EA021368B1 - Preparation of cardioprotective action - Google Patents

Abstract

A preparation of cardioprotective action contains 5 mg of nikorandil and 15 mg of trimetazidine as active ingredients, the preparation is produced by mechanical mixing them in fine-grained powders with the addition of auxiliary components. Preferably, the preparation is manufactured in the form of a tablet. In particular cases tablets are manufactured using a method of wet granulation or a method of direct pressing of plane-cylinder or biconvex shape, coated with films. The tablets manufactured by wet granulation method comprise auxiliary components: potato starch, microcrystalline cellulose and calcium stearate added by mechanical mixing them in fine-grained powders, with further tabletting with any component ratio in mg, given below:

Description

The drug treatment of patients with coronary heart disease (CHD) and hypertension (GB) is one of the most pressing problems of modern cardiology. With significant progress in surgical treatment methods (especially x-ray vascular), the problems of pharmacotherapy of coronary heart disease do not lose their relevance.

In the modern arsenal of cardiologists, there are three groups of basic antianginal drugs (nitro drugs, b-adrenergic blockers, calcium antagonists), which objectively affect the quality of life of patients with coronary artery disease. However, the effect on the life expectancy of only some b-adrenergic receptor blockers has been proven, and there are a number of contraindications to its use.

Organic nitrates are usually prescribed to relieve and prevent angina attacks. The most important means of stopping an attack of angina pectoris are short-acting nitrates (nitroglycerin and isosorbide dinitrate), and the quick action and recognized effectiveness of nitroglycerin make it possible to consider it the main tool for stopping angina attacks. However, the use of nitrates is not always convenient due to the development of tolerance to them and side effects that impede their use. In addition, organic nitrates and, especially, nitroglycerin should not be prescribed to patients with intolerance (or contraindications) to taking these drugs. It is also unknown whether nitrates improve prognosis in patients with stable angina pectoris with prolonged use.

Currently, the world continues to improve the already known groups of antianginal drugs and the search for new ways of pharmacological effects on the clinical course of IHD.

The directions of the search are based on the fact that myocardial viability in conditions of ischemia is provided by adaptation to hypoxia, which is mainly due to the phenomena of myocardial preconditioning and hibernation.

Preconditioning is a metabolic adaptation of the myocardium against the background of short repeated attacks of ischemia, with an increase in the resistance of the heart to longer attacks. The leading role in the development of the protective effect of ischemic preconditioning is played by mitochondrial ATP-dependent K + channels. It is known that the pharmacological discovery of ATP-dependent K + channels fully reproduces the protective effects of ischemic preconditioning.

Myocardial hibernation is a functional adaptation (inhibition of the contractile state) of a cardiomyocyte in response to a decrease in intracellular energy balance, in which there is a rapidly occurring violation of local contractility of the left ventricle in response to a moderate decrease in coronary blood flow. A hibernating myocardium is characterized by a chronic decrease in the contractility of cardiomyocytes while maintaining their viability. From the point of view of pathophysiological processes of adaptation to stressful situations, the myocardial hibernating mechanism of self-regulation, adapting the functional activity of the myocardium to the conditions of ischemia, i.e. a kind of protective reaction of a suffering heart to an inadequate decrease in coronary blood flow to the level of oxygen demand of the myocardium.

In recent years, considerable interest has been the study of the effectiveness of drugs of a new, quite promising group of potassium channel modulators (activators), the most famous representative of which is nicorandil.

Information is known about the cardiological activity of the drug nicorandil (KI No. 2102380).

