RU2468789C1 - Medication for prevention and treatment of atheroslerosis - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, medicine, pharmacology and represents medication for prevention and treatment of atherosclerotic lesion of blood vessels, as well as pre- and thrombotic states, which possesses hypolipidemic and anticoagulant and antithrombotic activity, and is made in dosed drug form in form of coated tablets, consisting of core, which contains active substance and auxiliary substances, characterised by the fact that core contains substance of sulfated arabinogalactan potassium salt as active ingredient, and ludipress, aerosol and sodium stearate as auxiliary substances, components in medication being in definite ratio in wt %.

EFFECT: invention ensures efficient treatment and prevention of atherosclerotic lesion of blood vessels, as well as pre- and thrombotic states.

4 cl, 5 tbl

Description

The invention relates to the pharmaceutical industry, medicine, pharmacology, and for the production of agents for the prevention and treatment of atherosclerosis.

Atherosclerotic damage to blood vessels is the most common cause of mortality and disability in industrialized countries. It is based on violations of the hemostatic system and deterioration of the rheological properties of blood, as well as violations of lipid metabolism in the body, leading to various cardiovascular pathologies (strokes, heart attacks, thromboembolism, etc.).

According to the World Health Organization, the number of people suffering from cardiovascular diseases is constantly growing. In Russia, due to unfavorable environmental conditions and a decrease in the quality of life, a surge in the development of cardiovascular pathology is observed. All this forms a steady acute demand for lipid-lowering drugs, which is currently made up only by imported expensive means of various chemical structure groups (statins, fibroic acid derivatives), which in turn are not always effective and have a large number of side effects.

The high demand for lipid-lowering drugs in the world market is evidenced by the fact that sales of these drugs in the period from 1985 to 2000 increased from $ 250 million to $ 2.64 billion, in 2008 this figure was only for one group of drugs ( statins) amounted to about $ 50 billion. This indicates a constant increase in the number of patients with various disorders of lipid metabolism in the body.

A possible approach to solving the issues of prevention and treatment of atherosclerosis is the use of funds aimed both at normalizing blood hemostasis and reducing the overall level of lipids, as well as at changing individual components of the blood lipid spectrum.

This class of potential lipid-lowering drugs includes heparinoids - natural, synthetic and semi-synthetic substances that act like heparin, but differ in chemical structure, molecular weight and some pharmacological properties. Heparinoid-based drugs are widely used in foreign practical medicine, however, units are used as lipid-lowering drugs. They do not meet the main requirement for modern lipid-lowering drugs - their mandatory oral use, since heparinoids are extremely easily destroyed in the digestive tract, as a result of which their absorption and entry into the blood are disturbed.

On the Russian pharmaceutical market, at present, this class of interesting biologically active substances is represented only by the expensive imported drug Wessel Due F ^® (sulodexide) 250 LU capsules (liposemic units), 600 LU / 2 ml injection solution manufactured by Alfa- Wassermann SpA »Italy. It is the only one that has an oral dosage form in the form of capsules, which is used, however, not as a lipid-lowering agent, but only as a direct-acting anticoagulant for the prevention and treatment of angiopathies of various localization, although its use as a means for the secondary prevention of coronary atherosclerosis and its complications is proven by clinical trials: 6-month use of the drug along with antithrombotic gives a pronounced hypolipidemic effect. In patients with unstable angina pectoris and severe stable angina pectoris (III, IV functional class), Wessel Due F ^® reduced total cholesterol by 25%, low density lipoproteins - by 27%, triglycerides - by 37% [Aronov D.M. Hypolipidemic effect of low molecular weight heparin - sulodexide (Vesel duet F) in patients with coronary artery disease / D.M. Aronov, M.G. Bubnova, N.V. Petrova, V.P. Zykova, A.S. Odintsova, A.M. Olferiev . // Wedge, pharmacol. ter. - 1995. - No. 3. - S.24-26]. According to a large, multicenter, placebo-controlled study involving more than 4 thousand patients with acute myocardial infarction, half of whom received 1 Wessel Due F ^® for 1 year 2 times a day, Wessel Due F ^® significantly reduces the frequency lethal outcomes, non-fatal myocardial infarction and other exacerbations of coronary heart disease, as well as the frequency of thrombosis of the left ventricle of the heart (IPO-V2-STUDY, JACE) [Aronov D.M. Modern methods of treatment of atherosclerosis / D.M. Aronov. // Ter. arch. - 1997. - No. 11. - S.75-81].

