Combined medical drug of bioflavonoid and amino acid for complex therapy of diseases

Abstract

The invention relates to the creation, production and use of a drug for parenteral use in the form of a concentrate for preparing a solution for infusions and complex treatment and rehabilitation after diseases. A medicinal product in the form of a concentrate for the preparation of an infusion solution, containing as active substances a bioflavonoid and an amino acid, auxiliary substances-stabilizers, auxiliary substances-solubllizers and water for injections, which differs in that, as a bioflavonoid, it contains a native form of a flavonoid containing more 95% (+-2R,3R)-enantiomers of 2,3-dihydro-2-(3,4- dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-OH,as an amino acid it contains the L-isomer of 2- amino-5-guanidinepentanoic acid, and as auxiliary solubilizers it contains polyvinylpyrrolidone with a molecular weight of 8000 (PVR), as auxiliary stabilizers it contains cysteine, sodium metabisulfite, ascorbic acid, sodium sulfite, sodium bisulfite, disodium edetate or their combinations, with the following ratio of components, wt. %: native form of flavonoid containing more than 95% (+-2R,3R)-enantiomers 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-OH 0.75-1.55 L-isomer of 2-amino-5-guanidinepentanoic acid 0.5-1.22 polyvinylpyrrolidone 8000 6.0-9.0 and / or cysteine 0.08-0.2 and / or sodium sulfite 0.2-0.4 and / or sodium metabisulfite 0.1-0.5 and / or ascorbic acid 0.05-0.2 and / or disodium edetate 0.05-1.0 and / or sodium bisulfite 0.1-0.5 the rest is water.

Description

[0001] Combined medical drug of bioflavonoid and amino acid for complex therapy of diseases

[0002] Scope of the invention:

[0003] The invention belongs to medicine and the chemical-pharmaceutical industry, in particular to the creation, production and use of a drug for parenteral use in the form of a concentrate for the preparation of a solution for infusions and complex treatment and rehabilitation after diseases, especially:

[0004] 1) ischemic heart disease, atherosclerosis of heart and brain vessels, atherosclerosis of peripheral vessels;

[0005] 2) acute myocardial infarction and acute cerebrovascular accident;

[0006] 3) micro- and macroangiopathy; especially diabetic angiopathy - as a result of complications of diabetes;

[0007] 4) pneumonia, including caused by Covid-19; postoperative complications;

[0008] 5) acute and chronic hepatitis of various etiologies, liver failure, intoxication of the body.

[0009] Modern medicine and pharmacy recognize the importance of using medicinal products of natural origin. The difference of this approach lies in the reduction / elimination of side effects from taking chemical drugs (Mashkovsky, M.D. "Medicines", - M., 2000. - Vol. 1). and a positive effect on the body as a whole.

[0010] Along with this, the use of complex and combined therapy is considered a rational trend, the advantages of which are the use of different mechanisms of action with an impact on several links of pathogenesis, mutual potentiation of the effect, reduction of the severity of side effects, increase in bioavailability due to the positive effects of the interaction of components (for example, the formation of soluble complexes).

[0011] A well-known combined remedy for the treatment of cardiovascular diseases for oral use [UA 36998, A61K 31 / 00, 10.11.2008], which contains L-arginine asparaginate, a preservative, a sweetening component, a food flavoring and purified water, additionally contains potassium asparaginate , magnesium asparaginate, di-L-arginine succinate.