Nicorandil is an antianginal drug that has the properties of a venodilator and arteriolodilator. The double mechanism of the antispasmodic effect is due to the presence of a nitrate group and a nicotinic acid amide residue in its molecule, as a result of which the properties of organic nitrates and potassium channel activators are combined. By opening ATP-dependent potassium channels, nicorandil causes hyperpolarization of the cell membranes of the smooth muscles of arteries and arterioles, which leads to their relaxation. The nitrate-like effect is manifested by the relaxation of smooth muscles, mainly veins. By opening ATP-dependent potassium channels, nicorandil fully reproduces the protective effect of ischemic preconditioning, prepares the heart for ischemia: it contributes to the energy conservation of the heart muscle and prevents irreversible cellular changes in it. Nicorandil has been proven to be a highly effective antianginal and cardioprotective drug, which significantly reduces the risk of death from cardiovascular causes, as well as myocardial infarction (1track! 1430; Noppaka 8., WaЬe Α., Washch N. e! A1. Ekspy otί tsotapy op sagyuuazsyag euepy ίη П Ш Ш \ \ ί 1 1 1 1 1 ((((((((((2010) : 503-509).

Due to systemic and coronary vasodilation, it balancedly reduces pre- and afterload on the heart (unlike calcium nitrates and antagonists, which act mainly on pre- or afterload, respectively). The drug has a cardioprotective effect, and is also recommended as a tool for the treatment of stable angina pectoris. Nicorandil also has a beneficial positive effect on cerebral circulation in patients with ischemic stroke.

To obtain the antianginal effect during monotherapy with nocorandil, the minimum dose is 1 021368 - 20 mg / day - 10 mg of nicorandil 2 times after 12 hours, if necessary, the dose is increased to 40 mg / day - 20 mg of nicorandil 2 times a day.

It is known (KI No. 2147301) that nicorandil is currently regarded as the most effective treatment for angina pectoris | K.8ak; p. At 1. SagFo1odu, 1989, 63, 2 _) - 10_)].

A study of the acute toxicity of nicorandil with the introduction of reg 08 in animals showed that the drug belongs to the group of moderately toxic substances. LI ₅₀ for it is 475 mg / kg [K.8aka1, At. 1. SagFo1odu, 1989, 63, 2 _) - 10_)].

Known medicines containing nicorandil and auxiliary components that stop angina attacks and reduce the need for nitrates (EA No. 200700191, 8I No. 1194278, 1277894).

The closest technical solution (prototype) can be considered KI No. 2147301.

A disadvantage of the known technical solutions is that with monotherapy, the administration of nicorandil in doses used in Europe and Russia (20-60 mg per day) is usually accompanied by side effects.

Side effects from the central nervous system: headache, dizziness, tinnitus, often limit the patients' desire to take such a drug and cause refusal to take nicorandil.

In this regard, it is relevant to create a combined drug with a low content of nicorandil, while maintaining therapeutic efficacy and reducing side effects inherent in nicorandil.

To study the effectiveness of nicorandil in combination with other drugs, 32 patients underwent combination therapy. Nicorandil was prescribed in daily doses of 20-40 mg against the background of continuous administration of atenolol (50 mg 2 times a day) or verapamil (retard form) - 240 mg per day. According to acute paired pharmacodynamic tests, the studied compositions had a beneficial effect on exercise tolerance: an increase in TFN was noted when it was additionally prescribed for therapy with atenolol or verapamil in patients with stable exertional angina or concomitant arterial hypertension. There were various side effects characteristic of taking nicorandil in daily doses of 20-40 mg. However, reducing the dose of nicorandil below 20 mg per day with both atenolol or verapamil, and as monotherapy significantly reduced the effectiveness of the treatment. Thus, the composition of nicorandil in combination with atenolol or verapamil does not create any new effect when used, compared with monotherapy with nicorandil.

A study of the effectiveness of the composition of nicorandil in combination with trimetazidine was also conducted.

Trimetazidine dihydrochloride is used for the prevention of angina pectoris, for the treatment of ischemia, dizziness of vascular origin (KI No. 2367438, 2377989).

