RU2620163C2 - Means for ischemia treatment, method for its production and method for ischemia treatment (versions) - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention is a means for ischemia treatment containing a complex of ethyl 2-(2-(1-methylguanidino)acetamido)acetate salt as an active principle, as well as a method for the preparation of the ischemia treatment means and a method for ischemia treatment. It is proposed to create versions of the ischemia treatment means representing a complex of ethyl-2-(2-(1-methylguanidino)acetamido)acetate salt with sugars, fibrinolytic enzymes and mannitol.

EFFECT: means with increased efficiency and stability.

28 cl, 28 tbl, 25 ex

Description

The invention relates to medicine, in particular to pharmacy, and relates to medicinal compositions used to treat acute and chronic cerebrovascular disorders, as well as coronary heart disease and similar diseases of the cardiovascular system.

Ischemic damage to the brain and myocardium, leading to stroke and myocardial infarction, is usually caused by a violation of blood circulation in the cardiovascular system of the body. The latter initiates pathophysiological changes in the cells, leads to a decrease in the content of high-energy compounds, primarily ATP, in the tissues [Reichelt K.L. Thechemicalbasisfortheintoleranceofthebraintoanoxia. Ac-taAnesthesiol. Scand. 1978], acidosis due to accumulation of lactate, destruction of astrocytes [HertzL. Theastrocyte-neuronlactatesshuttle. J. Cereb. Blood-FlowMetab. 2004; 24: 1241-8], compression of brain capillaries [AmesAIII, et al. Cerebral ischemia II. The no-reflow phenomenon. Amer. J. Pathol., 1968; 52: 437-53].

A large group of drugs is known that improve tissue energy metabolism, activate integrative functions of the brain, and increase brain resistance to damaging factors (Goodman E. Gilman's. The Pharmacological Basis of Therapeutics, 11 ed, McGraw-Hill, Medical Publ. Division, New York 2006; RU 1746886, 1991; WO 96/08527, 1996). Among them, in particular, are preparations containing thrombolytics as an active (active) substance, antiplatelet agents, in particular aspirin, xanthines, nootropics (piracetam), vinpocetine, etc.

The disadvantages of most of these drugs are a narrow spectrum of action, a significant number of side effects and contraindications, low neuroprotective activity, limited use in acute and chronic cerebral ischemia [The Cochrane Library, Issue 4, 2002. Oxford].

So, the use of thrombolytics for myocardial ischemia has been shown, however, complications when used in high doses are observed in 12.8% of cases. [Wardlaw J.M. et all, Thrombolysis for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford]. The use of anticoagulants in the treatment of ischemic stroke does not allow effective treatment of stroke and has significant limitations [Gubitz G. Et all, Anticoagulants for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library. Issue 4, 2002. Oxford]; enteric aspirin can only be used to prevent ischemic stroke, but not in its acute period [Gubitz G. et all, Antiplatelet therapy for acute ischemic stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford]. Adverse effects of piracetam on mortality are observed in the immediate period after ischemic stroke and in the postischemic period [Ricci S., Celani MG, Cantisani AT, Righetti E. Piracetam for acute ischaemic stroke (Cochrane Review) In: The Cochrane Library, Issue 4 2002. Oxford]. The use of methylxanthines and vinpocetine for ischemia also has significant limitations due to their insufficient safety [Bath P.M. Wet all, Pentoxifylline, propentofylline and pentifylline for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford; Bereczki D., Fekete I. Vinpocetine for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford].

In connection with the foregoing, the development of drugs for the treatment and prevention of ischemia remains an important task today.

Since ischemic damage to cells, including brain neurons, is a cascade of pathological processes [P. Lipton. Ischemic Cell Death in Brain Neurons. Physiological Reviews, Vol. 79, No. October 4, 1999; Shaheen E. Lakhan et all, Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J. of Translational Medicine 2009, 7: 97], it is advisable to develop new neuroprotectors - drugs that inhibit the main links of the ischemic cascade [Larry In Goldstein. Neuroprotective therapy for acute ischaemic stroke: down, but not out. The Lancet, 2004, 363, 414; Gary H. Danton and W. Dalton Dietrich. The Search for Neuroprotective Strategies in Stroke. AJNR Am. J. Neuroradiol. 25: 181-194, February 2004].

Neuroprotection (cytoprotection) in case of ischemia should be aimed at restoring blood flow, normalizing energy tissue metabolism, reducing the depolarization of cell membranes, inhibiting free radical processes and platelet activation factors [R. Lipton. Ischemic Cell Death in Brain Neurons. Physiological Reviews, Vol. 79, No. 4, October 1999].

A promising direction of cytoprotection aimed at the prevention and treatment of ischemia is the use of creatine amides and their derivatives (RU 2354645, 2009; US 8,350,077 B2).

Thus, the neuroprotective activity of creatine amides in brain ischemia is shown [Burov S.V et all, Creatinyl amino acids - new hybrid compounds with neuroprotective activity. J. Pept. Sci. 2011. V. 17. N. 9. P. 620-626], the possibility of using for the treatment of myocardial infarction a composition containing sodium creatine phosphate as the active substance. [P. Lipton. Ischemic Cell Death in Brain Neurons. Physiological Reviews, Vol. 79, No. 4, October 1999].

A synthetic analogue of phosphocreatine, the drug Neoton, has been shown to be effective for parenteral intravenous administration of 1-5 g per day for 5-10 days. With a heart attack, Neoton exhibits anti-ischemic, antiarrhythmic and antioxidant effects, increases the oxygen capacity of the blood, has a mild diuretic effect. [V.J. Teshchuck et all, J. of Health Sciences. 2014; 04 (03): 073-080. ISSN 1429-9623 / 2300-665X]. However, Neoton does not show antiaggregant and thrombolytic activity. In this case, the drug Neoton is not used entrally due to its rapid decomposition in the gastrointestinal tract.

Closest to the claimed group of inventions essentially is a tool that exhibits neuroprotective activity in ischemia, containing creatine amides synthesized and studied by the authors [RU 2 354 645, 2009] of the general formula NH = C (NH ₂ ) -N (CH ₃ ) -CH ₂ -CO-NH-R * X, where R is the amino acid residue of an aliphatic, aromatic or heteroaromatic amino acid or a derivative thereof, which is amino acid esters, amino acid amides or peptides; X is a low molecular weight organic or mineral acid or water.