[0012] The well-known drug "Korvityn®" (CJSC Borshchagivskyi KhFZ, Kyiv, Ukraine) in the form of a powder lyophilized for the preparation of a solution for injections, which is a complex of quercetin with polyvinylpyrrolidone, and contains auxiliary substances - sodium hydroxide. It is used in complex therapy of acute violation of coronary blood circulation and myocardial infarction, treatment and prevention of reperfusion syndrome during surgical treatment of patients with obliterating atherosclerosis of the abdominal aorta and peripheral arteries. Corvitin normalizes cerebral hemodynamics in ischemic lesions, reduces the coefficient of asymmetry cerebral blood flow in ischemic stroke. There is a known patent on the method of obtaining corvitin [UA 23996, A61K9 / 14, 35 / 68, C08F271 / 02, 15.12.2000] by dissolving quercetin in a solution of polyvinylpyrrolidone in 95% ethyl alcohol with subsequent distillation, which is characterized by the fact that the dry residue dissolve in water, neutralize with caustic soda solution to pH 6.5-7.0, filter and dry. The disadvantage of this method is the complexity and multi-stage technology, the need for complex and energy-intensive equipment for distillation and lyophilization of the product. A known drug in the form of a concentrate for the preparation of an infusion solution, which contains an active substance based on a bioflavonoid, auxiliary substances and water for injections, as a bioflavonoid contains dihydroquercetin, additionally contains meglumine, and as auxiliary substances contains polyvinylpyrrolidone with a molecular weight of 8000 or polyethylene oxide 400, or propylene glycol 1,2, or their combinations [UA118075, A61K31 / 33 A61P9 / 00 C07C215 / 06 C07D311 / 32 A61K31 / 133, 12.11.2018].

[0013] A known drug in the form of a concentrate for the preparation of an infusion solution, which contains an active substance based on a bioflavonoid, auxiliary substances and water for injections, as a bioflavonoid contains dihydroquercetin, additionally contains trometamol, and as auxiliary substances contains polyvinylpyrrolidone with a molecular weight of 8000 or polyethylene oxide 400, or propylene glycol 1,2, or their combinations [UA118076, A61K31 / 33 A61P9 / 00 A61K31 / 133 C07C215 / 06 C07D3U / 32, 12.11.2018].

[0014] The closest to the claimed product is a medicinal product in the form of a concentrate for the preparation of an infusion solution containing an active ingredient based on a bioflavonoid, arginine, excipients and water for injections, which differs in that the bioflavonoid contains dihydroquercetin, and excipients contain polyvinylpyrrolidone with a molecular weight of 8000 or polyethylene oxide 400, or propylene glycol 1.2, or their combinations [UA117389, A61K31 / 33 C07C229 / 26 C07C215 / 06 C07D279 / 04 A61K31 / 197 A61K31 / 13 3 A61P9 / 00, 25.07.2018].

[0015] Due to the lack of medicines under the [117389, 118075, 118076] there is an insufficient level of stability, which determines the shelf life, the duration of which is an important factor of safety, efficiency and improvement of economic indicators in the industrial production and sale of drugs.

[0016] The basis of the claimed invention is the task of creating a stable combined medicinal product with two active substances (API) - a bioflavonoid in its native form, containing more than 95% (+-2R,3R)- enantiomers of 2,3-dihydro-2-( 3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH and the L- isomer of 2-amino-5-guanidinepentanoic acid, with such a qualitative and quantitative composition of components that will ensure the stability of the drug during the entire shelf life (24-36 months) and will expand the spectrum of pharmacological action due to the complex and synergistic effect of active substances.

[0017] The task is solved by the fact that the drug in the form of a concentrate for the preparation of an infusion solution containing as active substances bioflavonoid and amino acid, auxiliary substances-stabilizers, auxiliary substances-solubilizers and water for injections. According to the invention contains active substances: native form of bioflavonoid containing more than 95% (+-2R,3R)-enantiomers of 2,3-dihydro- 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H -l-benzopyran-4-OH and L-isomer of 2-amino-5- guanidinepentanoic acid, and as auxiliary substances-solubilizers it contains polyvinylpyrrolidone with a molecular weight of 8000 (PVP), as auxiliary substances-stabilizers it contains cysteine, sodium metabisulfite, ascorbic acid, sodium sulfite, sodium bisulfite, disodium edetate or their combination, with the following ratio of components, mass . %: native form of flavonoid containing more than 95% (+-2R,3R)-enantiomers

[0018] 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH 0.75-1.55

[0019] L-isomer of 2-amino-5-guanidinepentanoic acid 0.5-1.22 polyvinylpyrrolidone 8000 6.0-9.0 and / or cysteine 0.08-0.2 and / or sodium sulfite 0.2-0.4 and / or sodium metabisulfite 0.1-0.5 and / or ascorbic acid 0.05-0.2 and / or disodium edetate 0.05-1.0 and / or sodium bisulfite 0.1-0.5 the rest is water.

