LV12491B - Pharmaceutical composition - Google Patents

Abstract

Invention relates to the field of medicine and particularly to a pharmaceutical composition containing 3-(2,2,2-trimethylhydrazinium)-propionate dihydrate (known as mildronat) and an angiotensin-converting enzyme(ACE) inhibitor useful as a combined preparation for treatment of cardiovascular diseases. Enelapril ((S)-1-{N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl}-L-proline) is used as ACE inhibitor. A preferable ratio of mildronat and enelapril in the composition is from 8:1 to 12:1.

Description

PHARMACEUTICAL COMPOSITION

The invention relates to pharmaceutical compositions for use in medicine, in particular pharmaceutical compositions for the treatment of cardiovascular diseases associated with circulatory disorders of various origins and localization, angina pectoris, myocardial infarction, arrhythmias, hypertension, myocarditis as well as heart failure.

For the treatment of cardiovascular diseases, 3- (2,2,2-trimethylhydarzinium) -propionate dihydrate, also known as mildronate, quaterih and THP (British Patent No. 2105992), is used as a medicinal product. THP is used to treat various circulatory disorders and related ischemic conditions. However, the effect of THP, for example on chronic heart failure, is not always sufficient as it only partially observes a decrease in left ventricular systolic pressure contractility, but does not influence the change in diastolic function in chronic heart failure due to myocardial infarction.

A number of ACE inhibitors are also known, such as (S) -1- {N- [1 (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl} -L-proline, which is known as the antihypertensive agent enalapril (U.S. Patent No. 4,374,829). , whose action involves the inhibition of angiotensin converting enzyme. Also, enalapril has a positive effect on systolic function in the post-myocardial infarction period, but has no significant effect on diastolic function.

The object of the invention was to provide a pharmaceutical composition suitable for treating, for example, advanced heart failure caused by myocardial infarction. This was unexpectedly achieved by combining mildronate with an ACE inhibitor, such as enalapril, in a pharmaceutical composition. This composition not only exhibits the expected cumulative or synergistic enhancement of the effects of both formulations, that is, a positive protective effect on the development of myocardial infarction, cardiac dysfunction and contractility (+ dp / dt), but also, unexpectedly, extremely strong cardiac effects. muscle relaxation (-dp / dt), diastolic pressure, and left ventricular size retention without signs of hypertrophy and dilation.

The proposed pharmaceutical composition provides a much better and more complete treatment of cardiovascular disease, in particular of chronic heart failure after myocardial infarction, compared to that observed with each of these components alone. This is an unexpected effect as THP has little or no effect on blood pressure and thus, THP could not be expected to significantly improve the effect of the known antihypertensive drug enalapril on cardiac muscle relaxation by decreasing diastolic end pressure while increasing the rate of relaxation (-dd). , which together exhibit an extremely positive effect on myocardial diastolic function. The use of a combination of known therapeutic agents THP (mildronate) and an ACE inhibitor such as enalapril in the treatment of chronic heart failure and in the prevention of the progression of this disease has been demonstrated in laboratory animals. Experimental myocardial infarction-induced progressive heart failure in rats was used as a well-established and clinically relevant model for chronic heart failure. Myocardial infarction was caused by ligation of the left coronary artery. Animals with myocardial infarction were treated with each of the active ingredients in the composition, as well as with a combination. The combination of mildronate and enalapril was found to reliably prevent a decrease in both systolic and diastolic function. No cardiac arrhythmia was observed with either combination.

Thus, a pharmaceutical composition comprising 3- (2,2,2-trimethylhydrazinium) propionate dihydrate (mildronate) and an ACE inhibitor (S) -1- {N- [1 (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl} -L-proline (enalapril) is recommended for the treatment of cardiovascular diseases and in particular heart failure and myocardial infarction and is more effective than each component of the pharmaceutical composition alone because unlike enalapril monotherapy, the combination of mildronate and enalapril protects against cardiac systolic from diastolic dysfunction and left ventricular dilatation and more effectively than mildronate monotherapy to prevent left ventricular hypertrophy. In summary, the pharmaceutical composition of mildronate and enalapril, rather than the administration of each agent alone, prevents the progression of heart failure and inhibits the development of hemodynamic and morphological symptoms of heart failure.

