EA003470B1 - Pharmaceutical combination of mildronate and enalapril - Google Patents

Abstract

1. Pharmaceutical composition, containing 3-(2,2,2-trimethylhydrazinium)propionate and angiotensin converting enzyme (ACE) inhibitor. 2. Pharmaceutical composition, according to Claim 1, where said ACE inhibitor is (S)-1-{N-1-(ethoxycarbonyl)-3-phenylpropyl-L-alanyl}-L proline or Enalapril. 3. Pharmaceutical composition, according to Claim 2, where the proportion of said active substances 3-(2,2,2-trimethyldrazinium) propionate dihydrate and (S)-1-{N-1-(ethoxycarbonyl)-3-phenylpropyl-L-alanyl}-L proline is within the range from 5:1 to 15:1, advisable from 8:1 to 12:1. 4. Use of the pharmaceutical composition according to any of the above Claims, for manufacturing of medicament providing for treatment of cardiovascular diseases.

Description

The present invention relates to pharmaceutical compositions for use in medicine, namely pharmaceutical compositions intended for the treatment of cardiovascular diseases, which are caused by circulatory disorders of various origins and localization, angina, myocardial infarction, arrhythmias, arterial hypertension, myocarditis, and heart failure.

Known medical use of the dihydrate 3 - (2,2,2-trimethylhydrazinium) propionate (THP) or the drug mildronate, quaterin, THP for the treatment of cardiovascular diseases (UK patent 2105992). TBG is used to treat various circulatory disorders and ischemic conditions caused by them. However, the effect of TBP with, for example, chronic heart failure, is not always satisfactory, since it only partially eliminates the decrease in systolic pressure and contractility of the left ventricle and does not affect the changes in diastolic function at all if heart failure results from myocardial infarction.

In the application AO 97 / 06794A described compositions for the treatment of cardiovascular diseases on the basis of TGP (mildronata) and γ butyrobetaine. ACE inhibitors are also described, for example, (8) -1- {Ν- [1- (ethoxycarbonyl) 3-phenylpropyl] -b-alanyl} -b-proline, known as an antihypertensive agent called enalapril (US Pat. No. 4,374,829) which acts by inhibiting the angiotensin-converting enzyme. However, enalapril in the post-infarction period has a positive effect only on the systolic function, but does not significantly affect the diastolic function.

Described compositions (EP-A-0566542) for the treatment of cardiovascular diseases, containing b-carnitine and an ACE inhibitor.

The aim of the present invention is to develop a pharmaceutical composition suitable for the treatment of progressive heart failure caused by myocardial infarction. This goal was unexpectedly achieved by combining a THP and an ACE inhibitor, for example, enalapril, into a pharmaceutical composition.

For such a composition, there is not only a summation of effects characteristic of each medicine separately, or a synegistic enhancement of these effects, i.e. a positive protective effect from the development of myocardial infarction, cardiac arrhythmias and contractility (+ άρ / άΐ), but also and an extremely pronounced effect on the ability of the muscle to relax (-ρ / άΐ) and increase diastolic pressure in the left ventricle, as well as preservation of the volume of the left ventricle without symptoms of hypertrophy or expansion.

Thus, the proposed pharmaceutical composition makes it possible to better and more fully treat cardiovascular diseases, namely, to treat chronic sedation in the post-infarction period more effectively than with the individual preparations indicated. This effect is completely unexpected, since TBG only slightly or not at all affects blood pressure, and it was impossible to expect that TBG significantly improve the effect of the known antihypertensive agent enalapril - to relax the heart muscle by lowering the final diastolic pressure and simultaneously increasing relaxation (-άρ / άΐ), which together manifests itself in an extremely positive effect on the diastolic function of the myocardium.

The usefulness of the combination of two well-known drugs - THP and an ACE inhibitor, for example, enalapril - in treating chronic heart failure and preventing further development of this disease has been proven experimentally.

