RU2483712C2 - Pharmaceutical composition possessing hepatoprotecting, hypolipidemic, immunostimulating and normalising kidney function action, and method of its obtaining - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical industry and deals with solid pharmaceutical composition, possessing high physical strength. Claimed invention also presents method of manufacturing solid pharmaceutical composition. Claimed pharmaceutical composition contains 7 varicoloured types of granules in form of capsule. Granules contain, wt %: nikotinamide 1-35; pyridoxine 0.1-8; calcium pantitenate 0.1-15, thiamin 0.1-30; tryptophan 1-30; tocoferol 0.5-5; ascorbic acid 0.1-50; 5-hydroxyanthranyl acid 0.01-10; Riboflavin 0.1-10; folic acid 0.1-6; cyanocobalomin 0.001-6; isoleucin 0.5-10; leucin 0.5-15; lysine 0.5-20; phenylalanine 0.1-5; threonine 0.1-5.0; valin 0.1-8.0; methionine 0.1-15; lactose 1-4.0; ergocalcioferol 1-95.0 and auxiliary substances for obtaining granules.

EFFECT: claimed composition possesses excellent properties of medication release and digectionin application composition possesses hepatoprotective hypolipidemic immunostimulating and normalising kidney activity action.

2 cl. 2 ex. 5 tbl

Description

The present invention relates to a solid pharmaceutical composition having high physical strength, which has excellent drug release and digestibility properties when applied and has a hepatoprotective, hypolipidemic, immunostimulating and normalizing activity of the kidneys. The present invention also provides a method of manufacturing a solid pharmaceutical composition.

The urgency of the problem is associated with an increase in the frequency and severity of liver diseases - the main organ of detoxification of exogenous poisons (the reasons for the increase in liver morbidity are environmental disadvantages in most parts of the world), as well as with concomitant diseases of the whole organism and the need to create drugs with an extended spectrum of action.

An additional and directly associated with the influence of environmental factors is a decrease in immunity in the population, leading to a significant increase in infectious lesions of the liver, and primarily viral hepatitis.

Regardless of the entry gate, the virus eventually enters the liver, where it has a direct toxic effect on the liver cells, which is combined with immune-mediated damage to their membranes.

A pharmaceutical composition is known comprising α-amino-methylthiobutyric acid (methionine) or β-amino-hydroxybutyric acid (threonine) (Patent RU No. 2283114).

Closest to the claimed composition in technical essence and the achieved result is the drug Moriamin Forte (http://www.moriamin-forte.ru/instruction.php).

The scope of the product is limited to use as a medicine.

The aim of the invention is to create a composition, the development of which takes into account all the shortcomings of the previously described products and which has hepatoprotective, lipid-lowering, immunostimulating and normalizing the activity of the kidneys in children and adults.

The composition can be used (by adjusting the course of administration and dosage) as a medicine or biologically active food supplement.

The technical task of the invention is the creation of a combined composition with a maximum shelf life, with an expanded spectrum of pharmacological action, with improved bioavailability and therapeutic activity, which allows to reduce the treatment time.

The technical task is solved due to the fact that the pharmaceutical composition in the form of a capsule contains 7 multi-colored types of granules:

1. The white granule contains nicotinamide, pyridoxine, calcium pantothenate, starch, lactose, cellulose, calcium carboxymethyl cellulose, titanium oxide in the following ratio of ingredients, in wt.%:

Nicotinamide 1-35 Pyridoxine 0.1-8 Calcium pantothenate 0.1-15 Lactose 1-20 Titanium oxide 0.1-20 Calcium Carboxymethyl Cellulose 1-11 Crystalline cellulose up to 100

2. The white granule contains thiamine mononitrate, starch, lactose, cellulose, carboxymethyl cellulose calcium, methyl cellulose, titanium oxide in the following ratio, in wt.%:

Thiamine 0.1-30 Starch 1-10 Cellulose 10-12 Calcium Carboxymethyl Cellulose 1-15 Cellulose 0.1-5 Titanium oxide 0.1-5 Lactose up to 100

3. The red granule contains L-tryptophan, tocopherol acetate, starch, lactose, crystalline cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, macrogol 6000, synthetic aluminum silicate in the following ratio of ingredients, in wt.%:

Tryptophan 1-30 Tocopherol 0.5-5 Starch 1-25 Crystalline cellulose 0.5-6 Calcium Carboxymethyl Cellulose 0.5-6 Hydroxypropyl cellulose 0.1-6 Macrogol 6000 0.1-2 Aluminum silicate 0.1-15 Dye 0.001-1 Lactose up to 100

4. The chocolate granule contains ascorbic acid, starch, lactose, crystalline cellulose, calcium carboxymethyl cellulose, methyl cellulose, macrogol 6000 in the following ratio of ingredients, in wt.%:

Vitamin C 0.1-50 Starch 0.5-10 Crystalline cellulose 5-7 Calcium Carboxymethyl Cellulose 1-10 Cellulose 0.1-6 Macrogol 6000 0,1-10 Dye 0.001-1 Lactose up to 100

5. The orange granule contains 5-hydroxyanthranilic acid, riboflavin, folic acid, cyanocobalomin, starch, lactose, crystalline cellulose, carboxymethyl cellulose calcium, hydroxypropylene cellulose, macrogol 6000 in the following ratio, in wt.%:

5-hydroxyanthranilic acid 0.01-10 Riboflavin 0,1-10 Folic acid 0.1-6 Cyanocobalamin 0.001-6 Starch 0.5-30 Crystalline cellulose 1-10 Calcium Carboxymethyl Cellulose 0.1-6 Hydroxypropylene cellulose 0.1-7 Macrogol 6000 0.1-5 Dye 0.001-1 Lactose up to 100

6. The yellow granule contains isoleucine, leucine, lysine, phenylalanine, threonine, valine, methionine, starch, lactose, cellulose, methyl cellulose calcium, hydroxypropyl cellulose, a dye in the following ratio, in wt.%:

Isoleucine 0.5-10 Leucine 0.5-15 Lysine 0.5-20 Phenylalanine 0.1-5 Threonine 0.1-5.0 Valine 0.1-8.0 Methionine 0.1-15 Lactose 1-4.0 Cellulose 1-11 Calcium Methyl Cellulose 1-3,0 Hydroxypropyl cellulose 0.1-1.0 Dye 0.001-1.0 Starch up to 100

7. The light yellow granule contains ergocalciferol in the following ratio, in wt.%:

Ergocalcioferol 1-95.0 Starch up to 100

Moreover, the essential distinguishing feature is the ratio of granules in the capsule: 1 white 17%, 2 white 7%, yellow 36%, orange 12%, red 8%, chocolate 13%, light yellow 7%.

Moreover, all types of granules may additionally contain one or more vitamins, one or more amino acids, one or more macro- or microelements, or another pharmaceutical preparation from the group of flavonoids, immunomodulators, hepatoprotectors, plant extracts. It is allowed to use an additional preservative (for example, potassium sorbate).

The proposed production method allows to extend the shelf life of the drug, and also reduces the area of contact of the active substances with each other, leading to a decrease in the activity of the drug. The composition is scientifically substantiated and selected based on the target orientation of the pharmacological activity of the composition.

Proteins are the main substance of the manifestation of life, making up cells, tissues, organs, and control the functions of the body.

Eight amino acids are released that are not synthesized in the body, and they are called indispensable.

Amino acids are required to combine blood and tissue proteins, to move existing amino acids, restore damaged tissues and form new proteins.

Vitamin C. Vitamin C is necessary for the normal development of the placenta, as well as increasing the body's resistance to infections. Vitamin C provides collagen synthesis and helps maintain healthy skin. It affects the formation of hemoglobin and the maturation of red blood cells.

Ergocalciferol regulates the exchange of Ca ²⁺ and phosphorus, the process of building a bone structure; increases the absorption of Ca ²⁺ in the intestine, protein synthesis in the small intestine, liver and bones; excretion of phosphates by the kidneys. Vitamin D3 is necessary for the formation of fetal bone tissue.

Nicotinamide stabilizes the processes of tissue respiration, fat and carbohydrate metabolism, the xenobiotic metabolism system. Nicotinamide normalizes microcirculation. Participates in the processes of tissue respiration, fat and carbohydrate metabolism.

Pyridoxine hydrochloride as a coenzyme takes part in the metabolism of amino acids and proteins, in the synthesis of neurotransmitters.

Retinol palmitate. Retinol is a necessary component for the normal function of the retina: it binds to opsin (the red pigment of the retina), forming visual rhodopsin purple, which is necessary for visual adaptation in the dark. Vitamin A is necessary for bone growth, normal reproductive function, embryonic development, for the regulation of division and differentiation of the epithelium (enhances the reproduction of skin epithelial cells, rejuvenates the cell population, inhibits keratinization processes). Vitamin A takes part as a cofactor in various biochemical processes.

Riboflavin is a catalyst for the processes of cellular respiration and peroxidation of endogenous substances and xenobiotics, glucuronidation.

Thiamine mononitrate plays an important role in the metabolism of carbohydrates and fats. The substance is necessary for the normal course of growth and development processes and helps to maintain the proper functioning of the heart, nervous and digestive systems. Thiamine, being a water-soluble compound, is not stored in the body and does not have toxic properties.

Vitamin E has antioxidant properties, protects unsaturated fatty acids in membranes from lipid peroxidation; participates in the formation of intercellular substance, collagen and elastic fibers of the connective tissue, smooth muscles of blood vessels, the digestive tract. Favorably affects peripheral blood circulation.

