RU2527347C1 - Stable liquid pharmaceutical composition of 3-(2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate complex, having antihypoxic, antioxidant and adaptogenic action - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a stable liquid pharmaceutical composition, which includes 3-(2,2,2-trimethylhydrazinium)propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate in amount of 0.1-50 wt %, auxiliary substances in amount of 0.01-50 wt % and water.

EFFECT: invention enables to obtain stable pharmaceutical compositions for injection, peroral and local application, having marked antihypoxic, antioxidant and adaptogenic action.

32 cl, 1 dwg, 14 tbl, 60 ex

Description

FIELD OF THE INVENTION

The invention relates to the field of medicine and veterinary medicine, namely to the development of convenient liquid stable dosage forms of a new biologically active compound, a complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate (hereinafter referred to as the "Complex"), which has antihypoxic, antioxidant and adaptogenic effects and high chemical resistance. Liquid dosage forms of the “Complex” can be intended both for parenteral administration, and for oral and topical administration, which is achieved by the introduction of the necessary auxiliary substances.

State of the art

The complex 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxy-pyridine disuccinate is a new biologically active compound (synthesized by NCC Agrovetzashchita LLC), obtained on the basis of two well-known antihypoxants (succinate 2-ethyl-6-methyl-3-hydroxypyridine and 3- (2,2,2-trimethylhydrazinium) propionate dihydrate), developed due to the fact that both of these substances have a number of physical and chemical properties that make it difficult to develop ready-made dosage forms.

Known pharmaceutical formulations based on 2-ethyl-6-methyl-3-hydroxypyridine (EMHPS) succinate in various dosage forms: injection solutions, granular powders, capsules, tablets for oral use, gels, dressings (RU 2065299, RU 2144822, RU 2145855, RU 2149648, RU 2293558, RU 2205640, RU 2398583, UA 74283, etc.). Liquid dosage forms have significant advantages, as allow you to get a quick effect, in particular, when using the injection method of administration, which is important for acute disorders - heart attacks, strokes, etc. Other liquid dosage forms - “drops”, are convenient for oral use in pediatrics and veterinary medicine. Dosage forms - “spray”, “gel”, are convenient for external use, including in surgery. However, EMHPS in aqueous solutions is easily oxidized with the appearance of intense tan staining and loss of pharmacological activity, and this effect is observed even in ampoules filled with an inert gas, because sufficient for staining is those minor amounts of air that remain during purging and fall into ampoules when sealed. The easy oxidizability of EMHPS is an obstacle to the development of the “drop” dosage form and the “spray” dosage form with a mechanical sprayer. In patent RU 2205640, publ. 06/10/2003 it was proposed to add an excess of succinic acid to stabilize injection solutions, however, the solution becomes strongly acidic, which leads to significant pain in the injections and irritation of the skin in the case of a “spray” form; at the same time, as practical experience has shown, it is not effective enough to protect against oxidation. In patent RU 2380089 publ. 01/27/2010 as a stabilizer that protects against oxidation, it was proposed to add sodium metabisulfite. In this case, the oxidation and staining of the EMHPS solution during storage is completely eliminated. However, this solution has the disadvantage that sulfites are highly allergenic and also cause asthma attacks in patients with appropriate bronchopulmonary pathology [see Special instructions for solutions in / in and / m administration of drugs Metadoxil and No-spa at http://www.webvidal.ru]. Even the oral administration of sulfites and pyrosulfites with food and pharmaceuticals stimulates the development of allergic reactions, the excretion of calcium from the body [Hugot D., Causeret J., Leclerc J. Effets d l'ingest on de sulfites sur l; excretion du calcium chez le rat. Ann. Biol. Anim. Biochim. Biophys., 5, 53-59 (1965)], destroys thiamine, Bn, biotin, causing clinically pronounced vitamin deficiency [Bhagat B., Lockett M.F., The effect of sulphite in solid diets on the growth or rats. Food Cosmet. Toxicol., 2, 1-13 (1964); Shtenberg A.J., Ignat′ev A.D. Toxicological evaluation of some combinations of food preservatives. Food Cosmet. Toxocol., 8, 369-380 (1970)], damages the bronchopulmonary system, heart, kidneys, thyroid gland [Harmful substances in industry. Inorganic and Organoelement Compounds: A Handbook. / Ed. prof. N.V. Lazareva, Pub. 7th re. and extra. L .: Chemistry, 1977, p. 65; Rehm H.J., Wittmann N. Beitrag zur Kenntnis der antimikrobiellen Wirkung der schwefligen Saure. II. Mitteilung. Die Wirkung der dissoziierten und imdissoziierten Saure auf verschiedene Mikroorganismen. Z. Lebensin. Unters. Forsch., 120 (6), 465-478 (1963)], inhibits vital enzymes [Gunnison A.F. Sulfite toxicity. A critical review of in vitro and in vivo data. Food Cosmet. Toxicol., 19, 667-682 (1981); Pfleiderer G., Jeckel D., Wieland T. Uber die Einwirkung von Sulit auf einige DPN hidrierende Enzyme, Biochem. Z., 328, 187-194 (1956)] has a mutagenic effect [Mukai F., Hawryluk I., Shapiro R. The mutagenic specifity of sodium bisulfate. Biochem. Biophys. Res. Commun. 39, 983-988 (1970)]. Since injection EMHPS is often used in large doses and for a long time [RU 2309664, publ. 11/10/2007; RU 2290930, publ. 01/10/2007; Reference VIDAL. Medicines in Russia: A Handbook. M .: AstraFarmService, 2011, p. B-856], the drawbacks of using sodium metabisulfite as a stabilizer for the injection form of the drug are obvious, because on the one hand, the induction of a fatal attack of bronchial asthma is possible, on the other hand, deepening and intensification of pathological changes in the cardiovascular system and kidneys, impaired thyroid function. In the clinical sense, the use of sulfites or pyrosulfites as stabilizers of EMHPS significantly narrows the scope of application of a highly effective drug, leaving a large group of patients without the need for adequate therapy.

It should be noted that the known EMGPS (mexidol, mexicor, mexiphine, etc.) has a number of physicochemical properties that impede the development of convenient liquid dosage forms:

1. EMHPS solutions have a pH from 4.2 to 4.5, and with an increase in pH above 5, the oxidation rate increases sharply and the solution turns brown in a few days

2. With increasing pH to physiological values (6–7), sparingly soluble disubstituted salt precipitates from concentrated (more than 5%) solutions of EMHPS

3. EMHPS forms poorly soluble complexes with many organic compounds (including cofactors — pyridoxalphosphate, riboflavin-5-nucleotide, etc.).

Even more technological problems are associated with the use of 3- (2,2,2-trimethylhydrazinium) propionate dihydrate (meldonium) - this drug is a very unstable hydrate that loses water and changes its quality even at temperatures above 25-3 ° C. Meldonium, on the other hand, is very hygroscopic. The substance of meldonium during storage cakes very quickly and requires subsequent grinding. In the manufacture of injection forms, the aqueous solution of meldonium strongly leaches the glass, and at the same time practically does not have buffering properties (and even, on the contrary, has a differentiating effect when the pH changes) - as a result, after sterilization and storage, the injection solution becomes alkaline above the permissible limit and the destruction of meldonium is accelerated with the formation of toxic trimethylamine. Quality control injection solutions of meldonium quickly destroy pH-sensitive glass electrodes, which also causes certain technological difficulties and leads to economic losses. Alkaline solutions of meldonium (with a pH above 8) are painful during intramuscular injection and can cause tissue necrosis.

Thus, the known liquid pharmaceutical formulations with antihypoxic effect, containing EMGPS or meldonium as the active substance, have a number of disadvantages that limit their use.

Disclosure of invention

The objective of the invention is to expand the range of stable pharmaceutical formulations with antihypoxic, antioxidant and adaptogenic effects, suitable for the manufacture of injection and infusion forms, as well as dosage forms for oral administration (drops, syrup) and external use (spray, gels, ointments). The problem is solved by using as an active substance highly active as an antihypoxant and antioxidant, and at the same time, a chemically stable complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate (hereinafter “ Complex"). At the same time, not only good stability of the dosage forms during storage is achieved, but also a pronounced synergistic effect of the complex fragments, expressed in an increase in the biological effect, while the toxicity of the complex compared with its fragments is greatly reduced. This is explained by the effect of the Complex on various elements of the pathogenetic mechanism during hypoxia: 2-ethyl-6-methyl-3-hydroxypyridine has a direct antioxidant effect on lipid peroxidation in cell membranes, and 3- (2,2,2-trimethylhydrazinium) propionate prevents the accumulation of short-chain fatty acids and the development of acidosis in the cytoplasm of the cell, normalizing metabolism under conditions of hypoxia.

When conducting clinical studies of the developed dosage forms of the drug, the Complex revealed a significant adaptogenic effect [see examples 43-48]. Like all sterically hindered phenols, the in vivo drug had a direct antioxidant effect for various pathologies, which manifests itself in a significant decrease in the level of peroxidation compared to the control in tissues of different organs; a pronounced antioxidant effect on liver cells can be considered as a hepatoprotective effect [examples 49]. At the same time, the protective effect is quite selective in relation to the tissues of macroorganisms - in relation to pathogens, the protective effect is not manifested, including to protozoa (babesia [example 43], pathogenic ticks [example 42]; The complex does not prevent the development of the acaricidal effect of amitraz.

The complex has a very high solubility in water, which facilitates the development of dosage forms of “drops” and “spray”. The high solubility of the Complex in the absence of a tendency to form poorly soluble products with different substances (which is typical for EMHPS) allows introducing a wide range of excipients into the composition of liquid dosage forms, as a result of which it is possible to develop drugs with the optimal pathogenetic therapeutic effect on a particular disease. In this case, it is possible to adapt the dosage form for a specific patient population - for example, for children and animals.

Of the significant auxiliary substances in stable liquid pharmaceutical compositions, the use of which is often necessary to solve the tasks, the following groups can be distinguished: preservatives-bacteriostats; flavoring additives; additives with local anesthetic effect; electrolytes; gelling agents and others.

For non-sterile oral and topical forms, the possibility of introducing the necessary amounts of bacteriostatic preservatives into the stable liquid pharmaceutical composition, in particular those inhibiting the growth of molds, is important. As such, you can use either individual substances that are approved for use in the food and pharmaceutical industries, or combinations thereof. Sorbic acid or its pharmaceutically acceptable salts, benzoic acid or its pharmaceutically acceptable salts are most effective and safe; but p-hydroxybenzoic acid esters (parabens) can also be used, alcohols such as 1,2-propylene glycol, benzyl alcohol, 2-phenoxyethanol are less effective.

In the process of research, it was found that traditional antibiotics with a relatively narrow spectrum of action, due to which they are not used as preservatives, in pharmaceutical formulations with a sufficiently high content of the Complex exhibit a bacteriostatic effect of such a wide spectrum that also makes it possible to use them as preservatives. This can be observed using doxycycline (as a base or a pharmaceutically acceptable salt), and / or azithromycin (as a base or a pharmaceutically acceptable salt), and / or spiramycin (as a base or a pharmaceutically acceptable salt), and / or roxithromycin (in as a base or a pharmaceutically acceptable salt), and / or clarithromycin (as a base or a pharmaceutically acceptable salt), and / or midecamycin (as a base or a pharmaceutically acceptable salt), and / or lincomycin (as a base or pharmaceutically acceptable salt), and / or clindamycin (as a base or a pharmaceutically acceptable salt), and / or chloramphenicol, and / or thiamphenicol, and / or florfenicol, and / or ciprofloxacin (as a base or a pharmaceutically acceptable salt), and / or benzidamine (as a base or a pharmaceutically acceptable salt), and / or terbinafine (as a base or a pharmaceutically acceptable salt), and / or naphthyne (as a base or a pharmaceutically acceptable salt), and / or hexetidine (as a base or a pharmaceutically acceptable salt). At the same time, the pharmaceutical compositions of the Complex, intended for topical use in surgery, when using highly effective antibiotics as preservatives in them, can have not only a wound healing, antioxidant, local immunostimulating effect, but also a direct effect on the pathogenic agent, which simplifies therapeutic procedures.

The possibility of using antibiotics as preservatives in pharmaceutical formulations with the Complex is realized by the fact that there is no formation of insoluble adducts of the Complex and antibiotic, which is typical, for example, for EMHPS and meldonium in an individual state.

Known quaternary ammonium salts can be used as bacteriostatic preservatives for the pharmaceutical compositions of the Complex: 1,2-ethylene bis- (N, N-dimethyl-carbodecyl-hydroxymethyl) ammonium dichloride, and / or decamethylene bis (trimethylammonium bromide), and / or 1,10-decamethylene bis (N, N-dimethylmethoxycarbonylmethyl) ammonium dichloride and / or benzyldodecyl dimethylammonium chloride and / or dodecyldimethyl (2-phenoxyethal) ammonium bromide and / or benzyldimethyl [3- (myristoyl) propyl] ammonium chloride, and / or

hexadecyltrimethyl ammonium bromide - in this case, no precipitation also forms, and a sufficiently wide spectrum of bacteriostatic activity of the composition is provided. To enhance additional beneficial effects (antibacterial effect, immunostimulating, etc.) or to improve consumer properties (rheology, appearance, smell, etc.), a combination of several preservatives-bacteriostats from among those indicated can be used. The concentration of bacteriostatic agents may be in the range of 0.01-5.0%, depending on the effectiveness of the antimicrobial action and the composition of the stable pharmaceutical composition. For example, solutions of the Complex with fructose [Example 18] require elevated concentrations of preservatives.

The use of a pharmaceutical composition with a very low (below 4.5) or very high (more than 7.5) pH is characterized by significant pain in the intramuscular injection, and in case of topical application, damage to the skin can occur. Therefore, it is advisable to introduce weak organic bases into the composition of these compositions, forming buffer systems and maintaining the pH value at the optimum level (acidity regulators). In this capacity, organic compounds with at least one nitrogen-containing group can be used - both relatively biologically inert (diisopropylamine and / or tert-butylamine) and possessing high biological activity in the spectrum required for the developed drug (2-dimethylaminoethyl ether of benzhydrol and / or 1-methyl-2 [2- (α-methyl-p-chlorobenzhydryloxy) ethyl] pyrrolidine, and / or N-dimethylaminoethyl-N- (p-chlorobenzyl) aminopyridine, and / or 3,6-dimethyl- 9- (2-methylpyridyl-5) ethyl-1,2,3,4-tetrahydro-γ-carboline, and / or 3-methyl-9-benzyl-1,2,3,4-t etrahydrocarboline, and / or N, N-di (2,4-xylyliminomethyl) methylamine, and / or (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1- naphthylmethylamine and / or (E) -N-cinnamyl-N-methyl-1-naphthylmethylamine and / or 1,3-bis (2-ethylhexyl) -5-methyl-1,3-diazinan-5-amine).

To control acidity, it is even more advantageous to use organic compounds with at least one nitrogen-containing group and at least one oxygen-containing proton donor group. Hydroxyl (e.g., monoethanolamine and / or diethanolamine and / or triethanolamine and / or dimethylaminoethanol and / or diethylaminoethanol and / or meglumine and / or trioxymethylamine and / or 2-ethyl 6-methyl-3-hydroxypyridine) or carboxyl (e.g. dexpanthenol and / or doxycycline (base) and / or azithromycin (base)). These compounds are characterized by high solubility in water, the absence of a pronounced odor, and slightly lower basicity of amino groups, which makes it easier to bring the pH to the desired level. A number of these compounds have significant, although not very pronounced, therapeutic activity - they exhibit hepatoprotective action (dimethylaminoethanol, ethanolamine), nootropic (dimethylaminoethanol), etc., which is also useful.

It is very convenient to maintain the required pH value using well-soluble amino acids that are themselves buffer systems, of which L-lysine and L-arginine are the most convenient technologically. In addition, glycine and / or L-α alanine and / or β-alanine can be used. These acidity regulators also have significant and beneficial biological activity. As the base, trimethylhydrazinium propionate dihydrate can be introduced, which forms a buffer system in aqueous solutions with hydrosuccinate ions included in the structure of the Complex molecule, in these cases the spectrum of biological activity of the pharmaceutical composition does not change, which sometimes matters. Trimethylhydrazinium propionate dihydrate can be administered as concentrated aqueous solutions or as a powder.

As additives to improve the taste of oral stable dosage forms, polyhydric alcohols, such as xylitol, and / or sorbitol, and / or sugar (fructose, etc.) can be used. True, it was experimentally established that the solutions of the Complex containing aldehyde sugar (glucose, etc.) gradually turn yellow; but fructose solutions are stable. It is known that sweet taste is perceived as pleasant, both by humans and by most animals, including birds. Therefore, stable liquid dosage forms with a pleasant sweet-sour taste are readily eaten by animals. Moreover, aqueous solutions of polyhydric alcohols have a high dissolving ability with respect to the Complex.

Highly effective and appropriate, as a taste-correcting additive, the introduction of glycyrrhizic acid or its pharmaceutically acceptable salts into the pharmaceutical composition. In addition to a very pronounced sweet taste, glycyrrhizic acid and its salts have anti-inflammatory, antibacterial and antiviral effects. It can also be used in combination with the above polyols.

For stable liquid dosage forms intended for external use in animals, an important task is the suppression of "licking", because dogs and cats are prone to licking wounds, as a result, the drug is removed from the “target” and the animal receives an unpredictable dose of biologically active substance, which can be dangerous. For many animal species, this problem is most simply solved by introducing pharmaceutically acceptable substances with a strong bitter taste into the composition of the preparation. The most famous alkaloid is quinine (in the form of a base or a pharmaceutically acceptable salt), which also has anti-inflammatory and antiprotozoal activity. However, quinine is currently expensive and not widely available. It has been experimentally established that well-known drugs also have high bitterness that prevents licking: piracetam and / or chloramphenicol and / or metronidazole, diphenhydramine (as a base or a pharmaceutically acceptable salt), thiamphenicol, flufenicol, lincomycin (as a base or pharmaceutically acceptable salts), clindamycin (in the form of a base or a pharmaceutically acceptable salt) and some others. At the same time, piracetam is a well-known nootropic, tissue metabolic antihypoxant and a good solvent for the Complex; also possesses the properties of pinetrant, facilitating the absorption of the Complex from the skin. Chloramphenicol, thiamphenicol, flufenicol, lincomycin, clindamycin and metronidazole are known effective antibiotics. Diphenhydramine is an active antihistamine that has a strong local anesthetic effect.