[0020] The active substances of the proposed drug are of natural origin.

[0021] 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH - biologically active substance of plant origin, bioflavonoid from the root part of larch wood, a powerful antioxidant, a unique natural acceptor of oxygen free radicals that has no analogues. In terms of its antiradical activity, it is considered a standard among other antioxidants, such as retinol (vitamin A), tocopherol (vitamin E), rutin, lipin, quercetin, and others, 3-5 times superior to them in terms of its biological activity. In addition, it is a powerful angio- and hepatoprotector, has anti-inflammatory, analgesic, immunocorrective properties.

[0022] Its anti-inflammatory and anti-allergenic effectiveness is known. It strengthens and restores connective tissue, helps reduce cholesterol levels, enhances the effect of many useful substances (vitamin C and vitamin E); improves blood microcirculation, prevents the formation of blood clots, reduces inflammatory phenomena, activates the processes of regeneration of the gastric mucosa, provides pronounced prevention of major diseases: cancer, cardiovascular diseases, brain diseases, etc., increases the resistance of body tissues to the harmful effects of excessive blood sugar, reduces the likelihood of diabetes and eases the course of forms that have already developed, such as angiopathy caused by diabetes; has a positive effect on the nervous system, activates nervous processes.

[0023] In terms of molecular structure, biological and pharmacological effects, 2,3-dihydro-2-(3,4- dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH is close to quercetin and rutin, but surpasses them in activity and has a wider spectrum of pharmacological action. 2,3-dihydro-2-(3,4- dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH, compared to quercetin, has less toxic and mutagenic properties.

[0024] Recent studies driven by the search for anti-Covid-19 drugs have shown that quercetin and its derivatives have antiviral activity (Cheng et al., 2015; dos Santos et al., 2014; Mehrbod et al., 2021). Based on these preliminary results, it has been suggested that flavonols and dihydroflavonols may inhibit the proactivity of core protease, which is an important enzyme required for viral replication in host cells, and this is the case for severe acute respiratory syndrome virus 2 (SARS-CoV-2), and human coronavirus 229 (HCoV- 229E). This was confirmed by the results of modeling docking of the ligand (quercetin and its derivatives) and the receptor (subsites of the viral protein). In vitro analyzes confirmed the prediction of docking modeling, the inhibitory activity of flavonols and dihydroflavonols on the main Mpro protease was revealed. It was found that, as in the case of SARS-CoV-2, replication of HCoV-229E also depends on Mpro activity in human cells, and the active site is conserved between HCoV229E and SARS-CoV-2. Accordingly, the obtained data may help to develop drugs for the treatment of both COVID- 19 and HCoV-229E diseases based on the antiviral activity of the investigated natural BARs. Published data show that 2,3-dihydro-2- (3,4-dihydroxyphenyI)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH showed significant inhibition of HCoV- 229E replication in Huh-7 ceils , which started at concentrations half that of quercetin. Therefore, 2,3- dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH may be useful for the treatment of COVID-19. This compound is a natural flavonoid whose bioavailability, metabolism, and toxicity have been thoroughly studied.

[0025] The prior art did not include studies on the purity and structure of the substance used. That is, it is possible to predict that a racemate or a non-enantiomerically pure mixture is used in the state of the art, the effect of such a substance on the body may differ from the effect of the biologically active isomer, so the side effects of the finished product are hardly predictable.

[0026] A racemate (also racemic mixture) describes a mixture of two (or more) bichemicals that are present in the same proportion to each other. They differ in their three-dimensional structure, which is the result of the corresponding arrangement of atoms.