As a model, progressive heart failure caused by experimental myocardial infarction in rats was used. This model is generally accepted and fairly reliably reproduces the clinical picture. Myocardial infarction was caused by the imposition of a ligature on the left coronary artery. Experimental infarction animals were treated with each individual preparation of the proposed combination, as well as their combination. Under the action of the combination proposed in the present invention, a significant prevention of a decrease in systolic and diastolic function was observed. In addition, in the group of animals receiving the combination according to the present invention, no heart rhythm disturbances were observed. Thus, a pharmaceutical composition containing 3- (2,2,2trimethylhydrazinium) propionate dihydrate and an ACE inhibitor, for example, (8) -1- {No. [1- (ethoxycarbonyl) 3-phenylpropyl] -E-alanyl} -E- Proline (enalapril) may be suggested for the treatment of cardiovascular diseases, namely, heart failure and myocardial infarction. The present composition is more effective than each of its components separately, and, in contrast to treatment with enalapril alone, the combination of TGP with enalapril protects not only from a deterioration of the systolic function of the heart, but also from a deterioration of the diastolic function, and also prevents an increase in the ventricle more effectively, than treating TBP individually.

Consequently, the pharmaceutical composition of THP and enalapril protects against progressive heart failure and prevents the development of hemodynamic and morphological symptoms more effectively than each of the components of the composition of drugs separately.

The ratio of THP to enalapril in the composition can be from 5: 1 to 15: 1, preferably from 8: 1 to 12: 1.

In cases where the active ingredients are administered parenterally in the form of injections or orally in the form of drops, syrup or beverage, the pharmaceutical composition contains the dihydrate 3 - (2,2,2-trimethylhydrazinium) propionate and (8) -1- {Ν- [1 - (ethoxycarbonyl) -3-phenylpropyl] -b-alanyl} -b-proline in an amount of from 0.5 to 40% of the total weight of the pharmaceutical composition, and distilled water, saline, glucose solution or buffer solution as a pharmaceutically acceptable solvent.

In cases where the active ingredients are administered in the form of tablets, drops, capsules, pills, granules or powder, the pharmaceutical composition contains from 0.01 to 0.5 g of 3- (2,2,2-trimethylhydrazinium) propionate dihydrate with (8 ) 1- {Ν- [1 - (ethoxycarbonyl) -3-phenylpropyl] -halanyl} -l-proline in each unit dose of tablets, drops, capsules, pills, granules or powder.

In cases where the active ingredients are introduced through the skin, their content in ointment, oil or patch is from 0.5 to 40% of the total mass of the dosage form.

In cases where the active ingredients are introduced rectally, their content in the suppository or microclyster is from 0.5 to 40% of the total mass of the dosage form.

The following examples, containing a detailed description of the advantages and methods of application of the proposed composition, are intended for a more complete understanding of the invention.

Examples

Example 1. Experimental treatment of heart failure and myocardial infarction.

The experiment was conducted on male white rats (weighing 310-355 g) of the Wistar line. Under anesthesia (pentobarbital 50 mg / kg), the thorax was opened under aseptic conditions, the heart bag was opened and the loop was tightened (a sterile Eisoi 6/0 thread, a non-traumatic needle) around the left coronary artery at the level of the left atstsi1a ai. The manipulation was monitored using a surgical microscope and ECG recording was performed. A ligature was applied to the coronary artery of the rat, the wound was sutured and the pneumothorax was removed. If during the operation there was a need for artificial respiration, the apparatus V 5КО was used (No. gso B | o-8y51st5. USA). For the prevention of postoperative infection, bicillin-1 (500,000 IU / kg intramuscularly) was injected.

h after the operation, the animals were weighed, the presence and severity of the heart attack were determined, and the animals were divided into 4 randomly formed groups. The fifth group of false control was formed from rats subjected to a false operation in which no ligature was superimposed on the coronary artery. Mortality during surgery and 48 hours after surgery was 29%. Death was caused mainly by ventricular fibrillation.

