroxypyridine succinate in liter 41 42 43 44 45 46 47 48 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Mar ganets, mg / l 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Table 7

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals

Mineral substance Serial number of pharmaceutical composition with 50 grams of 2-ethyl-b-methyl-3-hydroxypyridine succinate in liter 49 fifty 51 52 53 54 55 56 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Table 8

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 0.5% of the total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 50 grams of 2-ethyl-b-methyl-3-hydroxypyridine succinate in liter 57 58 59 60 61 62 63 64 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Table 9

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 75% of the total carbon in the pharmaceutical composition

Mineral substance Serial number of the pharmaceutical composition with 50 grams 2-ethyl-b-methyl-3-hydroxypyridine succinate per liter 65 66 67 68 69 70 71 72 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

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Table 10

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate in liter 73 74 75 76 77 78 79 80 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Table 11

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 0.5% of the total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-b-methyl-3-hydroxypyridine succinate in liter 81 82 83 84 85 86 87 88 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Manganese, mg / L 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Table 12

Pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 75% of the total carbon in the pharmaceutical composition

Mineral substance Serial number of pharmaceutical composition with 300 grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate in liter 89 90 91 92 93 94 95 96 Potassium, mg / L 0.01 0.02 0.1 0.22 5.0 27.7 60.0 90.0 Magnesium, mg / L 0.03 0.065 0.1 0.7 30.0 70.3 160.0 240 Iron, mg / L 0.01 0.027 0.03 0.25 21.0 24.5 60.0 90.0 Mar ganets, mg / l 0.005 0.006 0.01 0.06 1.0 7.5 10.0 16.3

Results of testing the antihypoxic activity of the drug Mexidol, dose *) 100 mg

Table 13

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.

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Table 14

The results of testing the antihypoxic activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals. Dose 100 mg.

Average life, min

Time Tv MIN Serial number of the pharmaceutical composition with 50 grams 2-ethyl-6-methyl-3-hydroxypyridine succinate per liter 49 fifty 51 54 55 56 thirty 33.6 36.2 36.9 36.9 36.9 37.0 60 37.4 38.2 38.9 38.9 38.9 38.9 90 38.0 38.9 39.5 39.8 39.7 39.7

Table 15

The results of testing the antihypoxic activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes ¹³ C. The dose of the drug is 100 mg. Average life, min

Time Tv min Serial number of the pharmaceutical composition with 50 grams 2-ethyl-6-methyl-3-hydroxypyridine succinate per liter 57 58 59 62 63 64 thirty 33.6 36.2 36.9 36.9 36.9 37.0 60 37.4 38.2 38.9 38.9 38.9 38.9 90 38.0 38.9 39.8 40.0 40.1 40.1

Table 16

The results of testing the antihypoxic activity of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes ¹³ C. The dose of the drug is 100 mg. Average life, min

Time Tv MIN Serial number of the pharmaceutical composition with 50 grams 2-ethyl-6-methyl-3-hydroxypyridine succinate per liter 65 66 67 70 71 72 thirty 33.7 36.9 37.1 37.8 37.8 37.8 60 37.7 38.9 39.3 39.9 39.9 39.9 90 38.1 38.9 40.5 40.9 40.9 40.9

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Table 17

Test results of the neuroprotective effect (on the model of ischemic stroke) of pharmaceutical compositions based on 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 hour. 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 5.4 5.4 5.3 5.2 5.1 5.0 5.0 Pharmaceutical formulations based drug 2- ethyl 6-methyl-3- hydroxypyridine succinate and minerals Farm. squad No. 25 5.0 5.1 5.2 5.3 5.4 5.3 5.2 5.1 5.0 5.0 Farm. squad No. 26 4.6 4.7 4.8 4.7 4.7 4.6 4.5 4.4 4.4 4.3 Farm. squad No. 27 4.5 4.5 4.7 4.6 4.6 4.5 4.5 4.5 4.5 4.5 Farm, composition No. 28 4.4 4.4 4.6 4.6 4.6 4.5 4.4 4.4 4.4 4.4 Farm. squad No. 29 4.3 4.3 4.4 4.5 4.6 4.5 4.3 4.3 4.3 4.3 Farm. squad No. 30 4.3 4.3 4.3 4.5 4.6 4.6 4.4 4.4 4.4 4.3 Farm. squad No. 31 - // - -AND- - // - - //. - // - -and- - // - -II- - // - -II-

