RU2538674C2 - Pharmaceutical composition possessing prolonged antiarrhythmic activity - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to pharmaceutical compositions possessing prolonged antiarrhythmic actions and applicable to correct the cardiac arrhythmia, including that of the ischemic origin. What is presented is a pharmaceutical composition with the prolonged antiarrhythmic acitivity containing bis[2-(diethylamino)]-N-(2,6-dimethylphenyl)acetamide L-glutaminate, L-glutamic acid, 2-aminoethane sulpho-acid and excipients.

EFFECT: prolonged antiarrhythmic action and stability of the dosage form (tablets, capsules for oral application or solution for injections).

3 cl, 4 tbl

Description

The invention relates to medicine, specifically to medicines used in the treatment of coronary heart disease and its complicating arrhythmias.

The problem of prevention and treatment of coronary heart disease is very relevant, since the death of patients suffering from diseases of the cardiovascular system, ranks first in the world among deaths from other diseases.

In addition, coronary heart disease is sometimes complicated by severe arrhythmia, and in the treatment of this disease it is necessary to use a combination of drugs with anti-ischemic and antiarrhythmic effects, which does not always give a positive result.

The aim of the invention is a pharmaceutical composition having prolonged antiarrhythmic activity.

The closest analogue of the claimed compound is the antiarrhythmic drug lidocaine widely used in medicine, which is on the List of Essential and Essential Medicines of the Russian Federation (approved by Decree of the Government of the Russian Federation of December 7, 2011 No. 2199-r).

However, it is known that lidocaine has significant shortcomings: a short duration of action, causes convulsions, cardiogenic shock, depresses breathing, etc. (Encyclopedia of Radar Medicines 2012, p. 531-532; MD Mashkovsky, Medicines, M., LLC " The New Wave ", 2002, vol. 1, pp. 294-295).

Also known is the compound N- (2,4,6-Trimethylphenylcarbamoylmethyl) -N-allylmorpholinium bromide under the name quaternidine, which exhibits anti-ischemic and antiarrhythmic effects in coronary heart disease (US Pat. RF 2105554). The disadvantage of this compound is its high toxicity and low breadth of therapeutic effect.

A number of derivatives of 2- (diethylamino) -N- (2,6-dimethylphenyl) acetamide with various carboxylic and dicarboxylic acids are claimed in RF patent No. 2223263. One of the compounds bis [2- (diethylamino)] - N- (2,6-dimethylphenyl) acetamide L-glutamate showed the highest antiarrhythmic index.

We carried out special in-depth experimental studies of this compound on various models of arrhythmia. Its high prolonged antiarrhythmic activity was established, which made it possible to develop a pharmaceutical composition based on this compound and offer it as a medicine for the treatment of arrhythmias.

The aim of the invention is the creation of a prolonged antiarrhythmic agent in the form of pharmaceutical compositions containing bis [2- (diethylamino)] - N- (2,6-dimethylphenyl) acetamide L-glutamate (1).

The technical result is achieved by the revealed new properties 1, namely: a prolonged action, an increase in the breadth of the therapeutic effect, a decrease in acute toxicity, and the creation of pharmaceutical compositions and a drug based on this compound.

The literature does not describe pharmaceutical compositions, dosage forms containing 1.

Two pharmaceutical compositions are proposed: a dosage form in the form of a solution for injection and a solid dosage form in the form of tablets or capsules for oral administration.

Given the specific physicochemical properties of compound 1, biologically and pharmaceutically acceptable excipients, as well as their ratios, were studied and selected.

A variety of preservatives were studied as auxiliary substances in the preparation of an injection: sugar (sorbitol, mannitol, xylitol, etc.), complexing agents, antioxidants, etc.

As substances of a basic and acidic nature to stabilize the pH of the solution, various organic and inorganic bases, acids, providing a pH of the solution from 4.0 to 5.0, were studied.

As a result of experimental studies, excipients were selected that ensure stability of 1 in dilute solutions of various concentrations (0.5-5.0%).

The proposed dosage form in the form of a solution for injection is obtained by gradually dissolving the components in water for injection. The dosage form contains bis [2- (diethylamino)] - N- (2,6-dimethylphenyl) acetamide L-glutamate, sugar, L-glutamic acid, 2-aminoethanesulfonic acid, trilon B in the following ratio, wt.%:

bis [2- (diethylamino) -N- (2,6-dimethylphenyl) acetamide L-glutamate] 0.5-5.0 Sahara 1.0-15.0 L-glutamic acid 0.5-1.0 2-aminoethanesulfonic acid 0.5-1.0 Trilon B 0.01-0.1

As preservative sugars, sorbitol, xylitol, D-mannitol are mainly used.