Each group consisted of 10 animals (the control group with a heart attack consisted of 12 animals), which were subjected to the following treatment (the substances were administered via a stomach tube):

I. Control with myocardial infarction (MI) 2 ml / kg 0.9% p-ra №1С1 reg o§ once a day for 28 days;

Ii. Myocardial infarction + TBP (MI + TBP) 50 mg / kg reg o§ once a day for 28 days;

Iii. Myocardial infarction + enalapril (MI + EN) - 5 mg / kg reg o§ once a day for 28 days;

Iv. Myocardial infarction + TBP + enalapril (MI + TBP + EN) - 50 + 5 mg / kg reg o§ once a day for 28 days;

V. Animals with a false operation (control).

During the whole course of treatment, the general condition of the animals was determined and weighed once a week. After the course of treatment (i.e., after 4 weeks), the animals were weighed again, anesthetized (pentobarbital 50 mg / kg 1.p.) and the symptoms of heart failure were determined: an ECG was recorded in the second standard arm, blood pressure in the aorta, pressure in left ventricle (catheter through the carotid artery), + br / b!, br / b! (with the help of Ro1udgarb1s 5U51esh KR 6000 No. Boy of Kobbei, Japan).

The following parameters were assessed: mean blood pressure, pulse frequency and rhythm, maximum and minimum pressure in the left ventricle, + br / b1, -br / b !, body weight, heart and left ventricle mass, area of infarction damage and volume of the left ventricle .

One month after the coronary artery ligation, animals that had not been treated had severe symptoms of heart failure: decreased systolic pressure in the left ventricle, increased pressure at the end of the diastoli, and decreased contractility of the left ventricle (Table 1). Six of the nine surviving rats were observed cardiac arrhythmias, mainly in the form of extrasystoles (Table 2). Mean blood pressure and pulse rate for all groups did not have statistically significant differences (Table 1).

Treatment of TBP for 28 days prevents from a decrease in systolic pressure and a decrease in the contractile ability of the left ventricle; however, the effect on diastolic pressure is much less pronounced.

The introduction of enalapril protects from a weakening of the systolic function of the heart (in terms of systolic pressure in the left ventricle and + ρ / выраж), but does not provide a pronounced protection against diastolic pressure decrease (Table 1). When both drugs were combined, no heart rhythm disturbances appeared (Table 2). During the course of treatment, the weight of the animals increased basically the same, there were no differences also in the mass of the heart (Table 3). When calculating the ratio of heart mass to body mass, an increase in the relative heart mass was found in animals that did not receive treatment, as well as in animals treated with THP. In contrast, in animals treated with enalapril or a combination of THP with enalapril, there were no differences in the mass of the heart or its parts from the false control values (Table 3).

Macroscopic analysis of the heart showed that coronary artery ligation causes transmural myocardial infarction in the free anterior wall of the left ventricle. A month after an artificial heart attack, the infarction zone is filled with interstitial tissue and forms a distinct scar. If treatment is started 48 hours after the call of myocardial infarction, it is not expressed in a significant effect on the area of infarction damage (Table 4).

During the month, the volume of the left ventricle increased significantly in the group of animals that did not receive treatment, compared with the false control group. The ventricle was dilated and hypertrophied (Tables 3 and 4). The results of the experiment show that the pharmaceutical composition of TGP with enalapril also significantly prevents an increase in the volume of the left ventricle (Table 4), and this effect unexpectedly exceeds the results obtained in the group where only enalapril was used for treatment.

During the 28-day period, no animals died in the groups receiving treatment, while in the group with myocardial infarction of 12 animals 3 died (Table 2).

Example 2. The use of the composition for the preparation of drugs.

Preparation of drugs based on the proposed composition

Thoroughly mix the following amounts of substances:

TBG 180g

Enalapril 20g

Lactose 150g

Magnesium stearate 2g

The mixture thus obtained is filled into hard gelatin capsules, thus obtaining a finished dosage form of a capsule containing 0.2 g of a mixture of active substances in each capsule.

Table 1

Hemodynamic parameters of cardiac activity in animals with heart failure caused by myocardial infarction after treatment of TGP, enalapril and a combination of two drugs in comparison with animals subjected to surgery without causing a heart attack (control)

