RU2545833C1 - Pharmaceutical composition with anti-ischemic and antioxidant activity and method for preparing it - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical composition with anti-ischemic and antioxidant activity in the form of tablets or capsules, and a method for preparing it. The composition contains 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid in an amount of 40 to 80 wt %, an amino-containing compound and pharmaceutically acceptable excipients. The amino-containing compound is specified in a group of trometamol, methyl glucamine and L-lysine; 1 mole of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid is accounted for 0.05 to 0.25 mole of the above amino-containing compound. The composition also contains lactose, microcrystalline cellulose, calcium stearate and other pharmaceutically acceptable excipients. According to the method for preparing the composition, taking 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid and amino-containing compound in molar ratio 1:0.05 to 1:0.25, pre-mixing, moisturising with a aqueous or alcohol solution of a binding agent, adding pharmaceutically acceptable excipients in such an amount to provide the content of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid from 40 to 80 wt %, granulating the mixture, drying and producing tablets or capsules according to the known technique.

EFFECT: implementing the above application.

6 cl, 7 tbl, 4 ex

Description

The present group of inventions relates to medicine and the pharmaceutical industry, in particular to oral compositions containing chemical compounds with anti-ischemic and / or antioxidant properties, and a method for their preparation.

Substances from a number of derivatives of malonic acid that have pacemaking properties are known [see, for example, A. with. 1780293 USSR, MKI S07C 233/54, A61K 31/16]. The ability and method of obtaining a composition that meets the requirements of the Global Fund, not tested.

The compound synthesized in SPhFA - 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid (hereinafter EPABK) is known and belongs to a number of malonic acid derivatives [RF Patent Application No. 2012105369 of the Russian Federation, RF patent 2167852].

However, the pharmacological properties and toxicity of this compound remained unexplored, which did not allow us to consider it as a possible substance of the drug.

Studies have shown that this compound both individually and as part of a pharmaceutical composition exhibits anti-ischemic and antioxidant activity in the experiment (Examples 4-6 in the description).

The anti-ischemic effect of EPABK and a pharmaceutical composition based on it is manifested in the form of a positive effect on the systolic size of the atrium and left ventricle, the absence of myocardial hypertrophy, and improvement of blood flow in the pulmonary artery. Against the background of the introduction of EPABC, such phenomena as aneurysm, synergy, akinesia were not detected, thrombosis was absent.

Against the background of the introduction of EPABC, an acceleration of myocardial repair processes and a decrease in the necrosis zone, an increase in the working time, and an improvement in myocardial contractile activity were observed.

The values of the antioxidant activity of the tested substance EPABK and the pharmaceutical composition based on it allows us to attribute this compound to substances with moderate antioxidant activity.

As a result of the study of acute toxicity with intraperitoneal and oral administration, it was found that the tested pharmaceutical substance can be classified as low-toxic and non-toxic substances.

It is known that the compositions of oral medicinal preparations include, in addition to the active substance, a number of excipients widely used in pharmaceutical technology: sugars, starch, MCC, cellulose derivatives, stearates, metal carbonates and hydrogen carbonates, various polymers, etc., which provide the required technological properties of granules and tablets: strength, flowability, disintegration, dissolution, etc. [see, for example: Belousov V.A. The effect of granulate quality on the technological parameters of tableted materials (Review) / V.A. Belousov // Chem.-farm. Journal. 1981. No. 12. S. 76-80; Voskoboinikova I.V. Modern excipients in the production of tablets. The use of macromolecular compounds for improving dosage forms and optimizing the technological process / I. V. Voskoboinikova [et al.] // Chem. Journal. 2005.V. 39. No. 1. S.22-28].