Previously, we have shown [Veselkina OS et al. Antithrombotic properties of CREAMIDE. Bulletin of the blood service of Russia, No. 3, p. 31-37, 2010], that the most active and safe representatives of creatine amides are salts of ethyl 2- (2- (1-methylguanidino) acetamido) acetate (hereinafter EGAA) - compounds where R is CH ₂ -C (O) - O-C ₂ H ₅ , and X is a low molecular weight organic or mineral acid of the general formula I:

Preparations containing salts of ethyl 2- (2- (1-methylguanidino) acetamido) acetate were used parenterally in the form of a solution of the active substance in water or saline containing nipagin, or enteral in a mixture with excipients in doses up to 280 mg / kg animals. The drugs were administered according to the following schemes:

- 1 hour before ischemia or

- 5 days before ischemia and 7 days after ischemia (assessment of the effectiveness of the drug for the prevention and treatment of ischemia) or

- 30 minutes after the induction of ischemia and then for 7 days after ischemia (assessment of the effectiveness of the drug for the treatment of acute ischemia).

The disadvantages of these drugs are insufficient efficacy during enteral administration, instability during storage in the form of a solution for parenteral administration for a period exceeding 5 days, which led to a loss of activity and a significant accumulation of impurities.

The disadvantage of using such a composition for the treatment of ischemia was the presence of nipagin in the parenteral preparation, the content of which in solutions for intravenous administration to humans is highly undesirable [Richard J. Lewis, Sr., Hazardous Chemicals Desk Reference, p. 752; F. Alan Andersen, Int. J. of Toxicology, 27 (Suppl. 4): 1-82, 2008).

The technical problem solved by the authors was the development of the composition of the agent (composition) based on EGAA for parenteral and enteral administration with increased efficiency, ensuring the stability of the compositions during long-term storage (at least 2 years), as well as a more effective technology for their use in ischemic diseases.

As part of the solution of the task, the authors suggested that the stability of EGAA can be improved by introducing substances that can protect the most vulnerable fragments of the EGAA molecule into the composition of the agent, forming complexes that are stable under storage and easily decomposed in the body.

The technical result was achieved by creating complexes of EGAA with pharmacologically acceptable components and using as complexing components of sugars, fibrinolytic substances (PV) and mannitol of the general formula I:

Where

X is a low molecular weight C ₁ -C ₄ organic or mineral acid,

A is a fibrinolytic substance or mannitol or sugar.

Preparations can contain either EGAA complexes (1), or a mixture of the ingredients that form these complexes in contact with the environment during preparation for use.

As sugars can be used polysaccharides and their derivatives, monosaccharides, oligosaccharides and their derivatives or mixtures thereof. As polysaccharides, the preparation may contain cellulose and its esters, starch and its esters, hyaluronic acid or salts of hyaluronic acid, chitosan, chondroitin sulfate, or mixtures thereof and the like. As monosaccharides, the preparation may contain glucose, fructose and their derivatives or mixtures thereof, and the like; sucrose, maltose, lactose, or mixtures thereof and the like can be used as oligosaccharides.

As fibrinolytic substances, streptokinase or urokinase are used.

Sugar complexes are obtained by treating EGAA in a "fluidized bed" with a solution of sugars in water, a mixture of water with alcohol or alcohol for 10-30 minutes. The resulting composition can be used for enteral administration, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, powders, granules or solutions.

A preparation with PV is obtained by mixing EGAA with fibrinolytic substances, based on the content of 0.05-2.0 g in the EGAA complex, fibrinolytic substances - 50000-5000000 ME, dissolution followed by freeze drying. The preparation of a solution for injection or infusion based on EGAA is carried out, as a rule, immediately before parenteral use.

The drug with mannitol is obtained by mixing the ingredients, based on the content in the EGAA complex of 0.05-2.0 g, mannitol - 0.01-2 g, dissolution followed by freeze drying of the mixture. The preparation of a solution for injection or infusion based on EGAA is carried out immediately before parenteral use.

Sterile pyrogen-free solvents are used as solvents - water, physiological saline, mannitol infusion solution 15%, glucose solution, magnesium sulfate solution, amino acid solutions for parenteral nutrition, Ringer's solution, etc.

Along with the active principle, the composition may contain auxiliary substances. As auxiliary substances in the composition of sugars, substances can be used that improve the conditions for the preparation, storage or use of the pharmaceutical composition, such as solvents, fillers, binders, disintegrants, lubricants, film formers, pigments, plasticizers, prolonging agents, flavorings, flavoring agents additives, stabilizers, preservatives, etc. For example, lactose, corn starch or its derivatives, cellulose or its derivatives, aerosil, talc, stearic acid or its salts, mannitol, amino acids and, can be used as excipients in tablets, coated tablets, dragees and hard gelatin capsules. etc. The composition for parenteral use for complexes with PV or mannitol may include excipients that provide porosity and form of lyophilized powder, improve its solubility, ensure storage stability, for example arginine, glycine or its esters, human serum albumin, magnesium salts, polyols and etc.

The treatment of ischemia using the claimed composition is carried out according to one of the following options:

- enteral by introducing into the body a dose of not less than 0.01 g, and optimally from 0.01 g to 1 g of the active substance daily in the form of tablets, coated tablets, dragees, hard gelatine capsules, powders or granules containing active substances from 0.01 to 0.50 g in a single dose. The course of use of such pharmaceutical compositions is from several weeks to several months;

- parenterally in the form of injections or infusions in a dose of not less than 0.05 g with a daily dose of not less than 0.05 g, optimally from 0.05 g to 6 g and an active substance content of from 0.05 to 2.0 g per dose . The resulting solution is administered intravenously by injection or by intravenous drip infusion. The course of parenteral use of pharmaceutical compositions can be from several days to several weeks.

The dosage of the EHAA complex during treatment can vary within a fairly wide range, which allows it to be adjusted in each case. The daily dose may be administered in a single dose or in divided doses.

Salts of ethyl 2- (2- (1-methylguanidino) acetamido) acetate of the general formula (I) were synthesized according to the method described previously [RU 2428414; US 2012/0277459].

