EA020040B1 - Solid dosage form having neuroprotective, antiamnesic, antioxidant, antihypoxic and anti-ischemic activity (variants) - Google Patents

Abstract

The invention relates to the pharmaceutical industry and the field of medicine and can be used in the creation and administration of solid dosage forms having neuroprotective, antiamnesic, antioxidant, antihypoxic and anti-ischemic activity. The aim of the present invention is to create a solid dosage form having neuroprotective, antiamnesic, antioxidant, antihypoxic and anti-ischemic activity, by means of using 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances,C isotopes andN isotopes. The technical results of the invention are a more rapid onset of therapeutic effect, an enhanced therapeutic effect with no increase in the concentration of the 2-ethyl-6-methyl-3-hydroxypyridine succinate preparation, and improved stability for the duration of the shelf life.

Description

The invention relates to the field of pharmaceutical industry and medicine and can be used to create and use solid dosage forms with neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic 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. For the treatment of acute cerebrovascular accidents, dyscirculatory encephalopathy, vegetovascular dystonia, atherosclerotic dysfunctions of the brain, neurotic and neurosis-like disorders with anxiety, for the relief of withdrawal symptoms in alcoholism, for the treatment of acute intoxication with antipsychotics and a number of other diseases using modern Russian drugs based on 6 -methyl-2ethyl-3-hydroxypyridine succinate, in particular Mexidol (Instructions for use of the drug Mexidol. Register Discount Room P № 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 (Lp: // et ^ et.uoy.hz / teh1yo1.y1t1). 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 the polar fractions of lipids (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 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 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, first of all, 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 affects the key basic links of 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 provides two options for solid dosage forms.

An analogue to each variant of the solid dosage form 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). A solid dosage form can be prepared from a pharmaceutical composition by known methods (in particular by evaporation).

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 solid dosage form variants is a medicine 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 product during the expiration date.

In addition, there is an analogue - RF patent 2156087, published on 09/20/2000. The patent describes a dietary supplement (BAA) for food, 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 dietary supplement described in the patent by known technologies can be made in the form of a solid form.

The disadvantage of the analogue is the impossibility of its use in the form of a drug. The impossibility of use is due to the low content of Mexidol in kilogram (liter), several orders of magnitude less than required for a solid dosage form.

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.

- 1 020040

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 solid dosage form (Mexidol. Registration number: LSR-002063/07 from 08/09/2007), made in the form of a powder containing 2-ethyl-6methyl-3-hydroxypyridine succinate. The prototype contains the active substance: 125 mg of 2-ethyl-6-methyl-3-hydroxypyridine succinate (ethylmethylhydroxypyridine succinate). The weight of the solid dosage form is 135 mg. Thus, the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the solid dosage form is 926 g / kg (grams of 2-ethyl-6methyl-3-hydroxypyridine succinate in a kilogram of solid dosage form).

The prototype contains auxiliary substances: lactose monohydrate, sodium carboxymethyl cellulose (sodium carmellose), magnesium stearate.

Solid dosage form belongs to the group of antioxidant agents.

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.

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 drug 2-ethyl-6-methyl-3-hydroxypyridine succinate can be represented as follows:

The ^ -H 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 C4H6O4. 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 "solid dosage form made in the form of a powder containing 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 broader formulation of the features consistent with the invention may be as follows: a solid dosage form in the form of a powder 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, insufficiently large therapeutic effect, low stability during the expiration date.

SUMMARY OF THE INVENTION

Let us define the terms.

Solid dosage forms are tablets, powders (including capsules), granules.

Pills are a solid dosage form. Tablets are made by compressing drugs. Tablets are of various shapes, in particular in the form of cylinders, balls, flattened balls.

Tablets are prescribed for oral administration. In some cases, tablets are used for the preparation of solutions, including injection, as well as for subcutaneous implantation (Esperal).

Powders are a solid dosage form with the property of flowability.

In some cases, powders are placed in capsules. Capsules are coatings for metered-dose powdered drugs used internally.

Granules are a solid dosage form in the form of grains (grains) of a round, cylindrical or other shape.

Shelf life - the period during which the solid dosage form retains its properties to the extent that ensures its intended use.

The present invention is the creation of an effective solid dosage form with neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity.

The problem is solved due to the fact that the solid dosage form, made in the form of a powder, contains 2-ethyl-6-methyl-3-hydroxypyridine succinate and differs from the prototype in that it additionally contains mineral substances, and the content of 2-ethyl-6-methyl -3-hydroxypyridine succinate in solid dosage form from 1.0 to 990.0 g / kg (grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form), mineral content in solid dosage form, mg / kg (milligrams mineral

- 2 020040 substance in a kilogram of solid dosage form):

potassium - 0.02-930;

manganese - 0.006-38.0;

iron - 0.027-24.5;

zinc is 0.065-72.8, and the solid dosage form is made in such a way that it contains ¹³ C carbon isotopes, and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.005 to 0.75 (from 0.5 to 75%), and the solid dosage form has neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity.

The problem is also solved due to the fact that the solid dosage form, made in the form of a powder, contains 2-ethyl-6-methyl-3-hydroxypyridine succinate and differs from the prototype in that it additionally contains mineral substances, and the content of 2-ethyl-6- solid-dosage form of methyl 3-hydroxypyridine succinate - from 1 to 990 g / kg (grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form), and the content of mineral substances in solid dosage form, mg / kg (milligrams of mineral in kilogram of tv dope dosage form):

potassium - 0.02-930;

manganese - 0.006-38.0;

iron - 0.027-24.5;

zinc is 0.065-72.8, and the solid dosage form contains ¹³ C carbon isotopes, and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.005 to 0.75 (from 0.5 to 75 %), in addition, the solid dosage form contains ¹⁵ Ν nitrogen isotopes, and the ratio of ¹⁵ Ν nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375 (from 0.01 to 13.8% ), and the solid dosage form has a neuroprotective, antiamnestic, antioxidant anti-hypoxic, anti-ischemic activity.

In solid dosage form, in addition to the active substance and minerals, a pharmaceutically acceptable excipient or pharmaceutically acceptable excipients, in particular lactose monohydrate, sodium caramelose, magnesium stearate or other pharmaceutically acceptable substances, are used.

In other words, the active substance of 2-ethyl6-methyl-3-hydroxypyridine succinate and minerals are the basis of the solid dosage form. And the pharmaceutically acceptable excipients in solid dosage form are the rest.

When describing the medicinal substances that make up the solid dosage form, the specific indicator C is used: the content of the drug substance (in grams) in kilogram of solid dosage form.