Known methods for producing tablets and granules for capsules, which include processes of mixing, moisturizing, granulating, drying, dry granulating (calibration), dusting, pressing [See, for example: Industrial technology of drugs / Ed. prof. IN AND. Chueshov. Kharkov: Publishing House of NFaU, 2013.V.1. S.207-253; Menshutin, N.V. Innovative technologies and equipment for pharmaceutical production / N.V. Menshutin, Yu.V. Mishina, S.V. Alves. M .: Publishing house BINOM, 2012.V.1. S.81-171; Gorodnichev, V.I. Optimization of the granulation process of medicinal powders in the fluidized bed / V.I. Gorodnichev, Hani M. El-Banna, B.V. Andreev // Chem.-farm. Journal. 1980. No. 10. S.72-77].

A solid dosage form comprising a therapeutically effective amount of aliskiren is known [US Pat. 2480210 RF, IPC A61K 31/16, A61K 31/137, A61K 9/20, A61K 9/30, A61J 3/10, A61P 9/10, A61P 9/00 RF. SOLID ORAL DOSAGE FORM AND METHOD OF TREATMENT].

Aliskiren-hemifumarate - part of its chemical structure is ethylene-1,2-dicarboxylic acid monoamide, is classified in the same class of drugs as the substance of the claimed composition. Aliskiren is recommended, including for the treatment of diseases of the cardiovascular system. When creating an oral form, including traditional excipients, for both active substances (aliskiren and the claimed) there were similar difficulties associated with the creation of drugs that meet the requirements of the pharmacopeia.

The oral form according to patent 2480210 and the method for its preparation are selected as prototypes for the claimed group of inventions.

In the process of developing tablets with 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid, it turned out that the introduction of the majority of known excipients and the use of traditional technology does not ensure compliance with at least two of the most important tablet indicators, namely, sufficient tablet strength and the release of the active substance required GF XI and XII, as well as the main foreign Pharmacopoeias (USP, BP, EP).

In terms of strength:

EPABK is a hydrophobic particles that practically do not have adhesion under pressure, i.e. compressibility. Since the dose of the active substance in the tablet should be quite high, of the order of 300 mg / tablet, i.e., in the tablet mass of 50-70%, the known binders do not provide tablets and granules of sufficient strength; the strength of tablets made using known binders (starch, gelatin, HPMC, PVP, etc.) does not exceed 2 kg. Such weak tablets are destroyed when trying to apply a film coating and during packaging.

In relation to release:

EPABK is practically insoluble and not wetted by water. Therefore, when determining the release according to the Dissolution test, less than 65% of the active substance passes from the tablet into the solution in 45 minutes, which does not meet the requirements of the Pharmacopoeia.

The objective of the proposed group of inventions is to develop a composition and method for producing a pharmaceutical composition in the form of tablets containing EPABA as an active substance, which would ensure the release of at least 75% of the active substance in 45 minutes in accordance with pharmacopoeial requirements and would have sufficient strength for subsequent technological operations i.e. at least 6 kg per tablet.

The problem is solved in that the pharmaceutical composition with anti-ischemic and antioxidant activity in the form of tablets or capsules contains 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid as the active component, an amine-containing compound selected from the group of trometamol, meglumine or L lysine, lactose, microcrystalline cellulose, calcium stearate and other pharmaceutically acceptable excipients, the content of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid in the composition being from 40 to 80 mass. %, and per mole of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid accounts for from 0.05 to 0.25 mol of the indicated amine-containing compound.

The problem is also solved in that the pharmaceutical composition as pharmaceutically acceptable excipients includes sucrose, magnesium carbonate, starch, mannitol, polyvinylpyrrolidone, disintegrants, antifriction and glidants, adopted in pharmaceutical technology.

The problem is also solved by the fact that the pharmaceutical composition can be in the form of tablets or capsules with a therapeutically effective dose of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid.