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Farm. composition No. 32 - // - - // - - // - - // - -AND- -AND- -AND- -AND- -II- -II- Farm. composition No. 33 5.0 4.9 5.1 5.2 5.3 5.3 5.2 5.1 5.1 5.0 Farm, composition No. 34 4.5 4.6 4.7 4.7 4.7 4.6 4.5 4.5 4.5 4,5 Farm. composition No. 35 4.5 4.5 4.7 4.6 4.6 4.5 4.5 4.5 4.5 4.5 Farm, composition No. 36 4.4 4.5 4.7 4.6 4.5 4.5 4.4 4.4 4.4 4.3 Farm. composition No. 37 4.3 4.3 4.4 4.6 4.5 4.5 4.3 4.3 4.3 4.2 Farm, composition No. 38 4.2 4.2 4.3 4.5 4.5 4.5 4.4 4.3 4.3 4.1 Farm. composition No. 39 - // - - // - - // - - // - -AND- -AND- -and- - // - -and- - // - Farm. composition No. 40 - // - -AND- -AND- -II- -AND- -AND- -H- */BUT -and- - // - Farm. composition No. 41 4.9 4.9 5.3 5.3 5.3 5.3 5.2 5.1 4.9 4.8 Farm. composition No. 42 4.8 4.8 5.1 5.3 5.4 5.3 5.2 5.1 4.7 4.6 Farm. composition No. 43 4.7 4.7 4.9 5.2 5.3 5.2 5.2 5.1 4.7 4.6 Farm. composition No. 44 4.6 4.7 4.9 5.2 5.3 5.3 5.3 5.1 4.7 4.6 Farm. composition No. 45 4.4 4.5 4.5 4.7 4.9 4.9 4.7 4.6 4.6 4.5 Farm. composition No. 46 4.4 4.4 4.5 4.7 4.6 4.6 4.6 4.4 4.4 4.4 Farm, composition No. 47 -AND- - // - - // - - // - -II- - // - -AND- -II- -AND- -II- Farm. composition No. 48 - // - - // - - // - -II- -AND- -AND- -II- -AND- -AND- -AND-

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Table 18

Test results of the neuroprotective effect (on the model of hemorrhagic stroke) of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances with ¹³ C carbon isotopes, and the neuroprotective effect of the drug mexidol. The number of rats that did not stay on the rotating rod for 2 min (the number of surviving rats)

Drug serial number pharmaceutical composition dose of 20 mg per day per rat Time after surgery, days one 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 preparation of 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 (U) 3 (9) 2 (9) 1 (8) 0 (8) Farm. composition No. 27 4 (U) 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 4 (10) 3 (U) 2 (9) 1 (8) 0 (8) Farm. composition No. 30 3 (10) 2 (U) 1 (9) 0 (9) 0 (9) Farm. composition No. 31 - // - - // - - // - - // - - // - Farm. composition No. 32 - // - - // - - // - - // - -AND- Farm. composition No. 33 5 (9) 4 (9) 3 (8) 1 (7) 0 (6) Farm, composition No. 34 5 (10) 3 (10) 2 (9) 1 (9) 0 (8) Farm. composition No. 35 4 (U) 3 (U) 2 (9) 1 (9) 0 (8) Farm. composition No. 36 4 (10) 3 (U) 2 (9) 0 (8) 0 (8) Farm. composition No. 37 4 (10) 3 (U) 2 (9) 1 (8) 0 (8) Farm. composition No. 38 3 (U) 2 (U) 1 (9) 0 (9) 0 (9) Farm. composition No. 39 - // - - // - - // - - // - -AND- Farm. composition No. 40 - // - - // - - // - - // - -AND- Farm, composition No. 41 5 (9) 4 (9) 3 (7) 1 (7) 0 (7) Farm. composition No. 42 4 (10) 3 (10) 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 (U) 2 (U) 1 (9) 0 (8) Farm. composition No. 45 4 (U) 3 (U) 1 (9) 1 (8) 0 (8) Farm. composition No. 46 3 (U) 2 (U) 1 (9) 0 (9) 0 (9) Farm. composition No. 47 - // - -AND- -AND- - // - -II- Farm. composition No. 48 - // - -and- -AND- -AND- -and-