[0027] If an atom has four bonds with four other different atoms or groups of atoms, that atom is said to be chiral. If a chemical compound has at least one chiral atom, the four binding partners can adopt two different configurations around the chiral atom.

[0028] This leads to the production of two substances, the so-called enantiomers, which are related to each other in their spatial structure, as an image and a mirror image, or like a glove on the left and right. Although they contain exactly the same atoms or groups of atoms, they cannot be brought into congruence and are therefore separated from each other, clearly distinguished. They are usually called (R) and (S) enantiomers.

[0029] Enantiomers often differ significantly in their physiological properties, which means that their differentiation or enantiomeric purity is of great importance in pharmacy. Each drug has a place of action in the human body, the so-called target, by which it is recognized by the body's own structures. These structures are mostly chiral and usually recognize only a certain enantiomer of a substance. Therefore, in the manufacture of drugs, it is extremely important that the product contains only the effective enantiomer. Otherwise, serious side effects can occur because the (often less effective) mirror- image enantiomer, for example, binds to a completely different place in the body and can cause an unwanted reaction.

[0030] It is also possible that the wrong enantiomer can be destroyed by an enzyme in the body before it even reaches its target. Or it binds to a transport protein and thus reaches an unwanted location in the body. The possibilities of interaction are extremely diverse, so side effects are hardly predictable if a racemate or a non-enantiomerically pure mixture is present in the product.

[0031] Enantiomers of a substance differ in their physical properties only in terms of their optical activity. A substance Is optically active when it changes a certain property of light when passing through it. This is one way of differentiating the corresponding enantiomers and is an important criterion when testing the purity of a potentially racemic mixture.

[0032] The 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH molecule contains two asymmetric carbon atoms - C-2 and C-3, therefore, exists In the form of 4 enantiomers (two pairs of stereoisomers).

[0033] 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH is a common natural compound of the flavonoid class isolated from larch. The molecule has two asymmetric carbon atoms (C2and C3 of the pyrone and pyran fragments of the molecules, respectively). Four enantiomers represent two pairs of diastereomers: trans-[(-)-2S,3S and (+)-2R,3R], cis-[(-)-2R,3S and (+)-2S,3R].

[0034] The main natural isomer used in this invention is the trans(+)-2R,3R-isomer of 2,3-dihydro-2-(3,4- dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran -4-OH. It is known that this natural isomer has the greatest biological activity.

[0035] The antioxidant activity of 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH depends on the purity of the product.

[0036] Industrial series of manufacturers of the substance 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy- 4H-l-benzopyran-4-OH, produced at present, differ in some physical and chemical parameters. The differences in the characteristics of 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l- benzopyran-4-OH can be explained by different technological conditions of their production: different process parameters (temperature, pressure, time, etc.), the use of different solvents for extraction, purification and crystallization also plays a significant role. Any parameter of the technological process, especially the use of an aqueous or anhydrous solvent, can affect the production of a product with a different quantitative composition of optical isomers. Accordingly, the produced substances have different levels of pharmacological effect and antioxidant activity.

[0037] The technology using ethyl acetate as an extractant allows you to protect the product from racemization and obtain at least 95% of the trans isomer (+- 2R,3R) 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7- trihydroxy- 4H-l-benzopyran-4-OH from the total amount isolated in the extraction process. This significantly increases the biological activity and pharmacological action of the produced substance 2,3- dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH.

[0038] Thus, the invention provides for the use of the most effective in terms of biological and pharmacological properties of the native form of bioflavonoid, containing more than 95% (+-2R,3R)-enantiomers of 2,3- dihydro-2-(3,4-dihydroxyphenyl)-3,5 ,7-trihydroxy-4H-l-benzopyran-4-OH.