Developed in the late 90s of the XX century by the All-Russian Research Institute of the Meat Industry named after V.M. Gorbatov RAAS, the domestic analogue of the modern drug "Wessel Due F ^® ", as well as the Aryloid drug Crynos Italy, registered in the USSR in those years [ Walenga, JM Non heparin glycosaminoglycan derived drugs / JM Walenga, D. Hoppensteadt, J. Fareed. // Semin. Thromb. Hemost. - 1991. - Vol.17, No. 2. - P.137-142] - the drug “Alipril” (enteric-coated tablets 0.075 g No. 10), which has undergone clinical trials: a 3-month course of treatment with this drug can reduce total cholesterol by 10-12%, low density lipoproteins by 16-18%, triglycerides by 21-35%, increase the level of high density lipoproteins by 20-21% [Gavrilov A.S. The drug for the treatment of atherosclerosis "Alipril" / A.S. Gavrilov, R.V. Ilyukhina, I.V. Isaeva, L.A. Lyublinskaya. // Chem.-farm. journal - 2001. - No. 7. - S.53-56] and approved for use as a drug for the treatment of lipid metabolism disorders, type II hyperlipoproteinemia (including those with low HDL) (VFS 42-2936-99 Alipril tablets, registration number 2000 / 27/4 from 01/26/2000), and has not been introduced into medical practice.

"Wessel Douie F ^® " and "Alipril" belong to the class of organ preparations obtained from the intestinal mucosa of pigs [US Patent 3936351, IPC A61K 35/38. Metod for preparing glucoronyl-glucosamino-glycan sulphates exhibiting antilipasaemic activity / Bianchini P .; Opocrin Srl, Modena, Italy. - No. 25371/73; declared 06/14/1973; publ. 06/13/1974; No. 479036 (Italy); Patent 2167663 Russia, IPC A61K 35/38. A method of obtaining heparinoid / Lisitsyn A.B., Ilyukhina R.V., Isaeva I.V., Lublinskaya L.A .; All-Russian Research Institute of the Meat Industry named after V.M. Gorbatova. - No.2000110706 / 14; declared 04/28/2000; publ. May 27, 2001].

Significant disadvantages of organizational drugs:

1. the presence in their composition of traces of protein and histamine-like substances, leading to the appearance of allergic reactions during use;

2. the complex composition of the active substance or substances, which is not always constant (both during production and during storage), leading to the lack of adequate methods for its standardization;

3. In addition, the soft capsules of the Wessel Dué F ^® preparation are gastric soluble, since they contain only gelatin and glycerin, excluding preservatives and dyes (sodium ethyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, titanium dioxide and red iron oxide) [ND 42-1421-00. Wessel Douai F (250 LE capsules). - M., 2000, reg. number: P No. 01112490 / 01-2000], which leads to partial destruction of the drug in the stomach. As a result, the effectiveness of the known drug is significantly reduced.

The Irkutsk Institute of Chemistry named after A.E. Favorsky SB RAS for the first time using the directed synthesis method to create a new representative of the class of semisynthetic heparinoids, developed an original pharmacologically active substance (Agsular®) with hypolipidemic and anticoagulant activity [Patent 2319707 Russia, IPC С07Н 3 / 02, C08B 37/00. A method of producing sulfated derivatives of arabinogalactan with anticoagulant and lipid-lowering activity / Kostyro Y.A., Ganenko T.V., Medvedeva S.A., Sukhov B.G., Trofimov B.A .; Irkutsk Institute of Chemistry named after A.E. Favorsky SB RAS. - No. 2007100464/04; declared 01/09/2007; publ. 03/20/2008; Certificate for the Agsular ^® trademark No. 398618 dated 01/19/2010]. According to preclinical studies on the effectiveness of the substance “Agsular ^® ” is not inferior to the drug “Wessel Due F ^® ” (anticoagulant and antithrombotic activity) and the drug “Zokor ^® ” (simvastatin) (hypolipidemic and anti-atherogenic activity) [Kostyro Y.A. Sulfated arabinogalactan - a promising domestic analogue of sulodexide / Ya.A. Kostyro, G.N. Kovalskaya. // Bulletin of the VSSC SB RAMS. - 2008. - No. 2, T.60. - S. 117].

Advantages of the original substance "Agsular ^® " in comparison with existing analogues.

1. "Agsular ^® " is a chemically pure biologically active substance with an established structure and standardization methods developed.