A solid dosage form for oral administration in the form of tablets, powder or granules in capsules is obtained both by preliminary granulation and the preparation of free-flowing powder for tabletting by direct compression or filling of capsules. This dosage form as excipients contains cellulose derivatives, microcrystalline cellulose, polyvinyl alcohol, sugars, stearic acid salts, 2-aminoethanesulfonic acid, L-glutamic acid, silicon dioxide, starches in the following ratio, wt.%:

bis [2- (diethylamino)] - N- (2,6-dimethylphenyl) acetamide L-glutamate 1.0-30.0 cellulose derivatives 0,0-20,0 starches 0,0-20,0 Sahara 1,0-20,0 L-glutamic acid 1.0-10.0 2-aminoethanesulfonic acid 1.0-10.0 silicon dioxide 0.1-3.0 stearic acid salts 0.1-3.0 opadra 1.0-10.0

It is advisable to use hydroxypropyl methylcellulose as cellulose derivatives. As sugars, sorbitol, xylitol or mannitol is preferably provided, which allows the use of the drug in patients with diabetes. 2-aminoethanesulfonic acid and L-glutamic acid further contribute to the improvement of metabolic processes in arrhythmic pathologies and also contribute to the effectiveness of the drug.

The claimed ratio of the components found experimentally, are optimal and allow to obtain a technical result in accordance with the task.

The presented examples illustrate the claimed invention.

Example 1

To 300 ml of water for injection, 50.0 g of sorbitol, 10.0 g of L-glutamic acid, 10.0 g of 2-aminoethanesulfonic acid, 0.5 g of Trilon B are gradually added with stirring to the resulting solution, 20.0 g of compound 1 , the volume of the solution is adjusted to 1000 ml, sterilizing filtration is carried out through 0.45 and 0.22 μm membrane filters, and 2 ml are poured into ampoules. The resulting solution meets the requirements of the State Pharmacopoeia XI and XII ed.

Example 2

Analogously to example 1, starting from 50.0 g of mannitol, 10.0 g of L-glutamic acid, 5.0 g of 2-aminoethanesulfonic acid, 0.5 g of trilon B, 30.0 g of compound 1. The resulting solution meets the requirements of the State Pharmacopoeia XI and XII ed.

Example 3

Screened powders of compound 1 (50.0 g), mannitol (15.0 g), microcrystalline cellulose (100.0 g), L-glutamic acid (20.0 g), 2-aminoethanesulfonic acid (20.0 g), silicon dioxide (5.0 g), corn starch (20.0 g), magnesium stearate (3.0 g) are thoroughly mixed to a homogeneous mass, tabletted, and 200 mg tablets are obtained containing 50 mg of compound 1 in each tablet. Tablets corresponds to the requirements of the State Pharmacopoeia XI and XII ed.

Example 4

From 50 g of hydroxypropyl methylcellulose, a 2% aqueous solution is obtained, to which 100.0 g of compound 1, 20.0 g of sorbitol, 30.0 g of L-glutamic acid, 30.0 g of 2-aminoethanesulfonic acid are added with stirring, the mixture is thoroughly mixed , granulated to a particle size of 1.0-1.5 mm, dried at 50-60 ° C, crushed to a size of 0.5-0.1 mm, the granules are mixed with 10.0 g of corn starch and 5.0 g of magnesium stearic acid . The resulting granules are placed in capsules. Each capsule contains 50 mg of compound 1. Capsules meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 5

Analogously to example 4, the obtained granules are tabletted, the tablets are coated with Opadrai (ready-made mixture for coating solid dosage forms, consisting of polyvinyl alcohol, macrogol, titanium dioxide). Get tablets containing 20 mg of compound 1 in each. Tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Pharmacological studies

Unlike quaternidine, compound 1 compares favorably with less toxicity with intraperitoneal, oral and intravenous routes of administration, as well as greater safety, as illustrated in Example 6.

Example 6

Acute toxicity 1 was studied in experiments on mice (n = 440, m = 18-20 g) with intraperitoneal and oral methods of administration, on cats (n = 15, m = 1.5-4.8 kg) with intravenous administration.

The LD ₅₀ index was calculated by the Miller and Taint method (Prince ML Belenky. Elements of a quantitative assessment of the pharmacological effect. - Riga: Publishing House of the Academy of Sciences of the LSSR, 1963. - 130 pp.). To determine acute toxicity upon intravenous administration (LD ₁₀₀ ), solutions in an isotonic sodium chloride solution were administered to animals until cardiac arrest stopped. The results of the study of the structural precursor of lidocaine, quaternidine, and also compound 1 are presented in table 1.