Calcium pantothenate, a component of coenzyme A, is involved in the processes of acetylation and oxidation of carbohydrates and fats, the synthesis of fatty acids and steroids from carbohydrates, in the implementation of glycolysis bonds, the Krebs cycle and the oxidation of fats. Calcium pantothenate is involved in the regeneration of the epithelium and endothelium, promotes wound healing, reduces the side and toxic effects of antibiotics and antibacterial drugs.

Cyanocobalamin together with folic acid is involved in the synthesis of nucleotides, in the formation of red blood cells and cells of the nerve membranes, it is necessary for the growth of the body.

Folic acid is a vital vitamin necessary for the growth and development of the circulatory and immune systems. The biological effect of folic acid: antianemic, preventing intrauterine abnormalities of the fetus, increasing mental and physical performance, nootropic, antidepressant, restoring the structure of nervous tissue; anti-atherosclerotic, stimulating the production of hydrochloric acid, strengthening the intestinal wall, antidiarrheal, protecting against intestinal parasites and pathogenic flora, estrogen-like, lactogenic; dermatropic, oncoprotective, etc. Folic acid is necessary for normal hematopoiesis, plays an important role in cell division, participates in the formation of the placenta, and ensures the growth and development of the fetus.

The method of producing granules consists in weighing the ingredients, mixing, granulating, drying the granules, weighing and mixing the granules with each other in a certain proportion, followed by encapsulation.

The invention is illustrated by the following examples of industrial implementation in a production environment.

Example 1

1. White granules. Nicotinamide is weighed in an amount of 1%, mixed with pyridoxine 0.1% and calcium pantothenate 0.1%, then lactose 1.0% is added, calcium carboxymethyl cellulose 1%, titanium oxide 0.1%, then up to 100 lactose is added with stirring %, the mixture is evenly moistened with 1% water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

2. White granules. Thiamine 0.10%, starch 1%, cellulose 1%, carboxymethyl cellulose calcium 1%, titanium oxide 0.1% and methyl cellulose 0.1% are mixed, then lactose is added in portions to 100% with stirring, evenly moistened with 1% water. The mixture is granulated through a granulator sieve, the granules are dried to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

3. Red granules. Tryptophan 1% is mixed with tocopherol 0.5%, starch 1%, hydroxypropyl cellulose 0.1%, crystalline cellulose 0.5%, calcium carboxymethyl cellulose 0.5%, macrogol 6000 0.1%, aluminum silicate 0.1%, dye 0.001%, added in parts in several stages with constant stirring of lactose to 100%, moisten 1% of water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

4. Chocolate granules. Ascorbic acid in an amount of 0.1% is mixed with starch 0.5%, crystalline cellulose 1%, calcium carboxymethyl cellulose 1%, methyl cellulose 0.1%, macrogol 6000 0.1% and dye 0.001%. Add parts in several stages with constant stirring lactose to 100%, moisten 1% water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

5. Orange granules. 5-Hydroxyanthranilic acid 0.01% is mixed with riboflavin 0.1%, folic acid 0.1%, cyanocobalomin 0.001%, starch 0.5%, crystalline cellulose 1%, calcium carboxymethyl cellulose 0.1%, hydroxypropylene cellulose 0.1% , macrogol 6000 0.1% and dye 0.001%. Add parts in several stages with constant stirring lactose to 100%, moisten 1% water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

6. Yellow granules. Isoleucine in an amount of 0.5% is mixed with leucine 0.5%, lysine 0.5%, phenylalanine 0.1%, threonine 0.1%, valine 0.1%, methionine 0.1%, lactose 1%, cellulose 1%, calcium methylcellulose 1%, hydroxypropyl cellulose 0.1%, dye 0.001%, added in parts in several stages with constant stirring of starch to 100%, moisten the mixture with 1% water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

7. Light yellow granules. Ergocalcioferol 1% is mixed with starch in an amount of 99%. If necessary, moisten the mixture with water in a small amount. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

The granules are mixed with each other in the amount of 1 white 17%, 2 white 7%, yellow 36%, orange 12%, red 8%, chocolate 13%, light yellow 7% and fill the capsules.

Hard gelatin capsules consisting of a lid and a body are used as capsules.