Trimetazidine (chemical name 1 - [(2,3,4-trimethoxyphenyl) methyl] piperazine (in the form of dihydrochloride)) has an antianginal, antihypoxic effect. Directly affecting cardiomyocytes and brain neurons, it optimizes their metabolism and function. The cytoprotective effect is due to increased energy potential, activation of oxidative decarboxylation and rationalization of oxygen consumption (increased aerobic glycolysis and blockade of fatty acid oxidation). It supports myocardial contractility, prevents a decrease in the intracellular content of ATP and phosphocreatinin. Under conditions of acidosis, it normalizes the functioning of ion channels, prevents the accumulation of calcium and sodium in cardiomyocytes, and normalizes the intracellular content of potassium ions. Reduces intracellular acidosis and phosphate concentrations due to myocardial ischemia and reperfusion. It prevents the activation of neutrophils in the ischemic zone, increases the duration of the electric potential, reduces the output of CPK from cells and the severity of ischemic damage to the myocardium, and helps to remove the myocardium from the hibernation state.

An object of the invention is the creation of an effective cardioprotective drug with minimal side effects and the expansion of the arsenal of cardioprotective drugs.

The technical result, which provides a solution to the problem, consists in improving the course of angina pectoris, protecting against complications from heart attack, worsening the course of angina pectoris, improving the prognosis of coronary heart disease, and also significantly improving cerebral circulation in patients with cerebral arteriosclerosis and dyscirculatory encephalopathy, with simultaneous reduction the severity of side effects, in particular dizziness and nausea, and an improvement in cognitive functions. In addition, the cost of the drug and the course of treatment as a whole is reduced.

The essence of the invention lies in the fact that the cardioprotective preparation contains nicodendil 5 mg and trimetazidine 15 mg as active substances, obtained by mechanical mixing in the form of fine crystalline powders, with the addition of auxiliary components.

Preferably, the preparation is in tablet form.

In particular cases of implementation, tablets are prepared by wet granulation or by direct compression, plane-cylindrical or biconvex, coated with a film coating.

The preparation in the form of tablets prepared by wet granulation contains auxiliary components: potato starch, microcrystalline cellulose and calcium stearate, added by mechanical mixing in the form of fine crystalline powders, followed by dosage form, at any of the components below, in mg

Name components Quantity per 1 tablet, g Quantity per 1 tablet, g Quantity per 1 tablet, g Nicorandil 0.005 0.010 0,020 Trimetazidine dihydrochloride 0.015 0,020 0,025 Starch potato 0.005 0.010 0.015 Cellulose m and croc 0,074 0.158 0.237 Calcium stearate 0.001 0.002 0.003 Total for 1 tablet; 0,100 0,200 0,300

The drug in the form of tablets prepared by direct compression, contains auxiliary components from the group: hypromellose; ludipress; microcrystalline cellulose; colloidal silicon dioxide (aerosil); magnesium stearate; calcium stearate.

The studies revealed and confirmed the great potential in the combined use of nicorandil and trimetazidine, due to the combination of the properties of these drugs, since the cardioprotective (protective against the heart muscle) effect is enhanced by correcting most adaptive maladaptive changes in the metabolism and contractile state of cardiomyocytes with the so-called new ischemic syndromes, as nicorandil, opening the ATP-dependent potassium channels, fully reproduces the protective effect of ischemic preconditioning and thereby prepares the heart for ischemia: it contributes to the energy conservation of the heart muscle, prevents the irreversible cellular changes occurring in it, and trimetazidine reduces intracellular acidosis and phosphate concentration due to myocardial ischemia and reperfusion, increasing the duration of the electric potential, reducing the output of CPK from the cells and the severity of ischemic damage to the myocardium , Displays the myocardium from hibernation state. At the same time, a new unexpected effect is that the decrease in intracellular acidosis and phosphate concentration realized by trimetazidine promotes a significantly more active opening of ATP-dependent potassium channels using nicorandil, while the opening of ATP-dependent potassium channels contributes to a significantly more active decrease in the output of CPK from cells and reduce the severity of ischemic myocardial damage with the help of trimetazidine.

As a result, the beneficial effect of nicorandil on cerebral circulation is potentiated, as well as the cytoprotective effect and antihypoxic effect of trimetazidine against brain neurons with optimization of their metabolism and functions: increasing the energy potential of neurons, rationalizing their oxygen consumption (enhancing aerobic glycolysis).