C = (Slv / Stlf) 1000 g / 1 kg where C is the content of the drug substance (in grams) in kilogram of solid dosage form;

Slv - weight of the drug substance (in grams) in solid dosage form, g;

Stlf - weight of solid dosage form, g.

Let us explain the formula. Suppose that in the declared solid dosage form contains 2-ethyl-6-methyl-3-hydroxypyridine succinate - 0.05 g (50 mg). Let the powder weigh 60 mg. Then we can write that the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate in solid dosage form is 833.33 g / kg. Or, in other words, the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate is 833.33 g per kilogram of solid dosage form.

For this example, C = 833.33 g / kg. From the above formula, you can determine the weight of Slv, knowing how much powder Stlf = 60 mg weighs.

Slv = (C 1 kg / 1000 g) Stlf = (833.33 / 1000) 60 = 50 g

The content of 2-ethyl-6-methyl-3-hydroxypyridine succinate in solid dosage form can be selected from a range of values. Then you can write: the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate in a solid dosage form is from 0.1 to 990 g / kg (grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate in a kilogram of solid dosage form).

Or, in other words, the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate is from 0.1 to 990 g per kilogram of solid dosage form.

This form of recording is convenient when describing the content of a drug (substance) or mineral substance in solid dosage form.

The technical results of the invention are to increase the rate of onset of the therapeutic effect (decrease the time of onset of the therapeutic effect

- 3,020,040 effects) while maintaining the duration of action without increasing the concentration of the drug 2-ethyl6-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 intensity free radical processes;

an increase in the therapeutic effect without increasing the concentration of 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 radical processes;

increased stability of the solid dosage form with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate over the expiration date.

Currently, an increase in the onset of the therapeutic effect is provided by the dosage of the drug and the time of its effect;

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

Here are some examples. A known dosage form (RF application No. 94015245, published on 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 (USSR author's certificate 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 active substance due to the introduction of mineral substances into the solid dosage form.

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.

Mineral substances (Fe, Cu, Ζη, etc.) in solid dosage form 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 application, 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 solid dosage form enhance its 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 variants of solid dosage forms considered in the invention, the rational ranges of the values of the content of mineral substances are as follows, mg / kg:

potassium - 0.02-930.0;

magnesium - 0.065-1050.0;

iron - 0.027-24.5;

- 4,020,040 zinc - 0.065-72.80;

Manganese - 0.006-38.0.

The invention and the biologically active additives (BAA) described in the patent of the Russian Federation 2156087, the ranges of the specific indicator M * (M **) for mineral substances partially overlap.

The indicator M * is the amount of mineral matter in milligrams per 1 mg of the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the invention or dietary supplement (RF patent 2156087).

The indicator M ** is the amount of mineral matter in milligrams per 1 mg of mexidol in a liter of dietary supplement. We suggested that the authors of the patented dietary supplement under the word mexidol had in mind the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, and the water from mexidol was taken into account in the composition of the dietary supplement water.

Therefore, in the formula, to ensure the novelty of the invention, mineral substances are declared together with ¹³ C and ¹⁵ Ν isotopes.

When developing the invention, it was found that an increase in 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 solid dosage form, an increase in the stability of the solid dosage form with the drug 2-ethyl-6-methyl-3 -hydroxypyridine succinate during the expiration date is provided by the introduction into the solid dosage form of certain minerals (a certain combination of minerals) in a quantity strictly defined for each mineral. As a result of the research, a weight range in solid dosage form 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, in some cases, worsens the therapeutic effect of the action of 2-ethyl-6-methyl-3-hydroxypyridine succinate. It was found that with an increase in the concentration of mineral substances in solid dosage form (above the stated ranges), they suppress the action of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate, 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 increasing the concentration of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate in solid dosage form, an increase in the stability of the solid dosage form with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate for expiration dates are ensured by partial replacement in solid dosage form of carbon isotopes ¹² C with carbon isotopes ¹³ C and partial replacement in solid dosage form with nitrogen isotopes ¹⁴ Ν by nitrogen isotopes ^{1 5} Ν.

List of figures

In FIG. 1 presents a chromatogram of an aqueous extract of the claimed solid dosage form with an EBO detector. The chromatogram shows the mass fraction of the components of the aqueous extract of a solid dosage form with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances containing carbon isotopes ¹³ C.

In FIG. 2 shows the left side (on an abscissa scale of 90 to 170) ¹³ C-NMR spectrum of a sample of the claimed solid dosage form.

In FIG. 3 presents the right side (on an abscissa scale of 10 to 85) ¹³ C-NMR spectrum of a sample of the claimed solid dosage form.

In FIG. 4 presents the ¹ H-NMR spectrum of a sample of the claimed solid dosage form.

In FIG. 5 shows an enlarged detail of the ¹ H-NMR spectrum of a sample of the claimed solid dosage form.

In FIG. 6 presents a chromatogram of an aqueous extract of the claimed solid dosage form with a UV detector (220 nm).

In FIG. 7 is a chromatogram of an aqueous extract of the claimed solid dosage form with a mass selective detector.

In FIG. Figure 8 shows the M8M8 molecular ion with a value of t / x = 138. where m is the molecular mass, ζ is the charge.

In FIG. Figure 9 shows the left-hand side of the М8М8 molecular ion with the value ιη / ζ = 355.

In FIG. Figure 10 shows the right-hand side of the M8M8 molecular ion with a value of ιη / ζ = 355.

In FIG. 11 is a diagram of a cavitation reactor for isotopic enrichment of various mixtures.

In FIG. 12 is a cross-sectional view of a cavitation reactor.

In FIG. 13 is a diagram of an isotope enrichment plant.

Information confirming the possibility of carrying out the invention

In FIG. 1-10 presents the test results of the first claimed variant of a solid dosage form with minerals, mg / kg:

potassium - 378.6;

Manganese - 3.8;

- 5 020040 iron - 0.8;

zinc - 1.43.

Tests of samples of solid dosage forms with a different composition of mineral substances are similar.

The invention is illustrated by the examples below.

Example 1 - a method of introducing minerals into water.

Example 2 - a method of obtaining a solid dosage form and verification of stability.

Example 3 - tests of solid dosage forms for general toxicity.

Examples 4-8 illustrate the effectiveness of the claimed solid dosage forms with neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity.

The studies were carried out using materials published in sources (1-5).

Example 1

The introduction of mineral substances into the solution (in water) 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.

For in-depth studies, when developing an application for an invention, the concentration of metals in solid dosage form was provided in the following ranges, mg / kg:

potassium - from 0.01 to 930;

manganese - from 0.006 to 38.0;

iron - from 0.01 to 24.5;

zinc - from 0.05 to 72.8.