The problem is also solved by the fact that the method of obtaining a pharmaceutical composition with anti-ischemic and antioxidant activity includes sieving and mixing the components, granulating, drying, compressing tablets or packing in hard gelatin capsules, with 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid and the indicated amine-containing compound, taken in a molar ratio of 1: 0.05 to 1: 0.25, are pre-mixed, the mixture is moistened with an aqueous or alcohol solution of a binding agent, then pharmaceutically added to the moistened mixture acceptable excipients, in such an amount as to ensure the content of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid in a total weight of from 40 to 80 wt.%, then the mixture is granulated, dried and tablets or capsules are prepared according to known technology .

The problem is also solved by the fact that a starch-sugar paste or an alcoholic solution of polyvinylpyrrolidone is used as a binding agent.

The essence of the proposed invention

In the course of studies, it was unexpectedly established (and this solves the problem) that when mixing EPABA with an organic compound containing an amino group, for example trometamol, N-methylglucamine or L-lysine, and then moistening the mixture with an aqueous-alcoholic solution or water, followed by addition excipients - lactose, MCC, mannitol, sodium bicarbonate, magnesium carbonate or other pharmaceutically acceptable excipients - a wet mass is obtained. After drying and granulation, the mass acquires good flowability, tablets are easily pressed from it, or granulate can be packed into capsules by known technology. When pressed, durable tablets are obtained which are suitable for filling and coating. The tablets may be coated with a protective or decorative shell in a cooler or in a fluidized bed apparatus by known methods.

The release of the active substance from the tablets obtained by the proposed method is 80-90% in 45 minutes, which corresponds to pharmacopoeial requirements.

The relative molar ratio of EPABA to the amine-containing compound was found to be significant.

If less than 5 mol% of an amine-containing compound is added per 1 mol of EPABC, the tablets are not strong enough and the release does not exceed 65% in 45 minutes.

If we introduce more than 25 mol% of an amine-containing compound per 1 mol of EPABK into the composition, the mass is viscous, difficult to granulate and dry, and low-tech in processing.

Without claiming a theoretically substantiated description of the process, it was experimentally found that a combination of 5 ÷ 25 mol.% EPABA with an amine-containing compound is necessary and sufficient to give the granulate and tablet mass positive technological properties that provide good compressibility and release of the active substance.

It was also established that the content of EPABA in the tablet mass should be no more than 80%. In the case of a higher content of EPABK, the tablet mass is poorly pressed, the tablets are fragile. In addition, tablets with an EPABC content exceeding 80% disintegrate within more than 30 minutes, which does not meet the requirements of the Pharmacopoeia for disintegration. A decrease in the content of EPABA in the tablet mass below 40% is impractical due to an excessive increase in the average weight of the tablet.

The technical results of the claimed inventions are:

Creating a composition and method for its preparation.

The release of the active substance from the tablet in an amount of at least 75% in 45 minutes, which corresponds to pharmacopoeial requirements;

The strength of the tablets is at least 6 kg per 1 tablet, which provides the possibility of subsequent technological operations - applying a film coating, packing on automatic lines.

The achievement of the technical result is proved by determining the strength, dissolution and disintegration of the tablets in accordance with pharmacopoeial methods.

The invention is characterized by the following examples.

As follows from the data in the tables, the samples with 40 to 80 weight percent of EPABA in the composition, as well as 10-20 molar percent of the amine-containing compound with respect to EPABK, turned out to be the most durable and with high release rates. In the region of the lower limit of the content of the amino compound - 5% or less, the tablet strength begins to decrease, and the% release of the active substance also decreases. In the absence of the amino compound (sample 9), the tablets are very weak, and the degree of release is reduced to 60% or less.

With the introduction of more than 25 mol.% Of the amino compound with respect to EPABK, the mass becomes very viscous when mixed and moistened, it is difficult to granulate and dry. As a result of this, losses increase, the process of obtaining becomes non-technological and difficult to reproduce.

Examples of the method of obtaining a pharmaceutical composition with EPABK in the form of tablets

Example 1. Obtaining the cores of tablets EPABK with granulation with aqueous starch paste.