A composition for enteral use was prepared by treating EGAA with sugars in the presence of a solvent in a "fluidized bed" for 10-30 minutes. As the solvent used water or a mixture of water with alcohol, or alcohol. The resulting mixture was granulated, dried, crushed, and, if necessary, auxiliary substances were introduced in a predetermined ratio using traditional technologies, such as dry mixing, compaction, using a “fluidized bed” plant, etc., were further pelletized or placed in gelatin capsules or in sachets and used for enteral administration.

The use of the EGAA complex with sugars for the preparation of compositions for enteral use allowed the effective release of the active substance during enteral administration of the composition, increased stability of the composition during long-term storage provided for the storage of pharmaceutical preparations, and also optimized the technology for preparing the compositions.

A composition for parenteral use was prepared as follows: EGAA, fibrinolytic substances and, if necessary, excipients or EGAA, mannitoli, if necessary, excipients, were dissolved in a nitrogen stream, the solution was subjected to sterile filtration, poured into sterile vials, lyophilized dried in vacuum at temperatures from (-) 50 to (+) 20 ° С, the bottles were corked in a stream of dry sterile nitrogen.

The preparation of compositions for parenteral administration made it possible to ensure their stability during long-term storage, to improve the solubility of the composition before administration, to use a wider range of auxiliary substances, for example, human serum albumin, amino acids.

The most effective field of application of the claimed agent (composition) according to the present invention is the treatment of ischemic damage to the brain and myocardium, in particular, chronic.

The most effective field of application of the claimed agent (composition) according to the present invention is the treatment of ischemic damage to the brain and myocardium, in particular, chronic cerebrovascular accident, ischemic stroke, coronary heart disease, myocardial infarction.

In the course of studies of compositions for enteral administration, the disintegration and dissolution of the compositions in the form of tablets were evaluated in accordance with the recommendations of Ph. Eur. 8.0. The environment for evaluating disintegration is water, for evaluating dissolution - 0.1 M hydrochloric acid solution, 0.05 M ammonium acetate solution (pH = 4.5), 0.05 M sodium phosphate solution (pH = 7.4), volume - 900 ml. The content of salts of ethyl 2- (2- (1-methylguanidino) acetamido) acetate in the compositions was determined by reverse phase HPLC, Zorbax Eclipse column 3.5 μm, C18, 3 × 150 mm. Mobile phase: a mixture of a 0.03 M sodium dihydrogen phosphate solution containing 0.012 M sodium octanesulfonate (pH 3.0) and acetonitrile in a volume ratio of 90:10. The flow rate of the mobile phase is 0.5 ml / min, the column temperature is 30 ° C, detection at 205 nm. The activity of fibrinolytic substances in the composition of parenteral drug compositions was determined by USP and / or Ph. Eur.

Specific examples of industrial applications of the claimed group of inventions are presented below.

Example 1. Obtaining tablets containing a complex of ethyl 2- (2- (1-methyl-guanidino) acetamido) acetate fumarate with hydroxypropyl cellulose (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate with hydroxypropyl cellulose.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate is treated for 25 minutes with a solution of hyprolose in a mixture of water: ethanol in a ratio of 50:50, in a "fluidized bed", dried.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) fumarate acetate with hydroxypropyl cellulose was dusted with anhydrous lactose, aerosil, MCC, sodium stearyl fumarate, talc and flavor, passed through a 0.8 mm sieve and tableted. Biconvex tablets are obtained, weighing 250 mg and a dosage of the active substance 25 mg.

Disintegration of the tablets: 9 min. Dissolution of the tablets provides the release of 93% ethyl 2- (2- (1-methylguanidino) acetamido) fumarate acetate in 30 minutes (0.1 M HCI).

Example 2. Obtaining coated tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate with a mixture of cellulose and acetylphthalyl cellulose (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate with a mixture of cellulose and cellulose acetate. Ethyl 2- (2- (1-methylguanidino) acetamido) acetate tartrate is mixed with microcrystalline cellulose, the mixture is treated with a solution of acetylphthalyl cellulose in ethyl alcohol in a "fluidized bed" for 20 minutes, dried, and ground.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate, dusted with talc and lactose anhydrous, silicon dioxide anhydrous, passed through a sieve with a diameter of 0.8 mm, tableted. Get the core of a biconvex form weighing 76 mg, coated in a coator. The weight of the coated tablet is 80 mg. Disintegration of the tablets: 14 min. Dissolution: the release of 97% ethyl 2- (2- (1-methylguanidino) -acetamido) tartrate acetate in 30 minutes (0.05 M solution of ammonium acetate).

Example 3. Obtaining tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate acetate with lactose (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate acetate with lactose.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate acetate is treated with lactose in the presence of water, in a "fluidized bed" for 10 minutes, dried, crushed.

Getting pills.

The ethyl 2- (2- (1-methylguanidino) acetamido acetate acetate complex was dusted with ethyl cellulose, modified starch, azrosil for 10 minutes, calcium stearate was added, and stirred for another 2 minutes. The mixture is passed through a sieve with a diameter of 0.8 mm and tableted. Oblog tablets with a risk, weighing 700 mg and a dosage of 300 mg of active substance are obtained.

Disintegration of the tablets: 7 min. Dissolution: release of 97% ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate in 30 minutes (0.05 M ammonium acetate solution).

Example 4. Obtaining tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate

with chondroitin sulfate (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate with chondroitin sulfate.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate is treated with a solution of chondroitin sulfate in a mixture of water: alcohol (40:60) for 10 min, in a "fluidized bed", dried, crushed.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) phosphate acetate and chondroitin sulfate was dusted with microcrystalline cellulose, calcium phosphate dihydrate, sodium stearyl fumarate was added, and the mixture was stirred for 2 minutes. The mixture is passed through a sieve with a diameter of 0.8 mm, tableted. Get tablets with a cylindrical shape with a risk, weighing 500 mg, with a dosage of active substance 200 mg.

Disintegration of the tablets: 10 min. Dissolution of tablets: release of 95% ethyl 2- (2- (1-methylguanidino) acetamido) phosphate acetate in 30 min (0.1 M HCI).

Example 5. Obtaining tablets containing a complex of ethyl 2- (2- (1-methyl-guanidino) acetamido) acetate hydrochloride

with chitosan (option 1).