In addition, studies have been conducted on the extremely high content of minerals in solid dosage form. 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, cobolt, nickel, and chromium. A.1.3.2.1 source (6).

In addition, other solid dosage forms were studied containing a preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate with minerals calcium, copper, cobalt, chromium, magnesium, sodium and molybdenum. For studies, the concentrations of these metals in solid dosage form were provided in the following ranges, mg / kg:

copper - from 0.0001 to 2.3;

cobalt - from 0.0001 to 0.75;

chromium - from 0.001 to 1.58;

molybdenum - from 0.0001 to 1.59;

calcium - from 0.0008 to 30.0;

magnesium - from 0.065 to 1050.0;

sodium - from 1.00 to 1750.0.

Example 2

For example, we describe the preparation of one solid dosage form with potassium, manganese, zinc and iron of a certain concentration.

8 l of distilled water are poured into a stirred reactor. Then, the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate - 10 g is loaded into the reactor, a solution with potassium (total potassium content - 378.6 mg) is poured, a solution with manganese is added (total manganese content is 3.8 mg ), pour the solution with iron (total iron content - 0.8 mg), fill the solution with zinc (total zinc content - 1.3 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 and passed through a filter. Then, auxiliary substances are added to the solution: lactose monohydrate, sodium carboxymethyl cellulose (sodium carmellose), magnesium stearate with a total dry weight of 133.7 mg. Then carry out the evaporation and drying of the solid dosage form.

The solid dosage form was investigated by the method of 'H NMR and ¹³ C NMR.

As a result of research found:

¹ H NMR (360 MHz, IM8O-b ₆ ): 6.98 (d, 1 = 7.9 Hz, 0.96H); 6.84 (d, 1 = 7.9 Hz, 0.96H); 5.5-3.9 (m, 3.73H); 3.9-2.8 (m, 10.35H); 2.64 (q, 1 = 7.2 Hz, 2.05H); 2.54-2.45 (m, 1.93H); 2.41 (s, 4.14H); 2.30 (s, 3.03H); 2.15-1.2 (m, 2.87H); 1.121 (t, 1 = 7.2 Hz, 3H);

¹³ C NMR (360 MHz, ΌΜ8Ο-66): 173.66; 149.48; 148.53; 146.74; 121.96; 120.87; 103.84; 96.70; 92.08; 81.33; 75.51; 73.29; 72.17; 71.41; 70.68; 69.83; 68.20; 60.71; 40.44; 39.5; 28.95; 25.01; 22.99; 12.54.

The control showed high-quality performance of the solid dosage form.

Similarly, other claimed solid dosage forms with minerals and 2-ethyl-6-methyl-3-hydroxypyridine succinate were prepared and controlled.

It was found that the H-NMR spectra and ¹³ C-NMR spectra are not sensitive to a slight change in the amount and concentration of minerals in solid dosage form.

Studies of stability (shelf life) showed that the resulting

- 6 020040 ZOM solid dosage forms are stable and retain their baseline for 3.5 years. UV spectrophotometry and other of the above studies were carried out every six months for 3.5 years. Installed increased stability of the claimed solid dosage forms for 3.5 years compared with Mexidol. Mexidol showed stable properties for 3 years. In mexidol, sodium metabisulfite stabilizer provides stability.

Example 3

Tests for general toxicity were carried out by intraperitoneal injection of a solution (2 ml) obtained from a solid dosage form based on 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals in rats. In solid dosage form, a 75% content of carbon isotopes of ¹³ C and 13.9% content of nitrogen isotopes of ¹⁵ обеспеч was provided.

For studies of the concentration of mineral substances in solid dosage form selected, mg / kg:

potassium - 1330;

magnesium - 1950;

iron - 124;

zinc - 172;

Manganese - 138;

copper - 30;

cobalt - 3.75;

chromium 4.98;

molybdenum - 4.98;

calcium - 130;

sodium - 1990.

LO ₅₀ is up to 3000 mg / kg, which makes it possible to attribute the claimed solid dosage forms to non-toxic substances.

With prolonged use of a solid dosage form based on 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals in rats, no changes in the organs and tissues of the body were detected (were insignificant).

Example 4

The antioxidant activity of a solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances, and containing carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν, was compared with the antioxidant activity of mexidol by the chemiluminescent method (7).

Powdered mexidol tablet containing 2-ethyl-6-methyl-3-hydroxypyridine succinate - 125 mg, excipients: lactose monohydrate, sodium carboxymethyl cellulose (sodium carmellose), magnesium stearate with a total dry weight of 133.7 mg, compared with solid drug a form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals (serial numbers of solid dosage forms 33-48). For comparison, solid dosage forms were dissolved in distilled water.

Each of the solid dosage forms No. 33-48 contains a preparation of 2-ethyl-6-methyl-3hydroxypyridine succinate - 483 mg / kg, as well as powdered excipients, including substances included in the shell - 133.7 mg.

The total weight of the solid dosage form is 258.7 mg.

The comparison results are given in table. nine.

According to antioxidant activity (AOA), solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances and carbon isotopes ¹³ C and nitrogen ¹⁵ Ν were found to be superior to mexidol by up to 20% .

Solid dosage forms with serial numbers 33, 39, 41, 47 did not exceed Mexidol.

Solid dosage forms with serial numbers 40 and 48 were inferior in terms of effectiveness to Mexidol. The content (concentration) of mineral substances of these solid dosage forms inhibit the action of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate.

Therefore, solid dosage forms with serial numbers 33, 39, 40, 41, 47 and 48 to use as an antioxidant agent is not advisable.

Studies on the antioxidant activity of solid dosage forms were also carried out according to the method (8). The results are basically the same as above.

Example 5

The antihypoxic activity of solid dosage forms based on the preparation of 2-ethyl-6-methyl3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C and isotopes ¹⁵ Ν was compared with the antihypoxic activity of the drug 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.

The experiments recorded the life expectancy of animals after cessation of air access

- 7 020040 to the heat chamber. Animals were placed in a heat chamber individually.

Mexidol tablets were crushed to a powdery form, dissolved in distilled water and injected once intraperitoneally 30, 60 and 90 minutes before placing the mice in a heat chamber and stopping air from entering the heat chamber.

The time from the introduction of the drug to the placement of mice in a heat chamber and the cessation of air access in the table. 10-14 is indicated by TV in minutes.

Each solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals was dissolved in water and 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 solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances, and those containing carbon isotopes ¹³ C, with the antihypoxic activity of the drug mexidol are given in table. 10, 11 and 13.

The results of comparing the antihypoxic activity of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals containing carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν, with antihypoxic activity of the drug mexidol are given in table. 10, 12 and 14.