2. The basis flowsheet producing substance "Agsular ^®» is chemical modification (sulphation) vegetable polysaccharide - arabinogalactan, the resulting complex wasteless processing timber Siberian larch (Larix sibirica Ledeb.) [Russian Patent 2256668, IPC S08V 37/00. A method of obtaining arabinogalactan / Babkin V.A., Kolzunova L.G., Medvedeva E.N., Malkov Yu.A., Ostroukhova L.A .; Irkutsk Institute of Chemistry named after A.E. Favorsky SB RAS. - No. 2003122811/04; declared 07/21/2003; publ. July 20, 2005]. The content of arabinogalactan in the wood reaches about 15%, so from 1 m ^{3 of} unused large-tonnage waste from forest processing - lumps of Siberian larch with a moisture content of 52% can be obtained up to 26-54 kg of arabinogalactan.

3. The substance "Agsular ^® " inherits the structural organization of the original biopolymer of arabinogalactan, which is fundamentally important for the implementation of the membrane-acting action through receptor-mediated endocytosis by the cells of the body [US Patent 5478576, IPC A61K 38/14, C07K 17/00. Arabinogalactan derivatives and uses thereof / Jung C., Enriquez P., Palmacci S., Josephson L., Lewis JM; Advanced Magnetics, Inc. - No. 900686; declared 06/17/1992; publ. 12/26/1995]. First of all, liver cells, the richest asialoglycoprotein receptors, where the substance Agsular ^® can regulate the synthesis of blood coagulation factors, as well as the synthesis and metabolism of cholesterol, bile acids and triglycerides, thus allowing the prevention and treatment of atherosclerotic damage to blood vessels with maximum efficiency with a minimum of side effects.

4. The substance “Agsular ^® ” is a potassium salt of sulfated arabinogalactan and is a weak acid (pKa = 3.16; pH of _{aqueous solutions} = 5.1), as a result of which it has good absorption in the stomach [I. Muravyov. Biopharmaceutical fundamentals of the technology of drugs and their use in the activities of pharmacies GAPU MH RSFSR: Guidelines / I.A. Muraviev, V.D. Kozmin, N.F. Kononikhina. - Pyatigorsk :, 1983. - 44 p., Ill.]. In addition, all sulfate groups in the biopolymer macromolecule are ether-bonded, which complicates acid cleavage, which increases the resistance of the Agsular ^® substance to acid hydrolysis under the action of gastric juice. These data confirm the high rate of relative bioavailability of the Agsular ^® substance when taken orally, equal to 54.4%, indicating the stability of the test compound in the gastrointestinal tract of experimental animals [Kostyro, Ya.A. Experimental pharmacokinetics of sulfated arabinogalactan in various routes of administration / Y.A. Kostyro, G.N. Kovalskaya, O.A.Silizerseva, O.P. Ilyina. // Pharmacy. - 2008. - No. 1. - S. 45-46].

Considering the physicochemical properties and specific pharmacological activity (hypolipidemic and anticoagulant) of the Agsular ^® substance, its most rational oral dosage form is tablets or capsules.

Earlier, we made an attempt to create a tablet dosage form of the Agsular ^® drug (prototype: Y. Kostyro. Development of a production technology, study of the properties of sulfated arabinogalactan and creation of a tablet dosage form of an anticoagulant and lipid-lowering drug: abstract of dissertation: Candidate of Pharmaceutical Sciences :.. 15.00.01, 15.00.02 / Ya.A.Kostyro - M., 2008. - 23 p] tablets were prepared by direct compression of the main active ingredient -preparata "Agsular ^®» with auxiliaries as entirely. omogatelnyh substances were taken microcrystalline cellulose or polyvinylpyrrolidone, silicon dioxide and lactose storage time of such tablets -. not more than two years due to the hygroscopicity of potassium salt of sulfated arabinogalactan, and tablets were not protected by a cover from the impact of atmospheric moisture.

The aim of the invention is the creation of a medicinal product based on the substance "Agsular ^® " in the form of solid dosage forms for oral administration, which will expand the range of lipid-lowering drugs and direct-acting anticoagulants of domestic production and ensure national security in the country in the field of drug supply to the population.

The technical result of this invention is the development of effective oral dosage forms based on the substance "Agsular ^® " for the prevention and treatment of atherosclerosis.

The technical result is achieved in that the dosage form having hypolipidemic, anticoagulant and antithrombotic action consists of a core (capsule mass) containing Agsular ^® substance and excipients as an active active principle. The tablet-dissolving shell of the tablet or gelatin capsule is used only to protect the dosage form from exposure to atmospheric moisture, as the Agsular ^® substance is highly hygroscopic (20.07%). As an auxiliary substance of the core (capsule mixture), ludipress, aerosil, calcium stearic acid are used, with the following components in wt.%:

Agsular ^® 47.0-62.0 Ludipress 30.0-47.5 Aerosil 4.0-6.2 Calcium stearic acid 1.0;

and the shell contains the following components in wt.%:

Ethyl cellulose 24.5-29 Lauryl sulfate 0.9-1.7 Cetyl alcohol 1.7-3.3

The protective shell, including ethyl cellulose, lauryl sulfate and cetyl alcohol, is applied in an amount of 1-2% by weight of the tablet.