Thus, the inventive preparation, which is a composition consisting of two known drugs, provides a synergistic effect previously unknown from the prior art - the mutual influence of drugs, providing an increase in the specific protective effect of ischemic preconditioning with the same dose of nicorandil or, equivalently, providing the same protective effect of ischemic preconditioning with a reduced dose of nicorandil, at the same time, the specific effect is significantly enhanced the effect of trimetazidine in relation to the protection of the myocardium from ischemic damage and its removal from the state of hibernation, which allows to provide the same protective effect of trimetazidine with a reduced single dose on admission. The mutual antihypoxic effect of drugs against brain neurons is also potentiated, as a result of which the use of a drug containing a combination of nicorandil and trimetazidine at doses lower than the therapeutic ones significantly reduces the manifestations of discirculatory encephalopathy and improves brain functioning in conditions of chronic hypoxia in patients with cerebral arterial sclerosis. .

This ensures the effective implementation of the cardioprotective effect due to the correction of most adaptive maladaptive metabolic changes, the contractile state of cardiomyocytes and a more pronounced antihypoxic effect against brain neurons in patients with cerebral artery atherosclerosis with improved central nervous system functioning in conditions of chronic hypoxia without significant side effects. At the same time, the cost of medical treatment of patients with atherosclerosis and related pathology, which has high social significance for the health care system, is reduced.

The side effect of trimetazidine is rarely recorded and is reduced to an individual reaction of increased sensitivity to the drug. Trimetazidine, as a rule, is prescribed for coronary heart disease for the prevention of angina attacks (in combination therapy) orally, with food, 20 mg 2-3 times a day (40-60 mg / day).

For the production of a combined drug, it is possible to use a wide range of modern auxiliary substances for the formation of pharmaceutical compositions, including for the production of tablets by both direct compression and wet granulation.

It is possible to use the entire spectrum of modern excipients for the formation of pharmaceutical compositions.

In any of these cases, tablets can be made both flat-cylindrical and biconvex with a film coating using Orabgu II, consisting of polyvinyl alcohol, macrogol (polyethylene glycol), talc, titanium dioxide, red dye (crimson Ponceau 4K and sunset yellow, in the form of aluminum varnish).

Examples of the composition of the tablets of the claimed drug in the production by wet granulation (industrial production) are shown in the table.

Name components Quantity per 1 tablet, g Quantity per 1 tablet, g Quantity per 1 tablet, g Nicorandil 0.005 0.010 0,020 Trimetazidine Dihydrochloride 0.015 0,020 0,025 Starch potato 0.005 0.010 0.015 Cellulose microcrystalline 0,074 0.158 0.237 Calcium stearate 0.001 0.002 0.003 Total for 1 tablet: 0,100 0,200 0,300

It is possible to divide the tablets indicated in this table into parts to obtain the desired amount of active substances per reception.

The substances nicorandil and trimetazidine dihydrochloride are crystalline powders with large cylindrical crystals.

A brief description of the manufacturing process of the combined preparation based on nicorandil and trimetazidine dihydrochloride by wet granulation.

The calculation of the components is given for 1.0 / 2.0 / 3.0 kg of granulate, respectively, for each of the prescriptions (10 thousand tablets of each dosage).

The substances nicorandil and trimetazidine dihydrochloride are crystalline powders with large cylindrical crystals.

To ensure uniformity of dosage, substances are crushed, then they are sieved through a No. 23 sieve. Microcrystalline cellulose and calcium stearate are sieved through a No. 23 sieve, and potato starch is sieved through a No. 46 sieve.

Pre-prepare a humidifier solution - 1.0% starch paste in an amount of 0.5 / 1.0 / 1.5 kg, respectively, for each of the prescriptions. To do this, potato starch in an amount of 0.005 / 0.01 / 0.015 kg, respectively, for each of the prescriptions is loaded into the container, pour it with a small amount of cold purified water and mix thoroughly until a homogeneous suspension is formed. The resulting suspension with constant stirring is poured into a container containing hot purified water with a temperature of 60-70 ° C. The resulting solution was thoroughly mixed and cooled to room temperature, and then filtered.