[0039] The second active substance of the proposed medicinal product is a biomolecule, that is, a molecule present in organisms that is important for one or more typical life processes, such as cell division, morphogenesis, or development. Arginine is a conditionally indispensable amino acid. The physiological need of tissues and organs of most mammals for arginine is satisfied by its endogenous synthesis and / or intake with food, however, for young individuals and adults in conditions of stress or illness, this amino acid becomes essential. Arginine serves as a necessary precursor for the synthesis of proteins and many biologically important molecules, such as ornithine, proline, polyamines, creatine and agmatine. However, the main role of arginine in the human body is to be a substrate for the synthesis of nitric oxide.

[0040] Arginine ((S)-2-amino-5-guanidinopentanoic acid) is an amino acid that is known as D- and L-form, and the biologically active isomer is L-arginine, which is formed in a living organism in the process of natural biosynthesis. It is an active and versatile cellular regulator of numerous vital functions of the body, it exhibits important protective effects in the critical state of the body. Biological properties inherent in L- arginine, determine a wide range of its pharmacological properties and explain the high therapeutic efficiency of this amino acid in cardiology, pediatrics, obstetrics and other fields of medicine for diseases of various etiology and pathogenesis. Various international scientific studies have allowed to determine the mechanism and place of action of L-arginine as a means of pathogenetic therapy for diseases of the heart and blood vessels. Basically, in the world generally accepted indications for the use of drugs with L- arginine in cardiology are: myocardiopathies, chronic heart failure, arterial hypertension, including essential secondary and after heart transplantation, angina pectoris, hypercholesterolemia, atherosclerosis, coronary heart disease, intermittent claudication.

[0041] In recent decades, the interest in this amino acid as a component of medicines with different therapeutic effects has not decreased. L-Arginine is a precursor to nitric oxide, which is released from endotheliocytes and promotes vasodilation. L-Arginine has anti-hypoxic, membrane-stabilizing, anti-hypertensive, antioxidant and anti-radical activity, exhibits a hypocholesterolemic effect, plays a certain role in normalizing the functional state of the endothelium of coronary vessels. L-Arginine participates in the synthesis of proline, polyamine, agmatine, is involved in the processes of fibrinogenolysis, inhibits the adhesion of leukocytes, and has a membrane depolarizing effect. The ability of L-arginine to activate the processes of energy supply of the heart muscle, to restore Intermediate exchange and protein exchange in the myocardium, is another mechanism of its cardioprotective effect.

[0042] Thus, to achieve the claimed result, the present invention provides for the use of the L-isomerof 2-amino- 5-guanidinepentanoic acid (L-arglnlne).

[0043] Polyvinylpyrrolidone (PVP, povidone) is the most famous representative of water-soluble carbochain polymers with an amide group in the side substituent, which differ in the degree of polymerization and molecular weight. It is used as an auxiliary substance (carrier, stabilizer, extender, solubilizer, etc.) with antibiotics, enzymes, and other substances), and also as an active pharmaceutical ingredient - plasma substitute, detoxifier, antidote. Solutions of the low-molecular polymer periston-H (Germany) and Necompensan (Austria) are used as disinfectants. Low molecular weight PVP can also be used as an antidote for antibiotic overdose. It has an antiseptic, disinfectant, antifungal, antiprotozoal, antimicrobial effect (pharmacological group D08AG02, G01A Xll, R02A A15, D11A C06 - antiseptic drugs).

[0044] There is evidence that PVP solutions reduce the permeability of capillaries, have a protective effect in case of radiation damage, binding the products of protein decomposition formed during irradiation. PVP does not affect metabolism, hematopoiesis, blood coagulation, immunobiological processes in the blood.

[0045] PVP is compatible with such auxiliary substances as polyalcohols, simple and complex ethers, amides, glycerides, etc., as well as with polymers, oligomers, plasticizers. Easily forms soluble complexes with many APIs of inorganic and organic nature, as well as toxic substances, dyes, vegetable tannins, halogens and other compounds. Solutions and suspensions of many pharmaceutical substances become more stable when PVP is added. It is also used to prolong the effect of API. The degree of toxicity reduction depends on the molecular weight of the polymer: the lower it is, the higher its detoxification properties.

[0046] It is used in medicines for humans and in veterinary preparations for intravenous use (for detoxification), as well as in solutions, tablets, aerosols, ointments.