On the model of acute normobaric hypoxic hypoxia (in a heat chamber), it was found that most of the solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and minerals increased the life expectancy of mice by 5-9% 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 solid dosage forms. This is clearly seen in the table. 13 and 14. The claimed solid dosage forms increase the speed of the onset of the therapeutic effect, which brings together the values of life expectancy at Tv = 60 min and Tv = 90 min.

An increase in the therapeutic effect was achieved without increasing the concentration and amount of the drug 2ethyl-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 to the above studies, an additional comparison was made of the antihypoxic effect of the composition of Mexidol and Semax (Mexidol + Semax composition) and the antihypoxic effect of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances with carbon isotopes ¹³ C and nitrogen ¹⁵ Ν and the peptide sequence Me1-C1pH18-Rie-Pro-C1o-Pro (semax) in a model of acute normobaric hypoxic hypoxia in a heat chamber.

The weight ratio of Mexidol / Semax was 1 / 0.001-0.1.

In studies, the content of Semax in solid dosage form ranged from 0.001 to 99.0 g / kg.

It was found that the majority of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, semax and minerals (compared with the composition Mexidol + Semax) increased the life expectancy of mice to 10-15%.

Example 6

The neuroprotective effect of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances containing carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν, was compared with the neuroprotective effect of the drug mexidol (with the content of the drug 2-ethyl6-methyl-3 -hydroxypyridine succinate - 125 mg, which corresponds to a value of 483 g / kg solid dosage form).

Comparative studies were performed on white non-linear male rats weighing 220-240 g, in which ischemic stroke and hemorrhagic stroke were simulated.

Ischemic stroke in rats was reproduced by bilateral ligation of the common carotid arteries. Mexidol and the claimed solid dosage forms with serial numbers 17-32 were injected into the experimental animals inside peritoneally dissolved in distilled water (2 ml).

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. 15. The analysis of the results shown in the table showed that in rats who received intraperitoneal mexidol,

- 8 020040 neurological deficit was most pronounced (5.3 ± 0.1 points) 3 and 4 days after bilateral dressing 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 compositions based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C and nitrogen isotopes N at doses of 31 mg per day on the rat have a pronounced neuroprotective effect, in general, superior in severity of action in relation to neurological deficit mexidol.

Twenty four experiments were performed with rats who received an intraperitoneal dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, ¹³ C carbon isotopes and ¹⁵ K nitrogen isotopes. There were 12 rats in each experiment. 8-14% of animals.

Solid dosage forms with serial numbers 17 and 25 in terms of neuroprotective action practically do not exceed Mexidol. The neuroprotective effects of the remaining dosage forms are superior to the neuroprotective effect of Mexidol.

The most pronounced neuroprotective effect in solid dosage forms with serial numbers 18-22, 26-30.

The neuroprotective effect of solid dosage forms with serial numbers 23 and 31 is equal to the action of mexidol.

The neuroprotective effect of solid dosage forms with serial numbers 24 and 32 is significantly inferior to the action of mexidol.

The neuroprotective effect of solid dosage forms was tested on a hemorrhagic stroke (GI) model.

Hemorrhagic stroke in rats was reproduced by modeling local hemorrhage in the brain (the creation of HI with cerebral ischemia) and was performed according to the procedure (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.

Solid dosage forms were crushed and dissolved in 2 ml of distilled water to give an injection solution.

The studied solid dosage forms and mexidol were administered to animals intraperitoneally at a dose of 31 mg per day per rat.

The administration schedule was as follows: the first injection (half the daily dose) was performed 2 hours after the operation, the second injection (half the daily dose) was performed 4 hours after the operation.

Then the injections were carried out daily 1 time per 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. 16).

It was established that solid dosage forms with serial numbers 17, 23, 25 and 31 in terms of neuroprotective effect do not exceed Mexidol.

Solid dosage forms with serial numbers 24 and 32 are inferior to Mexidol in neuroprotective action.

Example 7

The anti-amnestic effect of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, ¹³ C carbon isotopes and ¹ ^ nitrogen isotopes was compared with the anti-amnestic effect of mexidol.

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

The effect of the studied solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate and the preparation Mexidol on amnesia (learning and memory processes) in mice was evaluated using the 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 solid dosage forms based on 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, ¹³ C carbon isotopes and ¹ ^ nitrogen isotopes and mexidol on amnesia was also evaluated using the scopolamine amnesia model after learning the conditioned passive avoidance reaction ( 10).

Solid dosage forms (dose of 31 mg - one quarter of a tablet) were ground to a powdery form and dissolved in 2 ml of distilled water to obtain an injection solution.

The drugs were administered once intraperitoneally 15, 30, 60, 90 and 120 minutes before the training of mice. The safety of the conditioned reaction of passive avoidance was checked 24 hours after the amnesiac effect.

On a model of amnesia caused by electroconvulsive shock, it was found that mice have solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ N and Mexidol is actively warning

- 9 020040 waiting for the development of amnesia of the conditioned reaction of passive avoidance (see table. 17).

Table analysis 17 shows that solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and carbon and nitrogen isotopes increase the rate of onset of the therapeutic effect while maintaining the duration of action without increasing the concentration of the active substance. There is also an increase in the therapeutic effect without increasing the concentration of the active substance.

Some effect can be achieved by increasing the dose of Mexidol or its concentration in the dose. In the experiments (see table. 17), the amount of Mexidol was increased from 31 to 62.5 mg per mouse.

On the model of scopolamine amnesia, it was found that mice have solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν, as well as mexidol prevent the development of conditional amnesia passive avoidance reactions (see tab. 18).

Solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν increase the onset of the therapeutic effect while maintaining the duration of action without increasing the concentration of the dosage form. There is also an increase in the therapeutic effect without increasing the concentration of the dosage form.

It has been established that 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 injection.

Example 8

The anti-ischemic effect of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, ¹³ C isotopes of carbon and ¹⁵ азота of nitrogen isotopes was compared with the anti-ischemic effect of mexidol. The comparison results are presented in table. nineteen.

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.

Solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and carbon and nitrogen isotopes and the preparation Mexidol were ground, dissolved in distilled water (2 ml), an injection solution was obtained, and then administered intraperitoneally during 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, drugs were administered 1 time per 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.

Solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon and nitrogen isotopes, as well as the preparation Mexidol significantly increased the survival of mice during the observation period (see Table 19).

The survival of mice increased with an increase in the dose of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the injection, as well as with an increase in the mineral content. It was also established that survival increased with an increase in the amount of carbon isotopes ¹³ C and nitrogen ¹⁵ Ν in solid dosage form.