Preparation of a complex of ethyl 2- (2- (1-methylguanidino) acetamido) hydrochloride acetate with chitosan.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate hydrochloride is treated with chitosan in the presence of a mixture of water: ethyl alcohol (50:50) for 10 min, in a "fluidized bed", dried, crushed.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate hydrochloride with chitosan is mixed with microcrystalline cellulose, lactose, talc and silicon dioxide for 10 minutes. The mixture is passed through a sieve with a diameter of 0.8 mm and tableted. Get cylindrical tablets weighing 70 mg, with an active substance content of 10 mg.

Disintegration of the tablets: 5 min. Dissolution of tablets: release of 98% ethyl 2- (2- (1-methylguanidino) acetamido) hydrochloride acetate in 30 min (0.1 M HCI).

Example 6. Obtaining tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) hemi succinate acetate

with fructose (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) hemi succinate acetate with fructose.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate hemisuccinate is treated for 25 minutes with a suspension of fructose in a mixture of ethyl alcohol - water (80:20), in a "fluidized bed", dried, crushed.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) hemisuccinate acetate with fructose is mixed in a blender with microcrystalline cellulose and crospovidone for 20 minutes, sodium stearyl fumarate is added, and mixed for 5 minutes. The mixture is passed through a sieve with a diameter of 0.8 mm, tableted. The mass of the tablet is a longong 1000 mg, the dosage of the active substance is 500 mg. Disintegration of the tablets: 12 min. Dissolution: release of 92% ethyl 2- (2- (1-methylguanidino) acetamido) hemisuccinate acetate in 30 minutes (0.05 M phosphate buffer, pH 7.4).

Example 7. Obtaining tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate

with a mixture of modified starch and D-glucuronic acid (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate with modified starch and D-glucuronic acid.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate is treated with an aqueous solution of a mixture of modified starch and D-glucuronic acid for 15 minutes, in a "fluidized bed", dried, crushed.

Getting pills.

The tabletting mixture is prepared by compacting. The complex is mixed with aerosil, povidone, magnesium citrate, passed through a compactor, dusted with starch, aerosil and stearic acid, passed through a sieve with a diameter of 0.8 mm and tableted. Get 200 mg tablets with a dosage of 100 mg of active substance.

Disintegration of the tablets: 8 min. Dissolution: release of 95% ethyl 2- (2- (1-methylguanidino) acetamido) fumarate acetate in 30 minutes (0.1 N HCI).

Example 8. Obtaining hard gelatin capsules containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) hemitartrate acetate

with a mixture of cellulose and chondroitin sulfate (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) hemitartrate acetate with a mixture of cellulose and chondroitin sulfate.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate hemitartrate is mixed with powdered cellulose, treated in a "fluidized bed" for 15 minutes with an aqueous solution of chondroitin sulfate, granulated, dried.

Filling capsules.

A complex of ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate with a mixture of cellulose and chondroitin sulfate is placed in No. 3 hard gelatine capsules. Ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate in each capsule: 150 mg.

Example 9. Obtaining cheek tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate

with methyl cellulose (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate with methyl cellulose.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate tartrate is treated for 15 minutes with a solution of methyl cellulose in a mixture of water: ethyl alcohol (60:40), in a "fluidized bed", dried.

Getting pills.

The complex is dusted with magnesium stearate, then tabletted. Biconvex tablets, weighing 140 mg, are obtained. Active substance content: 100 mg. Disintegration of the tablets: 5 min. Dissolution: release of 92% ethyl 2- (2- (1-methylguanidino) acetamido) tartrate acetate in 30 minutes (0.05 M phosphate buffer, pH 7.4).

Example 10. Obtaining a powder containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate

with a mixture of sodium hyaluronate and maltose, to obtain a solution for enteral administration (option 1).

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate with a mixture of sodium hyaluronate and maltose.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate is mixed with maltose, the mixture is treated for 15 minutes in a "fluidized bed" with sodium hyaluronate in a mixture of water: ethyl alcohol (40:60), dried and ground.

The complex is mixed with potassium asparaginate and sucrose, the powder is packaged in sachets. Before use, dilute in 100 ml of water.

Example 11. Obtaining a preparation for the preparation of solutions for infusion containing ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate

and streptokinase (option 2).

10 g of ethyl 2- (2- (1-methylguanidino) acetamido) phosphate acetate are dissolved in a stream of nitrogen in 200 ml of water, 5 g of albumin, 1.1 ml (1,000,000 IU) of streptokinase solution are added and dissolved with gentle stirring in a stream of nitrogen (Kraeber & Co GMBH). The solution is subjected to sterile filtration, poured into 10 ml into sterile vials, freeze-dried in vacuum at a temperature of (-) 20 to (+) 15 ° C. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen and stored at a temperature not exceeding 5 ° C, preventing freezing.

The moisture content of the composition: 2.4%, the dissolution time in 20 ml of water d / and does not exceed 1 min. The content of ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate in a bottle: 500 mg, streptokinase: 50,000 ME.

Immediately before the intravenous (further on / in) infusion, the contents of the vial are dissolved in 80 ml of saline.

Example 12. Obtaining a lyophilized powder for the preparation of solutions for infusion containing ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate

and streptokinase (option 2).

10 g of ethyl 2- (2- (1-methylguanidino) acetamido) phosphate acetate and 6 g of arginine hydrochloride are dissolved in a stream of nitrogen in 170 ml of water, the pH is adjusted to 6.8, adding potassium phosphate 20% solution, 4 g are introduced albumin and dissolved with gentle stirring, add 2.6 ml (2500000 ME) of streptokinase solution (Kraeber & Co GMBH), dissolve in a stream of nitrogen with gentle stirring, bring the volume to 200 ml. The solution is subjected to sterile filtration, poured into 20 ml in sterile vials, freeze-dried in vacuum at a temperature of (-) 20 to (+) 15 ° C. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen, stored at a temperature not exceeding 5 ° C, preventing freezing.

The moisture content of the composition: 3.2%, the dissolution time in 20 ml of water d / and does not exceed 1 min. The content of ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate in a bottle: 1000 mg, streptokinase: 250000 ME.

Immediately before iv infusions, the contents of the vial are dissolved in 50 ml of saline.

Example 13. Obtaining lyophilized powder for the preparation of solutions for infusion containing ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate

and streptokinase (option 2).