*) The number of rats that did not stay on the rotating rod for 2 minutes

**) The number of surviving rats at the time of control. 10 rats were provided for control.

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Table 19

Results of checking the effect of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and carbon isotopes ¹³ C, as well as mexidol on amnesia in mice caused by electroconvulsive shock.

The number of mice with amnesia of the conditioned passive avoidance reaction 24 hours after amnesic exposure,% (values rounded to the nearest whole number)

The drug, serial number The drug was administered once intraperitoneally for the pharmaceutical composition, 15, 30, 60, 90 and 120 minutes before training mice

dose of 20 mg per mouse fifteen thirty  60 90 120 Mexidol Mexidol, 20 mg 23 ' (21) 21 (twenty) 17 (fifteen) fifteen (thirteen) fifteen (thirteen) Pharmaceutical formulations based on the drug 2-ethyl-b-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 21 eighteen fifteen thirteen thirteen Farm. composition No. 30 twenty 17 14 12 12 Farm. composition No. 31 - // - - // - 14 12 -AND- Farm. composition No. 32 - // - - // - 14 12 - // - Farm. composition No. 41 23 21 17 fifteen 14 Farm. composition No. 42 22 twenty fifteen 14 14 Farm. composition No. 43 22 twenty sixteen fifteen 14 Farm. composition No. 44 22 twenty fifteen thirteen thirteen Farm. composition No. 45 twenty eighteen fifteen thirteen thirteen Farm. composition No. 46 nineteen 17 14 12 12 Farm. composition No. 47 - // - - // - 14 12 - // - Farm. composition No. 48 -AND- -AND- 14 12 - // -

*) The number of mice in each experiment is 30. **) Mexidol, dose of 40 mg per mouse.

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Table 20

Results of checking the effect of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes ¹³ C, as well as mexidol on amnesia in mice caused by scopolamine.

The number of mice with amnesia of the conditioned passive avoidance reaction 24 hours after amnesic exposure,% (values 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 ' nineteen fifteen thirteen thirteen

(21) (fifteen) (Yy) (TT) - 01) Pharmaceutical formulations based on the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals Farm. composition No. 25 23 eighteen 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 nineteen fifteen eleven eleven eleven Farm. composition No. 30 eighteen thirteen 10 10 10 Farm. composition No. 31 -II- 12 nine nine -II- Farm. composition No. 32 -II- - // - nine nine -II- Farm. composition No. 41 23 eighteen fifteen thirteen thirteen Farm. composition No. 42 22 17 fifteen thirteen thirteen Farm. composition No. 43 21 17 14 thirteen 12 Farm. composition No. 44 21 fifteen eleven eleven eleven Farm. composition No. 45 eighteen fifteen eleven eleven eleven Farm. composition No. 46 eighteen thirteen nine nine nine Farm. composition No. 47 - // - thirteen nine nine - // - Farm. composition No. 48 -AND- - // - nine nine - // -

*) The number of mice in each experiment is 30. *) Mexidol, dose of 40 mg per mouse.