[0047] Hydroxyl groups of flavonoids differ in their ability to oxidize under the action of various oxidants. The catechyl group of ring B is most easily oxidized, forming semiquinone anion radicals, which are then transformed into ortho-quinones. One of the ways in which solutions of easily oxidizable substances are stabilized is the introduction of direct and indirect antioxidants.

[0048] To prevent the destruction of the trans isomer (+)-2R,3R 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7- trihydroxy-4H-l-benzopyran-4-OH and to protect the product from racemization, it is proposed to introduce antioxidants into the composition of the drug, which were chosen from a number of substances that interfere with oxidative processes, with different mechanisms of action. Sodium metabisulfite, ascorbic acid, sodium bisulfite, sodium edetate, etc. were studied, in several concentrations.

[0049] Selected excipients are widely used in the production of solutions for injections. They are described in most of the world's leading pharmacopoeias, as well as in the Federal Drug Administration, included in the "List of names of auxiliary substances included in the composition of medicinal products", approved by the Order of the Ministry of Health of Ukraine No. 339 dated 19.06.2007.

[0050] The technical result achieved by the implementation of the invention consists in creating a means for the treatment of diseases, for example, in the form of a concentrate for preparing an infusion solution with such a qualitative and quantitative composition of components that ensures an increase in the level and expansion of the spectrum of specific activity, reduces or eliminates negative side effects , as a result of which a complex effect on the human body is provided.

[0051] The claimed composition and ratio of components are determined experimentally and ensure mutual enhancement of their activity (synergism), therapeutic effectiveness of the medicinal product, stability during storage, compliance with the requirements of the current pharmacopoeia.

[0052] Quantitative content of substances in the claimed product is determined by the required level of their specific activity. If the number of substances is less than the declared values, this level is not sufficient. If the number of stabilizers is below the declared level, the stabilizing action is not provided.

[0053] Application of native form of bioflavonoid containing more than 95% (+-2R,3R)-enantiomers of 2,3- dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4 -OH and the L-isomer of 2-amino- 5-guanidinepentanoic acid, with polyvinylpyrrolidone above the declared values, does not lead to a significant increase in the level of specific activity, may cause negative side effects, which are characteristic of their overdose. Addition stabilizers in the amount above the declared level does not allow further increase of the shelf life.

[0054] It is advisable to perform the composition with different forms of release, which provide the possibility of both parenteral administration of the composition, for example, in the form of an injection, infusion (drop) or other pharmaceutically acceptable form, and oral administration, for example, in the form of a syrup, pill, powder or other pharmaceutical form, as a result of which it is possible to use the composition to provide urgent help in various situations.

[0055] The advantage of the claimed drug is its development for parenteral use, as a result of which it is possible to use the drug for emergency care.

[0056] The advantage of the claimed means is the achievement of greater stability during storage, which Is expressed in the extension of the storage period up to 3 years. The invention is illustrated by the following examples of specific preparation of a medicinal product in the form of a concentrate for the preparation of an infusion solution.

[0057] The technological process of obtaining the claimed medicinal product can be carried out on typical equipment for the production of injection solutions in ampoules, which is equipped with the majority of enterprises in the pharmaceutical industry.

[0058] Example 1

[0059] The solution according to this example has the following ratio of components, wt. %: native form of bioflavonoid containing more than 95% (+-2R,3R)-enantlomers of 2,3-dihydro-2-(3,4- dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4- OH 0.75

[0060] L-isomer of 2-amino-5-guanidinepentanoic acid 0.5 polyvinylpyrrolidone 8000 6.0 sodium metabisulfite 0.1 ascorbic acid 0.05 sodium sulfite 0.05 disodium edetate 0.05 the rest is water.

