RU2456011C1 - Preparation flavosuccine for treating and preventing renal and urinary diseases - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry. The preparation for treating and preventing renal and urinary diseases contains herbal active substances, excipients and additionally contains active substances in the form of a buffer complex of sodium succinate, potassium succinate and magnesium succinate; the herbal active substances are presented by an extract of mixed sicklepod, birch leaves and linden blossom. The ingredients are taken in proportions as follows: the buffer complex of sodium succinate, potassium succinate and magnesium succinate 2.9%-17.3%; the extract of mixed sicklepod, birch leaves and linden blossom 1%-15%; the excipients - up to 100 ml. Sodium succinate, potassium succinate and magnesium succinate are taken in ratio 2.3:2.9:1.0. Mixed sicklepod, birch leaves and linden blossom are taken in ratio 6.0:3.0:1.0 and presented in the form of a solid or dry extract. The excipients include preservatives 0.01%-2.00%, sweetener 0.005%-60.0%, flavouring substances 0.001%-1.0%, solvents 1.0%-95.0% and a thickening agent 0.05%-5.0%.

EFFECT: preparation extends the spectrum of specific activity with a positive integrated effect on the renal and urinary systems.

3 ex, 8 tbl

Description

The invention relates to medicine and the pharmaceutical industry, in particular to agents for the treatment and prevention of diseases of the kidneys and urinary system.

Recently, the issue of treatment of diseases of the kidneys and urinary tract has become increasingly relevant. This is caused by a significant increase in the incidence of the disease with the severity of its course, with adverse treatment outcomes and even with high mortality. The annual incidence of kidneys and urinary system in the world is almost 11% among the adult population, and almost 4% is urolithiasis.

Treatment of the pathology of the urinary organs is carried out comprehensively with drugs belonging to different pharmacotherapeutic groups: drugs that promote the dissolution of urinary calculi, angioprotectors, antiplatelet agents, anti-inflammatory, antibacterial, anti-azotemic, diuretic, antispasmodics and herbal products.

The main advantages of herbal remedies for the treatment of kidney and urinary system diseases is the multivalent mechanism of their action: diuretic, anti-inflammatory, antispasmodic, antimicrobial, litholytic effect, good tolerability by patients, minimal side effects and complications with prolonged use, the possibility of using by patients of all age groups. When using medicinal plants and phytochemicals, it becomes necessary to prepare fresh solutions and to store already prepared ones. In this regard, the creation of ready-made dosage forms of herbal preparations is of great importance.

A known tool for the treatment of urological diseases described in the method of treating these diseases (patent of the Russian Federation No. 2108105, IPC: A61K 35/78, 1998) containing substances of plant origin. The product contains dry solids extract of α-pinene, β-pinene, camphene, borneol, anethole, fenhol, cineol and vegetable oils from anise seeds, nutmeg, Siberian fir needles, fennel seeds and medicinal sage grass with a weight ratio of 7: 1 : 2: 4: 30. The drug enhances blood flow in the kidneys, has a diuretic effect, dissolves urinary calculi, exhibits anti-inflammatory and analgesic effects. However, the preparation contains a large number of components, leading to instability of their composition and, as a result, to their insufficient effectiveness.

Known agent for the treatment of chronic urological diseases containing active substances of plant origin (patent of the Russian Federation No. 2308274, IPC: A61K 33/28, A61K 36/38, A61K 36/48, A61K 36/55, A61K 36/738, A61P 13 / 00, 2005). The product contains the active substances of plants: St. John's wort grass 18-22%, meadow clover grass 18-22%, flax seeds 17-21%, rosehips 8-12%, elecampane root 7-11% and field horsetail 18-22 % The tool is used to treat chronic diseases of the urogenital organs, such as chronic pyelonephritis, chronic cystitis, chronic urethritis. However, this tool is not effective in the treatment of acute diseases of the kidneys and urinary system.

Known agent for the treatment of urolithiasis (Ukrainian patent No. 20530, IPC: A61K 35/78, 2000) containing active substances of plant origin. The product contains avisan - 18-20% and extracts of horsetail - 18-20%, St. John's wort - 21-25%, mountaineer - the rest. The tool is used only in the treatment and prevention of urolithiasis.

Famous herbal tea "Uroflox" (Compendium 2006 - Medicines / Edited by V.N. Kovalenko, A.P. Viktorov. - K .: Morion, 2006. - T.2. - S. L1442) containing plant active substances 100 g of herbal tea contains active substances of plants: black elderberry flowers 20 g, St. John's wort grass 20 g, linden flowers 20 g, bearberry leaves 20 g, field horsetail 20 g. The tool is used to prevent and optimize the treatment of inflammatory diseases of the kidneys and urinary tract accompanied by a decrease in urinary and nitrogen excretory function, urine stone disease, with edema associated with pathology of the heart and bronchopulmonary system.However, this tool is not effective enough for acute diseases.