In a mortar, 60 g of EPABA are added in portions to 2 g of trometamol, mixing thoroughly after each serving is added. To the dry mixture are added 20 g of starch-sugar paste containing 2 g of beet sugar and 2 g of potato starch. The mass is thoroughly mixed and, for homogeneity, rubbed through a sieve with a hole size of 3.5 mm.

Then, 15 g of lactose, 7 g of microcrystalline cellulose and 10 g of sodium bicarbonate are added to the wet mass. The resulting mixture is rubbed through a sieve with a hole size of 2.5 mm, distributed on a tray and dried in a vacuum oven at (60-70) ° C to a residual moisture content of 2-4%.

The dried granulate is calibrated by rubbing through a sieve with a hole size of 1.0-1.5 mm. To the resulting powder, 1 g of polyplasdone XL, 1 g of calcium stearate are added and dusted in a dry powder mixer for 30 minutes.

Biconvex tablets with a diameter of 11 mm and an average weight of (0.500 ± 0.025) g are pressed from the resulting mixture.

The yield is 96 g (192 tablets). The properties of the obtained tablets are shown in table 2, example 3.

Example 2. Obtaining the cores of tablets EPABK with granulation with an alcoholic solution of PVP.

In a mortar, 50 g of EPABA are added in portions to 7.5 g of L-lysine, mixing thoroughly after each serving is added. 40 g of a 20% alcohol solution of PVP containing 8 g of PVP are added to the dry mixture. The mass is thoroughly mixed and wiped through a sieve with a hole size of 3.5 mm

Then, 10 g of lactose, 10 g of microcrystalline cellulose, 5 g of magnesium carbonate and 6.5 g of sodium bicarbonate are added to the wet mass.

The resulting mixture is rubbed through a sieve with a hole size of 2.5 mm, distributed on a tray and dried in a vacuum oven at 50 ° C to a residual moisture content of 2-3%.

The dried granulate is calibrated by rubbing through a sieve with a hole size of 1.0-1.5 mm. To the resulting powder, 2 g of polyplasdone XL, 1 g of calcium stearate are added and dusted in a dry powder mixer for 30 minutes.

Biconvex tablets with a diameter of 12 mm and an average weight (0.600 ± 0.030) g are pressed from the resulting mixture.

The yield is 91.2 g (152 tablets). The properties of the obtained tablets are shown in table.2, example 2.

Example 3. Obtaining cores of tablets EPABK with granulation with an aqueous starch paste and drying in a fluidized bed.

In a mortar, 100 g of EPABA are added in portions to 6.0 g of L-lysine, mixing thoroughly after each serving is added. 40 g of starch-sugar paste containing 6 g of beet sugar and 4 g of potato starch are added to the dry mixture. The mass is thoroughly mixed and wiped through a sieve with a hole size of 3.5 mm

Then, 18 g of lactose, 20 g of microcrystalline cellulose, 20 g of magnesium carbonate and 20 g of sodium bicarbonate are added to the wet mass and mixed until uniform.

The resulting mixture is rubbed through a 2.5 mm sieve. Wet granulate is placed in the fluidized bed dryer chamber and dried to a residual moisture content of 2-3%.

The dried granulate is calibrated by rubbing through a sieve with a hole size of 1.0-1.5 mm. To the resulting powder, 4 g of polyplasdone XL, 2 g of calcium stearate are added and dusted in a dry powder mixer for 30 minutes.

Biconvex tablets with a diameter of 12 mm and an average weight (0.600 ± 0.030) g are pressed from the resulting mixture.

The yield is 188 g (313 tablets). The properties of the obtained tablets are shown in table. 2, example 7.

Example 4. Antiischemic action

The anti-ischemic effect of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid (hereinafter EPABC) was studied in comparison with the anti-ischemic drugs used in the model of myocardial infarction performed by ligation of the left coronary artery in rats.

The most significant differences in the groups were obtained by: 1) the size of the left atrium, 2) the final systolic and diastolic sizes of the left ventricle, 3) the size of the necrosis zone in the myocardium.