From the table. Figure 19 shows that the survival rate of mice when using most solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, and carbon and nitrogen isotopes is higher than the survival rate of mice using only Mexidol.

Solid dosage forms 1, 7, 9, 15, 17, 23, 25, 31, 33, 39, 41, 47, 49, 55, 57, and 63 did not exceed the effect of Mexidol in their action. And solid dosage forms 8, 16, 24, 32, 40, 48, 56 and 64 were inferior to Mexidol in effectiveness. The decrease in the effectiveness of the drug 2-ethyl-6-methyl-3hydroxypyridine succinate is due to an excessive increase in the content of mineral substances in solid dosage form.

Thus, the application is described and the technical results of a solid dosage form made in the form of a powder containing 2-ethyl-6-methyl-3-hydroxypyridine succinate and which additionally contains minerals and the content of 2-ethyl-6-methyl-3 are confirmed -hydroxypyridine succinate in solid dosage form - from 1.0 to 990.0 g / kg (grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form), mineral content in solid dosage form, mg / kg (milligrams of mineral in ilogramme solid dosage form):

potassium - 0.02-930;

manganese - 0.006-38.0;

iron - 0.027-24.5;

zinc is 0.065-72.8, and the solid dosage form contains ¹³ C carbon isotopes, and the ratio of the number of isotopes

- 10 020040 carbon ¹³ C to the total amount of carbon in the solid dosage form is from 0.005 to 0.75 (from 0.5 to 75%), and the solid dosage form has neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity.

The above solid dosage form will be called solid dosage form No. 1.

The application is also described and the technical results of a solid dosage form made in the form of a powder containing 2-ethyl-6-methyl-3-hydroxypyridine succinate and which additionally contains minerals and the content of 2-ethyl-6-methyl-3-hydroxypyridine are confirmed succinate in solid dosage form - from 1.0 to 990.0 g / kg (grams of 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form), mineral content in solid dosage form, mg / kg ( milligrams of mineral to kilogram e solid dosage form):

potassium - 0.02-930;

manganese - 0.006-38.0;

iron - 0.027-24.5;

zinc is 0.065-72.8, and the solid dosage form contains ¹³ C carbon isotopes, and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.005 to 0.75 (0.5 to 75%) in addition, the solid dosage form contains ¹⁵ N nitrogen isotopes, and the ratio of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.01375 (from 0.01 to 13.9%), while the solid dosage form has a neuroprotective, antiamnestic, antioxidant, pro ivogipoksicheskoy, antiischemic activity.

The above solid dosage form will be called solid dosage form No. 2.

Studies of solid dosage form No. 1 with an expanded content of minerals were also conducted.

It was found that in addition to the above mineral substances in solid dosage form No. 1, any of the following mineral substances (except those contained in solid dosage form No. 1) can be added or added, mg / kg:

potassium - 0.02-930;

magnesium - 0.065-1050;

iron - 0.027-24.5;

zinc - 0.065-72.8;

calcium - 0.001-30.0;

sodium - 19-1750.0;

chromium 0.0012-1.58;

manganese - 0.006-38.0;

copper - 0.0003-2.3;

cobalt - 0.0003-0.75;

molybdenum - 0.0013-1.59.

Studies of solid dosage form No. 2 with an expanded content of minerals were also conducted.

It was found that in addition to the above mineral substances in solid dosage form No. 1, any of the following mineral substances (except those contained in solid dosage form No. 2) can be added or added, mg / kg:

potassium - 0.02-930;

magnesium - 0.065-1050;

iron - 0.027-24.5;

zinc - 0.065-72.8;

calcium - 0.001-30.0;

sodium - 19-1750.0;

chromium 0.0012-1.58;

manganese - 0.006-38.0;

copper - 0.0003-2.3;

cobalt - 0.0003-0.75;

molybdenum - 0.0013-1.59.

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 solid dosage forms based on the preparation of 2ethyl-6-methyl-3-hydroxypyridine succinate.

- 11 020040

It was found that increasing the stability of the claimed solid dosage forms over the shelf life can be achieved by replacing (from 0.5 to 75%) the carbon isotopes of ¹² C with carbon isotopes of ¹³ C. It is established that the carbon isotopes of ¹³ C in the molecules of the drug 2- ethyl 6-methyl-3-hydroxypyridine succinate slows down the chemical reactions that occur 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 non-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 solid dosage forms enriched in carbon ¹³ C isotopes, it was found that they have increased stability, they are non-toxic and, in addition, have increased neuroprotective, antiamnestic, antioxidant, antihypoxic, anti-ischemic activity compared to the solid dosage form, in which lacks carbon isotopes ¹³ C.

Methods for the production of a stable highly enriched non-radioactive carbon-13 isotope are widely used in Russian and world industry. Methods for producing the carbon-13 isotope by gas diffusion through porous walls, diffusion in a vapor 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 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 isotope (replacing ¹² C carbon isotopes with ¹³ C carbon isotopes) in a cavitation reactor designed by Professor V. I. Kormilitsyn. (Moscow Power Engineering Institute - Technical University).

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

In FIG. 11 is a diagram of a cavitation reactor for isotope enrichment of various mixtures, in particular hydrocarbon reagents, to obtain a preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate enriched in carbon isotope ¹² C. The reactor is located in a plant that contains a 6NK-6x1 pump, 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 the pump wheel 2950 rpm. Additionally, the installation contains tanks for reagents and measuring instruments.

The installation diagram is shown in FIG. eleven.

The cavitation reactor 1 (see Fig. 11) is made in the form of a flat Laval nozzle with cavitation bodies 2-9 in the channel 10.

In FIG. 12 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. 11, 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 to several thousand atmospheres and an increase in temperature to 1000 ° C are observed. 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 through pipeline 33 enters the separator with a porous partition, where the vapor

- 12 020040 gas 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, solutions (reagents) were obtained, and solid dosage forms containing the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate with a carbon content of ¹³ C from 0.5 to 75% of all carbon in solid dosage form.

Also, work was carried out to enrich the solutions with ¹⁵ S isotopes.

Substitution of nitrogen isotopes ¹⁴ with nitrogen isotopes ¹⁵ осуществ was carried out in the above cavitation reactor. When the reactor is operating, the reagent moves along the cavitator channel in direction 18. When flowing around cavitation bodies, the flow is divided into several flows. Beyond the cavitation bodies, cavitation areas arise. Upon entering the cavitation area, the reagent boils, cavitation bubbles appear, and when the cavitation area leaves the cavitation area, the cavitation bubbles collapse. In the experiment, nitrogen was supplied through the channels 24 and 25 in such a way that the gas fell into the cavitation zones.