For the treatment of wounds, various skin lesions, burns, it is advisable to introduce a sufficiently strong but safe anesthetic into the dosage forms for topical application. The use of highly soluble anesthetics of the amide or ether group (dicain, lidocaine, novocaine, pyrocaine, articaine) is possible, but often not safe due to the high absorption from the wound surface into the bloodstream and the manifestation of cardiotoxic effects. A number of drugs of this group in the process of metabolism can also form derivatives of p-aminobenzoic acid, which stimulates the growth of microflora in the wound (for example, novocaine). Therefore, it is more appropriate to use for this purpose preparations of other groups with a strong local anesthetic effect, among which the most well-known antihistamines are diphenhydramines (as a base or a pharmaceutically acceptable salt), and / or clemastine (as a base or a pharmaceutically acceptable salt) and / or dimebon (in the form of a base or a pharmaceutically acceptable salt), and / or mebhydroline (in the form of a base or a pharmaceutically acceptable salt), which, in addition to a local anesthetic, significantly e anti-inflammatory and immunomodulatory effects, as well as in some cases inhibiting the resistance of microflora to antibiotics. As a non-cardiotoxic anesthetic drug, benzofurocain (in the form of a base or a pharmaceutically acceptable salt), which also has a non-narcotic central analgesic effect and stimulates blood microcirculation in tissues, can be used. An effective anti-inflammatory drug benzidamine (in the form of a base or a pharmaceutically acceptable salt) has a strong local anesthetic effect in the absence of cardiotoxicity; in addition, it has a wide spectrum of antibacterial activity. The indicated aspects of the pharmaceutical activity of benzidamine make it expedient to use it in the Complex formulations intended for topical use.

It is possible to use acetylaminonitropropoxybenzene as an anesthetic, which, like benzidamine, has analgesic and antiseptic effects. All marked anesthetics can be used in the “Complex” formulations independently or in combination with each other.

In some cases, in severe diseases, the infusion of sufficiently diluted medicinal substances has certain advantages; this allows you to maintain a stable and optimal concentration of the drug in the bloodstream, while with other methods of administration, the concentration changes, especially in the case of rapidly metabolizing drugs. In patent RU 2398583, publ. 09/10/2010 an infusion solution based on EMHPS was proposed; Sodium chloride was proposed as an auxiliary substance, providing the necessary osmoticity of the drug. The complex, unlike EMHPS, allows the use in the composition of the infusion solution along with sodium, potassium, and / or magnesium, and / or calcium salts in concentrations equivalent to the concentration in the blood plasma, which ensures better tolerability of the drug, less likely side effects ( example 6); moreover, the complex itself is safer and does not exhibit neurotoxic effects characteristic of high doses of EMHPS, with a greater severity of therapeutic effects.

In surgery, for the effective use of antihypoxic antioxidants with a wound healing effect, preventing the development of fibrosis, stimulating local immunity, special dosage forms (sprays, gels) are needed. Sprays are convenient for applying to a wound or wetting napkins, but a gel is a more preferable form, since it is easy to apply on a wound surface and can be held for a long time in the desired area. Known development [RU 2259816, publ. 09/10/2005] EMGPS gel, however, it has not received widespread use, in particular due to a significant irritating effect. Based on the Complex, it is possible to develop a number of convenient and effective gels for surgery - both medical and veterinary (examples 26, 27). Gel forms are conveniently used in dentistry as an effective treatment for periodontal disease and other gum diseases (Example 28). Since meldonium and all its derivatives stimulate lymph circulation and have a therapeutic effect in various forms of lymphostasis; for this purpose, a technologically more convenient Complex can be used; in this case, the gel form is also convenient (Example 29). Various cellulose ethers — sodium carboxymethyl cellulose and / or methyl cellulose and / or hydroxypropyl cellulose and / or hydroxyethyl cellulose, mixed ethers such as hydroxyethyl methyl cellulose and others — can be used as gelling agents — rheological modifiers of rheological properties (example 26, 27). Polymers such as polyvinylpyrrolidone and / or special acrylate polymers of the odydrazh brand can be used as gelling agents - “thickeners”. Of great interest is the use of natural polymers - agar, and / or pectin, and / or hyaluronic acid and its pharmaceutically acceptable salts, and / or low molecular weight chitosan and its pharmaceutically acceptable derivatives, and / or gelatin, and / or polysaccharides, and / or chondroitins in the form of pharmaceutically acceptable salts. These rheological modifiers themselves have significant therapeutic effects (Example 28, 29).

The high stability of the Complex in aqueous solutions and the absence of the formation of poorly soluble adducts with acids and other pharmaceutical agents make it possible to develop complex effective stable dosage forms based on the Complex that contain natural metabolites that have certain therapeutic effects. Inosine and / or glycine and / or arginine and / or lysine can be used as natural metabolites. The known drug cytoflavin [http://www.rlsnet.ru/tn_index_id_23160.htm], which is a combination of succinic acid as an antihypoxant, riboxin, a number of cofactors and vitamins. Since succinic acid “in vivo” is a rather weak antihypoxant with a very fast metabolism, its replacement with a highly effective and safe Complex will significantly increase the therapeutic efficacy of the drug (example 7). As cofactors, riboflavin and / or cocarboxylase and / or pyrodoxalphosphate can be used

Oral stable liquid dosage form containing Complex, amino acids and vitamins with hepatoprotective and neuroprotective effects (a characteristic of all effective antioxidants), can be used in narcology, in particular for the quick and safe relief of withdrawal symptoms in alcoholism and drug addiction, as an adjuvant during the detoxification procedure (example 18).

The proposed liquid dosage forms based on the Complex are more stable than injectable preparations with EMHPS, however, given the technical conditions, it is advantageous to use carbon dioxide as a stabilizer. Filling the bottles under carbon dioxide or, at least, using carbon dioxide as an inert gas when filtering the solution through membranes, allows to slightly increase the stability of the complex aqueous solutions.

For oral liquid dosage forms that cannot be isolated from constant contact with the environment, experiments have shown that the introduction of oxidation inhibitors from the class of sterically hindered phenols capable of forming very stable radicals in chain oxidation reactions is effective, thus breaking off the radical chains . Because most of these oxidation inhibitors are very poorly soluble in aqueous systems, it is most convenient to use polyoxyethylated sterically hindered phenols, which also prevent the crystallization of the components of the pharmaceutical composition with significant cooling; this simplifies storage and transportation of products. Currently, polyoxyethylated tocopherol (trade name “Ferol A”) is available on the market, the most convenient as a stabilizer for liquid oral forms based on the Complex (see example 33, 39), this allows to increase the permissible shelf life up to 5 years and reduce the requirements for temperature conditions during storage and transportation of the drug. Synthetic water-soluble antioxidants of similar properties may also be used, for example polyoxyethylated ionol or polyoxyethylated 2,4,6-tritrebutylphenol.

Thus, the use of the Complex, which is stable to oxidation and hydrolysis, in liquid dosage forms allows us to develop a wide range of drugs with antihypoxic, antioxidant and adaptogenic effects for injection, oral and topical use. Examples of the implementation of the most relevant for medicine and veterinary medicine stable liquid dosage forms are given in examples 1-50, which, however, do not exhaust the entire spectrum of possible stable liquid dosage forms based on the "Complex".

The biological effects of some of the claimed stable pharmaceutical compositions are given in examples 40-50.

Brief Description of the Drawings

Figure 1 shows voltammograms of the current of oxygen electroreduction in the background electrolyte (phosphate buffer pH 6.86), depending on the process time.

Line 1 - in the absence of "Complex" (1)

Line 2 - after 60 seconds

Line 3 - after 120 seconds

Line 4 - after 180 seconds

Line 5 - line of the residual (background) current in the absence of oxygen in the solution. The concentration of the “Complex” is 0.5 mg / ml.

Example 1 (5% injection form)

1900 ml of water for injection is loaded into a pre-sterilized measuring cup with a capacity of 2 l, 100 g of the Complex are added with stirring with a glass rod, stirred until complete dissolution, water is added to a volume of 2 l. After the crystals of the Complex disappear, the solution is filtered through a filter bag with a pore diameter of 0.45 μm and 0.22 μm, poured in a stream of nitrogen into 2 ml ampoules of light-protective glass, sealed in a stream of nitrogen and sterilized by autoclaving at 122 ± 1 ° C for 8 minutes. Ampoules will be checked for mechanical impurities, pack 10 pieces in blisters, pack blisters in cardboard cases. Receive 976 ampoules, 97 packages, the solution in ampoules has the following parameters:

- the content of the main substance is 5.0%

- color - corresponds to the standard Y ⁷

- transparency - does not differ from water

Organic impurities:

- the content of 2,6-dimethyl-3-hydroxypyridine is less than 0.2% in terms of the basic substance

- the content of β-alanine - 0.6% in terms of the basic substance

- fumaric acid - not determined

- pH - 4.35

Ampoule packages are stored under normal conditions. After 3 years of storage, the following solution parameters

- the content of the main substance is 5.0%

- color - at the level of the standard Y ⁷

- transparency - does not differ from water

Organic impurities:

- the content of 2,6-dimethyl-3-hydroxypyridine is less than 0.2% in terms of the basic substance

- the content of β-alanine - 0.7% in terms of the basic substance

- fumaric acid - not determined

- pH - 4.7

Example 2 (2.5% injection form)

1900 ml of water for injection is loaded into a pre-sterilized measuring cup with a capacity of 2 l, with stirring with a glass rod, 50 g of the substance of the Complex are added, mixed until complete dissolution is added to a volume of 2 l. After the crystals of the Complex disappear, the solution is filtered through a filter bag with a pore diameter of 0.45 μm and 0.22 μm, poured under aseptic conditions in a stream of nitrogen into 2 ml ampoules of glass of class НС-3, sealed in a stream of nitrogen, and sterilized by autoclaving at 122 ± 1 ° C for 8 minutes. Ampoules will be checked for mechanical impurities, pack 10 pieces in blisters, pack blisters in cardboard cases. Receive 988 ampoules, 98 packages, the solution in ampoules has the following parameters:

- the content of the main substance is 2.5%

- color - does not differ from water

- transparency - does not differ from water

Organic impurities:

- the content of 2,6-dimethyl-3-hydroxypyridine is not detected

- the content of β-alanine - 0.5% in terms of the main substance

- fumaric acid - not determined

- pH - 4.48

Ampoule packages are stored under normal conditions. After 3 years of storage, the solution parameters are as follows:

- the content of the main substance is 2.5%

- color - at the level of the standard Y ⁷

- transparency - does not differ from water

Organic impurities:

- the content of 2,6-dimethyl-3-hydroxypyridine is not detected

- the content of β-alanine - 0.7% in terms of the basic substance

- fumaric acid - not determined

- pH - 4.51

Example 3 (50% drop)

In a pre-sterilized measuring cup with a capacity of 2 l load 1 kg of the substance of the Complex, 10 g of potassium sorbate, 1 g of sodium benzoate and 1 l of water for injection. The solution is slowly heated to 35-40 ° C with stirring, after complete dissolution, water is added to a volume of 2 l, the syrup is filtered off from mechanical impurities through a large-pore glass plate and poured into dark glass bottles equipped with droppers with a volume of 50 ml. Get 39 bottles, which are packaged in pencil cases.

Solution Parameters:

- content of the main substance - 50%

- color - corresponds to the standard Y ⁶

- transparency - corresponds to the standard 1

Organic impurities:

 - the content of 2,6-dimethyl-3-hydroxypyridine - 6.2% in terms of the basic substance

- the content of β-alanine - 0.6% in terms of the basic substance

- fumaric acid - not detected

- pH - 4.22

- taste - pronounced sour without unpleasant shades

- smell - barely noticeable, neutral

Ampoule packages are stored under normal conditions.

After 3 years of storage under normal conditions, the solution parameters are as follows:

- content of the main substance - 50%

- color - at the level of the standard Y ⁶

- transparency - corresponds to the standard 1

Organic impurities:

- the content of 2,6-dimethyl-3-hydroxypyridine is less than 0.2% in terms of the basic substance

- the content of β-alanine - 0.6% in terms of the basic substance

- fumaric acid - not determined

- pH - 4.21

- taste - pronounced sour without unpleasant shades

- smell - barely noticeable, neutral

In all viewed bottles, mechanical impurities, incl. associated with the crystallization of substances are absent.

Example 4 (spray 25%)

A 50% xylitol solution is preliminarily prepared, for which 1 liter of water for injection is loaded into a 2-liter beaker and 1 kg of xylitol is added with stirring. The dissolution of xylitol is accompanied by a significant decrease in temperature, so the glass is heated, maintaining a temperature of 20-25 ° C. The finished solution is filtered on a funnel with a large-pore glass plate. To prepare a solution for spray, 1 liter of xylitol solution is placed in a glass, the solution is heated to 25-30 ° C and 500 g of the substance of the Complex are added with stirring, stirred until dissolved and xylitol solution is added to a volume of 2 liters. 1 g of sorbic acid is added to the solution, stirred until dissolved and filtered through a filter with a large porous plate. The solution is Packed in dark glass bottles with a volume of 100 ml, equipped with a micropump ("spray"). Bottles are packed in cardboard cases.

The parameters of the solution at the time of packaging:

- content of the main (active) substance - 25%

- color - corresponds to the standard Y ⁶

- transparency - corresponds to the standard N1

Organic impurities:

- the content of 2,6-dimethyl-3-hydroxypyridine is not detected

- the content of Pβ-alanine - 0.5% in terms of the basic substance

- fumaric acid - not detected

- pH - 4.22

- taste - sweet and sour without unpleasant shades

- smell - barely noticeable, neutral

After three years of storage under normal conditions, the solution has the following parameters:

- content of the main (active) substance - 25%

- color - corresponds to the standard Y ⁶

- transparency - corresponds to the standard Y ⁶

Organic impurities:

- the content of 2,6-dimethyl-3-hydroxypyridine is not detected

- the content of β-alanine - 0.5% in terms of the main substance

- fumaric acid - not detected

- pH - 4.22

- taste - sweet and sour without unpleasant shades

- smell - barely noticeable, neutral

This finished dosage form is intended for introduction into the oral cavity of animals or convenient uniform application to food, as well as for irrigation of wound surfaces, wetting wipes in veterinary surgery.

This dosage form is intended for use in pediatrics and veterinary medicine.

Example 5 (50% drop)

The preparation of a solution for drops is carried out analogously to example 4, but 1 kg of the substance of the Complex is used. The solution is Packed in dark glass bottles of 100 ml, equipped with a dropper, the bottles are Packed in cardboard cases.

The parameters of the solution at the time of packaging:

- content of the main (active) substance - 50%

- color - corresponds to the standard Y ⁶

- transparency - corresponds to the standard N1

Organic impurities:

- the content of 2,6-dimethyl-3-hydroxypyridine is not detected

- the content of β-alanine - 0.5% in terms of the main substance

- fumaric acid - not detected

- pH - 4.19

- taste - pronounced sweet and sour, without unpleasant shades

- smell - weak, neutral

After three years of storage under normal conditions, the solution has the following parameters:

- content of the main (active) substance - 50%

- color - corresponds to the standard Y ⁶

The drug is intended primarily for use in veterinary medicine, namely in industrial pig breeding and poultry farming.

Example 6 (solution for infusion)

100 L of water for injection is loaded into an enameled reactor, with the stirrer turned on, 37 g of potassium chloride, 30 g of magnesium chloride, 33 g of calcium chloride (calculated as anhydrous), 300 g of sodium acetate trihydrate, 500 g of sodium chloride, 400 g of sodium gluconate are loaded , 100 g of the Complex. The solution was stirred for thirty minutes, then dimethylaminoethanol was added to a pH of 6.0 ± 0.1. The solution is stirred for 30 minutes and filtered through a packet of 0.45 and 0.22 μm membrane filters, creating pressure with carbon dioxide. The filtrate is poured under aseptic conditions into 250 ml dark glass bottles with rubber stoppers intended for infusion solutions.

The parameters of the solution at the time of filling the bottles:

- color - does not differ from water

- pH - 6.0

- osmolarity - 289 mosm / l

- the content of the Complex is 0.1%

- carbon dioxide content - 0.01%

Bottles are stored in the refrigerator, at a temperature from plus 5 ° C to plus 6 ° C, after 1 year the solution parameters:

- color - does not differ from water

- pH - 5.95

- osmolarity - 290 mosm / l

- the content of the Complex is 0.1%

This dosage form is intended for intravenous drip in severe cardiovascular and surgical pathologies, in the treatment of strokes.

The main indications for the use of the claimed funds are:

- acute cerebrovascular accident, subacute period of stroke, early and late post-stroke rehabilitation;

- discirculatory encephalopathy - both against the background of atherosclerotic lesions of the cerebral vessels, and against the background of hypertension (in the phase of decompensation, subcompensation and as planned maintenance therapy, in the compensation phase);

- posthypoxic, dysmetabolic and, above all, diabetic encephalopathy;

- vertebro-basilar insufficiency due to osteochondrosis of the cervical spine;

- acute period of traumatic brain injury, early recovery period after head injury, post-traumatic encephalopathy;

- epilepsy, episindrome;

- degenerative-dystrophic lesions of the nervous system, autonomic dysfunction syndrome;

- Parasomnic disorders

- polyneuropathies (dysmetabolic, primarily diabetic, compression-ischemic, post-traumatic, toxic, including alcoholic);

- exogenously organic diseases of the brain (as a result of previous neuroinfections, traumatic brain injury);

- with memory disorders and intellectual impairment in the elderly;

- periods of extreme loads;

- intoxication with ethyl alcohol and relief of alcohol withdrawal syndrome;

- anxiety disorders in neurotic and neurosis-like conditions;

- mild cognitive impairment of atherosclerotic genesis;

- acute intoxication with antipsychotic drugs (antipsychotics);

- acute purulent-inflammatory processes of the abdominal cavity (acute destructive pancreatitis, peritonitis), cholecystitis.

The solution of the "Complex" for infusion is administered intravenously dropwise - at a rate of 40-60 drops per minute. The dosage regimen is selected individually, depending on the severity of the disease. The recommended daily dose is 5-10 mg / kg. The maximum daily dose is 800 mg.

Example 7 (solution for infusion)

60.0 L of water for injection is loaded into an enameled apparatus with a stirrer; with stirring turned on, 10 kg of the Complex substance is loaded. Stirred for 30 minutes, then dimethylaminoethanol was added in small portions to a pH of 6.0 ± 0.1. 8 kg of dimethylaminoethanol is consumed in this procedure. 2 kg of inosine, 200 g of riboflavin mononucleotide, 120 g of cocarboxylase and 120 g of pyridoxalphosphate are loaded into the neutralized solution of the Complex with stirring; check the pH of the solution and adjust if necessary to a value of 6.0 ± 0.1 with the addition of dimethylaminoethanol. The prepared solution is filtered under pressure of carbon dioxide through a packet of membrane filters of 0.45 and 0.22 μm, the filtrate is poured into dark glass vials of 5 ml in aseptic conditions. Vials are stored under normal conditions for a year; receive after rejection of 19815 bottles.

The parameters of the solution at the time of bottling (the content of the components is determined by HPLC).