Differences between groups of intact animals and negative control were significant. The absence of stretching of the left atrium when using effective doses and regimens of administration of EPABK indicates a decrease in the severity of pathological changes in the myocardium due to acute and chronic heart attacks. So, with the intragastric administration of trimetazidine and EPABC, an improvement was noted in comparison with the negative control, and there is a tendency for greater efficacy of EPABC, the value approaches that of intact rats.

The final systolic size of the left ventricle (KCRzh), as well as the final diastolic size (KRLzh), characterizes the factor of contractility of the left ventricle of the myocardium, and therefore its pumping function. Differences between groups of intact animals and negative control were significant. Against the background of intragastric administration of EPABK, significant differences were observed compared with data obtained from untreated rats.

As can be seen from the data of table 4, in the control series of experiments, the size of the zone of necrosis in rats amounted to 22.0 ± 2.0% of the total mass of the myocardium. The size of the ischemic zone during this period of time was equal to 34.0 ± 2.6% of the total mass of the myocardium. Thus, the size of the necrosis zone amounted to 68.0 + 4.3% of the size of the ischemic zone.

The latter indicator, according to modern ideas, is one of the important characteristics of ischemic myocardial alteration, since it does not depend on the level of coronary artery ligation and, therefore, is considered as the most stable value. EPABK at a dose of 60 mg / kg reduced the size of the necrosis zone to 39 + 9.4% of the ischemic zone, which is significantly more than this indicator in the group of the drug for comparison of meldonium (column 5).

Example 5. Antioxidant effect

CCl ₄ poisoning is a classic model of liver peroxidation. The activation of lipid peroxidation with the introduction of CCl ₄ is judged by the accumulation of peroxidation products - diene conjugates (DCs), lipid hydroperoxides (GPs) and malondialdehyde (MDA) in the blood and liver of rats.

As can be seen from the above data (Table 7), EPABK has a pronounced antioxidant effect, of the same order as methylethylpyridinol and the classical antioxidant - tocopherol acetate.

Thus, when studying the specific effect of EPABK, it was found:

1. The anti-ischemic effect of EPABK and a pharmaceutical composition based on it is manifested in the form of a positive effect on the systolic size of the atrium and left ventricle, the absence of myocardial hypertrophy, and improvement of pulmonary blood flow. Against the background of the introduction of EPABC, such phenomena as aneurysm, synergy, akinesia were not detected, thrombus formation was absent.

2. Against the background of the introduction of EPABC, an acceleration of the myocardial repair processes and a decrease in the necrosis zone, an increase in the working time, and an improvement in the contractile activity of the myocardium were observed.

3. The values of the antioxidant activity of the test substance EPABK and the pharmaceutical composition based on it allow us to attribute this compound to substances with moderate antioxidant activity.

Example 6. Determination of acute toxicity of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid (hereinafter EPABK)

The studies were carried out on outbred mice and rats in accordance with accepted international rules and protocols.

The experiment established:

- with intraperitoneal administration of the substance to white outbred mice, males and females, the LD ₅₀ value was 2440 mg / kg;

- with intragastric administration of the substance to white outbred mice, males and females, the LD ₅₀ value exceeded 5010 mg / kg;

- with intraperitoneal administration of the substance to white outbred rats, males and females, the LD ₅₀ value was 6050 mg / kg;

- with intragastric administration of the substance to white outbred rats, males and females, the LD ₅₀ value was 8900 mg / kg.

In accordance with the gradation of Hodge and Sterner, the tested pharmaceutical substance can be classified as low-toxic and non-toxic substances.

With the introduction of the pharmaceutical composition containing EPABK, the calculation of the dose was made in terms of substance.

The specific anti-ischemic and antioxidant activity of the finished dosage form (tablet) of the malonic acid derivative (EPABA) in an effective dose for animals was studied (Table 2). The powder of ground tablets for the preparation of a suspension was dissolved in purified water and administered orally (intragastrically).