40 g of ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate are dissolved in a stream of nitrogen in 350 ml of water, 20 g of albumin, 5.3 ml (5,000,000 ME) of streptokinase solution are added and dissolved in a stream of nitrogen with gentle stirring. (Kraeber & Co. GMBH), bring the volume to 400 ml. The solution is subjected to sterile filtration, poured into 20 ml into sterile bottles, freeze-dried in vacuum at a temperature of (-) 20 to (+) 20 ° C. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen, stored at a temperature not exceeding 5 ° C, preventing freezing.

The moisture content of the composition is 2.3%, the dissolution time in 20 ml of water d / and does not exceed 1 min. The content of ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate in a vial: 2000 mg, streptokinase: 250,000 IU.

Immediately before IV infusions, the contents of the vial are dissolved in 90 ml of saline.

Example 14. Obtaining a lyophilized powder for the preparation of infusion solutions containing ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate and urokinase (option 2).

1 g of ethyl 2- (2- (1-methylguanidino) acetamido) succinate acetate is dissolved in a stream of nitrogen in 350 ml of water, dissolved in a stream of nitrogen with gentle stirring 4 g of mannitol, 5 g of albumin, 10.4 ml (10,000,000 ME) urokinase solution (Kraeber & CoGMBH), bring the volume to 400 ml. The solution is subjected to sterile filtration, poured into 20 ml in sterile vials, then freeze-dried in vacuum at a temperature of (-) 35 to (+) 25 ° C. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen, stored at a temperature not exceeding 5 ° C, preventing freezing.

Humidity of the composition: 2.9%, the dissolution time in 10 ml of water d / and does not exceed 1 min. Ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate content in vial: 50 mg, urokinase: 500,000 ME.

Immediately before IV infusions, the contents of the vial are dissolved in 30 ml of water for injection.

Example 15. Obtaining lyophilized powder for the preparation of solutions for infusion containing ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate and urokinase (option 2).

10 g of ethyl 2- (2- (1-methylguanidino) acetamido) fumarate acetate are dissolved in a stream of nitrogen in 150 ml of water, 2 g of mannitol, 4 g of albumin, 5.2 ml are added and dissolved in a stream of nitrogen with gentle stirring (5,000,000 ME) urokinase solution (Kraeber & CoGMBH), bring the volume to 200 ml. The solution is subjected to sterile filtration, poured into 20 ml in sterile vials, freeze-dried in vacuum at a temperature of (-) 30 to (+) 20 ° C. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen, stored at a temperature not exceeding 5 ° C, preventing freezing.

The moisture content of the composition: 2.9%, the dissolution time in 20 ml of water d / and does not exceed 1 min. The content of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate in a bottle: 1000 mg, urokinase: 500000 ME.

Immediately before IV infusions, the contents of the vial are diluted in 40 water, then mixed with 150 ml of saline.

Example 16. Obtaining a lyophilized powder for the preparation of solutions for infusion or injection containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate and mannitol (option 3).

250 g of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate and 100 g of mannitol are dissolved in a stream of nitrogen in 5 l of water, the solution is subjected to sterile filtration, poured into sterile 5 ml vials, freeze-dried in vacuum at a temperature from (-) 45 to (+) 20 ° С. The vials are closed with stoppers and caps in a stream of dry sterile air, stored at a temperature not exceeding 25 ° C, avoiding freezing.

Humidity of the composition: 0.5%, dissolution time in 10 ml of water d / and does not exceed 1 min. The content of the active substance in the bottle: 250 mg.

Immediately before the intravenous injection, the contents of the vial are dissolved in 10 ml of water d / and, during the intravenous infusion, the same solution is mixed with 50 ml of mannitol infusion solution 15%.

Example 17. Obtaining a lyophilized powder for the preparation of solutions for infusion or injection containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate

with mannitol (option 3).

20 g of arginine are dissolved in 10 l of water, adding about 5.7 g of succinic acid (up to pH 6.0), then 250 g of ethyl 2- (2- (1-methylguanidino) -acetamido) succinate acetate, 100 g of mannitol are added , 125 g of albumin, dissolved in a stream of nitrogen with slow stirring. The solution is subjected to sterile filtration, poured into 5 ml vials, freeze-dried in vacuum at a temperature of (-) 50 to (+) 20 ° С. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen and stored at a temperature not exceeding 25 ° C, preventing freezing.

Humidity of the composition: 0.7%, dissolution time in 10 ml of water for injection does not exceed 1 min. Content of ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate in a vial: 125 mg.

Immediately before IV infusions, the contents of the vial are dissolved in 5 ml of water d / and the solution is mixed with 100 ml of a solution of amino acids for parenteral nutrition.

Immediately before the injection, the contents of the vial are dissolved in 10 ml of a 5% glucose solution.

Example 18. Obtaining lyophilized powder for the preparation of solutions for infusion containing a complex of ethyl 2- (2- (1-methylguanidino) -acetamido) acetate fumarate

with mannitol (option 3).

20 g of ethyl 2- (2- (1-methylguanidino) acetamido) fumarate acetate and 20 g of mannitol are dissolved in 400 ml of water in a stream of nitrogen and with gentle stirring, the solution is subjected to sterile filtration, poured into sterile 20 ml vials, freeze-dried in vacuum at a temperature of (-) 45 to (+) 28 ° С. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen and stored at a temperature not exceeding 25 ° C, preventing freezing.

Humidity of the composition: 1.8%, the dissolution time in 40 ml of water d / and does not exceed 2 minutes The content of the active substance in the bottle: 1000 mg.

Immediately before use, the contents of the vial are dissolved in 40 ml of water d / and the solution is mixed with 150 ml of saline and injected intravenously.

Example 19. Obtaining lyophilized powder for the preparation of solutions for infusion containing a complex of ethyl 2- (2- (1-methylguanidino) -acetamido) phosphate acetate

with mannitol (option 3).

50 g of ethyl 2- (2- (1-methylguanidino) acetamido) phosphate acetate, 50 g of mannitol, 5 g of glycine are dissolved in 1 l of water, adjusted to pH 5.5 with orthophosphoric acid 20%, the solution is subjected to sterile filtration, poured into sterile vials of 40 ml, freeze-dried in vacuum at a temperature of (-) 50 to (+) 25 ° C. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen and stored at a temperature not exceeding 25 ° C, preventing freezing.