Example 2

1. White granules. Nicotinamide is weighed in an amount of 35%, mixed with pyridoxine 8% and calcium pantothenate 15%, then lactose 20%, carboxymethyl cellulose calcium 11%, titanium oxide 2%, then lactose up to 100% are added, the mixture is uniformly moistened with 1% water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

2. White granules. Thiamine 30%, starch 10%, cellulose 15%, carboxymethyl cellulose calcium 15%, titanium oxide 5% and methyl cellulose 5% are mixed, then lactose is added to 100% with stirring, the mixture is uniformly moistened with 1% water. The mixture is granulated through a granulator sieve, the granules are dried to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

3. Red granules. Tryptophan 30% is mixed with tocopherol 5%, starch 25%, hydroxypropyl cellulose 6%, crystalline cellulose 6%, calcium carboxymethyl cellulose 6%, macrogol 6000 2%, aluminum silicate 15%, dye 1.0%, lactose is added to 100%, moisturized 1% water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

4. Chocolate granules. 50% ascorbic acid is mixed with starch 10%, crystalline cellulose 9%, calcium carboxymethyl cellulose 10%, methyl cellulose 6%, macrogol 6000 10% and dye 1.0%. Lactose is added up to 100%, moistened with 1% water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

5. Orange granules. 5-Hydroxyanthranilic acid 10% is mixed with riboflavin 10%, folic acid 6%, cyanocobalomin 6%, starch 30%, crystalline cellulose 10%, calcium carboxymethyl cellulose 6%, hydroxypropylene cellulose 7%, macrogol 6000 5% and dye 1%. Lactose is added up to 100%, moistened with 1% water.

Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

6. Yellow granules. Isoleucine is mixed in an amount of 10% with leucine 15%, lysine 20%, phenylalanine 5%, threonine 5%, valine 8%, methionine 15%, lactose 4%, cellulose 11%, calcium methylcellulose 3%, hydroxypropyl cellulose 1%, dye 1 %, add with constant stirring starch to 100%, moisten a mixture of 1% water. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

7. Light yellow granules. Ergocalcioferol 5% is mixed with starch in an amount of 95%. If necessary, moisten the mixture with water in a small amount. Then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%. Ready granules are poured into the container.

The granules are mixed with each other in the amount of 1 white 17%, 2 white 7%, yellow 36%, orange 12%, red 8%, chocolate 13%, light yellow 7% and fill the capsules.

Hard gelatin capsules consisting of a lid and a body are used as capsules.

In practice, you can make changes and modify the described preferred embodiments of the present invention, without departing from the subject and objectives of the present invention, within the scope of the claimed claims.

A clinical study conducted for the composition prepared according to Example 2, confirms that treatment with the proposed composition can significantly improve the relative symptoms and laboratory parameters.

In the treatment of liver diseases, prescribing improves liver function, increases serum formation, reduces the number of dead cells and, therefore, obviously eliminates symptoms such as fatigue, apathy, liver pain, bile, bloating, as well as parameters such as ALT, AST and etc.

As for kidney diseases, especially in patients who need to restrict protein intake, the constant intake of a small amount of essential amino acids and vitamins, leading to an improvement in the negative nitrogen balance, an increase in bioaccumulation of non-essential amino acids, a decrease in nitrogen production and the fulfillment of the basic kidney function. Treatment with the proposed composition can reduce the usual symptoms of kidney diseases such as fatigue, abdominal pain, swelling, etc., an increase in the concentration of plasma albumin and essential amino acids, and a decrease in the concentration of non-essential amino acids.

Cirrhosis treatment

Objects and Method:

1. Patient selection

Patients diagnosed with cirrhosis of the liver with albumin in the range of 28-35 g / l. Patients were conditionally divided into two groups.

2. The method of treatment

Group for treatment (n = 10): 2 capsules three times a day for 6 weeks. Control group (n = 7): prototype tool

3. Study parameters

The following indicators were recorded before and after treatment.

Symptoms: fatigue, apathy, nausea, vomiting, liver pain, low temperature, etc.

All patients before treatment observed: ascites, slight pulmonary edema, etc.

Laboratory parameters were studied: albumin, globin, prothrombin time, bilirubin, titration in the gas phase, proper blood flow, platelet, etc.

4. Statistics

Tests X ² , N are used to compare the treatment and control groups, respectively.

Result

The results of a clinical study of patients with cirrhosis after treatment with the proposed composition are shown in tables 1, 2, 3, which indicate:

1. The proposed composition has shown significant effectiveness in eliminating symptoms of cirrhosis, such as fatigue and apathy;

2. The composition showed significant efficacy in ascites and removal of lower pulmonary edema in patients with cirrhosis.

3. The composition is obviously able to increase the amount of proteins and reduce prothrombin time, significantly reduce the level of globin, a large number of red cells and platelets, but does not improve laboratory parameters such as titration in gas form, bilirubin, etc.

4. The composition does not have a negative reaction in the treatment process.

5. The positive effect of the treatment of the proposed composition was achieved in a shorter time than the treatment of the composition of the prototype.