Groups of 30 animals were formed:

1L - a group of false-operated animals (intact control) - an animal’s chest was opened, followed by suturing under conditions similar to other groups, but without ligation of the left coronary artery;

2L - negative control (group of animals with simulated pathology, but left without treatment);

3L - a group of animals that were administered intragastric drug comparison trimetazidine in a therapeutic dose for rats of 6 mg / kg for 60 days;

4L - a group of animals that were injected with the test substance intragastrically in a dose effective for the study of the substance for 60 days;

5L is a group of animals that were given an oral drug comparing meldonium at a therapeutic dose for rats of 85 mg / kg for 60 days.

The anti-ischemic effect is manifested in the form of a positive effect on the systolic size of the atrium and left ventricle, the absence of myocardial hypertrophy, and improvement of the blood flow in the pulmonary artery. Against the background of the introduction of tablets, such phenomena as aneurysm, synergy, akinesia were not detected, there was no thrombosis. Based on the data obtained on the 29th and 60th day of therapy, treatment for 28 days can be considered sufficient, which is consistent with the timing of the main stages of post-infarction myocardial remodeling.

The anti-ischemic and antioxidant effect of GLF corresponds to those in terms of the released substance.

The safety of the finished dosage form of the derivative of malonic acid in acute and chronic experiments was studied. The obtained values of LD ₅₀ in mice and rats of different sexes when administered orally allow us to attribute the test drug to drugs with low toxicity. The values of LD ₅₀ exceed 2000 mg / kg

Long-term (16 weeks) administration of the finished dosage form (tablet) does not lead to changes in the main parameters of experimental animals of different sexes - there is no change in the composition of peripheral blood, biochemical parameters, hemostasis, or clinical parameters of urine. Against the background of the introduction of the test drug, the dynamics of body weight, indicators of the cardiovascular, urinary and central nervous systems do not change. Pathomorphological and histological studies did not reveal a damaging effect on the organs and tissues of experimental animals. There were no delayed toxic effects.

Claims (6)

1. A pharmaceutical composition with anti-ischemic and antioxidant activity in the form of tablets or capsules, characterized in that it contains 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid as an active component, an amine-containing compound selected from the group of trometamol, meglumine or L-lysine, lactose, microcrystalline cellulose, calcium stearate and other pharmaceutically acceptable excipients, the content of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid in the composition being from 40 to 80 wt.%, and on 1 mol 4 - ((3-oxo-3- toksipropanoil) amino) benzoic acid have from 0.05 to 0.25 moles of said amine compound. 2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable excipients include sucrose, magnesium carbonate, starch, mannitol, polyvinylpyrrolidone, disintegrants, antifriction and glidants, adopted in pharmaceutical technology. 3. The pharmaceutical composition according to any one of claims 1, 2, characterized in that it is made in the form of tablets with a therapeutically effective dose of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid. 4. The pharmaceutical composition according to any one of claims 1, 2, characterized in that it is in the form of capsules with a therapeutically effective dose of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid. 5. A method of obtaining a pharmaceutical composition with anti-ischemic and antioxidant activity according to claim 1 or 2, comprising sieving and mixing the components, granulating, drying, compressing the tablets or packing in hard gelatin capsules, characterized in that 4 - ((3-oxo-3 -ethoxypropanoyl) amino) benzoic acid and the indicated amine-containing compound, taken in a molar ratio of 1: 0.05 to 1: 0.25, are pre-mixed, the mixture is moistened with an aqueous or alcohol solution of a binding agent, then pharmaceutically added acceptable fillers in such an amount as to provide a content of 4 - ((3-oxo-3-ethoxypropanoyl) amino) benzoic acid in a total weight of from 40 to 80 wt.%, then the mixture is granulated, dried and tablets or capsules are prepared according to known technology. 6. The method according to claim 5, in which a starch-sugar paste or an alcoholic solution of polyvinylpyrrolidone is used as a binding agent.