The technical result is achieved by using, in contrast to the closest analogues, more modern auxiliary substances that improve the flowability and compressibility of the active substance, such as ludipress and calcium stearic acid. In addition, the technical result of the invention is also achieved by a previously unused method for the manufacture of an oral dosage form, according to which the substance Agsular ^® , ludipress, aerosil, calcium stearic acid are mixed. The resulting mixture is subjected to dry granulation, which includes obtaining briquettes with a diameter of at least 25 mm from the mixture of active and auxiliary substances, grinding them in a roller mill, fractioning the obtained granules on sieves, then, to obtain coated tablets, dusting of the granule fraction is carried out at least 1 mm calcium stearic acid, followed by tableting and applying a protective coating in the form of a 30% aqueous suspension containing the composition of the shell, in an amount of 1-2% by weight of the tablet, and to obtain caps l - granules (fraction size granules at least 1 mm) is filled into hard gelatin capsules size lid №1 - 00.

The essence of the claimed invention is as follows.

The original pharmacologically active substance “Agsular ^® ” is a semisynthetic heparinoid, which is sulfated arabinogalactan in the form of potassium salt and has hypolipidemic, anticoagulant and antithrombotic activity.

The use of ludipress as auxiliary substances (composition: lactose 91.0-95.0%, collidone 30 3.0-4.0% and collidone CL 3.0-4.0%), aerosil, calcium stearic acid in the claimed amounts allows to obtain storage forms of dosage forms (tablets and capsules) and ensures the release (at least 75%) of the Agsular ^® substance within 45 minutes, which fully complies with the requirements of the General Pharmacopoeia Monograph 42-0003-04 Dissolution.

The use of a combination of substances for coating a tablet, including ethyl cellulose, lauryl sulfate and cetyl alcohol, allows to obtain a high-strength, stable, easily soluble protective coating in the stomach, giving the tablet a pleasant appearance and protecting the active substance from atmospheric moisture.

The use of dry granulation makes it possible to obtain tablets of high strength with a small pressing force that fully comply with the requirements of GF XI, issue 2, OFS "Tablets" in all respects.

If it is not possible to apply a protective coating to the tablets, the granulate is placed in hard gelatin capsules with a cap No. 1 - 00 in size, as a result of which a dosage form (capsules) is obtained, which in its characteristics fully corresponds to GF XI, issue 2, OFS " Capsules. "

The technological process for industrial reproduction was determined by the results of experimental work, a summary of which is presented in table 1.

Table 1 Technological characteristics of tablet mixtures Name of components Tablet mixtures, wt.% No. 1 Number 2 Number 3 Number 4 The substance "Agsular ^® " 47.15 61.88 73.33 82.92 Ludipress 47.15 30.94 18.34 13.27 Aerosil 4.70 6.18 7.33 3.31 Calcium stearic acid 1.00 1.00 1.00 0.50 Flowability of the mixture to dry granulation, g / s 5.5 2.6 2.0 1,5 Flowability of the mixture after dry granulation, g / s 10.7 6.4 4.6 3,1 Compressibility (fracture strength), N 44.5 15.0 11,2 9.7 Bulk weight, kg / m ³ 1349.69 1269.94 1214.72 497.00 Size of Hard Gelatin Capsules one 0 00

As can be seen from the data presented in the table, only tablet mixtures No. 1 and 2 satisfy the technological requirements of the tabletting and encapsulation process [Borzunov E.E. Research in the field of physicochemical mechanics of tabletting of medicinal powdered substances: abstract Dis: Dr. Pharmac. Sciences: 15.00.01 / E.E.Borzunov. - Lviv, 1972. - 41 p .; Walter M.B. Step-by-step control in the production of tablets / M.B. Walter, O.L. Tyutenkov, N.A. Filippin. - M .: Medicine, 1982. - 208 p.].

The suitability of oral dosage forms (capsules, coated tablets), created on the basis of the substance Agsular ^® , as a means for the prevention and treatment of atherosclerotic damage to blood vessels and various thrombotic conditions, is proved by the results of preclinical studies.