The gas-vapor mixture obtained in the reactor, together with the reagent, enters the tank 28. Next, the gas-vapor mixture is fed through a pipe 33 to a separator with a porous baffle, where the gas-vapor mixtures with ¹⁴ Ы and ¹⁵ Ы are separated.

At the time of the development of the application for the invention, the reagent was enriched with a nitrogen isotope up to 13.9%.

Thus, solid dosage forms were obtained containing the preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate with a nitrogen content of ¹⁵ N from 0.01 to 13.9% of all nitrogen in solid dosage form.

When developing the application, studies were conducted to significantly increase the concentration of mineral substances in solid dosage forms. In the table. 1-8 solid dosage forms with a high content of minerals are numbered 7, 8, 15, 16, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63 and 64.

The studies found that solid dosage forms based on the preparation of 2-ethyl-6methyl-3-hydroxypyridine succinate and minerals of increased concentration have a reduced (even in relation to the drug mexidol) neuroprotective, antiamnestic, antioxidant, antihypoxic, anti-ischemic activity.

This must be considered when creating solid dosage forms.

Thus, the implementation of the claimed solid dosage forms provides an increase in the rate of onset of the therapeutic effect (decrease in the onset of the therapeutic effect) while maintaining the duration of action without increasing the concentration of the drug 2-ethyl6-methyl-3-hydroxypyridine succinate in the treatment of disorders of the nervous system, ischemia and central hypoxia 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 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 radical processes;

increased stability of the solid dosage form with the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate over the expiration date.

Table 1 Solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and with a carbon isotope content of ¹³ C equal to 0.5% of all carbon in the dosage form

Mineral substance The serial number of the solid dosage form with 1 gram of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form G ’ 2 3 4 5 6 7 8 Potassium mg / kg 0.01 0.02 100.0 378.6 930.0 1330.0 2500.0 4000.0 Manganese, mg / kg 0.005 0.006 0.1 3.8 38.0 138.0 250.0 750.0 Iron, mg / kg 0.01 0.027 0.2 0.8 24.5 124.0 250.0 750.0 Zinc mg / kg 0.05 0.065 0.1 1.43 72.8 172.0 250.0 750.0

*) The numbering of solid dosage forms is through.

- 13 020040

Table 2 A solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and with a carbon content of ¹³ C equal to 0.5% of all carbon in the dosage form and a nitrogen isotope content of ¹⁵ N, equal to 0.01% of all nitrogen in the dosage form

Minerals The serial number of the solid dosage form with 1 gram of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form nine 10 eleven 12 thirteen 14 fifteen sixteen Potassium mg / kg 0.01 0.02 100.0 378.6 930.0 1330.0 2500.0 4000.0 Manganese, mg / kg 0.005 0.006 0.1 3.8 38.0 138.0 250.0 750.0 Iron, mg / kg 0.01 0.027 0.2 0.8 24.5 124.0 250.0 750.0 Zinc mg / kg 0.05 0.065 0.1 1.43 72.8 172.0 250.0 750.0

Table 3

A solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 25% of all carbon in the dosage form

Minerals The serial number of the solid dosage form with 120 grams of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form 17 eighteen nineteen twenty 21 22 23 24 Potassium mg / kg 0.01 0.02 100.0 378.6 930.0 1330.0 2500.0 4000.0 Manganese, mg / kg 0.005 0.006 0.1 3.8 38.0 138.0 250.0 750.0 Iron, mg / kg 0.01 0.027 0.2 0.8 24.5 124.0 250.0 750.0 Zinc mg / kg 0.05 0.065 0.1 1.43 72.8 172.0 250.0 750.0

Table 4 A solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 25% of all carbon in the dosage form and a nitrogen content of ¹⁵ N equal to 1 % of total nitrogen in dosage form

Mineral substance The serial number of the solid dosage form with 120 grams of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form 25 26 27 28 29th thirty 31 32 Potassium mg / kg 0.01 0.02 100.0 378.6 930.0 1330.0 2500.0 4000.0 Mar ganese, mg / kg 0.005 0.006 0.1 3.8 38.0 138.0 250.0 750.0 Iron, mg / kg 0.01 0.027 0.2 0.8 24.5 124.0 250.0 750.0 Zinc mg / kg 0.05 0.065 0.1 1.43 72.8 172.0 250.0 750.0

Table 5 A solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 35% of all carbon in the dosage form

Mineral substance Serial number of the solid dosage form with 483 grams of 2-ethyl-b-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form 33 34 35 36 37 38 39 40 Potassium mg / kg 0.01 0.02 100.0 378.6 930.0 1330.0 2500.0 4000.0 Manganese, mg / kg 0.005 0.006 0.1 3.8 38.0 138.0 250.0 750.0 Iron, mg / kg 0.01 0.027 0.2 0.8 24.5 124.0 250.0 750.0 Zinc mg / kg 0.05 0.065 0.1 1.43 72.8 172.0 250.0 750.0

- 14 020040

Table 6 Solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and with a carbon content of ¹³ C equal to 35% of all carbon in the dosage form and a nitrogen isotope content of ¹⁵ Ν equal to 2 , 3% of all nitrogen in dosage form

Minerals The serial number of the solid dosage form with 483 grams of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form 41 42 43 44 45 46 47 48 Potassium mg / kg 0.01 0.02 100.0 378.6 930.0 1330.0 2500.0 4000.0 Manganese, mg / kg 0.005 0.006 0.1 3.8 38.0 138.0 250.0 750.0 Iron, mg / kg 0.01 0.027 0.2 0.8 24.5 124.0 250.0 750.0 Zinc mg / kg 0.05 0.065 0.1 1.43 72.8 172.0 250.0 750.0

Table 7

A solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and a carbon content of ¹³ C equal to 75% of all carbon in the dosage form

Mineral substance The serial number of the solid dosage form with 990 grams of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form 49 fifty 51 52 53 54 55 56 Potassium mg / kg 0.01 0.02 100.0 378.6 930.0 1330.0 2500.0 4000.0 Mar ganese, mg / kg 0.005 0.006 0.1 3.8 38.0 138.0 250.0 750.0 Iron, mg / kg 0.01 0.027 0.2 0.8 24.5 124.0 250.0 750.0 Zinc mg / kg 0.05 0.065 0.1 1.43 72.8 172.0 250.0 750.0

Table 8 Solid dosage form based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals and with a carbon content of ¹³ C equal to 75% of all carbon in the dosage form and a nitrogen isotope content of ¹⁵ Ν, equal to 13 9% of all nitrogen in dosage form