Humidity of the composition: 0.8%, the dissolution time in 80 ml of water d / and does not exceed 2 minutes The content of the active substance in the bottle: 2000 mg.

Immediately before IV infusions, the contents of the vial are dissolved in 80 ml of water d / and the solution is mixed with 250 ml of mannitol infusion solution 15%.

Example 20. Obtaining a lyophilized powder for the preparation of solutions for injection containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) phosphate acetate

with mannitol (option 3).

20 g of ethyl 2- (2- (1-methylguanidino) acetamido) phosphate acetate and 10 g of mannitol are dissolved in a stream of nitrogen in 1 l of water, adjusted to pH 5.5 with orthophosphoric acid 20%, the solution is subjected to sterile filtration, poured into sterile 5 ml vials, freeze-dried in vacuum at a temperature of (-) 45 to (+) 20 ° C. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen and stored at a temperature not exceeding 25 ° C, preventing freezing.

Humidity of the composition: 0.4%, dissolution time in 20 ml of water d / and does not exceed 1 min. The content of ethyl 2- (2- (1-methylguanidino) acetamido) acetate phosphate in a bottle: 100 mg.

Immediately before the injection, the contents of the vial are diluted in 20 ml of magnesium sulfate 5% solution.

Example 21. Obtaining a lyophilized powder for the preparation of solutions for injection containing a complex of ethyl 2- (2- (1-methylguanidino) -acetamido) phosphate acetate

with mannitol (option 3).

5 g of ethyl 2- (2- (1-methylguanidino) acetamido) phosphate acetate, 1 g of mannitol and 1 g of ethyl glycine are dissolved in 200 ml of water, the pH is adjusted to 5.5 with orthophosphoric acid 20%, the solution is subjected to sterile filtration, poured into sterile vials of 2 ml, freeze-dried in vacuum at a temperature of (-) 45 to (+) 35 ° C. Vials are closed with stoppers and caps in a stream of dry sterile nitrogen and stored at a temperature not exceeding 25 ° C, preventing freezing.

Humidity of the composition: 0.8%, dissolution time in 10 ml of water for injection does not exceed 1 min. The content of ethyl 2- (2- (1-methylguanidino) -acetamido) acetate phosphate in a bottle: 50 mg.

Immediately before injection, the contents of the vial are dissolved in 5 ml of saline.

Example 22. Obtaining compositions according to the composition proposed in the prototype [RU 2354645].

For a comparative assessment of the stability of the compositions according to the claimed composition, compositions of a composition identical to that described in [RU 2354645] are obtained. Composition 22a for enteral use is obtained as described for the composition of example 4, table 3 [RU 2354645].

Composition 22b for parenteral use is obtained as described for the composition according to example 4, table 3 [RU 2354645].

The resulting solution is subjected to sterile filtration, poured into sterile 2 ml vials and stored at a temperature not exceeding 25 ° C, avoiding freezing.

Example 23. Obtaining tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) hemi succinate acetate

with powdered cellulose.

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) hemi succinate acetate with cellulose powder.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate hemisuccinate is treated for 25 minutes with a suspension of powder pulp in a mixture of alcohol-water (80:20), in a "fluidized bed", dried.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) hemi succinate acetate and cellulose powder is mixed in a blender for 20 min with crospovidone, sodium alginate, croscarmellose sodium, dusted with sodium stearyl fumarate, stirred for 5 minutes. The mixture is passed through a sieve with a diameter of 0.8 mm, tableted. Obtain tablets oblong weighing 1000 mg, the dosage of the active substance is 500 mg. Disintegration of tablets - 12 minutes. Dissolution: release of 92% ethyl 2- (2- (1-methylguanidino) acetamido) hemisuccinate acetate in 30 minutes (0.05 M phosphate buffer, pH 7.4).

Example 24. Obtaining tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate

with sucrose

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate with sucrose.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate is treated for 25 minutes with a solution of sucrose in a "fluidized bed", dried.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) fumarate acetate with sucrose is mixed with MCC, succinic acid, talc for 15 minutes, sodium dusted with stearyl fumarate and flavor, passed through a 0.8 mm sieve and tableted. Receive biconvex tablets weighing 150 mg, the dosage of the active substance is 25 mg.

Disintegration of the tablets is 7 minutes. Dissolution of the tablets provides the release of 97% ethyl 2- (2- (1-methylguanidino) acetamido) acetate fumarate in 30 minutes (0.1 n HCI).

Example 25. Obtaining coated tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate

with D-gluuronic acid.

Obtaining a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate with mannitol.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate is treated for 10 min with an aqueous solution of D-gluuronic acid in a "fluidized bed", dried.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) succinate acetate with D-gluuronic acid is mixed with povidone, potassium succinate, polyvinyl alcohol, colloidal silicon dioxide for 10 minutes, calcium stearate is added, and stirred for another 2 minutes. The mixture is passed through a sieve with a diameter of 0.8 mm and tableted.

Get a cylindrical core weighing 600 mg and a dosage of 300 mg of active substance.

The cores are treated with a suspension containing titanium dioxide / iron oxide II (1: 1), hydroxymethyl propyl cellulose, shellac, dried.

Obtained coated tablets, weight 625 mg, active substance content 300 mg.

Disintegration of the tablet - 15 minutes. Dissolution: release of 95% ethyl 2- (2- (1-methylguanidino) acetamido) succinate acetate in 30 minutes (0.05 M solution of ammonium acetate).

Example 26. Obtaining enteric coated tablets containing a complex of ethyl 2- (2- (1-methylguanidino) acetamido) fumarate acetate

with maltose.

Preparation of a complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate with maltose.

Ethyl 2- (2- (1-methylguanidino) acetamido) acetate succinate is treated for 10 min with an aqueous solution of maltose in a "fluidized bed", dried.

Getting pills.

The complex of ethyl 2- (2- (1-methylguanidino) acetamido) succinate acetate with maltose is mixed with MCC, Eudragit L30 D, povidone, potassium succinate, silicon dioxide colloidal, calcium stearate for 10 minutes, calcium stearate is added, 2 more are mixed min The mixture is passed through a sieve with a diameter of 0.8 mm and tableted.

Get a cylindrical core weighing 230 mg and a dosage of active substance 100 mg.

The kernels are treated with a suspension containing sodium alginate, xanthan gum, iron oxide II, triethyl citrate, dried.