The total amount of purified water required to prepare the humidifier solution is 0.495 / 0.99 / 1.485 kg, respectively, for each of the prescriptions.

In the granulator dryer, the calculated amounts of the sifted components of nicorandil are loaded (0.05 / 0.1 / 0.2 kg, respectively, for each of the prescriptions); trimetazidine dihydrochloride (0.15 / 0.2 / 0.25 kg, respectively, for each of the prescriptions); microcrystalline cellulose (0.74 / 1.58 / 2.37 kg, respectively, for each of the prescriptions); potato starch (0.03 / 0.06 / 0.09 kg, respectively, for each of the prescriptions).

After that, the components are mixed in a granulator dryer for 5-10 minutes.

At the end of mixing, they begin to moisten the mixture of components with a humidifier solution.

Granulation is carried out at an inlet air temperature of 45 ± 5 ° C. After complete consumption of the humidifier solution, the resulting granulate is dried at an inlet air temperature of 45 ± 5 ° C to a residual moisture content of 1.0-2.0%.

At the end of drying, granulate is dusted; for this purpose, the calculated quantities of sifted dusting components are loaded into the product capacity of the dryer-granulator

- 4 021368 potato starch (0.015 / 0.03 / 0.045 kg, respectively, for each of the prescriptions); calcium stearate (0.01 / 0.02 / 0.03 kg, respectively, for each of the prescriptions).

Dusting is carried out in a fluidized bed in a granulator dryer for 1-2 minutes, after which the granulate is analyzed according to the indicators of Authenticity and Quantification (nicorandil and trimetazidine dihydrochloride).

The resulting granulate is passed to the tabletting step.

Tableting is carried out on a rotary press to obtain tablets with a dosage of 5 mg + 15 mg using punches with a diameter of 6 mm; to obtain tablets with a dosage of 10 mg + 20 mg, punches with a diameter of 8 mm are used; to obtain tablets with a dosage of 20 mg + 25 mg, punches with a diameter of 9 mm are used.

In the production of tablets by direct pressing, combinations of excipients are used as fillers: hypromellose (metocel K 4M Rtetst EP) or ludipress (lactose monohydrate, povidone, crospovidone), microcrystalline cellulose; colloidal silicon dioxide (aerosil); magnesium stearate or calcium stearate.

In the case of the production of tablets by direct compression, the crushed substances in calculated amounts are mixed with sifted excipients (fillers) and transferred to the tabletting stage. The diameter and average weight of the tablets in this case correspond to the ratios of substances (nicorandil and trimetazidine dihydrochloride) shown in the table, the compositions differ only in part of the proportions of excipients.

To test the cardioprotective effect (improving the course of angina pectoris, protecting against complications from heart attack, from worsening the course of angina pectoris) and the antihypoxic effect of the drug, including nicorandil and trimetazidine in several characteristic mass ratios, clinical trials were conducted.

The tests involved 140 patients from 28 to 76 years old, men and women with a diagnosis of Atherosclerosis. Atherosclerosis of coronary arteries, ischemic heart disease with stable angina pectoris ΙΙΙ-ΐν functional class. Atherosclerosis of precerebral and cerebral arteries, dyscirculatory encephalopathy.

Tests were conducted with the following options for the composition of the drug (tablets):

group (control): nicorandil with a dosage regimen of 10 mg 3 times a day;

group: nicorandil with a dosage regimen of 10 mg 2 times a day + trimetazidine with a dosage regimen of 20 mg 2 times a day;

group: nicorandil with a dosage regimen of 5 mg 3 times a day + trimetazidine with a dosage regimen of 15 mg 3 times a day;

group: nicorandil with a dosage regimen of 20 mg 2 times a day + trimetazidine with a dosage regimen of 25 mg 2 times a day.

If necessary, the tablets were divided according to the table into parts to obtain the right amount at the reception.