[0061] Water for injections is loaded into the reactor at a temperature of (50±5) oC. Next, the native form of bioflavonoid containing more than 95% (+-2R,3R)-enantiomers of 2,3-dihydro-2-(3,4-dihydroxyphenyl)- 3,5,7-trihydroxy- 4H-l-benzopyran-4-OH and the L-isomer of 2-amino-5-guanidinepentanoic acid, add polyvinylpyrrolidone 8000 and antioxidants. Stir for 15-20 minutes, until complete dissolution, cool to 20 °C, adjust the volume of the solution with water for injections to the required level, stir for 10 minutes. Filter through membrane filters with a pore size of 0.8-0.2 pm, fill sterile ampoules made of dark glass of 5 ml with the resulting solution, and seal. Preparation of the solution, filling and sealing of ampoules are carried out in an inert gas atmosphere. Ampoules sterilized with the solution at a temperature of 100 °C for 30 min.

[0062] Example 2

[0063] The solution according to this example has the following ratio of components, wt. %: native form of bioflavonoid containing more than 95% (+-2R,3R)-enantiomers of 2,3-dihydro-2- (3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4- OH 1.12 L-isomer of 2-amino-5-guanldinepentanoic acid 1.17 polyvinylpyrrolidone 80007.5 cysteine 0.4 sodium sulfite 0.2 disodium edetate 0.07 the rest is water

[0064] Water for Injections at a temperature of (80±5) oC is loaded into the reactor. Next, the native form of bioflavonoid containing more than 95% (+-2R,3R)-enantiomers of 2,3-dihydro-2-(3,4-dihydroxyphenyl)- 3,5,7-trihydroxy- 4H-l-benzopyran-4-OH and L-isomer of 2-amino-5-guanidinepentanoic acid, add polyvinylpyrrolidone 8000 and auxiliary substances. Stir for 15-20 minutes, until complete dissolution, cool to 20 °C, adjust the volume of the solution with water for injections to the required level, stir for 10 minutes. Filter through membrane filters with a pore size of 0.8-0.2 microns, fill 5 ml sterile ampoules of dark glass with the resulting solution, seal. Preparation of the solution, filling and sealing of the ampoules are carried out in compliance with all the rules and requirements of asepsis, using materials and methods that ensure sterility, prevent contamination of medicinal products and the development of microorganisms in them.

[0065] Example 3 The solution according to this example has the following ratio of components, wt. %: native form of bioflavonoid containing more than 95% (+-2R,3R)-enantiomers of 2,3-dihydro-2-(3,4- dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4- OH 1.5

[0066] L-isomer of 2-amino-5-guanidinepentanoic acid 1,2 polyvinylpyrrolidone 80009.0 sodium metabisulfite 0.3 ascorbic acid 0.2 sodium bisulfite 0.2 the rest is water

[0067] Water for injections is loaded into the reactor at a temperature of (95+5) oC. Next, the native form of bioflavonoid containing more than 95% (+-2R,3R)-enantiomers of 2,3-dihydro-2-(3,4-dihydroxyphenyl)- 3,5,7-trihydroxy- 4H-l-benzopyran-4-OH and L-isomer of 2-amino-5-guanidinepentanoic acid, add polyvinylpyrrolidone 8000 and auxiliary substances. Stir for 15-20 minutes, until completely dissolved, cool to 20 °C, adjust the volume of the solution with water for injections to the required level, stir for 10 min. Filter through membrane filters with a pore size of 0.8-0.2 pm, fill sterile ampoules made of dark glass Of 5 ml with the resulting solution, and seal. Preparation of the solution, filling and sealing of ampoules are carried out with gas protection. Ampoules with a solution are subjected to sterilizing filtration. Preparation of the solution, filtration, filling and sealing of ampoules are carried out under aseptic conditions in an atmosphere of inert gas.

[0068] Example 4

[0069] The samples obtained according to the above-mentioned examples 1-3 were stored in a place protected from light at a temperature not higher than 252C. Samples were monitored according to the indicators of the MKY project for 3 years.

[0070] For comparison, samples were prepared according to examples 1-3, but without the addition of antioxidants sodium metabisulfite, ascorbic acid and / or sodium sulfite. The samples were stored under the specified conditions and monitored according to the same indicators.