Mineral substance The serial number of the solid dosage form with 990 grams of the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate per kilogram of solid dosage form 57 58 59 60 61 62 63 64 Potassium mg / kg 0.01 0.02 100.0 378.6 930.0 1330.0 2500.0 4000.0 Manganese, mg / kg 0.005 0.006 0.1 3.8 38.0 138.0 250.0 750.0 Iron, mg / kg 0.01 0.027 0.2 0.8 24.5 124.0 250.0 750.0 Zinc mg / kg 0.05 0.065 0.1 1.43 72.8 172.0 250.0 750.0

Table 9 The results of comparing the antioxidant activity of a crushed Mexidol tablet with the antioxidant activity of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances, and containing ¹³ C carbon isotopes and ¹⁵ азота nitrogen isotopes (serial numbers of solid medicinal products Forms 33-48)

The serial number of the solid dosage form Antioxidant activity of a solid dosage form, Services Mexidol antioxidant activity, Services 33 3.75 34 3.93 35 3.95 3.75 36 4.27 37 4.29

- 15 020040

Table 10

The results of testing the antihypoxic activity of the crushed Mexidol tablets, dose * ⁾ 125 mg in 2 ml of injection

The time from the introduction of the drug to the placement of mice in the heat chamber and the cessation of air (TV), min Life span, min thirty 33.9 **) 60 38.1 90 38.7

*) The dose of the drug per mouse.

**) The average time for the tested mice in the experiment.

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Table 11 The results of testing the antihypoxic activity of a crushed Mexidol tablet with the antihypoxic activity of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, and carbon isotopes containing ¹³ C Life expectancy, min

Time Tv min The serial number of the solid dosage form with the drug 2-ethyl- 6-methyl-3-hydroxypyridine succinate 33 34 35 36 37 38 39 40 thirty 33.9 36.1 36.9 37.0 37.3 37.4 33.9 33.3 60 38.2 38.3 39.2 39.9 39.9 39.9 38.2 37.7 90 38.8 38.9 39.6 39.9 39.9 39.9 38.7 38.1

Table 12 The results of checking the antihypoxic activity of a crushed Mexidol tablet with the antihypoxic activity of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, and containing ¹³ C carbon isotopes and nitrogen isotopes ¹⁵ Ν Average life, min

Time Tv min The serial number of the solid dosage form with the drug 2-ethyl- 6-methyl-3-hydroxypyridine succinate 41 42 43 44 45 46 47 48 thirty 33.9 36.1 36.9 37.1 37.3 37.4 33.9 33.3 60 38.2 38.5 39.3 39.9 39.9 39.9 38.2 37.7 90 38.8 38.9 39.7 39.9 39.9 39.9 38.7 38.1

Table 13 The results of testing the antihypoxic activity of a crushed Mexidol tablet with the antihypoxic activity of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, and carbon isotopes containing ¹³ C Life expectancy, min

Time Tv min The serial number of the solid dosage form with the drug 2-ethyl- 6-methyl-3-hydroxypyridine succinate 49 fifty 51 52 53 54 55 56 thirty 33.9 36.7 36.9 37.3 37.4 37.4 33.9 33.3 60 38.2 38.5 39.5 39.9 39.9 39.9 38.2 37.7 90 38.8 38.9 39.7 39.9 39.9 39.9 38.7 38.1

Table 14 The results of verification of the antihypoxic activity of the crushed Mexidol tablet with the antihypoxic activity of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, and containing ¹³ C carbon isotopes and nitrogen isotopes Average life, min

Tv time MIN The serial number of the solid dosage form with the drug 2-ethyl- 6-methyl-3-hydroxypyridine succinate 57 58 59 60 61 ^Ί 62 63 64 thirty 33.9 36.7 36.9 37.3 37.4 37.4 33.9 33.3 60 38.2 38.6 39.6 39.9 39.9 39.9 38.2 37.5 90 38.8 38.9 39.8 39.9 39.9 39.9 38.7 38.0

- 17 020040

Table 15 Test results of the neuroprotective effect (on the model of ischemic stroke) of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C, nitrogen isotopes ¹⁵ Ν and the neuroprotective effect of the drug mexidol Measurements in points, M ± t, where t = 0.1

The drug, serial numbers of solid dosage forms, dose of 31 mg per day per 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, 31 mg 5.0 5.1 5.2 5.3 5.3 5.2 5.2 5.1 5.0 5.0

Solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon ¹³ C isotopes and nitrogen isotopes ^Ι5 Ν 17 5.0 5.1 5.2 5.3 5.3 5.3 5.2 5.1 5.0 5.0 eighteen 4.6 4.6 4.7 4.7 4.7 4.6 4.5 4.4 4.4 4.3 nineteen 4.5 4.5 4.6 4.6 4.6 4.5 4.5 4.5 4.5 4.5 twenty 4.4 4.4 4.5 4.5 4.5 4.5 4.4 4.4 4.4 4.4 21 4.3 4.3 4.4 4.5 4.5 4.5 4.4 4.3 4.3 4.3 22 4.3 4.3 4.3 4.4 4.4 4.4 4.4 4.4 4.4 4.3 23 5.0 5.1 5.2 5.3 5.3 5.2 5.2 5.1 5.0 5.0 24 5.0 5.1 5.4 5.5 5.5 5.3 5.2 5.1 5.0 5.0 25 5.0 5.0 5.1 5.2 5.3 5.2 5.2 5.1 5.0 5.0 26 4.5 4.5 4.6 4.6 4.6 4.6 4.5 4.4 4.3 4.3 27 4.5 4.5 4.6 4.6 4.6 4.5 4.5 4.5 4.5 4.5 28 4.4 4.4 4.4 4.4 4.4 4.4 4.4 4.4 4.4 4.4 29th 4.3 4.3 4.4 4.4 4.4 4.4 4.4 4.3 4.3 4.3 thirty 4.3 4.3 4.3 4.4 4.4 4.4 4.4 4.4 4.4 4.3 31 5.0 5.1 5.2 5.3 5.3 5.2 5.2 5.1 5.0 5.0 32 5.0 5.1 5.4 5.4 5.4 5.3 5.2 5.1 5.0 5.0

- 18 020040

Table 16

Results of testing the neuroprotective effect (on the model of hemorrhagic stroke) of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C, nitrogen isotopes ¹⁵ Ν and the neuroprotective effect of the drug mexidol Number of rats, not retained on a rotating rod for 2 min (number of surviving rats)