- Complex content - 10%

- inosine content - 2%

- the content of riboflavin mononucleotide - 0.2%

- cocarboxylase content - 0.12%

- the content of pyridoxalphosphate - 0.12%

- carbon dioxide content - 0.11%

- the solution is bright yellow, without a brown tint

- pH - 6.0

After one year of storage under normal conditions, solution parameters:

- Complex content - 10%

- inosine content - 2.0%

the content of riboflavin mononucleotide - 0.195%

- cocarboxylase content - 0.115%

- the content of pyridoxalphosphate - 0.118%

The solution is bright yellow, without sediment, without a brown tint; pH 5.9

In a similar preparation of a solution with ethyl methylhydroxypyridine succinate, a heavy precipitate precipitates when the base is added at a pH above 5; the filtered solution contains less than 3% antioxidant and reduced concentrations of the remaining components, after 2 weeks of storage, it turns dirty brown in the bottles, a precipitate forms in some of the bottles.

Metabolic drug. Pharmacological effects are due to the complex effect of the components that make up the drug. It stimulates the processes of cellular respiration and energy production, improves the processes of oxygen utilization by tissues, restores the activity of enzymes that provide an antioxidant effect, and has a direct antioxidant and antihypoxic effect.

The drug activates intracellular protein synthesis, promotes the utilization of glucose, fatty acids and GABA resynthesis in neurons via the Roberts shunt.

It has a positive effect on the bioelectric activity of the brain. The drug improves cerebral and coronary blood flow, activates metabolic processes in the central nervous system, reduces reflex disorders, helps restore impaired sensitivity and intellectual-mnestic brain functions. It has a positive effect on the parameters of the neurological status: it reduces the severity of asthenic, cephalgic, vestibulo-cerebellar, cochleovestibular syndrome, and also levels the disorders in the emotional-volitional sphere (reduces the level of anxiety, depression). Improves cognitive-mnestic functions and quality of life.

With the on / in the introduction helps to restore impaired consciousness. It has a quick awakening effect in post-anesthetic depression of consciousness. When using the drug in the first 12 hours from the onset of stroke, a favorable course of ischemic and necrotic processes in the affected area is observed (reduction of the focus), restoration of the neurological status and a decrease in the level of disability in the long term.

The drug is administered only intravenously in a dilution of 100-200 ml of a 5-10% glucose solution, 0.9% sodium chloride solution.

In acute violation of cerebral circulation, the drug is administered as early as possible from the onset of the development of the disease in a volume of 10 ml per administration with an interval of 8-12 hours for 10 days. In severe forms of the course of the disease, a single dose is increased to 20 ml.

With discirculatory encephalopathy and the consequences of cerebrovascular accident, the drug is administered in a dose of 10 ml of solution for 1 injection 1 time / day for 10 days.

With toxic and hypoxic encephalopathy, the drug is administered in a dose of 10 ml of solution for 1 injection 2 times / day after 8-12 hours for 5 days.

In a coma, the drug is administered in a volume of 20 ml for administration in a dilution of 200 ml of glucose solution.

In case of depression of consciousness after anesthesia, the drug is administered once in the same doses.

Example 8 (25% spray)

In a two-liter flask equipped with a stirrer, place 1 liter of water for injection; with the stirrer on, load 0.5 kg of piracetam and then 0.5 kg of the Complex, mix until completely dissolved. Without turning the stirrer off, add 20 g of benzofurocaine tartrate, 10 g of chloramphenicol and 5 g of p-hydroxybenzoic acid methyl ester. Mixing lead to complete dissolution; then monoethanolamine is added to a pH of 5.0-5.2 (consumption of 64 g of monoethanolamine). Water is added to 2 l of the total volume, the pH value is checked, which should remain in the range of 5.1 ± 0.1. The solution is filtered through a 0.22 μm membrane, poured into 50 ml polymer bottles equipped with a mechanical spray dispenser.

At the time of bottling, the solution has the following parameters:

- Content of the Complex - 25%

- the content of piracetam - 25%

- benzofurocain content - 1%

- pH - 5.1

- the solution is transparent, indistinguishable by color from water.

After two years of storage under normal conditions, the solution has the following parameters:

- Content of the Complex - 25%

- the content of piracetam - 24.8%

- benzofurocain content - 0.99%

- pH - 5.0

- color - at the level of ethanol Y ⁷

This dosage form is intended for use in veterinary surgery to accelerate wound healing. Piracetam included in the composition has a strong bitter taste, at the same time it is penetrant, facilitating the penetration of active substances through the detritus of purulent wounds and epithelium, and in addition, it is a tissue antihypoxant, enhancing the effect of the Complex. Chloramphenicol also has a strong bitter taste, at the same time it is a broad-spectrum antibiotic; piracetam and chloramphenicol prevent licking of the wound until the active substances are completely absorbed. Benzofurocain is a local anesthetic that also inhibits wound licking; at the same time, benzofuracoin has a central analgesic effect and improves microcirculation in inflamed tissues.

Example 9 (eye drops)

80 l of water for injection are loaded into the enameled reactor, 5 kg of the Complex and 0.5 kg of benzofurocaine tartrate are loaded with stirring, and stirred until complete dissolution. Then, meglumine is added in small portions to a pH of 5.5 (1.4 kg of meglumine is consumed). The solution was stirred, 0.4 kg of p-hydroxybenzoic acid methyl ester and 0.1 kg of p-hydroxybenzoic acid propyl ester were added, adjusted to 100 L with water for injection, stirred for 30 minutes and the pH was checked. The solution is filtered under pressure of carbon dioxide through a filter bag of 0.45 and 0.22 microns, Packed in disposable polymer droppers 2 ml.

The solution at the time of preparation has the following parameters:

- Complex content - 5%

- benzofurocain content - 0.5%

- pH - 5.5

- color - at the level of the standard Y ⁷

- transparency - does not differ from water

- carbon dioxide content - 0.08%

After two years of storage under normal conditions, the solution parameters did not change. This dosage form is intended for the treatment of eye diseases in humans and animals.

Example 10 (5% injection, under pressure of carbon dioxide)

80 l of water for injection is loaded into an enameled reactor with a stirrer, with the stirrer turned on, 5 kg of the Complex substance are loaded, stirred for 30 minutes, water for injection is added to a volume of 100 l, filtered under pressure of carbon dioxide through a filter bag of 0.45 and 0.22 microns; the solution is poured into 5 ml bottles of dark glass (nominal volume of 10 ml) under aseptic conditions.

At the time of bottling, the solution has the following parameters

- Complex content - 5%

- color - at the level of the standard Y ⁷

- transparency - does not differ from water

- pH - 4.22

- carbon dioxide content - 0.3%

After three years of storage under normal conditions, the solution has the following parameters:

- Complex content - 5%

- color - at the level of the standard Y ⁷

- transparency - does not differ from water

- pH - 4.31

- microbiological purity - lack of growth

This dosage form is intended for use in veterinary medicine, in the clinic of small pets (cats, medium-sized dogs, rodents, reptiles, birds).

Example 11 (5% injection, under pressure of carbon dioxide)

The solution preparation process is carried out similarly to experiment 10, the solution is poured into 10 ml into dark glass bottles with a nominal volume of 10 ml.

After three years of storage under normal conditions, the solution has the following parameters:

- Complex content - 5%

- color - does not differ from water

- transparency - does not differ from water

- pH - 4.33

- microbiological purity - lack of growth

- carbon dioxide content - 0.15%

This dosage form is intended for use in veterinary medicine, namely in the treatment of large (10-60 kg) dogs, mini-pigs.

Experiment 12 (injection)

80 L of water for injection is loaded into an enameled reactor with a stirrer, with the stirrer turned on, 10 kg of the Complex substance is loaded, stirred for 30 minutes, water for injection is added to a volume of 100 L, filtered under pressure of carbon dioxide through a filter bag of 0.45 and 0.22 μm. The solution is poured into 10 ml bottles of dark glass under aseptic conditions. At the time of bottling, the solution has the following parameters:

- Complex content - 10%

- color - corresponds to the standard Y ⁷

- transparency - does not differ from water

- pH - 4.19

- carbon dioxide content - 0.38%

After three years of storage under normal conditions, the solution has the following parameters:

- Complex content - 10%

- color - corresponds to the standard Y ⁶

- transparency - does not differ from water

- microbiological purity - no growth

- mechanical impurities - not detected

This dosage form is intended for use in veterinary medicine, namely in the treatment of productive animals (pigs, cattle, horses). Recommended single doses are shown in Table 1.

Table 1 Recommended doses of 10% solution of the Complex No. Animal The weight Single dose, ml one Horse 400-600 5 2 Cattle: calves up to 2 years old, 8-11 2-3 cows, heifers 450-500 10 3 Sow 200-250 5-10

Example 13 (drops)

60 l of water for injection is loaded into an enameled reactor and, with stirring, 40 kg of food sorbitol are heated, the solution is heated by supplying a coolant to a jacket to 25-30 ° C (dissolution of sorbitol is accompanied by a decrease in temperature); the solution is stirred for 30 minutes.

In a 6 liter glass flask equipped with a stirrer, 4 kg of dimethylaminoethanol and 1 kg of monoethanolamine are mixed.

From the reactor with a stirrer, the prepared sorbitol solution is poured into a polymer container, then 60 l of the prepared 40% sorbitol solution are loaded into the reactor from it; when the stirrer is on, 20 kg of the Complex are loaded and mixed until completely dissolved; with the stirrer on, 300 g of potassium sorbate and 100 g of sodium benzoate are charged. Then, without stopping stirring, the prepared mixture of amino alcohols (dimethylaminoethanol and monoethanolamine) is added in small portions to a pH of 4.5 (consumption of 1.2 kg of the mixture). The solution is stirred for 30 minutes, then a solution of sorbitol is added to a volume of 100 l and stirred for 30 minutes; without stopping mixing, the solution is filtered through a paper filter and Packed in 100 ml in glass bottles of dark glass, equipped with a dropper.

The parameters of the solution at the time of packaging:

- Complex content - 20%

- color - at the level of the standard Y ⁷

- transparency - at the level of standard No. 1

- taste - sweet and sour, without unpleasant shades;

- the smell is hardly perceptible, neutral.

After one year of storage under normal conditions, solution parameters:

- Complex content - 20%

- color - at the level of the standard Y ⁶

- transparency - at the level of standard No. 1

- taste - sweet and sour

- smell - barely noticeable, neutral

This dosage form is intended for oral use in veterinary medicine. Recommended doses for different animals are shown in Table 2.

table 2 Recommended single dose (20% of the Complex) (intake 2 times a day) Animal Weight, kg Doses note Active substance Solution number of drops g ml Cats 3-5 30 mg 0.15 0,126 7 Dogs less than 10 kg 30 mg 0.15 0,126 7 10-40 kg 60 mg 0.30 0.252 fourteen 40-60 kg 100 mg 0.5 0.42 22 dispensing pipette > 60 kg 200 mg 1,0 0.84 44 dispensing pipette Furry animals - 20-50 mg 0.1-0.25 0.084-0.21 5-11 dispensing pipette Birds - 5-6 mg / kg 0.025-0.03 g / kg 0.021-0.0252 ml / kg 1-2 per 1 kg of weight Horses 400-600 1000 mg 5,0 4.2 - dispensing pipette Cattle calves up to 2 weeks of cow, heifers 8-11 250 mg 1.25 1.05 56 dispensing pipette 450-500 1000 mg 5,0 4.2 - dispensing pipette Pigs Piglets, sows - 5-10 mg / kg 0.025-0.05 g / kg 0.021-0.042 ml / kg 1-2 per 1 kg of weight 200-250 500-700 2.5-3.5 2.1-2.94 - dispensing pipette Rodents: mice, rats, rabbits, chinchillas, guinea pigs - 20 mg / kg 0.1 g / kg 0.084 ml / kg 5 per 1 kg of weight

The active substance of the drug belongs to the group of antioxidants and is an inhibitor of free radical processes in the body. It has pronounced antioxidant, antihypoxic and membrane protective properties, has a therapeutic and prophylactic effect in hypoxia of various etiologies. The mechanism of action is the ability of the drug to reduce the processes of lipid peroxidation in cell membranes, bind free radicals, specifically affect energy metabolism, increasing the degree of energy of cells, increase the body's resistance to oxygen deficiency.

The active substance of the drug has a hepatoprotective effect, protecting the liver parenchyma with various intoxications, including caused by aflatoxin. The active substance of the drug is absorbed in the stomach and in the duodenum. It is excreted mainly with urine in the form of metabolites and in a small amount unchanged.

The complex according to the degree of exposure to the body belongs to low-hazard substances (hazard class 4 according to GOST 12.1.007-76), does not have locally irritating, cumulative, embryotoxic and teratogenic properties.

Application procedure

The complex is prescribed in drops to animals for therapeutic and prophylactic purposes in pathological conditions accompanied by hypoxia (oxygen deficiency) of organs and tissues.

The drug is used in acute, chronic cardiovascular and cardiopulmonary insufficiency, diseases accompanied by inflammatory processes, wound pathology (wounds, dermatitis, eczema, trophic ulcers, burns, frostbite), during recovery periods after diseases and operations, in veterinary geriatrics. The complex in drops is used in combination with specific and symptomatic therapy drugs, as well as during the continuation of the course of treatment after the end of the parenteral administration of the Complex solution. Drops are administered orally by mouth, regardless of the time of feeding the animals, or added to food or water. For therapeutic purposes, the Complex in drops is used twice a day for 10-30 days at the doses recommended in Table 2.

For prophylactic purposes, the Complex in drops is used in therapeutic doses indicated in Table 2, once a day for 15-30 days. If necessary, after 1-2 months the course of the drug is repeated.

In veterinary geriatrics ("Care for old animals"), the Complex is used in drops for dogs and cats over 7 years old in the spring-autumn period once a day for 30 days in a therapeutic dose (Table 2).

In productive livestock breeding, stress-protective action and antioxidant effects are most important, including the normalization of fertile functions. So, it is advisable to use the drug to increase the fertility of animals and reduce the number of cases of miscarriage, in order to increase the viability and survival of offspring. The drug reduces the duration of the service period in heifers and sows, reduces the duration of the period from childbirth to the time of hunting, increases the fertility of animals, prevents breast dysfunction. In industrial poultry and pig breeding, the drug eliminates the effects of stress caused by the close content of animals, increases the efficiency of feed, increases the weight gain per feed unit, mainly due to the meat component. When feeding the drug 2-3 days before transporting pigs to a meat factory due to the relief of stress, the quality of meat increases. In sports animals (horses, hounds), the drug increases resistance to hypoxia, protecting vital organs from ischemic damage. Because lactic acidosis caused by significant physical activity is blocked, animals quickly recover after competition.

The use of the Complex in drops does not exclude the use of other means of pathogenetic and symptomatic therapy.

Side effects and complications when using the Complex in drops in accordance with this instruction have not been established.

Example 14 (5% injection for small animals)

80 l of water for injection is loaded into an enameled reactor equipped with a mechanical stirrer, with the stirrer turned on, 5 kg of the Complex substance are loaded and mixed for 30 minutes. Then, in small portions, periodically taking a sample to check the pH, the substance trimethylhydrazinium propionate dihydrate (3.42 kg is consumed) is added to a pH of 4.5 ± 0.1. It is additionally mixed for 30 minutes, then water for injection is added to a volume of 100 l, cooled to + 10 ± 1 ° C and a pressure in the apparatus of 3 atm is created by supplying carbon dioxide (food grade). It is kept under stirring until the pressure drop stops (by periodically supplying carbon dioxide while maintaining 3 atm). Then the solution is filtered through a filter bag of 0.45 and 0.22 μm, poured under aseptic conditions, 5 ml into dark glass bottles (nominal volume of 10 ml or 5 ml).

The parameters of the solution at the time of bottling:

- Complex content - 5.0%

- color - better than standard Y ⁷

- transparency - indistinguishable from water

- pH - 4.50

- carbon dioxide content - 0.08%

After two years of storage under normal conditions, solution parameters:

- Complex content - 5.0%

- color - at the level of the standard Y ⁶

- transparency - indistinguishable from water

- pH - 4.51

This dosage form is intended for veterinary medicine, mainly for the treatment of domestic animals (cats, medium-sized dogs, rabbits, chinchillas, hamsters, rats). Recommended Dosages in Table 3

Table 3 Recommended single dose of 5% Complex (injection) for small pets; injection 1-2 times a day No. Animal Weight, kg Dose Note Active substance, mg Dose, ml one Mice 0,03 0.6 - 20 mg / kg 2 Hamster 0.05 1,0 - 20 mg / kg 3 Chinchilla 0.08 2.0 - 20 mg / kg four Rabbit 0.4-1 25 0.5 1-2 fifty 1,0 5 European mink 0.55-0.8 25 0.5 6 American mink 0.8-2.3 fifty 1,0 7 Nutria 5-7 one hundred 2.0 8 Cat 3-5 fifty 1,0 9 Dog <10 fifty 1,0 10-40 one hundred 2.0 10 Mini piggies 8-15 one hundred 2.0 eleven Pig pigs - 10 mg / kg 0.2 ml / kg 12 Rat 0.5 25 0.5

The active substance of the drug belongs to the group of antioxidants and is an inhibitor of free radical processes in the body. It has pronounced antioxidant, antihypoxic and membrane protective properties, has a therapeutic and prophylactic effect in hypoxia of various etiologies. The mechanism of action is the ability of the drug to reduce the processes of lipid peroxidation in cell membranes, bind free radicals, specifically affect energy metabolism, increasing the degree of energy of cells, increase the body's resistance to oxygen deficiency. The active substance of the drug has a hepatoprotective effect, protecting the liver parenchyma with various intoxications, including caused by aflatoxin. After using the drug, the active substance is rapidly distributed in the organs and tissues of the animal. It is excreted mainly with urine in the form of metabolites and in a small amount unchanged.

The complex 5% solution for injection according to the degree of exposure to the body belongs to moderately hazardous substances (hazard class 4 according to GOST 12.1.007-76) does not have locally irritating, cumulative, embryotoxic and teratogenic properties.

Application procedure

The complex 5% solution for injection is prescribed to dogs, cats and other small pets for therapeutic and prophylactic purposes, as well as as part of complex therapy for pathological conditions accompanied by hypoxia (oxygen deficiency) of organs and tissues. The injection form is used in cases where it is necessary to obtain a quick effect from the drug or it is difficult to use the oral form.

The drug is used in acute, chronic cardiovascular and cardiopulmonary insufficiency, diseases accompanied by inflammatory processes, wound pathology (wounds, dermatitis, eczema, trophic ulcers, burns, frostbite), during recovery periods after diseases and operations, in veterinary geriatrics.