The proposed composition can provide nutrition to tissue cells, accelerate the synthesis of proteins in the tissue and improve tissue metabolism. The present results of the study show that the treatment of patients with cirrhosis of the liver with the proposed composition can significantly improve the cellular function of the liver, as well as provide nutrition for liver cells, especially in the treatment of hypoalbuminia, the proposed composition is a drug with high efficiency, safety and ease of use

Treatment of chronic renal failure

1. Patients: 22 cases with chronic liver diseases, among which 12 men and 10 women aged 9-56 years (average 2.6 ± 8.2). Among standard diseases there are 7 cases of chronic nephritis, 3 cases of pyelitis, 2 cases of diabetic nephritis, 2 cases of gout of the liver. In addition, a control group of 10 people was recruited.

Drugs and dosage: The proposed composition 2 capsules three times a day for 31-54 days.

All patients with chronic liver disease accompanied by infection were treated after infection was detected, and patients with hypertension received treatment to restore pressure.

In each group, the main laboratory parameters were recorded before and after treatment, tested: blood and urine parameters, substance content: urea nitrogen (BUN), cretinin (Scr), the rate of purification of internal creatinine (Ccr), the total amount of protein in plasma (TP) Plasma Albumin (Alb), Calcium, Phosphorus, Glyceride (TG), Cholesterol (Ch) and Glucose (Glu).

Amino acids were determined by the exact construction of the chromatogram and analyzed using fluorometry, Millipore-Wates Cop apparatus. Sigma Cop., Which fixes standard samples of 16 amino acids.

1. The liver function and the results of the biochemical test are presented in table 1. A decrease in blood nitrogen and phosphorus, an increase in blood calcium, are shown (P <0.005). Other parameters are no different from those presented above.

2. Blood counts of SIL-2R, urine of SIL-2R in the experimental group were higher than those of the control group (P <0.01).

3. Differences in the compared groups are presented in table 2.

4. The amount of amino acids in the plasma was determined. Before treatment, 4 amino acids were detected, in a lower concentration than after treatment (See table 3).

This study shows that the use of the proposed composition, combined with a low protein diet, reduces the amount of nitrogen in urea in chronic liver disease and improves symptoms of high phosphorus and low calcium levels in the blood, as well as the effect on blood sugar and creatine in the blood . In addition, the above change does not increase at the end of the treatment period, which should be appropriate for each patient with liver disease, and only a diet cannot change blood dialysis. In the above group received treatment - blood dialysis.

After applying the proposed composition, patients of this group have a significant increase in the number of amino acids in plasma and a decrease in the number of minor amino acids. Thus, it is obvious that the composition modulates the level of various amino acids in their total amount, meanwhile, the concentration of phosphorus in the blood is obviously reduced. With prolonged treatment time, there is a need for further research to determine the effectiveness of treatment to improve liver condition.

The immunostimulating effect of the proposed drug was determined by the following indicators IgA (g / l), IgM (g / l), IgG (g / l), C3 (g / l), lymph cell transmission test (LTT,%), for 2 control and treatment groups. The treatment group took the proposed composition 2 capsules 2 times a day for 10 days.

The data obtained indicate that the claimed tool increases the body's defenses to the effects of carcinogen and other environmental factors (table 4).

The study of the lipid-lowering effect of the proposed composition on the level of lipids and LP in animals with experimental DLP of an atherogenic nature was carried out in rats and rabbits using models of the pathological condition.

To determine lipids, unified biochemical methods were used in accordance with the recommendations of the All-Russian Scientific Society of Cardiology (GFCF, 2004). The level of cholesterol in the blood serum of rats and rabbits was determined by the colorimetric enzymatic method (CHOD-PAP) using a set of reagents from Vital Diagnostics. Determination of HDL cholesterol in the blood serum of rats and rabbits was carried out by the above method using reagents of the same company after preliminary precipitation of atherogenic drugs. To determine the TG in the blood serum of rats and rabbits, a set of reagents from Vital Diagnostics was used [Wahlfeld A.W. In: Methods of enzymatic analysis. Acad. Press, NY; 1974: 1831]. The content of cholesterol in the liver was determined using the standard color Lieberman-Burchard reaction after extraction of a portion of the liver with a mixture of chloroform and carbinol [Bragdon G.H. In: Lipids and steroid hormons in clinical medicine. Ph. 1960: 6-10]. The content of TG in the liver was determined by the method of Neri and Frings (1973), modified by the authors, consisting in replacing the sorbent - a zeolite mixture with aluminum oxide [Okunevich IV, Sapronov NS, Indenbom M.L. Chem.-farm. g. 1999; 11: 14-16]. The content of total cholesterol in the rabbit aorta was carried out colorimetrically using the Lieberman-Burchard reaction after extraction of the sample. To prepare the chloroform extract, the aorta was ground with quartz sand [Ryzhenkov V.E., Khromov-Borisov N.V., Mosina I.V., Indenbom M.L. Farmakol. toxicol. 1979; 6: 632-635]. The content of cholesterol in the adrenal glands was determined by the extraction method, as described above, after homogenizing a tissue sample, extracting it with chloroform and applying the subsequent Lieberman-Burkhard reaction [Okunevich IV, Ryzhenkov V.E. Pat. fiziol. expert. ter. 2002; 2: 14-18].