[0071] Observation of samples without antioxidants was stopped after 0.5 years, because the color of the solution in the ampoules changed and sediment formed.

[0072] The table shows the results of studies of the most important indicators of sample quality during storage (3 years).

[0073] Table

[0074] Quality indicators of series obtained according to examples 1-3

[0075] The obtained samples of the drug meet the pharmacopoeia! requirements and the requirements of the Ministry of Health at the time of release and during storage (3 years). The qualitative and quantitative composition of the components, the technological parameters of obtaining the drug, which were observed during preparation, are exactly within the limits of the declared values.

[0076] On the basis of the above, it can be concluded that for the claimed remedy, by selecting the qualitative and quantitative composition of active and auxiliary substances, technological techniques, regimes and parameters of the technological process, the author was able not only to increase the level of bioavailability of a poorly soluble biologically active medicinal substance by the account of obtaining its soluble form, but also to achieve the required level of quality and stability of the injection solution.

[0077] Use of the claimed product based on natural substances - native form of bioflavonoid, containing more than 95% (+-2R,3R)-enantiomers of 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l- benzopyran-4-OH and the L-isomer of 2-amino-5-guanidinepentanoic acid in solutions for intravenous administration allows, as a result of converting the sparingly soluble flavonoid compound into a soluble state, to increase its bioavailability due to low toxicity and neutrality medium of aqueous solution, significantly reduce the severity of possible adverse reactions, and as a result of the addition of stabilizers- antioxidants cysteine, sodium sulfite, sodium metabisulfite, ascorbic acid, sodium bisulfite and disodium edetate or their combination to the composition of the drug, it allows to achieve the required level of quality and stability.

[0078] The composition of the claimed medicinal product, in the form of a concentrate for the preparation of an infusion solution, is theoretically and experimentally selected so that this concentrate is a solution and contains as active pharmaceutical Ingredients - bioflavonoid in its native form, containing more than 95% (+-2R,3R)- enantiomers of 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH and the L-isomer of 2-amino-5-guanidinepentanoic acid, as well as auxiliary substances: solubilizer polyvinylpyrrolidone 8000, stabilizers: sodium metabisulfite or ascorbic acid, or disodium edetate, or cysteine, or sodium sulfite, or their combination - in balanced quantities. The composition and technology of obtaining the product ensures stability, increased shelf life, a wide range and a high level of pharmacological effectiveness, primarily cardiotropic, as well as antihypoxic, immunomodulating, gastroprotective, etc., which fully confirms the fulfillment of the task set in the invention.

Claims

CLAIMSA medical drug in the form of a concentrate for the preparation of an infusion solution, containing as active substances a bioflavonoid and an amino acid, auxiliary substances-stabilizers, auxiliary substances- solubilizers and water for injections, which differs in that, as a bioflavonoid, it contains a native form of a flavonoid containing more 95% (+-2R,3R)-enantiomers of 2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7- trihydroxy-4H-l-benzopyran-4-OH, as an amino acid it contains the L-isomer of 2-amino-5- guanidinepentanoic acid, and as auxiliary solubilizers it contains polyvinylpyrrolidone with a molecular weight of 8000 (PVP), as auxiliary stabilizers it contains cysteine, sodium metabisulfite, ascorbic acid, sodium sulfite, sodium bisulfite, dlsodium edetate or their combinations, with the following ratio of components, wt. %: native form of flavonoid containing more than 95% (+-2R,3R)-enantiomers2,3-dihydro-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-OH 0.75-1.55L-isomer of 2-amino-5-guanidinepentanoic acid 0.5-1.22 polyvinylpyrrolidone 8000 6.0-9.0 and / or cysteine 0.08-0.2 and / or sodium sulfite 0.2-0.4 and / or sodium metabisulfite 0.1-0.5 and / or ascorbic acid 0.05-0.2 and / or disodium edetate 0.05-1.0 and / or sodium bisulfite 0.1-0.5 the rest is water.

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