The drug is highly effective for the prevention and treatment of toxicosis caused by the use of general anesthesia in surgical practice. For therapeutic and prophylactic purposes, the drug is administered subcutaneously, intramuscularly or intravenously (drip, at a rate of 60 drops per minute) in the recommended dose. The frequency of administration of the drug is once or twice a day for 5-15 days.

In veterinary geriatrics ("Care for old animals"), the Complex 5% injection is used for dogs and cats over 7 years old in the spring and autumn once a day for 10-30 days at a dose of 2.5 mg / kg of active substance ( 1.0 ml per 10 kg of body weight).

The dose, duration of the course and the frequency of use of the drug are prescribed by the attending veterinarian, depending on the physiological condition of the animal and the course of the disease.

The use of the Complex of 5% solution for injection does not exclude the use of other means of pathogenetic and symptomatic therapy.

Side effects and complications when using the Complex 5% solution for injection in accordance with these instructions have not been established.

Example 15 (5% injection for large animals)

The solution is prepared and bottled in the same manner as in Example 14, but 10 ml are packed in dark glass bottles. This dosage form is intended for use in veterinary medicine - the treatment of large dogs, mini-pigs and other animals weighing 10-60 kg. Recommended doses are in Table 4.

Table 4 Recommended single doses of 5% Complex (injection) for large domestic animals and productive animals; injection according to indications 1-2 times a day No. Animal Weight, kg Dose Note Active substance, mg Dose, ml one Horse 400-600 500 10 2 Cattle, calves up to 2 weeks 8-11 200-300 4-6 3 Cattle, cows, heifers 450-500 1000 twenty four Sows 200-250 500-1000 10-20 5 Sheeps 45-100 250-500 5-10 6 Rams 70-160 500-750 10-15 7 Large Breed Dogs 40-60 200-300 4-6 1 ml per 10 kg > 60 500 10

The active substance of the drug belongs to the group of antioxidants and is an inhibitor of free radical processes in the body. It has pronounced antioxidant, antihypoxic and membrane protective properties, has a therapeutic and prophylactic effect in hypoxia of various etiologies. The mechanism of action is the ability of the drug to reduce the processes of lipid peroxidation in cell membranes, bind free radicals, specifically affect energy metabolism, increasing the degree of energy of cells, increase the body's resistance to oxygen deficiency.

The active substance of the drug has a hepatoprotective effect, protecting the liver parenchyma with various intoxications, including caused by aflatoxin. After using the drug, the active substance is rapidly distributed in the organs and tissues of the animal. It is excreted mainly with urine in the form of metabolites and in a small amount unchanged.

The complex 5% solution for injection according to the degree of exposure to the body belongs to moderately hazardous substances (hazard class 4 according to GOST 12.1.007-76) does not have locally irritating, cumulative, embryotoxic and teratogenic properties.

Application procedure

The complex 5% solution for injection is prescribed to animals for therapeutic and prophylactic purposes, as well as as part of complex therapy for pathological conditions accompanied by hypoxia (oxygen deficiency) of organs and tissues. The injection form is used in cases where it is necessary to obtain a quick effect from the drug or it is difficult to use the oral form. The drug is used in acute, chronic cardiovascular and cardiopulmonary insufficiency, diseases accompanied by inflammatory processes, wound pathology (wounds, dermatitis, eczema, trophic ulcers, burns, frostbite), during recovery periods after diseases and operations, in veterinary geriatrics. The drug is highly effective for the prevention and treatment of toxicosis caused by the use of general anesthesia in surgical practice. For therapeutic and prophylactic purposes, the drug is administered subcutaneously, intramuscularly or intravenously (drip, at a rate of 60 drops per minute) in the recommended dose. The frequency of administration of the drug is once or twice a day for 5-15 days.

In productive livestock breeding, stress-protective action and antioxidant effects are most important, including the normalization of fertile functions. So, it is advisable to use the drug to increase the fertility of animals and reduce the number of cases of miscarriage, in order to increase the viability and survival of offspring. The drug reduces the duration of the service period in heifers and sows, reduces the duration of the period from childbirth to the time of hunting, increases the fertility of animals, prevents breast dysfunction. In industrial poultry and pig breeding, the drug eliminates the effects of stress caused by the close content of animals, increases the efficiency of feed, increases the weight gain per feed unit, mainly due to the meat component. When feeding the drug 2-3 days before transporting pigs to a meat factory, the amount of meat increases due to stress relief. In sports animals (horses, hounds), the drug increases resistance to hypoxia, protecting vital organs from ischemic damage. Because lactic acidosis caused by significant physical activity is blocked, animals quickly recover after competition.

The dose, duration of the course and the frequency of use of the drug are prescribed by the attending veterinarian, depending on the physiological condition of the animal and the course of the disease.

The use of the Complex of 5% solution for injection does not exclude the use of other means of pathogenetic and symptomatic therapy.

Side effects and complications when using the Complex 5% solution for injection in accordance with these instructions have not been established.

Example 16 (10% injection)

70 l of water for injection is loaded into an enameled reactor equipped with a mechanical stirrer, with the stirrer switched on, 10 kg of the Complex substance are loaded and mixed for 30 minutes. Then, the substance trimethylhydrosinium propionate dihydrate (4.51 kg is consumed) is added in small portions, periodically taking a sample to check the pH; addition lead to a pH of 4.5 ± 0.1. Additionally stirred for 30 minutes, add water for injection to 100 l, cooled to + 10 ± 1 ° C; at this temperature create a pressure of 3 atm by supplying carbon dioxide (food grade), withstand until the pressure drop stops; then the solution is filtered under pressure of carbon dioxide through a packet of membranes of 0.45 μm and 0.22 μm and poured into 10 ml vials of dark glass, under aseptic conditions.

The parameters of the solution at the time of bottling:

- Complex content - 10%

- color - at the level of the standard Y ⁷

- transparency - does not differ from water

- pH - 4.5

- carbon dioxide content - 0.05%

After two years of storage of the solution under normal conditions, the parameters of the solution:

- Complex content - 10%

- color - at the level of the standard Y ⁶

- transparency - at the level of standard No. 1

- pH - 4.65

This dosage form is intended for use in medicine and veterinary medicine in the treatment of productive animals and very large (over 60 kg) domestic animals and animals kept in zoos.

Table 5 Recommended single doses of 10% Complex (injection) for large domestic animals and productive animals; injection according to indications 1-2 times a day No. Animal Weight, kg Dose Note Active substance, mg Dose, ml one Horse 400-600 500 5 2 Cattle, calves up to 2 years old 200-300 2-3 3 Cattle, cows, heifers 450-500 1000 10 four Sows 500-1000 5-10 5 Sheeps 45-100 250-500 2,5-5 6 Rams 70-160 500-750 5-7.5 7 Large Breed Dogs 40-60 200-300 2-3 0.5 ml per 10 kg More than 60 500 5

The active substance of the drug belongs to the group of antioxidants and is an inhibitor of free radical processes in the body. It has pronounced antioxidant, antihypoxic and membrane protective properties, has a therapeutic and prophylactic effect in hypoxia of various etiologies. The mechanism of action is the ability of the drug to reduce the processes of lipid peroxidation in cell membranes, bind free radicals, specifically affect energy metabolism, increasing the degree of energy of cells, increase the body's resistance to oxygen deficiency. The active substance of the drug has a hepatoprotective effect, characteristic of the action of this group, protecting the liver parenchyma with various intoxications, including caused by aflatoxin.

After using the drug, the active substance is rapidly distributed in the organs and tissues of the animal. It is excreted mainly with urine in the form of metabolites and in a small amount unchanged.

The complex 10% injection for injection by the degree of exposure to the body belongs to moderately hazardous substances (hazard class 4 according to GOST 12.1.007-76) does not have locally irritating, cumulative, embryotoxic and teratogenic properties. Application procedure

The complex 10% solution for injection is prescribed to animals for therapeutic and prophylactic purposes, as well as as part of complex therapy for pathological conditions accompanied by hypoxia (oxygen deficiency) of organs and tissues. Injection form Complex 10% is used for large animals, mainly in productive animal husbandry, in cases where it is necessary to obtain a quick effect from the drug, or the use of the oral form is difficult.

The drug is used in acute, chronic cardiovascular and cardiopulmonary insufficiency, diseases accompanied by inflammatory processes, wound pathology (wounds, dermatitis, eczema, trophic ulcers, burns, frostbite), during recovery periods after diseases and operations, in veterinary geriatrics. The drug is highly effective for the prevention and treatment of toxicosis caused by the use of general anesthesia in surgical practice. For therapeutic and prophylactic purposes, the drug is administered subcutaneously, intramuscularly or intravenously (drip, at a rate of 60 drops per minute) in the recommended dose. The frequency of administration of the drug is once or twice a day for 5-15 days.

In productive livestock breeding, stress-protective action and antioxidant effects are most important, including the normalization of fertile functions. So, it is advisable to use the drug to increase the fertility of animals and reduce the number of cases of miscarriage, in order to increase the viability and survival of offspring. The drug reduces the duration of the service period in heifers and sows, reduces the duration of the period from childbirth to the time of hunting, increases the fertility of animals, prevents breast dysfunction. In industrial poultry and pig breeding, the drug eliminates the effects of stress caused by the close content of animals, increases the efficiency of feed, increases the weight gain per feed unit, mainly due to the meat component. When feeding the drug 2-3 days before transporting pigs to a meat factory, the amount of meat increases due to stress relief. In sports animals (horses, hounds), the drug increases resistance to hypoxia, protecting vital organs from ischemic damage. Because lactic acidosis caused by significant physical activity is blocked, animals quickly recover after competition.

The dose, duration of the course and the frequency of use of the drug are prescribed by the attending veterinarian, depending on the physiological condition of the animal and the course of the disease.

The use of the Complex of 10% solution for injection does not exclude the use of other means of pathogenetic and symptomatic therapy.

Side effects and complications when using the Complex of 10% solution for injection in accordance with this instruction have not been established.

Example 17 (spray)

In an enameled reactor equipped with a mechanical stirrer, load 60 l of water for injection, then with the stirrer on, load 20 kg of xylitol; the solution is cooled, so the mass in the reactor is heated to 20-25 ° C. At this temperature, 5 kg of the substance of the Complex, 100 g of the substance of quinine, 500 g of sodium sorbate and 100 g of sodium benzoate are loaded. The solution is stirred for 30 minutes, then 2-dimethylaminoethyl ether of benzhydrol is added in small portions from the mug to a pH of 5.0 ± 0.1. The solution is stirred for 30 minutes, adjusted to 100 L by adding water for injection and filtered from solids through a paper filter. The purified solution is Packed in 50 ml polymer bottles equipped with a mechanical dispenser.

The parameters of the solution at the time of release:

- Complex content - 5%

- the solution is transparent, yellowish (standard Y ⁵ )

- pH - 5.0

After two years of storage under normal conditions, the solution parameters did not change.

This dosage form is intended for use in the treatment of tick-borne infestations (scabies in humans, demodicosis, notoedrosis, sarcoptosis, heyletiosis, psoroptosis in animals). The drug has an antipruritic and wound healing effect, protects against combing and “biting” in animals, moderately inhibits the development of ticks, and has a bacteriostatic effect.

The drug can also be used as an additional local therapeutic agent in the treatment of skin lesions caused by protozoa. The drug has a wound healing effect, while it prevents fibrosis, the development of scar tissue; the drug also has a specific effect on the infectious agent, and has a significant anti-inflammatory effect.

Example 18

Into an enameled reactor equipped with a stirrer, 90 L of water for injection is charged. With the stirrer on, load 5 kg of fructose, 0.5 kg of Complex, 0.1 kg of potassium sorbate, mix for 30 minutes, then add 0.5 kg of pyridoxine pyroglutamate, 1.0 kg of glycine, and mix for another 30 minutes. After that, dexpanthenol is added in small portions to a pH of 5.5-5.6; then add 5 g of riboflavin and 10 g of the essence of "citrus", add water for injection up to 100 liters. With stirring, cool to 5 ° C, create pressure by supplying carbon dioxide in the reactor 3 atm, withstand until the pressure drop stops. The solution saturated with carbon dioxide is filtered through a paper filter and Packed in 100 ml in plastic bottles with a tightly closed lid. One bottle contains:

- Complex - 0.5 g

- fructose - 5 g

- pyroglutamate pyridoxine - 0.5 g

- glycine - 1.0 g

- panthenol - 0.5 g

The parameters of the solution at the time of packaging:

- Complex content - 0.5%

- fructose content - 5%

- glycine content - 1%

- panthenol content - 0.5%

- the content of pyroglutamate pyridoxine - 0.5%

- pH - 5.5

- taste - sweet and sour, pleasant

- color - lemon yellow

After one year of storage under normal conditions, solution parameters:

- Complex content - 0.5%

- fructose content - 5%

- glycine content - 1%

- panthenol content - 0.5%

- the content of pyroglutamate pyridoxine - 0.5%

- pH - 5.45

- taste - sweet and sour, without unpleasant shades

- color - lemon yellow

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 2 × 10 ² (the norm is not more than 10 ⁴ )

- the total number of mushrooms in 1 g is less than 10 (norm is not more than 10 ² )

- E. coli in 1 g - absent

- Salminella in 10 g - not available

- St. Aureus in 1 g - none

This dosage form is intended for the rapid relief of withdrawal symptoms of alcohol and drugs. A single dose - 100 ml, per day 2-3 times, until the manifestations of withdrawal symptoms disappear).

Example 19 (spray for surgery)

In an enameled reactor equipped with an anchor stirrer, 70 l of water for injection are charged; with stirring 10 kg of piracetam. After complete dissolution, load 10 kg of the substance Complex, 1 kg of metronidazole, 0.5 kg of sorbic acid and 0.1 kg of benzoic acid, 1 kg of diphenhydramine (hydrochloride). The solution was stirred for 30 minutes, then dexpanthenol was added in small portions to a pH of 5.5 ± 0.1. The solution is stirred for 30 minutes, up to 100 l of water for injection is added and filtered through a paper filter and Packed in 100 ml polymer bottles equipped with a dispenser.

The parameters of the solution at the time of release.

- Complex content 10%

- the solution is clear, yellowish

- pH - 5.5

After two years of storage under normal conditions, the solution parameters did not change.

The drug is intended for use in veterinary medicine, including in a complex of therapeutic procedures in the treatment of tick-borne infestations, for the treatment of superficial wounds in animals. The drug has an antipruritic, antiallergic, anesthetic effect, protects against licking and combing of wounds in animals, moderately inhibits the development of ticks and anaerobic microflora, including Clostridium, promotes the rapid healing of wounds without the formation of scar tissue. The drug can also handle wipes used in surgical practice.

Example 20 (spray for the treatment of circulatory disorders and lymph circulation)

In an enameled reactor equipped with an anchor stirrer, 90 L of water for injection is loaded, with the stirrer turned on, 10 kg of piracetam substance are loaded and mixed for 30 minutes. After that, the solution was brought to 100 l with water, stirred for 10 minutes and poured into a polymer container. 70 l of the prepared solution of piracetam are loaded into the reactor, then, with the stirrer turned on, 10 kg of the Complex, 0.5 kg of the substance pentoxifylline, 0.5 kg of racemic menthol, 0.5 kg of potassium sorbate are loaded; mix. Add 1 kg of dexpanthenol, mix, while the pH of the solution increases; adjust the pH to 5.5 with trimethylhydrazinium propionate dihydrate. The solution is stirred for 30 minutes, adjusted with water to a volume of 100 l. The solution is filtered under pressure through a paper filter, packaged in polymer bottles with a volume of 100 equipped with a dispenser-sprayer.

The parameters of the solution at the time of release:

- Complex content - 10%

- content of pentoxifylline - 0.5%

- color - corresponds to the standard Y ⁶

- transparency - corresponds to the standard 1

After two years of storage under normal conditions, solution parameters:

- Complex content - 10%

- pentoxifylline content - 0.49%

- color - corresponds to the standard Y ⁶

- transparency - corresponds to the standard 1

- Microbiological purity:

- the total number of aerobic bacteria in 1 g is 2.5 × 10 ² (the norm is not more than 10 ⁴ )

- the total number of mushrooms is less than 10 (the norm is not more than 10 ² )

This dosage form is intended for the treatment of circulatory disorders and lymphostasis in the lower extremities (thrombophlebitis without specific ulcers, edema, lymph circulation disorders, cellulite, etc. pathology), as well as frostbite of the I and II degrees.

Example 21 (drops)

In an enameled reactor equipped with an anchor stirrer, 80 L of water for injection is charged, with the stirrer turned on, 20 kg of sorbitol are loaded. Dissolution is accompanied by a decrease in temperature, so the mass is heated through a jacket to 20-25 ° C. Stirring is carried out for 30 minutes, water is added to 100 l, stirred for 10 minutes and the sorbitol solution is poured into a polymer container.

70 l of the prepared 20% sorbitol solution are placed in the reactor, with the stirrer turned on, 20 kg of the Complex substance, 0.5 kg of potassium sorbate and 0.1 kg of sodium benzoate are loaded. Stirred, then adjusted to pH 5.5 with the addition of L-arginine. The solution is stirred for 30 minutes, add a 20% solution of sorbitol to 100 l; add 20 ml of citrus essence, mix and filter through a paper filter and pack 50 ml in dark glass glass bottles equipped with droppers.

At the time of the spill, solution parameters:

- Complex content - 20%

- color - better than standard Y ⁷

- transparency - does not differ from water

- pH - 5.5

Parameters of the solution after one year of storage under normal conditions:

- Complex content - 20%

- color - corresponds to the standard Y ⁶

- transparency - corresponds to the standard No. 1

- pH - 5.54

- taste - sweet, sour with a touch of citrus, without unpleasant shades

This dosage form is intended for use in medicine and veterinary medicine. The drug improves the functional state of the cardiovascular system, normalizes blood pressure, improves the rheological properties of the blood, stimulates the immune system, including T-system of immunity. The drug has a normalizing and partly stimulating effect on fertile functions, especially in males. Promotes muscle growth, improves feed efficiency, accelerates the growth of animals.

Example 22 (drops for herbivores)

In an enameled reactor with a stirrer load 70 l of water for injection; when the stirrer is on, 20 kg of the Complex substance, 0.5 kg of potassium sorbate are loaded, stirred for 30 minutes. In small portions, with the stirrer working, L-lysine is added to a pH of 5.5, kept under stirring for 30 minutes, water is added to 100 L and filtered through a paper filter, Packed in 100 ml polymer bottles equipped with dosing pipettes.

The parameters of the solution at the time of packaging:

- Complex content - 20%

- color - corresponds to the standard Y ⁷

- transparency - does not differ from water

- pH - 5.5

After two years of storage under normal conditions, solution parameters:

- Complex content - 20%

- color - corresponds to the standard Y ⁶

- transparency - does not differ from water

- pH - 5.48

- Microbiological purity:

- the total number of aerobic bacteria in 1 g is 2.2 · 10 ² (the norm is not more than 10 ⁴ )

- total number of mushrooms - 15 (norm no more than 10 ² )

This dosage form is intended for use in veterinary medicine, namely for the treatment and prevention of herbivores (rodents, rabbits, chinchillas, cattle, horses, sheep, camels). Recommended single doses are given in Table 6; 2-3 receptions per day.