Research results

Hypolipidemic activity in DLP models.

Experience 1. Model of triton dyslipoproteinemia (DLP) in rats.

Hypolipidemic activity was studied in 60 male rats on a screening model of DLP caused by the detergent triton WR-1339 (225 mg / kg once, intraperitoneally). This model is characterized by the development of persistent hyperlipidemia - a significant increase in the level of cholesterol and triglycerides in the blood of rats (weighing 250-300 g) compared with the content of these indicators in intact animals [Shurr P.E., Shultz Y.R. Lipids 1972; 7 (1): 68-74].

The inventive preparation was administered to rats at a dose of 100 mg / kg orally twice (prior to administration and simultaneously with the administration of WR-1339 triton). After 10 hours, the degree of development of hyperlipidemia was determined by the level of cholesterol and triglycerides in the blood serum, which during therapy with the claimed drug there is a significant decrease in elevated cholesterol and triglyceride levels in the conditions of triton DLP: 25% and 50%, respectively.

Thus, a pronounced hypolipidemic effect was found in the model of tritone dyslipoproteinemia.

Experience 2. Hypolipidemic effect of the proposed composition on a model of chronic alimentary DLP in rats.

The experiments were conducted on 72 male rats (weighing 230-250 g) in the conditions of nutritional DLP, characterized by an increased level of lipids and LP in the blood serum and liver and at the same time a decrease in the content of anti-atherogenic HDL cholesterol in the blood. These disorders were caused by a diet containing 7.5% cholesterol, 30% a mixture of animal fats and warm sunflower oil (2: 1) and 500,000 MI of vitamin D2. The duration of the experiment was 21 days.

The proposed composition at a dose of 100 mg / kg was orally administered to rats for 21 days on the background of a special hypercholesterolemic diet (GHS diet). Serum levels of total cholesterol, TG, and HDL cholesterol were determined. Based on these indicators, atherogenic LDL cholesterol was calculated according to the generally accepted Friedwald formula. The Klimov formula (cholesterol - HDL cholesterol) / HDL cholesterol determined the value of the cholesterol atherogenicity index (IA). In the liver, the content of cholesterol and triglycerides was determined; feeding rats with GCS diet leads to the development of DLP: a 2.6-fold increase in cholesterol, 2.9-fold increase in cholesterol, and a 2.3-fold decrease in the concentration of anti-atherogenic HDL cholesterol. In addition, the calculated values of the cholesterol content of atherogenic LDL and cholesterol IA significantly increase, reflecting the development of At. Under these conditions, the use of the claimed drug causes a significant lipid-lowering effect: serum cholesterol and TT levels are reduced - by 31.7%, respectively. These facts indicate a positive prognosis in preventing the development of At in experimental animals during therapy.

Hypolipidemia

The drug was tested on 25 patients with lipid-lowering (aged 56-70 years) under stationary conditions).

The results of the study show that the drug has a pronounced lipid-lowering effect, manifested already on the 10th day of treatment with a progressive increase in the effect in its subsequent periods. So, the level of total cholesterol decreased by 15.6% (day 10), 21.0% (day 25) and 24.4% (3 months), triglycerides, respectively, by 32.9, 40.6, 44.7%, - lipoproteins by 15.0, 26.7, 24.3%. At the same time, the cholesterol content in low density lipoproteins (LDL-C - highly atherogenic lipoproteins) decreased more significantly - by 25.6, 36.9, 41.4% (10, 25 and 90 days of treatment, respectively), and the cholesterol concentration in high lipoproteins density (- cholesterol - HDL - antiatherogenic lipoproteins) increased, respectively, in terms of treatment by 20.6, 32.7, 32.7%.

The stability of the proposed composition was determined using the developed analytical analysis methods for each active substance in the composition.

Riboflavin, ascorbic acid, pyridoxine hydrochloride, nicotinamide, thiamine mononitrate, folic acid, retinol palmitate, ergocalciferol, alpha-tocopherol acetate, leucine, isoleucine, lysine hydrochloride, phenylalanine, threonine, valine, tryptinane. The determination is carried out by HPLC.

According to the data (table 5 - the results of studying the stability of the composition), the shelf life is 3 years.

The obtained results of pharmacological tests showed that the selected granule compositions and the granule ratio ensure the effectiveness of the drug: hepatoprotective, lipid-lowering, immunostimulating and normalizing kidney activity effects.

Based on the foregoing, it can be concluded that the proposed composition has several advantages in comparison with the prototype.

Examples of the execution of the present invention allow to expand the range of effective drugs.