Group of animals Pulse rate (abbr. / min) Mean blood pressure (mm Hg) Pressure in the left ventricle (mm Hg) Contractility of the left ventricle (mm Hg / s) systolic diastolic systolic diastolic Control 388 ± 25 118 ± 11 138 ± 10 4.1 ± 0.6 5030 ± 380 4280 ± 315 Myocardial infarction (MI) 400 ± 22 121 ± 14 123 * ± 12 14.0 ** ± 1.5 3725 ** ± 230 2420 ** ± 180 IM + TGP 370 ± 18 123 ± 10 136 ± 8 9.8 ± 1.4 # 4385 ± 360 # 3720-308 ” IM + EN 405 ± 23 120 ± 9 130 ± 11 8.8 * ± 1.2 # 4570-333 ” 3160 * ± 285 IM + TGP + EN 382 ± 12 116 ± 10 133 ± 8 6.9 ± 0.8 “ 4650 ± 311 # 4095 ± 210 "

* - p <0.05 from the control ** - p <0.01 from the control # - p <0.05 from the IM ## - p <0.01 from the IM & - p <0.05 from the IM + THP ⁰ - p <0.05 of MI + EN

table 2

The number of animals that survived the experiment and the analysis of cardiac arrhythmias

Group of animals Number of animals The number of animals with impaired heart rate at the beginning of the experience at the end of the experience Total Extrasystoles Ventricular tachycardia Conduction disturbances occasionally regularly Control ten ten 0 - - - - Myocardial infarction (MI) 12 9 6 * 2 four one one IM + TGP ten ten 2 # 2 - - - IM + EN ten ten 2 # one one - one IM + TGP + EN ten ten 0 # - - - -

* p <0.05 of control # p <0.05 of MI

Ί

Table 3 Body weight at the beginning and end of the experiment, heart weight in animals with heart failure caused by myocardial infarction (MI), treated with TBG, enalapril and a combination of two drugs, in comparison with animals. subjected to operations without calling a heart attack (control)

Group of animals Body weight, g Heart mass, g The mass of the left ventricle, g The ratio of the mass of the left ventricle to the mass of the heart The beginning of the experience End of experience Control 330 ± 15 452 ± 18 1.21 ± 0.15 0.77 ± 0.09 0.641 ± 0.11 Myocardial infarction (MI) 333 ± 17 440 ± 27 1.32 ± 0.25 1.082 ± 0.11 * 0.82 ± 0.14 * IM + TGP 320 ± 15 436 ± 23 1.3 ± 0.18 0.95 ± 0.1 * 0.73 ± 0.14 IM + EN 327 ± 13 447 ± 25 1.24 ± 0.13 0.85 ± 0.08 # 0.685 ± 0.1 # IM + TGP + EN 335 ± 14 445 ± 20 1.28 ± 0.16 0.89 ± 0.12 # 0.69 ± 0.11 #

* - p <0.05 of control # - p <0.05 of myocardial infarction

Table 4 The volume of the left ventricle and the area of the scar for animals with heart failure caused by myocardial infarction (MI) treated with THP, enalapril and a combination of two drugs, in comparison with

animals subjected to operation without calling inf arkta (control) Group of animals The volume of the left ventricle, cm ³ The area of infarction scar, mm ² Control 0,288 ± 0,09 - Myocardial infarction (MI) 0.7 ± 0.18 ** 72 ± 12 IM + TGP 0.5 ± 0.23 65 ± 11 IM + EN 0.62 ± 0.19 * 70 ± 15 IM + TGP + EN 0.4 ± 0.15 # ⁰ 63 ± 13

* - p <0.05 from control ** - p <0.01 from control # - p <0.05 from IM ⁰ - p <0.05 from IM + EN

Claims (4)

CLAIM 1. A pharmaceutical composition comprising 3- (2,2,2-trimethylhydrazinium) propionate dihydrate (THP) and an angiotensin converting enzyme (ACE) inhibitor. 2. The pharmaceutical composition according to claim 1, wherein said ACE inhibitor is (8) -1- {I- [1- (ethoxycarbonyl) -3-phenylpropyl] E-alanyl} -L-proline, i.e. enalapril. 3. The pharmaceutical composition according to claim 2, in which the ratio of these active compounds of dihydrate 3- (2,2,2-trimethylhydrazinium) propionate and (8) -1- {I- [1- (ethoxycarbonyl) 3-phenylpropyl] -E -alanyl) -E-proline of THP and enalapril is in the range from 5: 1 to 15: 1, preferably from 8: 1 to 12: 1. 4. The use of the pharmaceutical composition according to any one of claims 1 to 3 for the treatment of cardiovascular diseases.