Table 6 Recommended Single Dose (20% Lysine Stabilized Complex) Animal Weight, kg Doses note Active substance, mg Solution g ml number of drops one 2 3 four 5 6 7 Decorative mouse 0,03 0.6 3 · 10 ^-3 2.5 · 10 ^-3 Hamster 0.05 1,0 5 · 10 ^-3 4.2 · 10 ^-3 Rabbit 0.4-2.0 8,0-40 5 · 10 ^-3 -200 · 10 ^-3 34 · 10 ^-3 -170 · 10 ^-3 Chinchilla 0.08 1,6 Guinea pigs 0.7-1.0 14-20 Sheeps
Rams 45-100
70-160 450-1000
700-1600 2.25-4.2
3,5-4,2 1.9-3.5
2.9-3.5 5 10 mg / kg Pigs piglets 1-20 5-10 mg / kg 0.025-0.05 g / kg 0.021-0.042 ml / kg 1-2 Up to 2 months sows 200-250 500-700 2.5-3.5 2.1-2.94 - boar 320 1000 5,0 4.2 mini pig 8-15 80-150 0.4-0.75 0.3-0.83 Cattle calves up to 2
weeks 8-11 250 1.25 1.05 56 Calves up to 3 months 40-160 500 2,5 2.1 - cows, heifers 450-500 1000 5,0 4.2 - bulls 300-900 1000-1500 5.0-7.5 4.2-6.3 - Horses 400-600 1000 5,0 4.2 - Camels 500-800 1000-1500 5-7.5 4.2-6.3

Example 23 (spray)

In an enameled reactor equipped with an anchor stirrer, 70 l of water for injection is loaded, with stirring, 10 kg of piracetam are loaded; after complete dissolution, 10 kg of the substance of the Complex, 1 kg of the substance of dimebon, 0.5 kg of potassium sorbate and 0.1 kg of sodium benzoate are loaded; then, with stirring, in small portions, panthenol is loaded to a pH of 5.5 ± 0.1. The solution is stirred for 30 minutes, water is added to 100 l, filtered through a paper filter and Packed in 100 ml plastic bottles equipped with a dispenser.

The parameters of the solution at the time of release:

- Complex content - 10%

- dimebon content - 1%

- the solution is clear, yellowish (Y ⁵ )

- pH - 5.5

After two years of storage under normal conditions, the solution parameters did not change.

The drug is intended for use in medicine and veterinary medicine for the treatment of skin lesions of an allergic nature (eczema, neurodermatitis, allergic bullous dermatitis, etc.), as well as superficial (1-2 degrees) burns. The drug has a strong anesthetic and antipruritic effect, improves microcirculation, has an antihistamine and antiserotonin effect, and promotes wound healing.

Example 24 (spray)

In an enameled reactor equipped with an anchor stirrer, 80 L of water for injection is loaded, with the stirrer turned on, 5 kg of the Complex substance and 1 kg of mebhydroline hydrochloride are loaded, after 30 minutes, 0.1 kg of potassium sorbate and 0.1 kg of sodium benzoate are loaded; monoethanolamine is added with stirring to a pH of 5.5 ± 0.1. The solution is stirred for 30 minutes, add up to 100 l of water for injection, filtered through a paper filter and Packed in 100 ml polymer bottles equipped with a dispenser.

The parameters of the solution at the time of release:

- Complex content - 5%

- pH - 5.5

- the solution is transparent (indistinguishable from water)

- color - corresponds to the standard Y ⁶

After one year of storage under normal conditions, the solution parameters did not change.

The drug is intended for use in medicine and veterinary medicine as part of a comprehensive treatment of skin diseases of an allergic nature (eczema, dermatitis, etc.); It can also be used to relieve itching after bites of blood-sucking insects.

Example 25 (spray)

In an enameled reactor equipped with an anchor stirrer, load 80 l of water for injection; when the stirrer is on, load 20 kg of piracetam, after 30 minutes of mixing 10 kg of the substance of the Complex and 1 kg of the substance clemastine (in the form of a fumarate), mix for 30 minutes; add 0.5 kg of sorbic acid, 0.1 kg of benzoic acid and triethanolamine is added in small portions to a pH of 5.5 ± 0.1. The solution was adjusted to 100 L with water for injection, stirred for 30 minutes, filtered through a paper filter and Packed in 100 ml polymer bottles equipped with a dispenser-sprayer made of dark polymer mass.

The parameters of the solution at the time of release:

- Complex content - 10%

- the solution is almost colorless (corresponds to the standard Y ⁷ )

- pH - 5.50

After one year of storage under normal conditions, the solution has the following parameters:

- Complex content - 10%

- color - corresponds to the standard Y ⁶

- pH - 5.46

The drug is intended for use in medicine and veterinary medicine in the complex treatment of skin diseases of an allergic nature and others. When applied to intact skin, the drug exhibits a systemic stress-protective and mild sedative effect, which can be used in preparing productive animals for transportation.

Example 26 (gel)

80 l for injection, 10 kg of the Complex, 0.5 kg of potassium sorbate are loaded into the reactor equipped with a stirrer, and stirred for 30 minutes; then diethanolamine is added to pH 5.5, stirred for 30 minutes, water for injection up to 95 L is added and mixed. The solution is filtered into a clean enameled reactor equipped with a stirrer through a paper filter. After completion of the filtration, with the stirrer switched on, 5 kg of hydroxypropyl cellulose are loaded, the reactor is closed, pressure is created by supplying carbon dioxide of the “food grade” qualification; the mass is heated through the jacket of the reactor and stirred for 2 hours; the mass should become homogeneous, without inclusions of insoluble hydroxypropyl - cellulose. The gel is Packed in 50 ml polymeric tubes.

At the time of filling, the gel has the following parameters:

- colorless, transparent viscous gel, odorless

- Complex content - 10%

- pH - 5.5

After two years of storage under normal conditions, the gel parameters are as follows:

- colorless, transparent viscous gel without any odor

- Complex content - 10%

- pH - 5.56

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 2.5 × 10 ²

- total number of fungi in 1 g - single colonies (less than 10)

- E. coli in 1 g - none

- Salmonella 10 g - none

- St.aurens 1 g - none

This dosage form is intended for use in medicine and veterinary medicine in surgical practice, including for the treatment of burns of the 2nd-3rd degree, during skin grafting.

Example 27 (gel for surgery)

In an enameled reactor equipped with an anchor stirrer, 80 l of water for injection are loaded, with the stirrer turned on, 10 kg of Complex, 0.5 kg of metronidazole, 0.1 kg of dimebon, 0.5 kg of chloramphenicol, 0.1 kg of nipagin M and mix until completely dissolved . After that, diisopropylamine is added in small portions to a pH of 5.5 ± 0.1, then water is added to a volume of 95 l .; stirred for 30 minutes. Without stopping mixing, 5 kg of pharmaceutical grade sodium carboxymethyl cellulose are added in portions. The reaction mass through the jacket of the apparatus is heated to 40 ° C and stirred for 2 hours until complete heterogeneity. The resulting gel is packaged in 100 ml polymeric tubes.

At the time of release, the gel has the following parameters:

- Complex content - 10.0%

- the content of metronidazole - 0.5%

- the content of chloramphenicol - 0.5%

- pH - 5.5

- yellowish transparent gel of a very bitter taste, without foreign smell; after a short time, the mucous membranes during tasting lose their sensitivity (anesthetic effect).

After two years of storage under natural conditions, the product parameters are as follows:

- Complex content - 10.0%

- the content of metronidazole - 0.5%

- the content of chloramphenicol - 0.48%

- pH - 5.38

- yellow transparent gel of a very bitter taste, without foreign smell; after a short time during tasting, the mucous membranes lose their sensitivity (anesthetic effect)

- Microbiological purity:

- total number of aerobic bacteria in 1 g - no growth

- total number of fungi in 1 g - single colonies (less than 10)

- E. coli in 1 g - none

- Salmonella 10 g - none

- St.aurens 1 g - none

This dosage form is intended for use in veterinary surgery - in the treatment of superficial and deep wounds, inflammation caused by anaerobic microflora in the treatment of burns of the 2nd to 3rd degree, incl. infected with anaerobic and mixed microflora (in a complex of therapeutic measures).

Example 28 (gel for dentistry)

In an enameled reactor equipped with an anchor stirrer, load 60 l of water for injection; when the stirrer is on, 20 kg of xylitol are loaded; the solution is heated through a jacket to 20-25 ° C, because dissolution of xylitol is accompanied by a strong decrease in temperature. After dissolution of xylitol, 10 kg of the Complex, 0.12 kg of metronidazole, 0.5 kg of calcium sorbate, 0.1 kg of the substance 3-methyl-9-benzyl-1,2,3,4-tetrahydrocarboline hydrochloride are loaded into the reactor with the stirrer operating, 0.5 kg of menthol, the mass is stirred for 30 minutes, then dexpanthenol is added in small portions to a pH of 5.5; the reaction mass through the jacket of the reactor is heated to 40 ° C and in small portions load 1 kg of sodium hyaluronate; the mass is mixed until completely homogeneous, water is added to a volume of 1 liter. And again stirred for 1 hour until complete mass uniformity. The resulting gel is packaged in 50 ml polymeric tubes in a warm state.

The drug at the time of release has the following parameters:

- Complex content - 10%

- pH - 5.5

- transparent yellowish homogeneous gel with a “mint” smell, sweet and sour taste with a pronounced shade of bitterness and a strong smack of mint

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 1 × 10 ²

- total number of mushrooms in 1 g - 10

- E. coli in 1 g - none

- Salmonella 10 g - none

- St. Aurens 1 g - none

After one year of storage under normal conditions, the drug has the following parameters:

- Complex content - 10%

- pH - 5.48

- transparent yellow homogeneous gel with a “mint” odor, sweet and sour taste with a pronounced shade of bitterness and a mint flavor.

- Microbiological purity:

- total number of aerobic bacteria in 1 g - single colonies

- total number of mushrooms in 1 g - absent

- E. coli in 1 g - none

- Salmonella 10 g - none

- St. Aurens 1 g - none

This dosage form is intended for use in dentistry in humans and animals, primarily for the treatment of gum disease, periodontal disease, etc. diseases. The drug in addition to antioxidant and anti-inflammatory effects has a pronounced anesthetic and anti-allergic effect, and also exhibits an antimicrobial effect. The gel can be used as the basis for the treatment of toothpastes.

Example 29 (lymphatic drainage gel)

In an enameled reactor equipped with a stirrer, 70 l of water for injection are charged; when the stirrer is on, 15 kg of the Complex substance, 0.1 kg of peppermint oil, 0.5 kg of potassium sorbate, 0.5 kg of benzyl alcohol are loaded and mixed for 30 minutes. Then, meldonium is added in small portions to a pH of 5.5 ± 0.1. Add water to a volume of 100 l, mix for 30 minutes and check the pH (add meldonium at pH less than 5.5 ± 0.1). While stirring, add 1 kg of hyaluronic acid in small portions; the mass is heated to 40 C and stirred for 2 hours until the heterogeneities disappear, then cooled to 20 ° C and Packed in 100 ml polymer tubes.

The gel at the time of packaging has the following parameters:

- Complex content - 15%

- pH - 5.5

- transparent colorless viscous gel with a mint smell

- Microbiological purity:

- total number of aerobic bacteria - 2.5 × 10 ²

- the total number of mushrooms in 1 g - 5 × 10

- E. coli in 1 g - none

- Salmonella 10 g - none

- St. Aurens 1 g - none

After two years of storage under normal conditions, the gel parameters are as follows:

- Complex content - 15%

- pH - 5.45

- transparent, slightly yellowish viscous gel with a mint smell

- Microbiological purity:

- the total number of aerobic bacteria is 1.5 · 10

- total number of mushrooms in 1 g - absent

- E. coli in 1 g - none

- Salmonella 10 g - none

- St. Aurens 1 g - none

This dosage form is intended for the treatment of circulatory and lymphatic circulation disorders in the extremities - thrombophlebitis without trophic ulcers, lymphostasis, edema (not related to kidney pathology) in the complex of therapeutic measures, in the treatment of frostbite of the 1-2 degree, minor injuries without damage to the skin (bruises , sprain, etc.). The gel can be used as the basis of perfumery and cosmetic products with therapeutic and therapeutic effect.

Example 30 (gel for the treatment of uninfected wounds)

In an enameled reactor equipped with a powerful frame stirrer, 70 L of water for injection is loaded, heated to 40 ° C and 5 kg of chitosan succinamide are charged in 1 kg portions. Mixing is carried out until a homogeneous gel is obtained. The mass is cooled to 20-25 ° C and loaded with 10 kg of the substance of the Complex; mix until completely dissolved. A homogeneous, dull brownish gel with an acidic taste is obtained, pH 4.65. Benzhydrol 2-dimethylaminoethyl ether is added to the mass in small portions to a pH of 5.0 ± 0.1; 100 g of myristamidopropyl dimethylbenzene ammonium chloride are added as a preservative, water up to 100 L and stirred for another 30 minutes. The resulting gel is Packed in 100 ml polymer tubes.

At the time of filling, the gel has the following parameters:

- Complex content - 10.0%

- pH - 5.0

- a cloudy, jelly-like (non-flowing) gel with a brown tint of sour taste (mucous numb - anesthetic effect).

- Microbiological purity:

- total number of aerobic bacteria - 5 × 10

- total number of mushrooms in 1 g - 10

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

After two years of storage under normal conditions, the gel parameters are as follows:

- Complex content - 10.0%

- pH - 5.0

- unclear gel-like gel with a brown tint of sour taste with anesthetic effect

- Microbiological purity:

- total number of aerobic bacteria - absent

- total number of mushrooms in 1 g - absent

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

This dosage form is intended for the treatment of uninfected wounds (fresh, superficial, in surgery) in humans and animals, providing quick healing by first intention, prevents the formation of scar tissue, protects against infection. The gel is nontoxic, when animals lick toxic effects from the surface of wounds, including dysbiosis does not cause.

Example 31 (gel for the treatment of infected wounds, including anaerobic microflora, St. Aureus, etc.)

In an enameled reactor equipped with a powerful frame stirrer, 70 L of water for injection is loaded, heated to 40 ° C and 5 kg of chitosan succinamide are charged in 1 kg portions. Mixing is carried out until a homogeneous gel is obtained. Then it is cooled to a full 30 ° C, 10 kg of the Complex substance are added and mixed until completely dissolved. Get a brown gel with a pH of 4.65. The mass is sequentially loaded with 1 kg of ciprofloxacin base, 5 kg of florfenicol and 1 kg of metronidazole, stirred for 1 hour, and a uniform gel is obtained, pH 4.88. Benzhydrol 2-dimethylaminoethyl ether is added to the mass in small portions to a pH of 5.5, stirred for 30 minutes, 100 g of peppermint oil, water up to 100 L are added and stirred for another 30 minutes. Check the pH value, if necessary add diphenhydramine base. The gel is cooled to 20 ° C and Packed in 100 ml polymer tubes.

At the time of filling, the gel has the following parameters:

- Complex content (HPLC analysis) - 10.0%

- florfenicol content (HPLC analysis) - 5%

- the content of metronidazole (HPLC analysis) - 1%

- ciprofloxacin content (HPLC analysis) - 1%

- pH - 5.5

- brown muddy gel with a mint smell, very bitter taste, with anesthetic effect, soluble in water

- Microbiological purity:

- total number of aerobic bacteria - absent

- total number of mushrooms in 1 g - absent

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St.aureus 1 g - none

After two years of storage under normal conditions, the following parameters:

- Complex content (HPLC analysis) - 10.0%

- florfenicol content (HPLC analysis) - 5%

- the content of metronidazole (HPLC analysis) - 1%

- ciprofloxacin content (HPLC analysis) - 1%

- pH - 5.5

- a turbid gel of yellowish-brown color, with a mint smell, a very bitter taste with anesthetic effect, mixes with water to form a cloudy solution

- Microbiological purity:

- total number of aerobic bacteria - absent

- total number of mushrooms in 1 g - absent

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

This dosage form is intended for the treatment of infected and purulent wounds, prevention of purulent complications in surgery, prevention of anaerobic development, including clostridia, in fresh wounds of traumatic origin. The gel has a strong anesthetic effect, reduces swelling caused by inflammation, protects tissues from hypoxic damage, enhances phagocytosis, improves microcirculation in the wound area, eliminates lymphostasis.

Example 32 (gel for the treatment of infected wounds with fluoroquinolones and amphenicol resistant microflora, treatment of superficial lesions caused by protozoa and chlamydia, treatment of eye diseases, including those caused by chlamydia)

In an enameled reactor equipped with a powerful frame stirrer, 70 L of water for injection is loaded, heated to 40 ° C and 5 kg of chitosan succinamide are charged in 1 kg portions. Mixing is carried out until a homogeneous gel is obtained. The mass is cooled to 30 ° C, add 10 kg of the substance of the Complex and mix for 30 minutes; then benzhydrol 2-dimethylaminoethyl ether is added in small portions to a pH of 5.5. Without stopping stirring, to the mass add 1 kg of doxycycline monohydrate, then 1 kg of azithromycin, mix for one hour until a homogeneous gel is obtained; The pH of the resulting gel is 6.2 (should be 6.0-6.5, at a lower value add diphenhydramine base). To the mass add 0.1 kg of menthol and water for injection up to 100 l, mix for 1 hour and pack in 100 g polymer tubes.

The gel at the time of packaging has the following parameters:

- Complex content (HPLC) - 10.0%

- doxycycline content (HPLC analysis) - 1.0%

- the content of azithromycin (HPLC analysis) - 1.0%

- pH - 6.2

- bright yellow turbid gel with a characteristic mild odor

Example 33

In an enameled reactor equipped with a mechanical stirrer, 100 l of water are charged, with the stirrer turned on, 10 kg of chitosan succinamide and 1 kg of polyoxyethylated tocopherol are loaded; the mass is mixed until completely homogeneous (no flakes of chitosan succinate should remain). The resulting gel is poured into a plastic drum. 70 kg of gel are loaded into the reactor, with the stirrer turned on, 10 kg of the Complex are loaded, while the viscosity of the gel increases. Stir until completely dissolved; pH 4.8. Without stopping mixing, 5 kg of N, N-di (2,4-xylyliminomethyl) methylamine are added to the mass, stirred until a homogeneous mass, pH 5.1; benzhydrol 2-dimethylaminoethyl ether is added to the mass to a pH of 5.5 (9.5 kg is consumed). Chitosan succinamide gel up to 100 kg is added to the contents of the reactor, mixed; pH increases to 5.8 and the viscosity of the gel decreases slightly. The gel is Packed in 100 ml polymer tubes or 1 kg, 5 kg or 10 kg polymer drums.