The preclinical study of the Agsular ^® substance and oral dosage forms developed on its basis was carried out in accordance with the Guidelines for the experimental (preclinical) study of new pharmacological substances / Ed. V.P. Fisenko. - M .: CJSC IIA "Remedium", 2000. The results are presented in the form of relevant reports.

ACUTE TOXICITY STUDY

To determine indicators of acute toxicity, the drug (in the form of a freshly prepared aqueous suspension of ground tablets or capsule contents) was administered intragastrically to white mice and rats of both sexes through an atraumatic metal probe according to Litchfield-Wilcoxon. Calculations of average lethal doses were carried out according to VB Prozorovsky [Prozorovsky VB The express method for determining the average effective dose and its error / VB Prozorovsky, M.P. Prozorovskaya, V.M.Demchenko. // Farmakol. and toxicol. - 1978. - No. 4. - S.497-502]. To achieve large doses of the drug, administration was repeated at intervals of 20-30 minutes for 4 hours. Control animals received similar volumes of distilled water. Dosing was carried out in terms of the content of the active component in dosage forms.

The observation period was 14 days. Recorded indicators: mortality, time of death, symptoms of poisoning, daily observation of the general condition and behavior, weighing before administration, on days 7 and 14 of observation, volumes of feed and water consumption (for this the animals were placed in metabolic cages of the Italian company Texnoplast), autopsy and a macroscopic study of all dead and surviving animals at the end of the study (euthanasia in rodents was carried out by an overdose of ether), determination of mass coefficients of internal organs.

The dose-dependent oral dosage forms of the Agsular ^® preparation have lethal effects shown in Table 2.

table 2 The toxicity of the oral dosage forms of the drug "Agsular ^® " with the intragastric route of administration Kind of animal Floor LD ₅₀ (mg / kg) the mouse females 5950 ± 225 males 5320 ± 500 rats females 10000 ± 600 males 10400 ± 700

The death of animals during intragastric administration of lethal doses of oral dosage forms of the drug (more than 6 g / kg) was observed within 1.5-5 hours from the moment of administration with the effects of excitement, subsequent lethargy, lethargy, stunning, lateral position, sudden shallow breathing, convulsions in the atonal stage and paralysis.

The autopsy of dead animals during intragastric administration revealed, in addition to signs of venous congestion of internal organs, subpleural, subdural hemorrhages, as well as small hemorrhages in the medulla oblongata and in the cerebral hemispheres. In the remaining experimental animals receiving doses of less than 6 g / kg, ataxia, lethargy, lethargy, and a decrease in feed and water intake were observed on the first day. On the remaining days, the general condition and behavior of the animals receiving the study drug did not differ from those in the animals of the control group receiving water. Significant sex differences during intoxication and toxicometric indicators were not observed.

According to autopsy and macroscopic examination of internal organs, acute intragastric administration of the oral dosage forms of the Agsular ^® preparation in the studied doses to white mice and rats of both sexes does not cause macroscopic changes in the internal and endocrine organs, the brain, and also the gastric and intestinal mucosa.

Thus, the results of toxicometry, data of necropsy and observations of experimental animals in the post-toxicity period of acute poisoning make it possible to classify the oral dosage forms of the Agsular ^® drug as class V practically non-toxic drugs [Hodge, H. Clinical Toxicology of Commercial Products / H. Hodge et al. - Acute Poisoning. Ed. IV, Baltimor, 1975. - 427 p.].

The condition of the animals that survived acute intoxication indicates good tolerance and harmlessness of the oral dosage forms of the drug at doses that are ten times higher than the therapeutic ones. The therapeutic index of the drug is about 1000 (a single dose for humans is 10-15 mg / kg, and LD ₅₀ for rats with intragastric administration is about 10,000 mg / kg).

RESEARCH OF SUBSTITUTE AND CHRONIC TOXICITY Given the low toxicity of the drug shown in the acute experiment, recommendations of regulatory documents of the Ministry of Health of the Russian Federation and GLP rules, as well as the duration of the drug in humans and the maximum effective therapeutic dose (10-15 mg / kg per person per day) or 2 tablets (capsules) of a dosage form with an active ingredient content of 500 mg), a period of 1 month was chosen to evaluate subacute toxicity, and chronic administration was carried out for 3 months.

In experiments on rodents (rats of both sexes), oral dosage forms of the drug were administered intragastrically through a probe daily for 90 days in 3 doses: therapeutic - 15 mg / kg; the expected maximum is 1500 mg / kg (100 times greater than the therapeutic one, does not cause death of rats with a single injection) and the intermediate is 500 mg / kg.