Coated tablets are obtained, weight 250 mg, active substance content 100 mg.

Disintegration of the tablet - 12 minutes. Dissolution: release of 93% ethyl 2- (2- (1-methylguanidino) acetamido) succinate acetate in 30 minutes (0.05 M solution of ammonium acetate).

Example 27. The study of the stability of the compositions during storage.

When studying the stability of the compositions during long-term storage, it was proved (Table 1) that the claimed composition of the compositions for enteral and parenteral use provides the stability of the compositions during storage, many times higher than the stability of the compositions according to the composition described in the closest analogue [RU 2354645, 2009].

Example 28

Neuroprotective activity of pharmaceutical compositions for ischemic stroke.

The study was performed in vivo on a model of focal cerebral ischemia of male Wistar rats (weight 280 ± 25 g, 12-14 weeks) with occlusion of the left middle cerebral artery (SMA). Grouping: randomization method. Anesthesia - thiopental sodium at a dose of 60 mg / kg, intraperitoneally. Endovascular occlusion of MCA was performed according to the method of Koizumi, J. [Koizumi J. et all. Jpn. J. Stroke. 1986; 8: 1-8] as modified by Longa, E.Z. [Zea Longa et all. Stroke. 1989; 20: 84-91] and Belayev L. [Belayev, L. et al., Stroke, 27, 1616, 1996]. Duration of ischemia - 30 minutes, reperfusion - 48 hours. Ischemia was verified, animals with subarachnoid hemorrhage were identified (Doppler ultrasound of the cortical branch of the left middle cerebral artery); blood flow assessment to a depth of 0.4 cm ("Mini-Max-Doppler-K", a sensor with a radiation frequency of 25 MHz).

Criteria for exclusion of animals from the experiment: subarachnoid hemorrhage; low blood flow parameters in the cortical branch of the left middle cerebral artery; damage to the carotid arteries during surgery; severe inflammation in the wound after surgery.

The introduction of the compositions: intravenously or intragastrically with a rigid metal probe at different periods of ischemia / reperfusion. Before the introduction of the composition was diluted with saline.

In control, saline was administered.

Assessing the size of the damage: Animals were sacrificed, the brain was removed, the cerebellum and olfactory bulbs were cut off from the cerebrum, and 2 mm thick frontal sections were obtained. The area of the damage zone was determined after staining sections of triphenyltetrazolium chloride (MP Biomed., USA). The area of damage, the area of the hemispheres and their asymmetry coefficient, the ratio of the area of the damaged hemisphere to the area of the entire frontal section of the brain were calculated.

The determination of malondialdehyde (MDA) in the brain tissue after ischemia was carried out according to the method of M. Uchiyama. The protein content was determined by the Lowry method in the modification of G.L. Peterson. Static significance of differences: the value of Student's test, p, less than 0.05 was taken as confirmation of the significance of differences.

Thus, the high neuroprotective activity of the claimed compositions is shown for cerebral ischemia, both with parenteral and with their enteral administration.

Example 29

Cytoprotective activity of pharmaceutical compositions in experimental in vivo myocardial infarction.

Animals: male Wistar rats (weight 300 ± 30 g, 14-16 weeks), kept under 12/12 hours of light, treated with standard food and drinking water ad libitum. Grouping by randomization. The number of animals in the group is 8.

Anesthesia. Intraperitoneally, sodium thiopental, 60 mg / kg. Maintenance anesthesia: iv thiopental sodium infusion solution. The experiments were performed with mechanical ventilation through a tracheostomy (SAR-830P, Stoelting, USA, respiratory rate 50 / min, tidal volume 1.5-3 ml / 100 g weight). Access to the heart: by thoracotomy in the fourth intercostal space on the left; opening the pericardium, determining the localization of the common trunk of the left coronary artery (LCA), under which a polypropylene ligature was brought using an atraumatic needle (Cardiopoint, CV-301). Occluder: the ends of the ligature, covering the coronary artery, were drawn into the lumen of a polyethylene tube (diameter 1 mm, length 5-6 cm, PE 40), by displacing the tube to the heart, LCA occlusion was achieved, reperfusion in the opposite direction. A clamp was applied to the tube. The animals were on a thermostatic operating table, at a body temperature in the range of 37.0 ± 0.5 ° C. Blood pressure was measured using a pressure sensor (Baxter, USA) connected to the amplifier through a heparinized catheter inserted into the aorta through the common carotid artery. Heart rate, hemodynamic parameters were recorded.

Determination of the size of the anatomical risk zone and infarction zone. We used the generally accepted method of “double staining” with Evans blue and triphenyltetrazolium chloride — TTS (MP Biomed., USA). Myocardial slices 2 mm thick were cut in the transverse direction, 5 slices from the myocardium of each rat. The calculation of the area of the sections of the slices was carried out using the program Adobe Photoshop. The volume of the risk zone was calculated by multiplying the area of the Evans-negative section of the slice by its thickness, and the average value for 5 slices was calculated. Next, the sections were kept in a 1% TTC solution for 15 min at a temperature of 37 ° C.

The area of the infarction zone was calculated (TTC-negative areas within the risk zone), the average value for each rat with the number of slices n = 5, then the average for the group. Similarly, the volume of the heart attack zone was calculated as the ratio of the volume of the heart attack zone to the volume of the risk zone (Table 4).

The effectiveness of the administration of medicinal compositions in the acute and acute periods of myocardial infarction, a statistically significant decrease in ischemic-reperfusion damage to the left myocardial ventricle was shown (Table 5).

The above examples confirm the high pharmaco-biological activity of the claimed medicinal compositions for the treatment of cerebral ischemia, coronary heart disease, as well as the stability of the compositions during long-term storage.