Patients who participated in the trials were divided into 4 groups of 70 people.

Tests were carried out for 90 days. Initially, after 30 days and at the end of the study (after 90 days), Holter monitoring was performed to assess the number and duration of angina attacks during the day; transcranial dopplerography for the study of cerebral hemodynamics; the severity of dizziness and the degree of cognitive impairment were assessed according to the results of relevant tests, quality of life questionnaires were filled out in cardiological and neurological patients.

Periodically, ECG was recorded, control of ALT, AST, alkaline phosphatase. In the last 20 days of the course, physical activity increased with caution - classes in therapeutic gymnastics were conducted.

The test results are as follows.

During the trial period, patients included in the study use a drug made in accordance with their group. An attack of angina that occurs against the background of course application was stopped by an additional intake of nitroglycerin.

At the initial stage of observation of patients in the control group, angina attacks were observed in all patients in an amount from 2 to 8 attacks per day, on average (4.0 ± 0.32), were typical, lasting from 3 to 15 minutes. For their relief, patients used nitroglycerin tablets from 4 to 8 tablets.

A month later, according to Holter monitoring during the day, the number of anginal attacks in patients of the control group during therapy decreased by 48-53%, for the entire period - by 73%. According to Holter monitoring, the intensity and duration of angina attacks decreased during the day; in most patients, their duration did not exceed 5-8 minutes. According to transcranial Doppler ultrasound, blood flow in the midbrain, anterior cerebral and posterior cerebral arteries increased by 13-17% after a month, by 18-23% after three months, the severity of dizziness decreased, and cognitive functions improved slightly (Cognitive functions (lat. cognition) - higher brain functions: memory, attention, psychomotor coordination, speech, gnosis, praxis, counting, thinking, orientation, planning, etc.).

- 5 021368

At the initial stage of observation, patients of groups 2, 3, and 4 had angina attacks from 2 to 10 attacks per day, the attacks were typical and lasted from 5 to 15 minutes. For their relief, patients used nitroglycerin tablets. Also, in these patients there was a significant decrease in blood flow velocity in the midbrain, anterior cerebral and posterior cerebral arteries.

After two months, the number of anginal attacks in the 2nd and 3rd groups decreased by 50-58%, after three months the number of anginal attacks decreased by another 30-31%, i.e. up to 80-89%; in the 4th group, after two months, the number of anginal attacks decreased by 58-60%, and after three months another 31-32%, i.e. up to 92%. The intensity and duration of angina attacks decreased. In most patients, their duration did not exceed 3-7 minutes. The need for nitoglycerin decreased. In all patients, to stop an attack of angina, one tablet of nitroglycerin under the tongue was enough. The number and duration of angina attacks during the day decreased, confirmed by the results of Holter monitoring.

After two months in the 2nd and 3rd groups, the blood flow velocity in the midbrain, anterior cerebral and posterior cerebral arteries increased by 10-15%, after three months another 4-5%, i.e. up to 14-20%, the severity of dizziness decreased markedly, cognitive functions improved; in the 4th group, after two months, the blood flow velocity in the midbrain, anterior cerebral and posterior cerebral arteries increased by 15-20%, after three months another 5-6%, i.e. up to 20-26%. Dizziness decreased more pronounced, cognitive functions significantly improved.

A decrease in the number of additional tablets of nitroglycerin for the relief of angina attacks during the course of 3 months indicates the absence of tolerance to the drug nicorandil with trimetazidine with prolonged course use.

In groups 1-3, approximately the same cardioprotective effect was confirmed - a decrease in the number and duration of angina attacks according to Holter monitoring, at the same time, in the 4th group, the cardioprotective effect was more pronounced, but at the same time there was the greatest number of side effects mainly from the side CNS in the form of a headache (during the trial there were 9 refusals from further treatment); in group 1, the number of side effects in the form of a headache was less than in the 4th, but more (during the trial there were 7 refusals from further treatment) than in the 2nd; no adverse events were noted in the 3rd group.