It should be noted that during the experiment, the death of experimental animals was not observed, which indicates a low material cumulation of the studied oral dosage forms of the drug and a tendency to addiction.

Thus, the use of the oral dosage forms of the Agsular ^® preparation in rats of both sexes intragastrically once a day for 90 days at doses of 15, 500 and 1500 mg / kg does not affect the appearance, general condition and behavior of animals, does not negatively influence on the biochemical parameters of the blood and the basic physiological functions of the body, does not cause pathomorphological changes, which indicates good tolerability and relative harmlessness of the drug.

Based on the results of the subacute experiment, the safety index (IS) of the new drug was calculated, amounting to 16.9. The calculated safe course (RBC) of the drug in days is 1525.

In accordance with the classification of the dangers of drugs for clinical use (IB more than 5), Agsular ^® belongs to the III class of low toxic (low hazard) drugs.

RESEARCH OF SPECIFIC PHARMACOLOGICAL ACTION

To evaluate the lipid-lowering activity of the inventive solid dosage forms of the Agsular ^® preparation (coated tablets and capsules) for the prevention and treatment of atherosclerosis, their effect on the main lipid metabolism indices in rats was studied on a model of experimental hyperlipidemia induced by the use of a hypercholesterolemic diet that is oversaturated fats [Reproduction of diseases in animals for experimental and therapeutic research / Ed. N.V. Lazareva. - M .: MedGIZ, 1954].

For this, experimental animals consumed a homogeneous feed of the following composition:

casein - 5%;

sunflower oil mixed with pork fat - 40%;

glucose - 45%;

agar - 2%;

salts, vitamins - 4%;

cholic acid - 1%;

thiouracil-1%;

cholesterol - 4%.

In addition, rats were additionally intragastrically injected with a 10% cholesterol oil solution at a dose of 100 mg / kg.

Solid dosage forms "Agsular ^®" and reference drugs "Vessel Due F ^® capsules 250 LU» Alfa-Wassermann SpA manufactured, Italy and "Zocor ^® coated tablets, 10 mg" manufactured by «Merck Sharp & Dohme» formulation, The Netherlands was administered intragastrically at a dose of 100 mg / kg (108 LU / kg) an hour before the introduction of cholesterol for 1.5 months against the background of the above diet.

The intact group of rats received the usual vivar diet.

Blood sampling was carried out at the end of the study, 18 hours after the last injection. Moreover, animals during this period were deprived of food.

All laboratory tests were carried out according to standard methods [V. Menshikov. Laboratory research methods in the clinic: reference book / V.V. Menshikov, L.N.Dilekterskaya, R.P. Zolotnitskaya. - M .: Medicine, 1987; and Kolb V.G. Clinical Biochemistry / V.G. Kolb, B.C. Kamyshnikov. - M .: Minsk, Belarus, 1976. - S.150-171].

Animals slaughtered by decapitation underwent postmortem autopsy, and the aorta underwent histological examination.

Statistical processing of the experimental results was carried out according to Student and Fisher.

The experimental results are presented in tables 3 and 4.

Table 3 The effect of capsules of the drug "Agsular ^® " on the development of experimental hyperlipidemia in rats induced by the use of an atherogenic diet Group of animals Indicators of lipid metabolism, mmol / l IA XC total. HS-HDL HS-LDL HS-VLDLP TG Intact animals, n = 6 1.44 ± 0.19 0.99 ± 0.05 0.16 ± 0.12 0.27 ± 0.15 0.74 ± 0.11 0.45 GHS diet, n = 6 2.53 ± 0.18 * 0.98 ± 0.12 0.99 ± 0.30 * 0.56 ± 0.24 ** 1.34 ± 0.38 * 1,58 GHS-diet + capsules of the drug "Agsular ^® ", n = 6 1.59 ± 0.08 * 0.98 ± 0.06 0.27 ± 0.07 * 0.34 ± 0.07 0.37 ± 0.04 * 0.62 GHS-diet + capsules of the drug "Wessel Duet F ^® ", n = 6 2.06 ± 0.18 * 1.08 ± 0.15 0.57 ± 0.13 ** 0.42 ± 0.05 0.73 ± 0.13 * 0.94 Note - * p≤0.01; ** p≤0.05; comparisons are given: the second group from the first, the remaining groups from the second

Capsules of the drug “Agsular ^® ” and capsules of the drug “Wessel Duet F ^® ” when administered orally at doses of 100 mg / kg and 108 LU / kg, respectively, in terms of the active substance, positively affect the course of the atherogenic diet induced hyperlipidemia in rats, delaying its development and significantly reducing total cholesterol _{(total cholesterol.)} by 37.2% and 18.6% (p ≤ 0.01), cholesterol low density lipoprotein (LDL-C) by 72.7% and 42.4% ( p≤0.05), respectively. In addition, in the experimental group of animals treated with capsules of the Agsular ^® drug, a pronounced hypotriglyceridemic effect is observed, in which the level of triglycerides (TG) is significantly (p≤0.01) reduced by 72.4% compared with the model group of animals and exceeds this indicator in the experimental group of animals that received capsules of the drug "Wessel Due F ^® " by 26.9%.