Claims (31)

1. An agent for the treatment of ischemia containing, as an active principle, a salt complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate, which is a complex of the general formula I:

where X is a low molecular weight C ₁ -C ₄ organic or mineral acid, A is a fibrinolytic substance or mannitol or sugar. 2. The treatment for ischemia according to claim 1, characterized in that the salt content of ethyl 2- (2- (1-methylguanidino) acetamido) acetate in the complex is at least 20 wt.%. 3. The treatment for ischemia according to claim 1, characterized in that it contains at least one substance from the group of streptokinase and urokinase as fibrinolytic substances. 4. The tool according to p. 1, characterized in that as an active principle it contains a complex of a salt of ethyl 2- (2- (1-methylguanidino) acetamido) acetate in an amount of from 0.05 g to 2 g with fibrinolytic substances in amounts from 50,000 to 5,000,000 ME. 5. The tool according to claim 1, characterized in that, as an active principle, it contains a complex of ethyl 2- (2- (1-methylguanidino) -acetamido) acetate salt in an amount of from 0.05 g to 2 g with mannitol in an amount from 0.01 to 2 g. 6. The treatment for ischemia according to claim 1, characterized in that it contains at least one sugar from the group as sugars: polysaccharides and their derivatives, monosaccharides, oligosaccharides and their derivatives. 7. A means for treating ischemia according to claim 6, characterized in that it contains at least one sugar from the group as sugars: hydroxypropyl cellulose, ethyl cellulose, cellulose, acetylphthalyl cellulose, chitosan, chondroitin sulfate, hyaluronic acid and mixtures thereof. 8. The treatment for ischemia according to claim 6, characterized in that as monosaccharides it contains at least one monosaccharide from the group: glucose, fructose, D-glucuronic acid. 9. The treatment for ischemia according to claim 6, characterized in that as oligosaccharides it contains at least one oligosaccharide from the group: sucrose, maltose, lactose. 10. The agent for the treatment of ischemia in paragraphs. 1-9, characterized in that it is made in the form of lyophilized powder for the preparation of a solution for parenteral administration. 11. The agent for the treatment of ischemia in p. 1-9, characterized in that it is made in one of the forms selected from the group: tablet, including a tablet without a shell, a sublingual tablet, a coated tablet, a resorption tablet, a chewing tablet, capsule, pellet, powder for preparation solution for enteral administration, capsule or dragee for enteral administration. 12. The tool for the treatment of ischemia according to claim 10 or 11, characterized in that it additionally contains auxiliary substances. 13. The treatment for ischemia according to claim 12, characterized in that it contains at least one substance from the group of human serum albumin, sodium chloride, magnesium sulfate, natural amino acids or their esters as auxiliary substances. 14. The agent for treating ischemia according to claim 13, characterized in that it contains arginine or glycine, or glycine ethyl ester, as natural amino acids. 15. A means for treating ischemia according to claim 11 or 12, characterized in that it contains at least one substance from the group of excipients, binders, disintegrants, lubricants, film-forming substances, pigments, plasticizers as auxiliary substances . 16. The treatment for ischemia according to claim 15, characterized in that it contains at least one substance from the group consisting of sugars and their derivatives, magnesium salts, crospovidone, copovidones, saccharin and its salts, sodium salts, as fillers potassium salts, citric acid and its salts, succinic acid, tartaric acid or its salts. 17. The agent for treating ischemia according to claim 15, characterized in that it contains at least one substance from the group of sucrose, cellulose ethers, polyvinylpyrrolidone, gelatin, alginic acid or its salts, shellac, polyvinyl alcohol, as binders methacrylic acid and its copolymers, sodium carboxymethyl cellulose. 18. A means for treating ischemia according to claim 15, characterized in that it contains at least one substance from the group of croscarmellose sodium, corn starch, pregelatinized corn starch, crospovidone, croscarmellose calcium salt as baking powder. 19. The treatment for ischemia according to claim 15, characterized in that it contains at least one substance from the group consisting of sodium stearyl fumarate, calcium stearate, magnesium stearyl fumarate, calcium stearyl fumarate, stearic acid, colloidal dioxide as a sliding lubricant silicon. 20. The agent for treating ischemia according to claim 15, characterized in that it contains at least one substance from the group consisting of titanium dioxide, talc, iron salts, dyes, kaolin as a pigment. 21. The agent for treating ischemia according to claim 15, characterized in that it contains at least one substance from the group consisting of polysorbates, glycerin and its esters, polyethylene glycol, propylene glycol, dibutyl phthalate, triethyl citrate, triacetin, povidone, mineral oils, vegetable oils. 22. The treatment for ischemia under item 15, characterized in that when executed in the form of tablets, provided with a shell, or in the form of dragees, as a coating it contains at least one substance from the group consisting of cellulose ethers, sodium carboxymethyl- cellulose and its derivatives, povidones, copovidones, methacrylic acid and its copolymers, sucrose, ready-to-coat mixtures containing cellulose and its esters, povidones, copolymers of vinylpyrrolidone with vinyl acetate, shellac, gelatin, xanthan gum, gum arabic, alginic kis lot and its salt. 23. The method of obtaining funds under item 1, characterized in that when receiving the complex with sugar, the salt of ethyl 2- (2- (1-methylguanidino) -acetamido) acetate is treated with a solution of sugar in a "fluidized bed" for 10-30 minutes followed by the introduction of, if necessary, auxiliary substances and the preparation of funds based on the finished mixture. 24. The method of obtaining funds according to claim 1, characterized in that when receiving the complex with fibrinolytic substances, the salt of ethyl 2- (2- (1-methylguanidino) acetamido) acetate is mixed with fibrinolytic substances and, if necessary, auxiliary substances, dissolved in water in nitrogen flow, the solution is subjected to sterile filtration and freeze-dried. 25. The method of producing the agent according to claim 1, characterized in that when receiving the complex with mannitol, the salt of ethyl 2- (2- (1-methylguanidino) acetamido) acetate is mixed with mannitol and, if necessary, auxiliary substances, dissolved in water in a stream of nitrogen , the solution is subjected to sterile filtration and freeze-dried. 26. A method of treating ischemia by introducing into the body an agent containing, as an active principle, a salt complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate of the general formula I, characterized in that an agent containing a salt complex of ethyl-2 is administered - (2- (1-methylguanidio) acetamido) acetate with sugars according to claim 1, enteral at a dose of not less than 0.01 g. 27. A method of treating ischemia by introducing into the body an agent containing a salt complex of ethyl 2- (2- (1-methylguanidino) acetamido) acetate of general formula I, characterized in that it is administered parenterally after dissolution in sterile pyrogen-free solvents immediately before administration, at a dose of at least 0.05 g. 28. The method according to p. 27, characterized in that as sterile pyrogen-free solvents use a solvent from the group consisting of water, physiological solution, mannitol infusion solution 15%, glucose solution, magnesium sulfate solution, Ringer's solution, amino acid solution for parenteral nutrition.