Drug serial number Time after surgery, days solid drug one 2 3 10 14 form, dose of 31 mg per day per day day day day day the rat Mexidol Mexidol, 31 mg 4 ’(9) 4 (9) 3 (8) 1 (7) 0 (6) Solid dosage forms based on the drug 2-ethyl-6-methyl-3-hydroxypyridine succinate, mineral substances isotopes carbon ¹³ С and nitrogen isotopes ^Ι5 Ν 17 4 (9) 4 (9) 3 (8) 1 (7) 0 (6) eighteen 4 (U) 3 (9) 2 (9) 1 (8) 0 (8) nineteen 4 (10) 3 (U) 2 (9) 1 (8) 0 (8) twenty 4 (U) 3 (U) 2 (9) 1 (8) 0 (8) 21 4 (U) 2 (U) 2 (9) 1 (8) 0 (8) 22 3 (U) 2 (U) 1 (9) 0 (9) 0 (9) 23 4 (9) 4 (9) 3 (8) 1 (7) 0 (6) 24 5 (9) 4 (9) 4 (8) 2 (7) 0 (6) 25 5 (9) 4 (9) 3 (8) 1 (7) 0 (6) 26 5 (U) 3 (U) 2 (9) 1 (9) 0 (8) 27 4 (U) 3 (10) 2 (9) 1 (9) 0 (8) 28 4 (U) 3 (10) 2 (9) 0 (8) 0 (8) 29th 4 (U) 2 (10) 2 (9) 1 (8) 0 (8) thirty 3 (U) 2 (U) 1 (9) 0 (9) 0 (9) 31 4 (9) 4 (9) 3 (8) 1 (7) 0 (6) 32 5 (9) 4 (9) 4 (8) 2 (7) 0 (6)

*) 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.

- 19 020040

Table 17

Results of checking the effect of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, ¹³ C carbon isotopes, ¹⁵ N nitrogen 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 amnesic exposure,% (values rounded to the nearest whole number)

The drug, the serial number of solid dosage forms, a dose of 31 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, 31 mg 22 ’ (2 g) twenty (twenty**) 17 * * (fifteen ) fifteen (1L 14 (thirteen**) Solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ K 17 22 twenty 17 fifteen 14 eighteen 22 twenty fifteen 14 14 nineteen 22 twenty sixteen fifteen 14 twenty 21 nineteen fifteen 12 12 21 21 eighteen fifteen 12 12 22 twenty 17 12 eleven eleven 23 22 twenty 17 fifteen 14 24 23 22 nineteen 17 sixteen 25 22 twenty 17 fifteen 14 26 22 twenty fifteen 14 14 27 22 nineteen sixteen 14 14 28 21 eighteen thirteen eleven eleven 29th twenty 17 thirteen and eleven thirty twenty 17 12 and AND 31 22 twenty 17 fifteen 14 32 23 23 nineteen 17 sixteen

*) The number of mice in each experiment is 15.

**) Mexidol, dose of 62.5 mg (half a tablet, powdered) per mouse.

- 20 020040

Table 18

Results of checking the effect of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C, nitrogen isotopes ¹⁵ Ν, 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)

The drug, the serial number of solid dosage forms, a dose of 31 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, 31 mg 22 ' nineteen fifteen thirteen thirteen (21) (eighteen) (14) (12) (12) Solid dosage forms based on the drug 2-ethyl-b-methyl-3-hydroxypyridine succinate, ¹³ C mineral carbon and ^из5 Ν nitrogen isotopes substances isotopes 17 22 nineteen fifteen thirteen thirteen eighteen 22 nineteen thirteen thirteen thirteen nineteen 22 twenty 12 12 12 twenty 21 nineteen 12 AND eleven 21 twenty eighteen 12 eleven eleven 22 twenty 17 12 eleven eleven 23 22 nineteen fifteen thirteen thirteen 24 23 twenty 17 fifteen fifteen 25 22 nineteen fifteen thirteen thirteen 26 22 nineteen thirteen thirteen thirteen 27 22 twenty 12 12 12

28 21 nineteen 12 AND eleven 29th twenty 17 eleven eleven eleven thirty twenty 17 eleven AND eleven 31 22 nineteen fifteen thirteen thirteen 32 23 twenty 17 fifteen fifteen

*) The number of mice in each experiment is 15.

**) Mexidol, dose of 62.5 mg (half a tablet, powdered) per mouse.

- 21 020040

Table 19

Results of testing the effect of solid dosage forms based on the preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate, minerals, carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ N, 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

The drug, the serial number of solid dosage forms. The concentration of 2-ethyl-b-methyl-Zhydroxypyridine succinate was 1 g / l The number of surviving mice on the 7th day after bilateral ligation of the common carotid arteries,% (values rounded to the nearest whole number) Powdered Mexidol Tablet The concentration of the drug 2-ethyl-6-methyl- 3-hydroxypyridine succinate: 1g / kg 87 120g / kg 91 483g / kg 95 990g / kg 97 Solid dosage forms based on the preparation 2-ethyl-6-methyl-3- hydroxypyridine succinate, minerals, carbon isotopes ^{| 3} C and nitrogen isotopes ^Ι5 Ν one 87 2 89 3 90 4 91 5 93 6 93 7 87 8 85 nine 87 10 89 eleven 91 12 91 thirteen 94 14 94 fifteen 87 sixteen 85 17 91 eighteen 92 nineteen 93 twenty 93 21 94 22 94 23 91 24 89 25 91 26 92 27 93 28 94 29th 94 thirty 94 31 92 32 88 33 95

- 22 020040

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Claims (2)

CLAIM 1. A solid dosage form in the form of a powder having neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity, containing 2-ethyl6-methyl-3-hydroxypyridine succinate, characterized in that it contains ¹³ C minerals and carbon isotopes in the following ratio of components: the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the solid dosage form is from 1.0 to 990.0 g / kg, the mineral content in the solid dosage form, mg / kg: potassium - 0.02-930; manganese - 0.006-38.0; iron - 0.027-24.5; zinc - 0,065-72,8, the ratio of the number of carbon isotopes ¹³ C to the total amount of carbon in solid dosage form is from 0.005 to 0.75. 2. A solid dosage form in the form of a powder having neuroprotective, antiamnestic, antioxidant, antihypoxic, antiischemic activity, containing 2-ethyl6-methyl-3-hydroxypyridine succinate, characterized in that it also contains mineral substances and isotopes of carbon ¹³ C and nitrogen ¹⁵ Ν in the following ratio of components: the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the solid dosage form is from 1.0 to 990.0 g / kg, the mineral content in the solid dosage form, mg / kg: potassium - 0.02-930; manganese - 0.006-38.0; iron - 0.027-24.5; zinc - 0.065-72.8, the ratio of the number of carbon isotopes ¹³ C to the total amount of carbon in the solid dosage form is from 0.005 to 0.75, the ratio of the number of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.