Table 4 The effect of the tablets of the drug "Agsular ^® " on the development of experimental hyperlipidemia in rats induced by the use of an atherogenic diet Group of animals Lipid metabolism Atherogenic coefficient, total cholesterol / ph mmol / l g / l XC total. TG FL β-LP Intact animals, n = 6 1.60 ± 0.10 2.80 ± 0.10 2.90 ± 0.20 1.90 ± 0.10 0.55 ± 0.06 GHS diet, n = 6 3.10 ± 0.30 * 5.00 ± 0.40 * 2.00 ± 0.20 * 4.40 ± 0.50 * 1.55 ± 0.11 * GHS-diet + tablets of the drug "Agsular ^® ", n = 6 1.50 ± 0.20 * 2.30 ± 0.20 * 2.70 ± 0.20 1.80 ± 0.20 * 0.56 ± 0.08 * GHS-diet + tablets of the drug "Zokor", n = 6 1.30 ± 0.20 * 2.10 ± 0.20 * 3.20 ± 0.20 * 1.50 ± 0.10 * 0.41 ± 0.03 * Note - * p≤0.05; comparisons are given: the second group from the first, the remaining groups from the second

The tablets of the Agsular ^® preparation and the tablets of the Zokor ^® preparation, when administered orally at doses of 100 mg / kg, calculated on the active substance, also positively affect the course of the hyperlipidemia induced by the atherogenic diet in rats, delaying its development and significantly reducing the total cholesterol (cholesterol) _total. ) 51.6% and 58.1% (p≤0.05), the level of atherogenic lipoproteins (β-LP) is 40.9% and 65.9% (p≤0.05), respectively. As well as when using the capsules of the Agsular ^® preparation in the experimental group of animals treated with the tablets of the Agsular ^® preparation, a pronounced hypotriglyceridemic effect is observed, in which the level of triglycerides (TG) is significantly (p≤0.05) reduced by 54.0% compared with the model group of animals and is not inferior to the value of this indicator in the experimental group of animals receiving tablets of the drug "Zokor ^® " (58.0%).

Autopsy of experimental animals that did not receive treatment revealed fat strips and spots of pale yellow color on the aorta. At the same time, atherosclerotic plaques with xanthoma cells were histologically determined. In groups of animals treated with coated tablets and capsules of the Agsular ^® preparation, the aorta morphologically did not differ from the aorta of intact animals. Moreover, the effectiveness of the claimed solid dosage forms was not inferior to the effectiveness of the comparison products.

Thus, coated tablets and capsules of the Agsular ^® preparation possess not only lipid-lowering activity, which is manifested in hypocholesterolemic and hypotriglyceridemic action, but also have anti-atherosclerotic effect.

In clinical practice, the drug "Wessel Duet F ^® " is used as a direct-acting anticoagulant with an antithrombotic effect [I. Kazakova The use of sulodexide in the treatment of chronic glomerulonephritis / I.A. Kazakova. // Pharmacy. - 2003. - No. 4. - S. 29-32]. As you know, hyperlipidemic conditions are accompanied by a violation of the blood hemostasis system, which leads to thrombosis. Therefore, on the model of experimental hyperlipidemia induced by the use of an atherogenic diet in rats, the anticoagulant and antithrombotic activity of the solid dosage form of the Agsular ^® preparation in the form of capsules was studied in comparison with the Wessel Duet F ^® preparation. The results of the study are presented in table 5.