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Table 21

Results of checking the effect of pharmaceutical formulations based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and carbon isotopes ¹³ C, 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 concentration of the drug 2- ethyl 6-methyl-3- hydroxypyridine succinate was 1g / l 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 was 1g / l (ZOOg / l) 93 (96) Pharmaceutical formulations based on the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate and mineral substances 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

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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 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

Literature

1. Voronina T.A., Ostrovskaya R.U. Guidelines for the study of the nootropic activity of pharmacological substances // Guide to the experimental (preclinical) study of new pharmacological substances. / Ed. Fisenko V.P. - M., 2000 .-- S. 153-158.

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.

3. 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, no. 6. - S. 1041-1047.

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 State Sanitary and Epidemiological Supervision 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, no. 6. - S. 1041-1047.

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

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

10. Guidance on the experimental (preclinical) study of new pharmacological substances. Ed. RU. Khabrieva. - M.: Ministry of Health of the Russian Federation, 2005.

11. MeSga \ with S.R., Rakyauap A.O., \ Uep0e1 O.T. NETWORK 1 ίηίατεΐίοη ίη 1Hc MoidBai dsbn ehasegba1eb bb rspo | - 1976. - Uo1. 7, Νο. 5. - R. 485-488.

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12. Sish1n K., Wapbie E.R., Sat / and E., NaeGe1u ^ .E. EGGes! οί (Do not have to pay one go! At (Ko 135057) Iropperab 1eagntg apb tetogu sh gobeby // P5usNorNagtaso1. - 1982. - Uo1. 78. - P. 104-111.

13. Separation of isotopes. Physical Encyclopedia.

LRP: //b1s.asabet1s.gi/b1s.p5G/eps_rLu51s5/1071/ISOTOPES.

13 15 18

14. Nanotechnology and the inclusion of atoms of deuterium H, carbon C, nitrogen N and oxygen O in the molecules of amino acids and proteins.

Fire: //5at11b.yi/o/o1ed_no_t/bositep15apb5eytd5o1edto5sht1bokitep1upap1ebpo1oduaotk1) isete1oto \ uberp] a211PG.1t1

15. R.F. Ganiev, V.I. Kormilitsyn, L.I. Ukrainian. Wave technology for the preparation of alternative fuels and the efficiency of their combustion. - M .: Scientific and Publishing Center Regular and chaotic dynamics, 2008. - 116 p.

Claims (3)

CLAIM 1. The pharmaceutical composition for injection, with neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity, containing 2-ethyl-6-methyl-3-hydroxypyridine succinate, characterized in that it contains minerals in the following ratio, mg / l: 2-ethyl-6-methyl-3-hydroxypyridine succinate - 1 · 10 ³ -300 · 10 ³ ; potassium - 0.020-27.7; magnesium - 0.065-70.3; iron - 0.027-24.5; manganese is 0.006–7.5, and the pharmaceutical composition contains ¹³ C isotopes of carbon, the ratio pC = ^ ³ 'C / W.'. where pS is the ratio of the amount of carbon isotopes ¹³ C to the total amount of carbon in the pharmaceutical composition; Ν ^Ι3 ' ^ί '. ' - the number of carbon isotopes ¹³ C in the pharmaceutical composition; NС - the total amount of carbon isotopes in the pharmaceutical composition is from 0.005 to 0.75. 2. A pharmaceutical composition for injection with neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity, containing 2-ethyl-6-methyl-3-hydroxypyridine succinate, characterized in that it contains minerals in the following ratio, mg / l: 2-ethyl-6-methyl-3-hydroxypyridine succinate - 1 · 10 ³ -300-10 ³ ; potassium - 0.020-27.7; magnesium - 0.065-70.3; iron - 0.027-24.5; Manganese - 0.006-7.5. 3. The pharmaceutical composition for injection according to any one of claims 1, 2, characterized in that the pH value is from 4 to 7.