Also in groups 1-3, approximately the same increase in blood flow velocity was confirmed in the midbrain, anterior cerebral and posterior cerebral arteries, and a decrease in the severity of dizziness. Moreover, in 2-3 groups, when performing tests, a more significant improvement in cognitive functions was noted. In the 4th group, the blood flow velocity in the cerebral arteries increased slightly more, the severity of dizziness decreased significantly without a significant improvement in cognitive functions compared with groups 2-3, but the largest number of side effects from the central nervous system in the form of headache was noted.

When using the claimed remedy, patients of the 3rd group did not experience side effects characteristic of known agents for the prevention of angina attacks, both containing and not containing nicorandil - headache, dizziness, excessive fatigue, nausea, flushing of the face, chills. At the same time, not only the need for nitroglycerin was reduced, but the number and duration of angina attacks during the day was also significantly reduced, which was confirmed by the results of cholera monitoring. Also, in patients of the 3rd group, the blood flow velocity in the midbrain, anterior and posterior cerebral arteries significantly increased, the severity of dizziness was clinically significantly reduced, and cognitive functions improved.

Thus, a preparation containing a combination of nicorandil 5 mg + trimetazidine 15 mg with a dosing regimen 3 times a day fully provides a solution to the problem of combining them in this combination - primarily cardioprotective action (improving the course of angina pectoris, protecting against complications - from heart attack, from worsening angina pectoris), which improves the prognosis of coronary heart disease, and also significantly improves cerebral blood circulation in patients with atherosclerosis of the cerebral arteries and dyscirculatory encephalopathy with a decrease in the severity of the head cognition and improvement of cognitive functions.

Deviations of the contents of the active ingredients from the nominal values are possible within the accuracy of the measurements. The combined use of these drugs has great potential, because Effective implementation of the cardioprotective effect is ensured due to the correction of most adaptively maladaptive changes in the metabolism and contractile state of cardiomyocytes, as well as the antihypoxic effect of the drug. Moreover, the drug has both a protective effect of the type of ischemic preconditioning and protects the heart from hibernation. Such a beneficial effect from the use of the composition allows to minimize the dose of nicorandil and trimetazidine and to avoid adverse side effects from them. At the same time, a reduction in consumption (saving) of nicorandil, which is on average 3 times more expensive than trimetazidine, as well as trimetazidine, is ensured.

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As a result, an effective cardioprotective drug with minimal side effects was created and the arsenal of cardioprotective drugs was expanded.

Claims (8)

CLAIM 1. A cardioprotective drug containing nicorandil 5 mg and trimetazidine 15 mg as active ingredients in the form of a mechanical mixture of fine crystalline powders with the addition of auxiliary components. 2. The drug according to claim 1, characterized in that it is made in the form of tablets. 3. The drug according to claim 2, characterized in that the tablets are prepared by wet granulation. 4. The drug according to claim 2, characterized in that the tablets are prepared by direct compression. 5. The drug according to any one of claims 2 to 4, characterized in that the tablets are made flat-cylindrical or biconvex 6. The drug according to any one of claims 2 to 4, characterized in that the tablets are coated with a film coating. 7. The drug according to claim 3, characterized in that it contains auxiliary components: potato starch, microcrystalline cellulose and calcium stearate, added by mechanical mixing in the form of fine crystalline powders, followed by dosage form, with any of the components below, in mg Name components Quantity per 1 tablet, g Quantity per 1 tablet, g Quantity per 1 tablet, g Nicorandil 0.005 0.010 0,020 Trimetazidine dihydrochloride 0.015 0,020 0,025 Starch potato 0.005 0.010 0.015 Cellulose microcrystalline 0,074 0.158 0.237 Calcium stearate 0.001 0.002 0.003 Total for 1 tablet: 0,100 0,200 0,300 8. The drug according to claim 4, characterized in that it contains auxiliary components from the group: hypromellose; ludipress; microcrystalline cellulose; colloidal silicon dioxide (aerosil); magnesium stearate; calcium stearate.