Table 5 The effect of capsules of the drug "Agsular ^® " on the coagulometric parameters of blood of rats with the development of experimental hyperlipidemia induced by the use of an atherogenic diet Group of animals APTV, s Platelet Hemostasis Er 10 ¹² / L Tr 10 ⁹ / L Agrescreen test, s Intact animals, n = 6 20.67 ± 3.49 3,50 ± 0,56 168.67 ± 64.16 15.83 ± 1.68 GHS diet, n = 6 17.83 ± 2.92 3.37 ± 0.47 260.50 ± 62.93 ** 20.50 ± 2.91 * GHS-diet + capsules of the drug "Agsular ^® ", n = 6 27.58 ± 3.19 * 3.12 ± 0.62 219.33 ± 41.36 29.00 ± 12.82 GHS-diet + capsules of the drug "Wessel Duet F ^® ", n = 6 26.83 ± 2.14 * 3.40 ± 0.46 180.83 ± 45.40 ** 38.17 ± 14.86 ** Note - * p≤0.01; ** p≤0.05; comparisons are given: the second group from the first, the remaining groups from the second

A significant increase in platelet aggregation time under the influence of a universal aggregation inducer (agrescreen test) in animals of the model group by 29.5% (p≤0.01) compared with the control (intact animals) is also accompanied by a significant increase in the total number of platelets (Tr) by 54.4% (p≤0.05), which indicates a risk of developing a prethrombotic condition, accompanied by platelet dysfunction.

Both studied oral forms in the form of capsules of the Agsular ^® and Wessel Due F ^® drugs have an antiplatelet effect: the development time of platelet aggregation is extended by 83.2% and 141.1% compared with the control (intact animals), respectively. In this case, a decrease in platelet level by 15.9% (capsules of the drug "Agsular ^® ") and by 30.6% (capsules of the drug "Wessel Due F ^® ") compared with the level of platelets in the hyperlipidemic blood of animals of the model group.

At the same time, the capsules of the Agsular ^® preparation have a pronounced anticoagulant effect when administered orally, so the decrease in blood coagulability by the APTT test (activated partial thromboplastin time) reaches 54.68% (p≤0.01) compared with this indicator in the model group of animals , that is, it causes "therapeutic" hypocoagulation of blood plasma (an increase in the APTT by 1.5 times). A similar effect was observed with the use of Wessel Dué F ^® capsules: a decrease in blood coagulability by the APTT test reaches 50.48% (p≤0.01) compared with this indicator in the model group of animals, that is, it causes “therapeutic” hypocoagulation blood plasma (increase in APTT by 1.5 times).

Thus, as a result of the experiment, a positive effect of the Agsular ^® capsules for oral administration on the blood hemostasis indices for induced hyperlipidemia in rats was found to be comparable with the effect of the Wessel Dué F ^® capsules, which manifests itself in the form of an anticoagulant effect with an antithrombotic effect .

Claims (4)

1. Means for the prevention and treatment of atherosclerotic damage to blood vessels, as well as pre- and thrombotic conditions, having lipid-lowering and anticoagulant and antithrombotic effects, made in dosage form in the form of coated tablets, consisting of a core containing the active active ingredient and auxiliary substances, characterized in that the core contains, as an active active principle, the substance of the potassium salt of sulfated arabinogalactan, and as the use of excipients ludipress, aerosil and calcium stearic acid in the following components, wt.%:
Potassium salt of sulfated arabinogalactan 47.0-62.0 Ludipress 30.0-47.5 Aerosil 4.0-6.2 Calcium stearic acid 1.0;
and is covered with a protective shell, including ethyl cellulose, lauryl sulfate and cetyl alcohol, which protects the active substance that is part of the tablet from moisture, the mass fraction of the protective shell is 1-2% by weight of the tablet. 2. The tool according to claim 1, characterized in that the protective shell dissolves in the stomach and contains ethyl cellulose, lauryl sulfate and cetyl alcohol in the following ratio, wt.%:
Ethyl cellulose 24.5-29 Lauryl sulfate 0.9-1.7 Cetyl alcohol 1.7-3.3 3. Means for the prevention and treatment of atherosclerotic damage to blood vessels, as well as pre- and thrombotic conditions, having lipid-lowering and anticoagulant and antithrombotic actions, performed in a dosage form in the form of capsules, the capsule mixture in which contains the active active substance and excipients, characterized the fact that the substance of the potassium salt of sulfated arabinogalactan is used as an active active principle, and as an auxiliary Sub- stances - ludipress, calcium stearate and aerosil next Content, wt.%:
Potassium salt of sulfated arabinogalactan 47.0-83.0 Ludipress 13.0-47.5 Aerosil 3.0-7.5 Calcium stearic acid 0.5-1.0
and the capsule mixture is placed in hard gelatin capsules No. 1-00. 4. The use of tools according to claim 1 or claim 3, containing the substance of the potassium salt of sulfated arabinogalactan, for the prevention and treatment of atherosclerotic damage to blood vessels, as well as pre- and thrombotic conditions, where the unit dose of the substance of the potassium salt of sulfated arabinogalactan is from 250-500 mg and the daily dose is from 500 to 1000 mg.