Table 1 Comparative toxicity data of compound 1 and analogues The studied indicators Lidocaine Quaternidine one LD ₅₀ b / w, 200 ± 15 * ** 54 ± 4 ** 166 ± 5 * mg / kg (173 ÷ 227) (46 ÷ 62) (176 ÷ 194) (M ± m) n = 80 n = 60 n = 100 Mice LD ₅₀ per 297 ± 14 * ** 450 ± 26 ** 630 ± 26 * os, mg / kg (271 ÷ 324) (400 ÷ 500) (578 ÷ 689) (M ± m) LD ₁₀₀ iv 128 ± 7 * ** 47 ± 4 ** 148 ± 4 * mg / kg (M ± m) n = 5 n = 6 n = 4 Cats Note: * - differences when compared with quaternidine are significant at p <0.05; ** - differences when compared with lidocaine are significant at p <0.05.

From the data proposed in the table it is clearly seen that the claimed compound is close in toxicity, lidocaine with intraperitoneal administration and less toxic than the quaternary derivative of trimecaine - quaternidine. When administered orally, acute toxicity 1 was less than that of lidocaine and quaternidine. A lethal intravenous dose of 1 for cats is also lower than that of quaternidine and lidocaine.

Antiarrhythmic activity of compound 1 and its closest analogues in ventricular arrhythmias in the late stage of experimental myocardial infarction in dogs

Ventricular arrhythmia in the late stage of experimental myocardial infarction was reproduced in mature dogs of both sexes weighing 7.0-15.0 kg. Violation of coronary blood flow in animals was caused by the method described in sources: Harris A.S. Delayed development of ventricular ectopic rhythm following experimental coronary occlusion. // Circulation Res. - 1950 .-- Vol. 1. - N6. - P.1318-1328 and Gendenstein E.I., Kostin Y.V. The antiarrhythmic effect of trimecaine with ventricular arrhythmias // Cardiology. - 1976. - No. 1. - S.128-131.

The test results of the claimed compounds and analogues are given in table.2.

table 2 Antiarrhythmic activity of compound 1 in experimental myocardial infarction in dogs No. p / p Test compound The nature of the initial rhythm The nature of the rhythm after the introduction of the substance Number of animals The beginning of the effect, min The duration of the effect, min Arrhythmia Suppression,% Heart rate abbreviations Ectopic Contraction Rate Heart rate BSEC In experience With full effect (%) one Lidocaine 191 ± 9 143 ± 24 175 ± 3 0 6 2 (33) one 4-6 61 ± 11 2 Quaternidine 206 ± 10 159 ± 25 188 ± 6 0 5 5 (100) 16 ± 4 536 ± 56 one hundred 3 one 191 ± 9 143 ± 24 175 ± 3 0 10 10 (100) 15 ± 5 500 min observation one hundred

The introduction of compound 1 at a dose of 8.3 mg / kg allowed to suppress arrhythmia in 100% of experiments. The duration of the antiarrhythmic effect was at least 500 minutes of observation. The complete antiarrhythmic effect developed on average 15 minutes after administration.

Thus, in strength and duration of the antiarrhythmic effect, compound 1 is not inferior to quaternidine and lidocaine.

The activity of compound 1 and quaternidine in aconitine arrhythmia model in rats and mice

Arrhythmia was reproduced according to the method of Yu.I. Vikhlyaev and N.V. Kaverina (1958) (Prince Kaverina N.V., Berdyaev S.Yu., Kushchuk E.P., Paskhina O.E. Guidelines for the study of antiarrhythmic activity of new pharmacological substances // Guide to the experimental (preclinical) study of new pharmacological Substances / Under the editorship of V.P. Fisenko. - M., 2000. - p. 210). Aconitine nitrate was administered to animals at a dose of 50 μg / kg. The research results are presented in table 3.

Table 3 Test drug Dose,
mg / kg n With arrhythmia (%) HP onset time, s Duration without HP, min ED ₅₀ , mg / kg AI The control - 19 19 31 ± 12 90.0 ± 8.0 - - Lidocaine 2,5 6 6 68 ± 22 67.0 ± 12.0 5 9 four 135 ± 15 41.0 ± 6.0 8.47 ± 1.9 23.5 10 9 3 186 ± 38 35.0 ± 6.0 fifteen 9 0 - - Quaternidine 0.5 5 5 100 ± 24 136.0 ± 26 1,5 6 four 140 ± 60 57.0 ± 8.0 2.09 ± 0.58 25.8 2.0 eleven 6 200 ± 35 64.0 ± 13.0 4.0 6 0 - - Compound 1 1,0 9 8 89 ± 21 100.0 ± 13 2.1 9 6 96 ± 33 84.0 ± 18.0 2.0 ± 0.58 43.5 4.2 9 3 154 ± 13 45.0 ± 13.0 8.3 9 0 - - Notes: ED ₅₀ - effective dose, HP - rhythm disturbances,
AI - antiarrhythmic index.