Parameters of gel at the time of release:

- Complex content - 10.0%

- the content of N, N-di (2,4-xylyliminomethyl) methylamine - 5%

- pH - 5.8

- viscous cloudy gel, with a slight "fishy" smell

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 5 × 10 ² CFU

- total number of fungi in 1 g - single colonies (less than 10)

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

After two years of storage under natural conditions, the gel parameters are as follows:

- Complex content - 10.0%

- content of N, N-di (2,4-xylyliminomethyl) methylamine - 4.9%

- pH - 5.8

- viscous cloudy yellowish gel with a noticeable "fish" smell

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 1 × 10 ² CFU

- total number of fungi in 1 g - single colonies (less than 10)

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St.aureus 1 g - none

The drug is intended for use in veterinary medicine, for the treatment of diseases of tick-borne etiology (demodicosis, notoedrosis, sarcoptosis, heyletiosis, psoroptosis, etc.) in animals, including in productive livestock and poultry farming. The drug has a strong toxic effect on ticks at any stage of development, at the same time it suppresses itching, exhibits a wound healing and bacteriostatic effect.

Example 34

60 l of purified water are loaded into an enameled reactor equipped with a powerful anchor stirrer, with the stirrer turned on, 5 kg of hydroxyethyl cellulose are added in small portions and mixed until the gel is completely uniform. 15 kg of monoethanolamine lauryl ethoxysulfate, 1 kg of alkyl amidopropyl carboxy betaine and 3 kg of monoethanolamides of aliphatic acids of coconut oil are loaded into the mass, mixed until a uniform gel is obtained. To the mass, without stopping stirring, 5 kg of the Complex are added in portions, stirred, then 1 kg of N, N-di (2,4-xylyliminomethyl) methylamine, 0.5 kg of (E) -N-cinnamyl-N-methyl-1 are added naphthylmethylamine, 100 g tetramethrin and 50 g piperonyl butoxide; mix until the gel is completely uniform. Then, in small portions, 1,3-bis (2-ethylhexyl) -5-methyl-1,3-diazinan-5-amine is added to a pH of 5.5, with stirring, 50 g of citronella oil and water are added to perfume to 100 l, stirred for 2 hours and Packed in polymer tubes of 100 g

The resulting gel shampoo contains the following concentrations of active substances at the time of packaging:

- Complex (HPLC analysis) - 5.0%

- N, N-di (2,4-xylyliminomethyl) methylamine (HPLC analysis) - 1.0%

- (E) -N-cinnamyl-N-methyl-1-naphthylmethylamine (HPLC analysis) - 0.5%

- pH 5.5

- A thick, unclear gel with a pleasant characteristic odor, when diluted in water, forms a dense foam.

After two years of storage under normal conditions, the gel has the following parameters:

- Complex (HPLC analysis) - 5.0%

- N, N-di (2,4-xylyliminomethyl) methylamine (HPLC analysis) - 0.87%

- (E) -N-cinnamyl-N-methyl-1-naphthylmethylamine (HPLC analysis) - 0.5%

- pH - 5.5

- A thick, unclear gel with a pleasant characteristic odor, when diluted in water, forms a dense foam.

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 15 × 10 ² CFU

- total number of mushrooms in 1 g - absent

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

This liquid dosage form is intended for the primary treatment of stray animals (when placed in a nursery, etc.) that are carriers of various types of ectoparasites and often pathogenic fungi (microsporia, etc.). The drug can be used for prophylactic treatment of pets in contact with stray animals. The drug can also be used in medicine for close indications.

Example 35 (mouthwash)

In an enameled reactor equipped with an anchor stirrer, load 80 l of purified water, with the stirrer on, load 0.5 kg of low molecular weight sodium hyaluronate, mix until a homogeneous solution is obtained; without stopping mixing, load 37 g of potassium chloride, 30 g of magnesium chloride, 33 g of calcium chloride (in terms of anhydrous), 300 g of sodium acetate trihydrate, 500 g of sodium chloride, 400 g of sodium gluconate, 5 kg of xylitol and 5 kg of Complex; the mass is stirred until complete dissolution, then 100 g of benzidamine are added, stirred for 30 minutes and hexetidine is added in small portions to a pH of 5.5. 100 g of eucalyptus oil, 50 g of glycyrrhizic acid of ammonium salt and water up to 100 l are added to the resulting solution, stirred for 1 hour and the pH is checked, if necessary add hexetidine or Complex. The resulting solution is filtered from mechanical impurities and packaged in 100 ml in polymer bottles.

The parameters of the solution at the time of release:

- Complex content - 5.0%

- benzidamine content - 0.1%

- pH - 5.5

- a liquid with a higher viscosity than water, with a pronounced characteristic smell of eucalyptus, a pleasant sweet and sour taste with a slight bitterness.

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 2.8 × 10 ² CFU

- the total number of mushrooms in 1 g - 2.6 × 10

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

Parameters of the solution after three years of storage under normal conditions:

- the content of the Complex is 4.98%

- benzidamine content - 0.10%

- pH - 5.5

- a liquid with a higher viscosity than water, with a pronounced characteristic smell of eucalyptus, a pleasant sweet and sour taste with a slight bitterness.

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 1.1 × 10 ² CFU

- the total number of mushrooms in 1 g - 0.8 × 10

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

This liquid dosage form is intended for use in medicine, namely for the treatment of diseases of a bacterial and viral nature in the oral cavity - stomatitis, gingivitis, glossitis, various forms of tonsillitis, pharyngitis, etc .; liquid dosage form is used for rinsing; The complex increases the immune response, and auxiliary components, in addition to the stabilizing effect on the quality parameters of this dosage form, have an inhibitory effect on pathogens of bacterial, fungal and viral nature. Benzidamine also has a local anesthetic, decongestant, anti-inflammatory effect. This dosage form with high efficiency can be used in the complicated form of diphtheria, accompanied by edema with the threat of stenosis, as a means in addition to specific therapy in conditions that do not allow surgical intervention.

Example 36 (dental spray)

80 l of water for injection are loaded into an enameled reactor equipped with an anchor stirrer, 0.5 kg of sodium hyaluronate, 10 kg of Complex, 100 g of benzidamine and 100 g of glycyrrhizic acid are loaded with stirring. The mass is stirred until complete dissolution, then hexetidine is added in small portions to a pH of 5.5. The solution is stirred for one hour, add water to 100 l, then re-check the pH value; if necessary, correct as in example 35. The solution is filtered from mechanical impurities and Packed in 50 ml polymer bottles equipped with a dispenser.

The parameters of the solution at the time of release:

- Complex content - 10.0%

- benzidamine content - 0.1%

- pH - 5.5

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 2.8 × 10 ² CFU

- total number of mushrooms in 1 g - single colonies

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

After two years of storage under normal conditions, the solution parameters are as follows:

- Complex content - 10.0%

- benzidamine content - 0.1%

- pH - 5.5

- Microbiological purity:

- total number of aerobic bacteria in 1 g - single colonies

- total number of mushrooms in 1 g - single colonies

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

This dosage form is intended for the treatment of diseases in humans and animals localized in the oral cavity - tonsillitis; bacterial, fungal or viral etiology. The benzydamine in the presence of the Complex inhibits the growth of various types of microorganisms, i.e. exhibits both the properties of a preservative pharmaceutical composition and an antibacterial therapeutic agent.

The composition also exhibits anti-inflammatory, wound healing, decongestant effect, improves microcirculation of blood and lymph in inflamed tissues, and has a local anesthetic effect. Glycyrrhizic acid has a sweet taste, ensuring the acceptability of the pharmaceutical composition for animals, and at the same time has anti-inflammatory and antiviral effects. The spray form is convenient for use in veterinary medicine.

Example 37 (gel for joints)

In an enameled reactor equipped with an anchor mixer with a powerful drive, load 95 l of purified water; when the mixer is switched on, 5 kg of chondroitin sulfate are loaded in small portions, mixed until a homogeneous viscous solution is obtained. The resulting gel is loaded with water up to 100 L, stirred for 30 minutes, then part (30 L) is poured into a plastic drum. To the residue in the reactor are added 10 kg of piracetam, 5 kg of the Complex and 5 kg of benzidamine in the form of a base, while after dissolving the components, pH 4.95. To the mass in small portions add trioxymethylaminomethane to a pH of 5.5, while slightly decreasing the viscosity of the solution; 0.5 kg of D-glucosamine succinate is added to the mass and the pH is again adjusted by the addition of trioxymethylaminomethane. To the resulting gel, add 100 g of menthol, add a solution of chondroitin sulfate, mix for 1 hour and pack in 100 ml polymer tubes.

Gel parameters at the time of packaging:

- Complex content - 5.0%

- benzidamine content - 5%

- pH - 5.5

- viscous almost transparent gel of a very bitter taste, with a pleasant mint smell, yellowish

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 1.5 × 10 ² CFU

- total number of mushrooms in 1 g - 1.1 × 10 ² CFU

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

Parameters of the gel after three years of storage under normal conditions:

- Complex content - 5.0%

- benzidamine content - 4.88%

- pH - 5.45

- viscous turbid gel of a very bitter taste, with a pleasant mint smell,

- Microbiological purity:

- total number of aerobic bacteria in 1 g - single colonies

- total number of mushrooms in 1 g - single colonies

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

This liquid dosage form of the Complex is intended for use in a complex of therapeutic measures in the treatment of arthritis (autoimmune, traumatic, with gout, etc.). The gel is applied topically in the joint, for a long time, until relief of pain; the effect is largely associated with the antioxidant effect of the Complex, its ability to stimulate microcirculation in the tissues of the blood and lymph, and the normalization of the immune effect. The combination of the Complex with piracetam has a strong bitter taste, which prevents the drug from licking animals when used in veterinary medicine, at the same time it has a penetrant effect, enhancing the absorption of the Complex and other components through the skin. Benzidamine in this embodiment is a preservative, inhibiting the growth of microorganisms during storage, at the same time it is an anti-inflammatory and analgesic therapeutic agent, the effect of which is enhanced in the presence of the Complex

Example 38 (gel for surgery)

95 l of purified water is loaded into an enameled reactor equipped with an anchor mixer with a powerful drive, and when the mixer is switched on, 5 kg are loaded in small portions (eudragit E 100), stirred until complete dissolution, the reactor is heated to 40 ° C. After complete dissolution, without stopping mixing, through the lower descent pour 30 l of gel into a polymer drum; after cooling to 25 ° C, 10 kg of the Complex, 5 kg of lincomycin (base) and 5 kg of ciprofloxacin (base) are added to the mass in the reactor, the mass is stirred until complete dissolution. Then, in small portions, benzhydrol 2-dimethylaminoethyl ether is added to a pH of 5.5; the mass is stirred for 1 hour, add a solution of eudragit E 100 to 100 l, stirred for 1 hour and check the pH; at pH below 5.5, benzhydrol 2-dimethylamino-ethyl ether is added. The resulting gel is Packed in 100 ml polymer tubes.

Gel parameters at the time of packaging:

- Complex content (HPLC method) - 10.0%

- lincomycin content (HPLC method) - 5.0%

- ciprofloxacin content - 5.0%

- pH - 5.5

- viscous gel, almost transparent, odorless, slightly yellowish, very bitter taste.

- Microbiological purity:

- the total number of aerobic bacteria in 1 g - 1.8 × 10 ³ CFU

- total number of mushrooms in 1 g - 2 × 10 ² CFU

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

After three years of storage under normal conditions, the gel parameters are as follows:

- Complex content (HPLC method) - 10.0%

- lincomycin content (HPLC method) - 4.89%

- ciprofloxacin content - 5.0%

- pH - 5.48

- viscous gel, yellowish, transparent, odorless, very bitter taste.

- Microbiological purity:

- total number of aerobic bacteria in 1 g - no growth

- total number of mushrooms in 1 g - single colonies

- E. coli in 1 g - absent

- Salmonella 10 g - none

- St. aureus in 1 g - not available

This dosage form is intended for use in veterinary surgery, including for the treatment of wounds infected with multiple resistant microorganisms. Lincomycin in the composition of the composition is a preservative, however, it gives a bitter taste, which prevents licking of animals. The drug can also be used in medicine.

Example 39 (drops with a long shelf life)

60 l of purified water are loaded into an enameled reactor and, with stirring, 40 kg of food sorbitol are heated, the solution is heated by supplying a coolant to a jacket to 25-30 ° C (dissolution of sorbitol is accompanied by a significant decrease in temperature); the solution is stirred for 30 minutes.

In a 6 liter glass flask equipped with a stirrer, 4 kg of dimethylaminoethanol and 1 kg of monoethanolamine are mixed.

In a 2-liter glass, load 1 liter of purified water, with stirring, load 300 g of potassium sorbate and 100 g of sodium benzoate. The solution is filtered.

The prepared sorbitol solution is poured from the reactor into a polymer container, then 60 l of the prepared sorbitol solution are loaded from it into the reactor; turn on the stirrer and with the stirrer on, load 20 kg of the Complex and 0.67 kg of polyoxyethylated tocopherol with a basic substance content of 75.1% (trade name "Ferol A"). The solution is stirred for 30 minutes, then the prepared solution of potassium sorbate and sodium benzoate is poured. Then, without stopping stirring, the prepared mixture of amino alcohols (dimethylaminoethanol and aminoethanol) is poured in small portions to a pH of 4.5; consumed 1.2 kg of the mixture. The solution is stirred for 30 minutes, then the previously prepared sorbitol solution is added to a volume of 100 l, it is stirred for 30 minutes, then it is filtered through a double paper filter and 1000 ml are filled into plastic cans.

The parameters of the solution at the time of packaging:

- Complex content - 20%

- colorless transparent solution with a slight characteristic odor

- density - 1.2 g / cm ³

- pH - 4.5

- toxicity in a test dose of 0.125 ml per mouse - non-toxic

- microbiological purity - withstands the test

After five years of storage, the product parameters remained virtually unchanged:

- Complex content - 20%

- slightly yellowish solution with a faint characteristic odor, has a slight opalescence

- density - 1.2 g / cm ³

- pH - 4.5

- toxicity in a test dose of 0.125 ml per mouse - non-toxic

- microbiological purity - withstands the test

Product samples according to example and example 13 were simultaneously stored in the refrigerator at a temperature of + 5 ° C ± 1 ° C; the sample of example 13 partially crystallized; when the samples were heated to room temperature, the crystals dissolved. Samples supplemented with Ferol A did not form crystals under the same conditions.

Example 40 (study antihypoxic activity of the Complex)

In the experiment we used the peroral composition of Example 3 and tablets of the Mexidol preparation purchased at the pharmacy (125 mg tablets No. 50, series 1400812, manufactured by ZiO Health CJSC).

A measure of the sensitivity of animals to acute hypobaric hypoxia was the life time at the "height". For this purpose, the coefficient of protection efficiency (CEC) was calculated, which was the ratio of life in experience to life time in control. Materials and methods:

Preparations Complex and Mexidol were administered orally to rats at doses of 65 mg / kg, 20 mg / kg and 30 mg / kg intragastrically (via tube). In the experiment, a total of 70 animals were used, 10 animals in each group, 10 intact. Testing was performed on day 14 after the start of the experiment (after the first injection of the drug).

Each animal was "raised" to a critical height (11.5 thousand m) at a speed of 165 m / s, where it was located at an atonal state.

results

According to the results of studies to identify the effect of drugs on the resistance of rats to acute hypobaric hypoxia (see Table 7), it was found that all drugs had high antihypoxic activity on the 14th day of the study. It manifested itself in a significant extension of the life of experimental animals at a “height” in comparison with their counterparts in the control groups. The oral administration of the Complex significantly increased the resistance of animals to acute hypobaric hypoxia, which resulted in an increase in the life time at the “height”. The Protection Effectiveness Coefficient (CEC) of the Complex was 5.3, which exceeded the indicators for other drugs by almost 2 times (CEC for Mexidol - 3.9).

Table 7 The effectiveness of the protection of drugs in acute hypobaric hypoxia in rats Route of administration VL in the control group, sec Experimental group VZh on the 14th day of the experiment KEZ * Intragastric (oral) 62.5 ± 7.2 Mexidol 247 ± 18.9 3.9 The inventive drug (Complex) 335 ± 36.38 5.3 * - Protection efficiency coefficient = (Life time in experience) / (Life time in control) VZh - life time at "height" (before the appearance of atonal breathing)

Example 41 (study of antihypoxic activity of the Complex)

In the experiment, we used the injection preparation according to Example 1 and ampoules of 5% Mexidol purchased in a pharmacy (ampoules of 2 ml No. 10, series 870812, manufactured by MC Ellara LLC).

A measure of the sensitivity of animals to acute hypobaric hypoxia was the life time at the "height". For this purpose, the coefficient of protection efficiency (CEC) was calculated, which was the ratio of life in experience to life time in control.

Materials and methods

Drugs Complex and Mexidol were administered to rats parenterally at doses of 65 mg / kg, 20 mg / kg and 30 mg / kg intramuscularly. In the experiment, a total of 70 animals were used, 10 animals in each group, 10 intact. Testing was performed on day 14 after the start of the experiment (after the first injection of the drug).

Each animal was "raised" to a critical height (11.5 thousand m) at a speed of 165 m / s, where it was located at an atonal state.

results

According to the results of studies to identify the effect of drugs on the resistance of rats to acute hypobaric hypoxia (see Table 8), it was found that all drugs had high antihypoxic activity on the 14th day of the study. It manifested itself in a significant extension of the life of experimental animals at a “height” in comparison with their counterparts in the control groups. The parenteral administration of the Complex significantly increased the resistance of animals to acute hypobaric hypoxia, which resulted in an increase in the life time at the “height”. The Protection Effectiveness Coefficient (CEC) of the Complex was 11, which exceeded the indicators for other drugs by more than 2 times (CEC for Mexidol - 5.4).

Table 8 The effectiveness of the protection of drugs in acute hypobaric hypoxia in rats Route of administration VL in the control group, sec Experimental group VZh on the 14th day of the experiment KEZ * Intramuscularly (parenterally) 62.5 ± 7.2 Mexidol 338 ± 67.3 5,4 The inventive drug (Complex) 691.5 ± 114.6 11.0 * - Protection efficiency coefficient = (Life time in experience) / (Life time in control) VZh - life time at "height" (before the appearance of atonal breathing).

Example 42 (determination of acaricidal activity of the Complex gel according to example 33)

The experiment was performed on ticks Dermanyssus gallinae. Ticks were collected at the Oredezh poultry farm (Leningrad Region, Gatchinsky District). The collected ticks were at the stage of nymphs and adults.