Table 1 Results of biochemical analysis before and after treatment Parameter Before treatment After treatment BUN (mmol / L) 44.76 ± 12.78 29.64 ± 9.60 * Scr (mol / L) 1034.28 ± 495.04 1105.32 ± 459.31 Ccr (ml / min) 5.94 ± 3.32 5.93 ± 1.79 Alb (g / l) 39.21 ± 6.72 39.21 ± 5.62 TP (g / l) 69.42 ± 7.82 72.82 ± 5.62 Hb (g / l) 81.72 ± 21.32 80.71 ± 31.42 Calcium (mmol / L) 1.78 ± 0.62 2.29 ± 0.86 * Phosphorus (mol / L) 2.20 ± 0.86 1.62 ± 0.92 TG (mmol / L) 1.32 ± 0.42 1.42 ± 0.32 Gh (mmol / L) 7.75 ± 3.32 6.98 ± 2.12 Glucose (mmol / L) 5.06 ± 0.41 5.12 ± 0.82

table 2 Change in SIL-2R in blood and urine (u / ml) Blood Urine Control group 110.05 ± 38.89 82.01 ± 13.84 Before treatment 244.68 ± 19.36 * 162.82 ± 78.32 After treatment 117.04 ± 35.01 94.32 P <0.0519.30 - Comparison of the control and treatment groups, P <0.01

Table 3 The concentration of plasma in amino acids before and after treatment Before treatment After treatment Threonine 141.62 ± 31.16 195.14 ± 47.62 Valine 232.42 ± 41.92 * 329.40 ± 53.08 Methionine 32.61 ± 13.92 36.79 ± 25.31 Isoleucine 60.80 ± 10.32 * 100.86 ± 25.04 Leucine 106.43 ± 55.16 156.26 ± 42.79 Phenylalanine 84.15 ± 35.94 ** 220.81 ± 62.73 Tryptophan 29.74 ± 10.02 * 57.94 ± 15.49 Lysine 177.61 ± 44.63 189.87 ± 30.75 Total Essential Amino Acids 1008.28 ± 81.72 * 1145.22 ± 60.41 Asparagine 54.08 ± 12.73 ** 18.32 ± 5.86 Serine 93.66 ± 27.21 * 147.32 ± 39.06 Glutamic acid 155.03 ± 51.92 ** 62.81 ± 22.80 Glycine 442.47 ± 82.95 ** 223.35 ± 41.12 Alanine 562.73 ± 131.11 ** 343.18 ± 71.01 Tyrosine 80.57 ± 40.47 83.28 ± 34.47 Histidine 182.01 ± 29.86 * 151.86 ± 26.81 Arginine 159.51 ± 26.20 * 132.21 ± 40.31 Total Non-Essential Amino Acids 1730.52 ± 123.53 ** 1162.41 ± 80.52 The ratio of the total number of basic amino acids to the total number of non-basic amino acids 0.582 ± 0.094 ** 0.985 ± 0.117 * P <0.05; ** P <0.01

Table 4 The result of the analysis of immunity in two groups Items Treatment group Control group t P IgA 1.53 ± 0.05 1.09 ± 0.10 3.96 <0.001 IgM 1.36 ± 0.40 1.39 ± 0.47 0.04 > 0.05 IgG 10.10 ± 1.57 8.09 ± 1.30 9.52 <0.001 C3 1.42 ± 0.14 0.80 ± 0.26 1.35 > 0.05 LTT 57.03 ± 10.71 41.82 ± 11.79 5.16 <0.001

Claims (2)