This model allows us to judge the breadth of the therapeutic effect of the presented compounds, its closest analogues and structural precursor. The breadth of the therapeutic effect was judged by the value of the antiarrhythmic index, defined as the ratio of LD ₅₀ with the intraperitoneal route of administration to ED ₅₀ on the aconitine model of arrhythmias.

The experiment shows that compound 1 effectively eliminates atrial arrhythmia caused by intravenous administration of aconitine nitrate. Moreover, the value of the antiarrhythmic index calculated for 1 is much higher than those of quaternidine and lidocaine, therefore, compound 1 has a greater breadth of therapeutic effect than the compared analogues, which indicates its greater safety with equivalent activity.

Study of the effect of compound 1, lidocaine and quaternidine on experimental mortality with prolonged administration to animals under stress

Currently, to assess the safety of long-term antiarrhythmic therapy, a new method is used to assess the safety of potential antiarrhythmic drugs (Balashov V.P., Balykova L.A., Shuvalova E.N. et al., Bull. Exp. Biol. And honey. - 2002. - t.133. - No. 5. - p. 598-600). The method is based on modeling 6-hour immobilization stress in white mice daily for 6 weeks.

The results of the study of compound 1, lidocaine and quaternidine are presented in table 4.

Table 4 The effect of compound 1 on experimental mortality under stress Group The number of dead animals Abs. % Without immobilization (n = 20) 0 0 Immobilization (control; n = 40) 12 30,0 +1 (n = 40) fourteen 35.0 + lidocaine (n = 40) 21 52.5 * + quaternidine (n = 40) 16 40,0 Note: * p <0.05 when compared with control.

All compounds were administered at a dose of 5% of LD ₅₀ when administered intraperitoneally to mice. 1 - at a dose of 8.3 mg / kg intraperitoneally, lidocaine - 10 mg / kg, quaternidine - 2 mc / kg.

In the control, immobilization led to the death of some animals, and mortality after 6 weeks was 30%. Lidocaine significantly increased the mortality of mice under stress. Quaternidine showed a tendency to its increase, and the percentage of death of animals with the introduction of 1 was the smallest of all considered substances.

The data presented indicate that compound 1 exhibits pronounced antiarrhythmic properties in models of ventricular and atrioventricular (aconitine) arrhythmias, comparable to the properties of the closest analogue (quaternidine) and superior to the antiarrhythmic properties of the structural precursor (lidocaine).

The duration of the effect of compound 1 corresponds to a similar indicator of quaternidine and significantly exceeds the duration of the effect of lidocaine. An important advantage of the claimed compound is its large breadth of therapeutic effect, compared with the same indicator for lidocaine and quaternidine. In addition, under conditions of prolonged immobilization stress with a 6-week administration, compound 1, unlike lidocaine, does not increase the mortality of experimental animals.

The prolongation and effectiveness of the compound 1 contained in the proposed pharmaceutical compositions is confirmed by pharmacological studies.

Thus, the modification of lidocaine by the method of its complexation with L-glutamic acid allows one to obtain a more effective and safe compound for the treatment of cardiac arrhythmias than its structural predecessor and the closest analogue.

Claims (3)

1. A pharmaceutical composition having prolonged antiarrhythmic activity, characterized in that it contains bis [2- (diethylamino)] - N- (2,6-dimethylphenyl) acetamide L-glutamate, L-glutamic acid, 2-aminoethanesulfonic acid and pharmaceutically acceptable excipients substances. 2. The pharmaceutical composition for oral administration according to claim 1 is in the form of tablets or capsules, characterized in that it contains bis [2- (diethylamino) -N- (2,6-dimethylphenyl) acetamide L-glutaminate, sugars, cellulose derivatives, organic acids, starches, salts of stearic acid, film coating in the following ratio of components, wt.%:
bis [2- (diethylamino)] - N- (2,6-dimethylphenyl) acetamide L-glutamate] 1.0-30.0 cellulose derivatives 0,0-20,0 starches 0,0-20,0 Sahara 1,0-20,0 L-glutamic acid 1.0-10.0 2-aminoethanesulfonic acid 1.0-10.0 silicon dioxide 0.1-3.0 stearic acid salts 0.1-3.0 opadra 1.0-10.0 3. The pharmaceutical composition according to claim 1 is made in the form of a solution for injection, characterized in that it contains bis [2- (diethylamino)] - N- (2,6-dimethylphenyl) acetamide L-glutamate, sugar, L-glutamic acid , 2-aminoethanesulfonic acid, Trilon B in the following ratio of components, wt.%:
bis [2- (diethylamino)] - N- (2,6-dimethylphenyl) acetamide L-glutamate] 0.5-5.0 Sahara 1.0-15.0 L-glutamic acid 0.5-1.0 2-aminoethanesulfonic acid 0.5-1.0 edetate disodium salt (Trilon B) 0.01-0.1