A 5% gel of the Complex with amitrase obtained in Example 33 was applied to the bottom of 2 Petri dishes with a thin layer. Next, ticks were placed on the gel: nymphs (10 individuals) in a Petri dish No. 1 and adults (10 individuals) in a Petri dish No. 2 . During the experiment, viability of ticks was constantly monitored (ticks starved for 1 month before the experiments).

Table 9 presents data on the timing of the death of ticks after starting contact with the drug.

The time of death of ticks in contact with the Complex Developmental stages Tick death time Nymphs Petri dish number 1 5-31 min Imago Petri dish number 2 3-10 min

Conclusion: the gel of the Complex with amitraz exhibits pronounced acaricidal activity in an in vitro experiment.

Example 43 (study of the adaptogenic activity of the drug)

The tests were carried out in the veterinary clinic "Nine Lives" in Ryazan. In the experiment used the injection drug of example 11.

The drug was administered to dogs of different breeds (Labrador, Caucasian Shepherd, Spitz, Kurzhaar, German Shepherd) aged 5 months to 3-11 years. Gender: 4 males and 3 females. The drug was administered in combination with antibiotics, general stimulating agents (vitamins, hepatoprotectors) and diuretic drugs. When babesiosis used the drug babesan 12%. On the basis of clinical and laboratory microscopic studies in dogs, the diagnosis was established: babesiosis (piroplasmosis) with severe heart and respiratory failure. A 10% solution of the Complex was administered intramuscularly to dogs weighing up to 10 kg at a dose of 0.1 ml / kg; weighing 10-40 kg - 1 ml; weighing 40-60 kg - 2 ml per animal daily once or twice for 3-5 and 10-15 days (the duration of the course of therapy depending on the form of the course of the disease). In dogs, when prescribing a three - five-day intramuscular injection course of a 10% solution of the Complex in combination with antibiotics (bicillin), general stimulating drugs (furosemide), symptoms of babesiosis and complications in the form of heart and respiratory failure were not detected. 3-5 days after the start of the course of complex theapia with the use of the Complex, an improvement in the general condition was observed (decrease in body temperature to normative indicators, increased appetite), there were no signs of heart and respiratory failure. Side effects in a clinical study have not been established.

The control group of animals was two Caucasian shepherd dogs, a German shepherd, a schnauzer. Gender: 2 males, 2 females. The diagnosis is babesiosis (pyroplasmosis) with severe heart and respiratory failure. The treatment of animals is identical to the treatment of the experimental group, with the exception of the introduction of the Complex. From group 1, the animal died, in one animal normalization of the indicators occurred after 6 days, in two after 14 days Conclusion: 10% solution of the Complex, used in doses of 0.5 to 2 ml per animal intramuscularly once or twice for 3-5 and 7-10 days in combination with antibiotics, antitoxic and general stimulating agents, prevents complications of babesiosis of dogs in the form of cardiopulmonary insufficiency, helps to reduce recovery time to two weeks and improves the course of the rehabilitation period.

Example 44 (study of the adaptogenic activity of the drug)

The tests were carried out in the departments of "Khirino" and "Stenkino" of the breeding plant of Avangard LLC, Ryazan district, Ryazan region.

In the experiment used the injection drug of example 12.

The drug was administered to animals of two types of young cattle (calves 2.5-2.4 months old - 12 individuals) and young pigs (pigs in the weaning group - 12 individuals, gilts for fattening - 5 individuals). Among 12 calves - 7 heifers and 5 bulls. Of the 12 piglets of 60 days of age, 6 are mumps, 6 are boletus, and pigs for fattening are boletus 110-120 days. The complex was administered in combination with antibiotics and general stimulating agents (vitamins) for bronchopneumonia and independently in cases of another pathology.

Based on clinical and laboratory studies in calves, the following diagnoses were made: bronchopneumonia, cardiopulmonary failure, enterocolitis, eimeriosis, and strongyloidosis. Clinical and laboratory studies of piglets in the weaning group confirmed the diagnosis of bronchopneumonia, enterocolitis, stunted growth and development, vitamin A, D hypovitaminosis, balantidosis, isosporosis, and in the fattening group (I and II) - balantidiosis, ascariasis and esophagostomiasis.

The drug was administered intramuscularly to calves at a dose of 2 ml per animal twice daily for 10-15 days; piglets in the weaning group - at a dose of 0.1 ml / kg once or twice depending on the severity of the pathology for 5-7-10 days; complex therapy for bronchopneumonia and dysbiosis included the use of antibiotics (enroxil, bicillin, dysparkol), vitamins and trace elements (eleovit + sedimin). Among calves, a five-day intramuscular injection of the drug in combination with antibiotics and animal vitamins with symptoms of bronchopneumonia and diarrhea was not detected. In calves suffering from bronchopneumonia, an improvement in the general condition was established for 2-4 days of the therapeutic course (lack of signs of cardiopulmonary insufficiency, nasal discharge, decreased body temperature, increased appetite and motor activity). The general condition of sick piglets improved by 3-5 days of complex treatment (increased appetite, decreased body temperature to standard values, physical activity, and the absence of symptoms of bronchopneumonia). In calves that are lagging in growth and development, and piglets - hypotrophy significant changes in the clinical condition were not observed. Side effects of the drug in clinical studies have not been established. The control group of animals was not isolated for economic reasons (the possibility of death in the absence of etiotropic treatment).

Conclusion: the drug used in doses of 1-1.5 to 2 ml per animal intramuscularly daily once or twice for 5-7 or 10 days in combination with antibacterial and general stimulating therapy prevents complications of bronchopneumonia, cardiopulmonary insufficiency, enterocolitis various etiologies, including parasitic, helps to reduce recovery time to two to three weeks, improve the course of the rehabilitation period in animals.

Example 45 (study of the adaptogenic activity of the drug according to example 12)

The tests were carried out in the Federal State Unitary Enterprise “Suida of the Russian Agricultural Academy”, Gatchina district, Leningrad region.

The tests were carried out on calves aged 3-20 days in an amount of 50 individuals for the prevention of diarrhea of young cattle.

The drug was administered intramuscularly at a dose of 5 mg / kg according to the active substance, which corresponded to 0.05 ml / kg, once a day for 10 days. Among animals that received a 10-day course of intramuscular administration of the drug, calves with diarrhea were not detected. Side effects during the tests were not identified.

In the control group of animals (50 individuals) at the end of the experiment - moderate diarrhea was detected in 21 calves.

Conclusion: the drug, administered intramuscularly at a dose of 5 mg / kg once a day for 10 days, prevented the manifestation of diarrhea in newborn calves.

Example 46 (study of the adaptogenic activity of the drug according to example 12)

The tests were carried out in the Federal State Unitary Enterprise “Suida of the Russian Agricultural Academy”, Gatchina district, Leningrad region.

The tests were carried out on calves aged 60-90 days in the amount of 30 individuals suffering from cough, wheezing, fever, and decreased appetite. The drug was administered intramuscularly at a dose of 5 mg / kg according to the active substance, which corresponded to 0.05 ml / kg, twice a day for 15 days in combination with anti-inflammatory therapy. Within 2-3 days, the clinical signs of pneumonia stopped, the general condition of the animals improved, and appetite increased. Side effects during the tests were not identified.

The control group of animals was not allocated for economic reasons (the possibility of death of animals in the absence of effective treatment).

Conclusion: the drug, administered intramuscularly at a dose of 5 mg / kg, twice a day for 15 days in combination with anti-inflammatory therapy, reduced the recovery period of calves to 2-3 weeks, improved the course of the recovery period in animals.

Example 47 (study of the adaptogenic activity of the drug according to example 12)

The tests were carried out in the private farm Smagina V.V. v. Konstantinovsky Petrovsky district, Stavropol Territory.

The tests were conducted on young pigs at the age of 3 months of large white breed during weaning from sows to identify the ability of the drug to reduce the damaging effects of stress factors on the body. Observations were carried out for 1 month. Individuals were divided into two groups of 6 individuals each. The control group received a standard diet for this age group.

The experimental group received a standard diet + drug "Complex" 10% 0.1 ml / kg of live weight 1 time per day for 5 days.

The use of the drug improved the physiological state and productivity of young pigs under the influence of stress factors (change in diet and conditions). In animals of the experimental group, an increase in food intake was noted, the number of cases of diarrhea was reduced in comparison with control animals. Side effects during the tests were not identified.

Table The study of the adaptogenic activity of the drug "Complex" Group Weight of piglets at the beginning of the experiment, kg Weight of piglets at the end of the experiment, kg The average daily gain, g Frequency of case of diarrhea,% The control 20.07 ± 0.95 42.37 ± 1.06 743 ± 56 fifty Experience 19.63 ± 0.91 44.23 ± 0.70 824 ± 48 16.6

Conclusion: the average daily gain in live weight when using the drug compared with the control group increased by 10.9%, the incidence of dyspepsia decreased by 33.4%.

Example 48 (study of the adaptogenic activity of the drug)

The study of the effect of the Complex on the body of productive poultry (broiler chickens) was carried out by adding the drug (according to example 13) to the standard diet in daily doses of 10 mg / kg from the first day of life (group 2) and from 14 days of age (3- I am a group). The weight gain of the bird was determined by a change in the immunocompetent organs. The 1st experimental group (control) received a standard diet without supplementation.

Thymus, cloacal bursa and spleen are the main organs in the body of the bird, responsible for the formation of immune protection. In the experiment, we studied the weight changes in these organs in intact broiler chickens in the age aspect, as well as when using 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate. The absolute mass of the thymus at day old in chickens was 0.26 g in the control, 0.24 g in the first experimental group, and 0.29 g in the second

We found that in all chickens, the absolute mass of the thymus increased with age. If in diurnal age the difference in the absolute thymus mass between the intact and experimental livestock was not established, then in all subsequent age periods the thymus mass in experimental chickens was greater compared to the control. At two weeks of age, the weight of the thymus in experimental chickens of the first group exceeded this indicator in the control by 0.24 g, in the second experimental group - by 031 g. At 32 days of age, the differences were: in the first experimental group - by 1.62 g, in the second - by 2.49 g.

The maximum increase in the absolute mass of the thymus in chickens and in the control and experimental groups was noted in the period from 14 to 32 days of age.

Our studies showed that after hatching in intact chickens, the absolute weight of the bursa in the control group was 0.117 ± 0.01 g, in the first experimental group - 0.116 ± 0.04 g, in the second 0.118 ± 0.02 g. Throughout the entire growing period in intact chickens, the absolute weight of the bursa increased, reaching a maximum size of 32 days: in the control, 1.23 ± 0.02 g; in the first experimental group - 1.27 ± 0.06 and in the second - 1.32 ± 0.01 g.

Tracing the changes in the absolute mass of the spleen of chickens, it was noted that by the time of hatching in the chickens in the control group, its weight corresponded to 0.03 g, in the experimental group - 0.02 g. In intact broilers, the spleen continued to grow up to 32 days of age up to 2.32 g , in the first experimental - up to 2.44 g, in the second - 2.56 g.

The complex had no significant effect on changes in the weight of the spleen of chickens. Thus, the use of Complex broiler chickens has a positive effect on growth (see Table 11), the safety of birds and hematopoiesis (see Table 12), which can be described as a pronounced adaptogenic effect.

Table 11 Change in bird gain Time, day Mass g the control 2 group 3 group one 40.07 ± 1.89 39.77 ± 1.68 40.36 ± 1.57 fourteen 438.44 ± 18.1 487.17 ± 15.4 509.7 ± 16.2 35 2122.6 ± 21.3 2182, ± 33.4 2261.3 ± 29.7

Table 12 Change in the main parameters of hematopoiesis in birds Age of chickens, days Red blood cells, × 10 ¹² / l Hemoglobin, g / l White blood cells × 10 ⁹ / L Control group one 1.89 ± 0.06 71.2 ± 0.05 27.1 ± 0.8 fourteen 1.93 ± 0.02 75.4 ± 0.1 31.2 ± 1.1 32 2.2 ± 0.01 75.3 ± 0.06 35.9 ± 1.0 2 experimental group one 2.02 ± 0.02 72.6 ± 0.06 29.1 ± 0.7 fourteen 2.04 ± 0.01 76.8 ± 0.03 31.2 ± 0.5 32 2.34 ± 0.03 * 77.7 ± 0.11 * 37.3 ± 0.4 3 experimental group one 1.97 ± 0.21 71.2 ± 0.4 25.5 ± 0.4 fourteen 2.18 ± 0.21 * 76.1 ± 0.6 30.5 ± 0.2 * 32 2.42 ± 0.41 * 88.1 ± 0.9 * 38.1 ± 03 * * - P <0.05

Example 49 (study antioxidant activity)

Nonlinear white mice weighing 25-30 g were used in the experiment. To reproduce the pathological process, the influenza virus A / PR / 8/34 (HINI) was used, obtained from the Museum of the Research Institute of Influenza of the Russian Academy of Medical Sciences and adapted to white mice. The antioxidant effect of the drug was evaluated by the change in the level of peroxidation in the tissues of organs (lungs and liver) after intranasal infection of experimental and control mice under mild ether anesthesia at a dose of 0.01 LD ₅₀ (lethal dose) of 50 μl. The preparation according to example 13 (drops) was administered to animals intragastrically in terms of the active substance at a dose of 50 mg / kg.

In each group, 20 mice were used. A control group of mice (without prophylaxis) received distilled water.

Animals were killed on day 14 after infection, the lungs and liver were removed and used for biochemical and pathomorphological studies. The level of lipid peroxidation was determined, which was estimated by the content of malonic aldehyde in the lung and kidney homogenate. For this, the lungs and liver of experimental animals were ground in a mortar with quartz sand with 1 ml of physiological saline, 0.6 ml of homogenate was diluted with two volumes of phosphate-buffered saline, 0.2 ml of 50% trichloroacetic acid was added, and centrifuged for 10 min at 4000 g to precipitate proteins. 1 ml of 0.8% thiobarbituric acid was added to the supernatant and the samples were heated in a boiling water bath for 20 minutes. The content of the reaction products was determined by the optical density of the solution at a wavelength of 532 nm and was converted to whole tissue homogenate.

The antioxidant activity of the tissue was evaluated based on the ability of the homogenate of the lung tissue and liver to inhibit the oxidation of egg yolk phospholipids induced by ferrous iron. For this, the egg yolk was diluted 1:50 with phosphate buffered saline. To 0.1 ml of a suspension of yolk, 1.7 ml of tissue homogenate diluted 3 times with the same buffer and 20 μl of a 10 mM FeSO ₄ solution were added. Samples were incubated for 15 min at 37 ° C, 0.2 ml of 50% trichloroacetic acid was added, centrifuged to remove precipitated proteins, 1 ml of 0.8% thiobarbituric acid was added to the supernatant, and kept for 20 min in a boiling water bath. The samples measured the optical density at a wavelength of 532 nm. In the control sample without tissue homogenate, the level of peroxidation was taken as 100%. The reliability of the results was evaluated using Student's criterion.

Comparative results obtained in various experimental groups of animals are presented in table 13.

The use of the drug led to a significant increase in the antioxidant activity of tissues.

Table 13 The intensity of lipid peroxidation and antioxidant activity in the tissues of the lungs and liver p / p Experimental group Biochemical parameters Lung tissue Liver tissue The level of lipid peroxidation ED50 Antioxidant activity of lung tissue (% of control sample without tissue) Morphological indicators (frequency of detection of lung damage in relation to the total number of animals examined) The level of lipid peroxidation ED ₅₀ Antioxidant activity of liver tissue (% of control sample without tissue) Morphological indicators (frequency of detection of liver damage in relation to the total number of animals examined) one Intact animals 0.06 ± 0.01 73.5 ± 5 0/20 0.03 ± 0.01 86.6 ± 5 0/20 2 Group without treatment 0.48 ± 0.02 38.0 ± 6 20/20 0.56 ± 0.02 21.0 ± 7 11/20 3 The preparation according to example 13 0.24 ± 0.02 95.0 ± 6 3/20 0.11 ± 0.02 98.8 ± 7 0/20

Example 50 (study antioxidant activity)

To take voltammograms and calculate the antioxidant activity of the preparations, we used the AOA analyzer (produced by NLP Poliant LLC, Tomsk) with a three-electrode electrochemical cell (10 ml) connected to it, consisting of a glass-graphite indicator electrode, a silver chloride comparison electrode, and auxiliary glassy carbon electrode.

A phosphate buffer solution of 0.025 mol / L (equimolar mixture of Na ₂ PO ₄ and KH ₂ PO ₄ ) with a pH of 6.86 was used as the background electrolyte. The test samples were dissolved in distilled water, acidified with a HCl solution (chemically pure) to a pH of 2.0 (acidification is necessary for better dissolution of the samples in the background electrolyte). A stock solution of the test substances was prepared with a concentration of 0.1 g / ml. Concentrations of different orders were created in the electrochemical cell: 0.05 mg / ml, 0.5 mg / ml and 1 mg / ml.

10 ml of phosphate buffer was placed in an electrochemical cell.

The study of the antioxidant properties of the samples was carried out by recording voltammograms of the cathodic oxygen reduction without and with the subsequent addition of solutions of the studied samples. Shooting conditions: indicator electrode - glass graphite, reference electrode - silver chloride, auxiliary electrode - glassy carbon, potential region (E) from 0 to minus 1.2 V, potential sweep speed: W = 40 mV / s.

After adding the analyte, the solution was stirred for 10, followed by calming the solution for 20 s. The solution activation time was 60 s. It was recommended to strictly control the mixing and calming times of the solution to increase the accuracy of determination.

To study the antioxidant properties of the studied substances by voltammetry, we used a model oxygen electroreduction reaction (EV), which takes place on a glass-graphite electrode in the potential range from 0 to minus 1.2 V by a mechanism similar to oxygen reduction in living cells [EIKorotkova, YAKarbainov, AV Shevchuk, J. Electroanal. Chem., 518, 56-60 (2002)]. In figure 1. a visual voltammogram of the oxygen evolution in the absence and presence of the "Complex" is presented. The nature of the change in the current of oxygen EM in the presence of the rest of the investigated substances was identical.

When the test substances were introduced into the electrochemical cell, the current of oxygen evolution initially increased (curve 1 of Figure 1), and then decreased with increasing process time, which was associated with the interaction of the antioxidant with molecular oxygen and its reduction products (curves 2-4, Figure 1 ) In this case, the half-wave potential of oxygen with the introduction of the investigated substances was shifted to the positive potential region (see Figure 1).