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

In the case of the parenteral administration of the active compounds by injection or orally as drops, syrup or drink, the pharmaceutical composition contains 3- (2,2,2-trimethylhydrazinium) -propionate dihydrate and (S) -1- {N- [l- (ethoxycarbonyl) ) -Phenylpropyl] -L-alanyl} -L-proline in an amount of 0.5-40% by weight of the total dosage form and as a pharmaceutically acceptable solvent distilled water, saline, glucose or buffer.

In the case of administration of the active substances in the form of tablets, capsules, capsules, dragees, granules or powder, the pharmaceutical composition contains from 0.01 to 0.5 g of 3- (2,2,2-trimethylhydrazinium) -propionate dihydrate and (S) Mixture of -1- {N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl} -L-proline in one tablet, capsule, capsule, dragee, granule or powder.

When the active compounds are administered transcutaneously, their content in ointment, oil or patches is 0.5-40% of the total weight of the formulation.

In the case of rectal administration of the active compounds, their content in the suppository or microclimate is 0.5-40% by weight of the total dosage form.

The properties and uses of the proposed pharmaceutical composition are described in further detail in the Examples which serve to better understand the invention.

EXAMPLES

Example 1:

Experimental treatment of heart failure and myocardial infarction

Experiments were carried out on male Wistar rats (310 - 355 gr). In pentobarbital anesthesia (50 mg / kg i.p.) and aseptic opening of the thoracic and cardiac wall was performed and a thread loop (Eticon 6/0 sterile suture with atraumatic needle) was plastered around the left coronary artery at the level of the left atrium. The operation microscope was used to evaluate the quality of the manipulation and to perform coronary artery ligation in rats intended for the experiment. In parallel, an ECG was recorded, wound closure, and pneumothorax removal performed. When performing surgery, use artificial respiration as needed using a V 5kG (Narco Bio - Systems, USA). For postoperative infection prevention i.m. Bicillin-1 (500,000 i.v. / kg) was administered. 48 hours after surgery, the animals were weighed and evaluated for severity and severity of the infarction, and the animals were randomized into 4 groups (group 5 - sham control group - sham operated rats - animals that do not have coronary artery at surgery). Surgery and 48-hour mortality combined account for an average of 29%. The main cause of death is ventricular fibrillation. In each group, 10 animals (12 in the infarction control group) were given the following treatment (by gavage):

I - Myocardial Infarction Control (MI), (2 ml / kg 0.9% NaCl p.o. lx / day - 28 days);

II - Myocardial Infarction + Mildronate (MI + Mildronate) (50 mg / kg p.o. lx / day - 28 days);

III - Myocardial Infarction + Enalapril (MI + Enalapril) (5 mg / kg p.o. lx daily for 28 days);

IV - Myocardial Infarction + Mildronate + Enalapril (MI + Mildronate + Enalapril) (50 + 5 mg / kg p.o. lx daily for 28 days);

V - False operated animals (control)

During the treatment course, the general condition of the animals and weekly body weight were assessed.

At the end of the treatment course (4 weeks), the animals were re-weighed, anesthetized (pentobarbital 50 mg / kg ip), and symptomatic heart failure was recorded - standard ECG lead II, aortic blood pressure, left ventricular pressure (catheterized via carotid artery) and + dp / dt, -dp / dt (with Polygraphic System RP 6000 Nihon Kohden, Japan).

The following parameters were evaluated: mean blood pressure, pulse rate and rhythm, maximum and minimum left ventricular pressure, + dp / dt, -dp / dt; animal weight, cardiac and left ventricular mass, infarction scar area, and left ventricular volume.

One month after coronary artery ligation in untreated animals, the myocardial infarction group (MI) showed marked symptoms of cardiac insufficiency: decreased left ventricular systolic pressure, increased end-diastolic pressure, and decreased left ventricular contractility (Table 1). Six of the nine surviving rats had cardiac arrhythmias, mainly extrasystoles (Table 2), but the mean blood pressure and pulse rate were not statistically different between the groups (Table 1).

A course of treatment with mildronate for one day protects against systolic pressure and a decrease in left ventricular contractility, but the effect on diastolic pressure is less pronounced (Table 1).

The use of enalapril protects against a decrease in cardiac systolic function (judged by left ventricular systolic pressure and + dp / dt) (Table 1), but there is little protection against the reduction in diastolic function (Table 1). The combination of mildronate and enalapril reliably reverses the decline in both systolic and diastolic function (Table 1). No cardiac arrhythmia was observed with the combination of both agents (Table 2).