1. A composition having hepatoprotective, hypolipidemic, immunostimulating and normalizing kidney activity, containing vitamins and excipients, characterized in that it consists of seven types of granules, the white granule containing nicotinamide, pyridoxine, calcium pantothenate, starch, lactose, cellulose, calcium cellulose carboxymethyl, titanium oxide in the following ratio of ingredients, wt.%:
Nicotinamide 1-35 Pyridoxine 0.1-8 Calcium pantothenate 0.1-15 Lactose 1-20 Titanium oxide 0.1-20 Calcium Carboxymethyl Cellulose 1-11 Crystalline cellulose up to 100,
the white granule contains thiamine mononitrate, starch, lactose, cellulose, carboxymethyl cellulose calcium, methyl cellulose, titanium oxide in the following ratio, wt.%:
Thiamine 0.1-30 Starch 1-10 Cellulose 10-12 Calcium Carboxymethyl Cellulose 1-15 Cellulose 0.1-5 Titanium oxide 0.1-5 Lactose up to 100,
the red granule contains L-tryptophan, tocopherol acetate, starch, lactose, crystalline cellulose, calcium carboxymethyl cellulose, hydroxypropicellulose, macrogol 6000, synthetic aluminum silicate in the following ratio of ingredients, wt.%:
Tryptophan 1-30 Tocopherol 0.5-5 Starch 1-25 Crystalline cellulose 0.5-6 Calcium Carboxymethyl Cellulose 0.5-6 Hydroxypropicellulose 0.1-6 Macrogol 6000 0.1-2 Aluminum silicate 0.1-15 Dye 0.001-1 Lactose up to 100,
the chocolate granule contains ascorbic acid, starch, lactose, crystalline cellulose, calcium carboxymethyl cellulose, methyl cellulose, margarol 6000 in the following ratio of ingredients, wt.%:
Vitamin C 0.1-50 Starch 0.5-10 Crystalline cellulose 5-7 Calcium Carboxymethyl Cellulose 1-10 Cellulose 0.1-6 Markogol 6000 0,1-10 Dye 0.001-1 Lactose up to 100,
the orange granule contains 5-hydroxyanthranilic acid, riboflavin, folic acid, cyanocobalomin, starch, lactose, crystalline cellulose, calcium carboxymethyl cellulose, hydroxypropylene cellulose, macrogol 6000 in the following ratio, wt.%:
5-hydroxyanthranilic acid 0.01-10 Riboflavin 0,1-10 Folic acid 0.1-6 Cyanocobalamin 0.001-6 Starch 0.5-30 Crystalline cellulose 1-10 Calcium Carboxymethyl Cellulose 0.1-6 Hydroxypropylene cellulose 0.1-7 Macrogol 6000 0.1-5 Dye 0.001-1 Lactose up to 100,
the yellow granule contains isoleucine, leucine, lysine, phenylalanine, threonine, valine, methionine, starch, lactose, cellulose, methyl cellulose calcium, hydroxypropyl cellulose, a dye in the following ratio, wt.%:
Isoleucine 0.5-10 Leucine 0.5-15 Lysine 0.5-20 Phenylalanine 0.1-5 Threonine 0.1-5.0 Valine 0.1-8.0 Methionine 0.1-15 Lactose 1-4.0 Cellulose 1-11 Calcium Methyl Cellulose 1-3,0 Hydroxypropyl cellulose 0.1-1.0 Dye 0.001-1.0 Starch up to 100,
a light yellow granule contains ergocalciferol in the following ratio, wt.%:
Ergocalcioferol 1-95.0 Starch up to 100 2. The method of obtaining a composition according to claim 1, having hepatoprotective, hypolipidemic, immunostimulating and normalizing the activity of the kidneys in the form of seven granules, the white granules containing nicotinamide, which is mixed with pyridoxine, calcium pantothenate, then with lactose, calcium carboxymethyl cellulose, titanium oxide, then lactose is added in portions with stirring, the mixture is uniformly moistened with water, then the mixture is granulated through a granulator sieve, the granules are dried to a residual moisture content of not more than 0.5%, ready to gr pouches are poured into a container, white granules are prepared, thiamine, starch, cellulose, calcium carboxymethyl cellulose, titanium oxide and methyl cellulose are mixed, and lactose is added in portions with stirring, moistened evenly with water, the mixture is granulated through a granulator sieve, the granules are dried to a residual moisture content of not more than 0, 5%, and the finished granules are poured into a container, then red granules are prepared, tryptophan is mixed with tocopherol, starch, hydroxypropyl cellulose, crystalline cellulose, calcium carboxymethyl cellulose, ma Rogol 6000, aluminum silicate, dye is added in parts by several techniques, with constant stirring, lactose, moistened with water; then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%, ready granules are poured into the container, then chocolate granules are prepared, ascorbic acid is mixed with starch, crystalline cellulose, calcium carboxymethyl cellulose, methyl cellulose, macrogol 6000 and dye , added in parts in several stages with constant stirring, moisten the lactose with water, then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%, and then The granules are poured into a container, then orange granules are prepared, mixed with 5-hydroxyanthranilic acid with riboflavin, folic acid, cyanocobalomin, starch, crystalline cellulose, calcium carboxymethyl cellulose, hydroxypropylene cellulose, macrogol 6000 and the dye is added, stirring slightly with stirring, stirring a little with stirring water, then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%, ready granules are poured into a container, then cook yellow granules, mix isoleucine with leucine, lysine, phenylalanine, threonine, valine, methionine, lactose, cellulose, calcium methylcellulose, hydroxypropyl cellulose, dye, add starch in parts in several stages with constant stirring, moisten the mixture with water, then granulate the mixture through a granulator sieve, granules are dried to a residual moisture content of not more than 0.5%, the finished granules are poured into a container and light yellow granules are prepared, ergocalcioferol is mixed with starch, if necessary, moisten the mixture with water in a small amount, then granulate the mixture through a granulator sieve, dry the granules to a residual moisture content of not more than 0.5%, ready granules are poured into a container, and granules are mixed together in an amount: white 17%, white 7%, yellow 36%, orange 12%, red 8%, chocolate 13%, light yellow 7%, and fill the capsules.