Biologically active sulfur-containing substances (BASS) such as glutathione, cysteine, lipoic acid interact in a similar way with oxygen. The antioxidant activity of the compounds under study was evaluated at different concentrations using the kinetic criterion [E.I. Korotkova, O.A. Avramchik, M.S. Yusubov et al., Chemical Pharm. Zh., 37 (9), 55-56 (2003)], reflecting the amount of oxygen and its active radicals that reacted with an antioxidant in a minute of time, K (μmol / (l · min)):

$$K=\frac{C0}{t}(\mathrm{one}-\frac{I}{I_0})\left(\mathrm{one}\right)$$

where I is the current of oxygen electroreduction in the presence of the studied substances in solution, μA;

I ₀ - current electroreduction of oxygen in the absence of the investigated substances in solution, µA;

With ₀ - the initial concentration of oxygen in solution, µmol / l;

t is the reaction time, min

Based on the results of the determinations, a graph of the dependence of the function (1-I / I ₀ ) on time (t) was constructed, then, according to formula (1), the coefficient of antioxidant activity of the studied substances was determined - K [E. Korotkova, O.A. Avramchik, M.S. Yusubov et al., Chem. Zh., 37 (9), 55-56 (2003)].

Table 14 presents the results of determining the coefficients of antioxidant activity of the studied compounds and some standard BASS.

Table 14 The values of the coefficients of antioxidant activity of the investigated substances and some standard BASS (n = 3) Substance name The concentration in the cell, mg / ml K, μmol / l · min Complex, substance 0.05 2.74 ± 0.05 0.5 3.12 ± 0.03 1,0 5.02 ± 0.07 Complex injection solution according to example 12 0.05 0.95 ± 0.05 0.5 2,30 ± 0,03 1,0 5.42 ± 0.02 Complex, oral form according to example 13 0.05 0.92 ± 0.04 0.5 2.12 ± 0.05 1,0 6.73 ± 0.02 Glutathione 1,0 4.35 ± 0.03 Cysteine 1,0 3.44 ± 0.05 Lipoic acid 1,0 4.86 ± 0.02

As can be seen from table 14, the studied substances (the Complex in the form of a substance, injection solution and oral form) showed good antioxidant activity relative to standard antioxidants.

Methods for the preparation of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate complex,

where EMGP is 2-ethyl-6-methyl-3-hydroxypyridine

TMHP - 3- (2,2,2-trimethylhydrazinium) propionate

EMGPS - 2-ethyl-6-methyl-3-hydroxypyridine succinate

TMHP DG - 3- (2,2,2-trimethylhydrazinium) propionate dihydrate

Complex - complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate

Example 51 (synthesis from EMHPS, succinic acid and TMHP DG)

255.27 g of EMHPS (1 mol), 118.09 g of succinic acid (1 mol), 182.26 TMHP DG (1 mol) are placed in a flask of a rotary film evaporator (FIR), the mass is stirred during rotation of the flask (speed 60 rpm) and heated to 45-50 ° C; this forms a viscous liquid. The contents of the flask are poured onto a fluoroplastic tray and dried under a vacuum of 0.9 at at 30-35 ° C to constant weight. The hardened product is ground in a ball mill, additionally dried at 20-25 ° C under vacuum for 5 hours. Get 519, 6 g (1 mol) of the Complex (yield 100% of theory).

Description: white crystalline powder

Elemental analysis:

Calculated,%: С 58.00, Н 8.20, N 9.22, О 24.58

Found,%: C 57.47, H 8.33, N 9.18, O 25.02

pH of a _{10% solution} = 4.08

pH _{0.01 M solution} = 4.17

IR spectrum (in KBr), cm ^-1 : 3440 (valent. —OH); 3045.44 (NH, mld); 2360 ÷ 2780 (valent.-OH, assoc. Group); 2922.49 (valence. -CH ₃ , -CH ₂ ); 1705.47 (-C = O, carbon. To-you); 1637.00, 1571.42 (-C = O, mld); 1385.30 (deform. -CH ₃ , -CH ₂ -); 1306.22 (-C-O-, carbon. To-you); 1218.47 (deform. -OH); 1185.68 (valence. -CO in COO ^- , salts of carbon, acids); 849.12 (deform. Ar-H).

UV spectrum (in water): λ _max = 195 nm, λ _min = 214 nm, λ _max = 224 nm, λ _min = 245 nm, λ _max = 295 nm

Solubility: very easily soluble (GP XII, p. 92).

Example 52 (synthesis from EMHPS and succinate TMHP)

255.27 g of EMHPS (1 mol), 264, 31 g of 3- (2,2,2-trimethylhydrazinium) propionate succinate (1 mol) are placed in a flask of a rotary film evaporator, 50 ml of acetone are added. Fluoroplastic balls are introduced into the flask and the mass is stirred while the flask is rotating (rotation speed 60 rpm) for 2 hours at room temperature. The resulting bulk mass is discharged onto a fluoroplastic tray and dried to constant weight and no odor of acetone. Get 519, 6 g of the Complex (yield 100% of theory) with the following parameters:

Description: white crystalline powder

Elemental analysis:

Calculated,%: С 58.00, Н 8.20, N 9.22, О 24.58

Found,%: C 58.20, H 8.21, N 9.20, O 24.39

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360-2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Example 53 (synthesis from EMHP, succinic acid and TMHP succinate)

 137.18 g of 2-ethyl-6-methyl-3-hydroxypyridine (1 mol), 264, 31 g of 3- (2,2,2-trimethylhydrazinium) propionate succinate (1 mol) and 118 are placed in a flask of a rotary film evaporator 09 g succinic acid (1 mol). Fluoroplastic balls and 50 ml of diethyl ether are placed in the flask; turn on the drive and rotate the flask for 1 hour at room temperature. After that, without stopping stirring, a vacuum of 0.9 ata is applied; after 30 minutes the vacuum is removed, the flask is removed and the contents are unloaded onto a sieve. After sieving, 512.5 g of the Complex are obtained (yield 98.6% of theory, loss during sieving) with the following parameters:

Description: white crystalline powder

Elemental analysis:

Calculated,%: С 58.00, Н 8.20, N 9.22, О 24.58

Found,%: C 57.98, H 8.21, N 9.19, O 24.62

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360-2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Example 54 (synthesis from EMHP, succinic acid and TMHP succinate)

137.18 g of 2-ethyl-6-methyl-3-hydroxypyridine (1 mol), 264, 31 g of 3- (2,2,2-trimethylhydrazinium) propionate succinate (1 mol) and 118 are placed in a flask of a rotary film evaporator 09 g succinic acid (1 mol); add 30 ml of acetone. Fluoroplastic balls are placed in the flask and the mass is stirred during the rotation of the flask (rotation speed 60 rpm). The mass first sticks together, after 30 minutes it hardens and turns into a powder. The process is carried out for 3 hours at room temperature; after that, the mass with balls is unloaded on a pallet, dried until there is no smell, and then sieved. After sieving, 518.5 g of the Complex are obtained (yield 99.8% of theory, loss during sieving) with the following parameters:

Description: white crystalline powder

Elemental analysis:

Calculated,%: С 58.00, Н 8.20, N 9.22, О 24.58

Found,%: C 57.68, H 8.24, N 9.18, O 24.90

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Example 55 (synthesis from EMHP, succinic acid and dehydrated TMHP DG)

182.22 g (1 mol) of TMHP DG is dried at 80 ° C and a vacuum of 2 mm Hg. Art until theoretical weight loss corresponding to complete dehydration (2-3 hours); when the change in mass ceases, moisture is checked according to Fisher (should be less than 0.1%). Coarse-grained powder becomes a powdery white fine powder, while not having significant hygroscopicity (Fischer moisture change in contact with air occurs very slowly until a monohydrate forms, which is more hygroscopic and quickly absorbs moisture from the air).

After dehydration, 146.2 g of TMHP (1 mol) with a moisture content of 0.1% (Fischer) are obtained. This powder is transferred to an RPI flask, 236.18 g of succinic acid (2 mol) and 137.18 g of recrystallized EMHP (1 mol) are loaded therein. Fluoroplastic balls and 100 ml of hexane are placed in the flask; turn on the drive and mix the mass while rotating the flask (rotation speed 60 rpm) for 3 hours at room temperature. First, the mass agglomerates, then crumbles into powder. At the end of the process, the product is dried on a fluoroplastic tray to a constant weight and odorless hexane and then sieved. After sieving, 517.9 g of the Complex are obtained (99.7% of theory yield, sieving loss) with the following parameters:

Description: white crystalline powder

Elemental analysis:

Calculated,%: С 58.00, Н 8.20, N 9.22, О 24.58

Found,%: С 58.32, Н 8.24, N 9.17, О 24.27

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Example 56

The synthesis is carried out analogously to example 5, but as a “wetting agent” use 100 ml of heptane. Get 518.8 g of the Complex (yield 99.8% of theory).

Description: white crystalline powder

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Example 57

The synthesis is carried out analogously to example 5, but as a “wetting agent” use 50 ml of petroleum ether (with a boiling range of 50-70 ° C). Obtain 518.6 g of the Complex (yield 99.8% of theory).

Description: crystalline powder with a barely noticeable cream tint

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Example 58

The synthesis is carried out analogously to example 5, but 40 ml of methyl ethyl ketone are used as a “wetting agent”. After completion of the synthesis, the mass is separated from the balls, dried under vacuum of 10-15 mm Hg. first 2 hours at room temperature, then 3 hours at 30 ° C until there is no smell of methyl ethyl ketone. Get 516.2 g of the Complex (yield 99.3% of theory).

Description: white crystalline powder

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Example 59

The synthesis is carried out analogously to example 3, but as a “wetting agent” use 50 ml of tetrahydrofuran. Obtain 515.3 g of the Complex (yield 99.2% of theory).

Description: crystalline powder, white with a faint yellowish tint

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Example 60

The synthesis is carried out analogously to example 3, but 50 ml of dioxane are used as a “wetting agent”. After completion of the synthesis, the mass is separated from the balls, unloaded onto a fluoroplastic tray and dried under a vacuum of 0.98 ata at 30-35 ° C until a constant mass and no smell of dioxane. Get 516.8 g of the Complex (yield 99.5% of theory).

Description: crystalline powder, white with a yellowish tint

IR spectrum, cm ^-1 : 3440; 3,045.44; 2360 ÷ 2780; 2922.49; 1,705.47; 1637.00, 1571.42; 1385.30; 1306.22; 1218.47; 1,185.68; 849.12.

Claims (32)

1. A stable liquid pharmaceutical composition with antihypoxic, antioxidant and adaptogenic effects, containing the following components, wt.%:
3- (2,2,2-trimethylhydrazinium) propionate- 2-ethyl-6-methyl-3-hydroxypyridine disuccinate 0.1-50 Excipients 0.01-50 water for injections up to 100 2. The stable pharmaceutical composition according to claim 1, characterized in that it contains bacteriostatic preservatives at a concentration of 0.01-5.0% as auxiliary substances. 3. The stable pharmaceutical composition according to claim 2, characterized in that sorbic acid or its pharmaceutically acceptable salts and / or benzoic acid or its pharmaceutically acceptable salts and / or p-hydroxybenzoic acid esters (parabens) are used as bacteriostatic preservatives. and / or 1,2-propylene glycol and / or 2-phenoxyethanol and / or gasoline alcohol and / or doxycycline (as a base or a pharmaceutically acceptable salt) and / or azithromycin (as a base or a pharmaceutically acceptable salt) , and / or spiramycin (as based I or a pharmaceutically acceptable salt), and / or roxithromycin (as a base or a pharmaceutically acceptable salt), and / or clarithromycin (as a base or a pharmaceutically acceptable salt), and / or midecamycin (as a base or a pharmaceutically acceptable salt), and / or lincomycin (as a base or a pharmaceutically acceptable salt), and / or clindamycin (as a base or a pharmaceutically acceptable salt), and / or chloramphenicol, and / or thiamphenicol, and / or florfenicol, and / or ciprofloxacin (as a base or a pharmaceutically acceptable salt) and / or benzidamine (as a base or a pharmaceutically acceptable salt), and / or terbinafine (as a base or a pharmaceutically acceptable salt), and / or naphthyne (as a base or a pharmaceutically acceptable salt), and / or hexetidine (as base or pharmaceutically acceptable salt), and / or 1,2-ethylene-bis- (N, N-dimethyl-carbodecyl-hydroxymethyl) ammonium dichloride, and / or decamethylene-bis (trimethylammonium bromide), and / or 1.10- decamethylene bis (N, N-dimethylmethoxycarbonylmethyl) ammonium dichloride and / or benzyldiodecyl dimethyl ammonium chloride and / or dodecyldimethyl - (2-phenoxyethyl) ammonium bromide, and / or benzyldimethyl [3- (myristoylamino) propyl] ammonium chloride, and / or hexadecyltrimethylammonium bromide. 4. A stable liquid pharmaceutical composition according to claim 1, characterized in that it contains acidity regulators as auxiliary substances. 5. A stable liquid pharmaceutical composition according to claim 4, characterized in that organic compounds with at least one nitrogen-containing group are used as acidity regulators. 6. The stable liquid pharmaceutical composition according to claim 5, characterized in that diisopropylamine and / or tert-butylamine and / or 2-dimethylaminoethyl ether of benzhydrol and / or 1-methyl-2 are used as compounds with a nitrogen-containing group [2- ( α-methyl-p-chlorobenzhydryloxy) ethyl] pyrrolidine, and / or N-dimethylaminoethyl-N- (p-chlorobenzyl) aminopyridine, and / or 3,6-dimethyl-9- (2-methylpyridyl-5) ethyl-1, 2,3,4-tetrahydro-γ-carboline, and / or 3-methyl-9-benzyl-1,2,3,4-tetrahydrocarboline, and / or N, N-di (2,4-xylyliminomethyl) methylamine, and / or (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthylmethyl amine and / or (E) -N-cinnamyl-N-methyl-1-naphthylmethylamine; and / or 1,3-bis (2-ethylhexyl) -5-methyl-1,3-diazinan-5-amine. 7. A stable liquid pharmaceutical composition according to claim 4, characterized in that as acidity regulators it contains organic compounds with at least one nitrogen-containing group and at least one oxygen-containing proton donor group. 8. A stable liquid pharmaceutical composition according to claim 7, characterized in that as an oxygen-containing proton donor group, the acidity regulator contains carboxyl. 9. The stable pharmaceutical composition of claim 8, wherein L-lysine and / or L-arginine and / or trimethylhydrazinium propionate dihydrate and / or glycine and / or L-α alanine are used as an acidity regulator, and / or β-alanine, and / or dexpanthenol, and / or doxycycline (base), and / or azithromycin (base). 10. A stable liquid pharmaceutical composition according to claim 7, characterized in that as an oxygen-containing proton donor group, the acidity regulator contains hydroxyl. 11. The stable liquid pharmaceutical composition of claim 10, characterized in that monoethanolamine and / or dimethylaminoethanol and / or diethylaminoethanol and / or diethanolamine and / or triethanolamine and / or 2-ethyl-6 are used as an acidity regulator -methyl-3-hydroxypyridine, and / or meglumine, and / or trioxymethylaminomethane. 12. The stable pharmaceutical composition according to claim 1, characterized in that as an auxiliary substance contains taste-correcting additives. 13. A stable liquid pharmaceutical composition according to claim 12, characterized in that sweet substances are used as taste-correcting additives. 14. The stable liquid pharmaceutical composition according to item 13, wherein xylitol and / or sorbitol and / or fructose and / or glycyrrhizic acid or its pharmaceutically acceptable salts are used as taste-correcting additives. 15. A stable liquid pharmaceutical composition according to claim 12, characterized in that bitterness is used as taste-correcting additives. 16. The stable liquid pharmaceutical composition of claim 15, wherein quinine (as a base or a pharmaceutically acceptable salt), and / or piracetam, and / or chloramphenicol, and / or metronidazole, and / or diphenhydramine (as a base or a pharmaceutically acceptable salt), and / or thiamphenicol, and / or florfenicol, and / or lincomycin (as a base or a pharmaceutically acceptable salt), and / or clindamycin (as a base or a pharmaceutically acceptable salt). 17. A stable liquid pharmaceutical composition according to claim 1, characterized in that it contains local anesthetics as auxiliary substances. 18. A stable liquid pharmaceutical composition according to claim 17, characterized in that benzofurocain (as a base or a pharmaceutically acceptable salt), and / or diphenhydramine (as a base or a pharmaceutically acceptable salt), and / or clemastine ( as a base or a pharmaceutically acceptable salt), and / or Dimebon (as a base or a pharmaceutically acceptable salt), and / or mebhydroline (as a base or a pharmaceutically acceptable salt), and / or benzidamine (as a base or a pharmaceutically acceptable salt) , and / or acetylaminonitropropoxybenzene. 19. A stable liquid pharmaceutical composition according to claim 1, characterized in that as auxiliary substances contains salts of sodium, and / or potassium, and / or magnesium, and / or calcium in concentrations equivalent to plasma concentrations. 20. A stable liquid pharmaceutical composition according to claim 1, characterized in that as auxiliary substances contains rheological modifiers. 21. The stable pharmaceutical composition according to claim 20, characterized in that cellulose ethers and / or polyvinylpyrrolidone and / or acrylate polymers (odrazhita) and / or natural polymers are used as rheological modifiers. 22. The stable liquid pharmaceutical composition according to claim 21, characterized in that sodium carboxymethyl cellulose and / or methyl cellulose and / or hydroxypropyl cellulose and / or hydroxyethyl cellulose and / or hydroxyethyl methyl cellulose are used as cellulose ethers. 23. The stable liquid pharmaceutical composition according to item 21, characterized in that as natural polymers use hyaluronic acid or its pharmaceutically acceptable salts, and / or pectin and / or agar, and / or low molecular weight chitosan and its pharmaceutically acceptable derivatives, and / or gelatin and / or polysaccharides and / or chondroitins in the form of pharmaceutically acceptable salts. 24. The stable liquid pharmaceutical composition according to claim 1, characterized in that it further comprises natural metabolites in therapeutic quantities. 25. A stable liquid pharmaceutical composition according to claim 24, characterized in that inosine and / or glycine and / or arginine and / or lysine are used as natural metabolites. 26. A stable liquid pharmaceutical composition according to claim 1, characterized in that it further comprises cofactors and / or vitamins. 27. A stable liquid pharmaceutical composition according to claim 26, characterized in that riboflavin and / or cocarboxylase and / or pyrodoxalphosphate are used as cofactors. 28. A stable liquid pharmaceutical composition according to claim 1, characterized in that it further comprises stabilizers. 29. A stable liquid pharmaceutical composition according to claim 28, characterized in that oxidation inhibitors are used as stabilizers. 30. A stable liquid pharmaceutical composition according to clause 29, characterized in that spatially hindered phenols or their derivatives are used as oxidation inhibitors. 31. The stable liquid pharmaceutical composition according to claim 30, characterized in that polyoxyethylated tocopherol and / or polyoxyethylated ionol and / or polyoxyethylated 2,4,6-tritrebutylphenol are used as derivatives of spatially hindered phenols. 32. A stable liquid pharmaceutical composition according to claim 1 in the form of a solution, gel, spray.

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