During the course of the treatment, the weight of all animals increased in a similar manner, and the weight of the heart did not differ from each other (Table 3). However, when calculating the heart weight / body weight ratio, there was an increase in cardiac mass in the untreated myocardial infarction group as well as in the mildronate-treated myocardial infarction group. In contrast, in the animal groups treated with enalapril or alone, from the false control group (Table 3).

Macroscopic analysis of the heart shows that coronary artery ligation causes a transmural myocardial infarction in the anterior free wall of the left ventricle. Within a month of myocardial infarction, the infarction area is filled with connective tissue and forms a well-defined scar. The initiation of a treatment course 48 hours after the initiation of a myocardial infarction does not significantly affect the area of the infarction scar (Table 4).

In the untreated myocardial infarction group, the volume of the left ventricle increased significantly (2.4-fold) compared to the fake-operated animals without infarction (control) - it is dilated and hypertrophied (Tables 3 and 4). The results of the experiment show that the pharmaceutical combination of mildronate and enalapril also significantly protects against increased left ventricular volume (Table 4), with unexpectedly better results in animals treated with enalapril.

none of the treated and control animals died during the one-day treatment course, but 3 of the 12 myocardial infarction control animals did not survive to the end of the experiment (Table 2).

Example 2:

Use of the composition in the preparation of a medicament Mix thoroughly:

180 g mildronate, g enalapril,

150 g of lactose, g of magnesium stearate and the reconstituted mixture are filled into 0.35 g hard gelatine capsules to give the final dosage form with 0.2 g of active ingredient in each capsule.

Table 1

Cardiac haemodynamic parameters in animals with heart failure due to myocardial infarction, animals treated with mildronate, enalapril and a combination of both, compared to operative animals but without infarction (Control)

Left ventricular contractility (mm Hg / s) α Ό I 4280 ± 3l5 2420 ** ± l80 3t 00 © m Ή © CN Γ— cn and oo il * © THIS m o 3t 3t © rM CN +1 And Os © Tf + dp / dt 5O3O ± 38O 3725 ** ± 230 % © THIS cn + l and 00 cn % cn cn cn 44 © Γ- ΙΑ % m · 44 © and Ό Left ventricular pressure (mm Hg) Diastolic this © -h and + i * * © rt · * + i * 00 o \ % CN + i * 00 oo 3t 3t OO +1 Os THIS Systolic ! 38 ± 10 I23 * ± l2 136 ± 8 ! 30 ± ll 133 ± 8 Mean blood pressure (mm Hg) + i 00 I2l ± l4 ! 23 ± 10 OS s CN 116 ± 10 Heart rate (contraction / min) 388 ± 25 400 ± 22 00 + l © Γ- Γη f 405 ± 23 ' 382 ± 12 Animal group Control Myocardial Infarction (MI) MI + Mildronate MI + Enalapril MI + Mildronate 1 + Enalapril

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Table 4

Left ventricular volume and myocardial infarction area in animals with myocardial infarction-induced heart failure (MI), animals treated with mildronate, enalapril and a combination of both, compared to operative animals but without myocardial infarction (Control)

Group of animals Volume of left ventricle (cm ³ ) Infarction Scar Area (mm ² ) Control 0.28810.09 - Myocardial infarction (Ml) 0.710.18 ** 72112 Ml + Mildronate 0.510.23 65111 Ml + Enalapril 0.6210.19 * 70115 Ml + Mildronate + Enalapril 0.410.15 ^{# 0} 63113

* - p <0.05 versus control ** - p <0.01 versus control ^# - p <0.05 versus M1 ⁰ - p <0.05 versus M1 + enalapril

Claims (4)

A pharmaceutical composition comprising 3- (2,2,2-trimethylhydarzinium) propionate dihydrate or mildronate and an agiotensin converting enzyme (ACE) inhibitor as a combined preparation for the treatment of cardiovascular diseases. The pharmaceutical composition of claim 1, wherein said ACE inhibitor is (S) -1- {N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl} -Lproline or enalapril. 3. The pharmaceutical composition of claim 2, wherein said active ingredient is The ratio of 3- (2,2,2-trimethylhydrazinium) propionate dihydrate to (S) -1- {N- [1 (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl} -L-proline ranges from 5: 1 to 15: 1, preferably 8: 1 to 12: 1. Use of a pharmaceutical composition according to any of the preceding claims for the manufacture of a medicament for the treatment of cardiovascular diseases.