Known collection for the treatment of diseases with metabolic disorders described in the method of treatment of these diseases (patent application of the Russian Federation No. 95109232, IPC: A61K 35/78, 1997), containing the active substances of plants: highlander 1-10%, horsetail 0, 1-10%, heather ordinary 10-50%, burdock ordinary 0.1-50%, astragalus woolly 0.1-20%, plantain large 0.1-20%, nettle 0.1-30%, stellate 0 , 1-20%. The tool has an anti-inflammatory, diuretic effect, contributes to the destruction of kidney stones. This remedy is not effective enough in the treatment of other kidney diseases.

Known agent for the treatment of chronic pyelonephritis described in the method of phytotherapy of chronic pyelonephritis (Ukrainian patent No. 17707, IPC: A61K 36/00), containing plant active substances, parts by weight: lingonberry leaves - 3, highlander grass - 2, birch buds - 2, the root of Rhodiola rosea - 2, the root of licorice - 1. The tool has limited use.

Known collection for the treatment of pyelonephritis (patent of the Russian Federation No. 2155054, IPC: A61K 35/78, 2000), containing active substances of plants, parts by weight: bearberry leaves - 3.5, birch leaves - 20.0, birch buds - 7.0, the mountaineer's grass - 14.0, the St. John's wort grass - 6.0, the three-parted grass - 14.0, the yarrow grass - 4.0, the fruits of dill - 7.0, the rose hips - 14.0, Melissa officinalis herb - 7.0, licorice root - 3.5. The collection positively affects the course and formation of remission and exhibits antimicrobial, anti-inflammatory, diuretic, litholytic, immunocorrective properties and a mild sedative effect.

Known collection for the treatment and prevention of urological diseases (patent of the Russian Federation No. 2098118, IPC: A61K 35/78, 1997) containing active substances of plant origin. The collection contains components, parts by weight: birch buds 0.8-1.2, stigmas of corn 1.8-2.2, grass horsetail 1.8-2.2, grass yarrow 0.8-1.2, grass a series of 0.8-1.2, centaury grass 1.8-2.2, bearberry leaves 0.8-1.2, blackcurrant leaves 0.8-1.2, hazelnut leaves 0.8-1.2 , pear leaves 0.8-1.2, lovage root 0.8-1.2. The collection normalizes the activity of the urinary tract, increases sexual function.

The medicinal product “Urolesan” is known (Compendium 2006 - Medicinal preparations / Edited by V.N. Kovalenko, A.P. Viktorov. - K .: Morion, 2006. - V. 2. - S. L1441), containing the active substances of the plant origin and other substances.1 ml of the preparation contains substances of plant origin: fir oil 0.0676 g, peppermint oil 0.0169 g, castor oil 0.09295 g, liquid extract of wild carrot fruit 0.19435 g, hop cones 0.2788 g, oregano herbs 0.19295 g and excipient Trilon B. The agent is used in the treatment of urolithiasis and gallstone minutes diseases, urinary diathesis, acute and subacute calculous pyelonephritis and chronic cholecystitis, biliary dyskinesia. The drug can cause allergic reactions.

Known drug "Level" (Compendium 2006 - Medicines / Edited by VN Kovalenko, AP Viktorova. - K .: Morion, 2006. - T.2. - S. L1439) containing the active substances of the plant Origin and excipients.The product contains substances in the form of tincture, 100 ml of which contains extracts from plants: common oregano - 0.75 g, odoriferous grass - 0.3 g, highlander grass - 1 g, seed oats - 1 g , chicory root - 0.15 g and excipients: sugar, ethyl alcohol 45%. with inflammatory diseases of the genitourinary organs and kidney stones.

Known drug "Cyston" (Hymalaja Drug company, India), (Compendium 2006 - Medicines / Edited by V.N. Kovalenko, A.P. Viktorov. - K .: Morion, 2006. - V. 2. - C L1594). The tablet of the preparation contains active substances of plant origin in the form of extracts from the flowers of the Dodomocarpus siliculose - 65.0 mg, stalks of the saxifraga - 49.0 mg, stalks of the hearty madder - 16.0 mg, filmworm rizomy - 16.0 mg, rough red salmon seeds - 16.0 mg aerial parts of onosmi bracts - 16.0 mg, return of ashen - 16.0 mg, powders from things Stv: silicon lime - 16.0 mg, peeled mineral resin - 13.0 mg, treated with an aqueous extract of common basil grass, creeping fruit seeds, bashful mimosa seeds, two-flowered dolichos seeds, aromatic peony, field horsetail, teak tree seeds and excipients. only with urolithiasis, crystalluria, urinary tract spasm.

Known drug "Hofitol" (Lab Rosa-Phytopharma, France), (Compendium 2006 - Medicines / Edited by V.N. Kovalenko, A.P. Viktorov. - K .: Morion, 2006. - V. 2. - S.1536-1537). The tablet of the preparation contains an active substance of plant origin in the form of a dry aqueous extract from the juice of fresh leaves of field artichoke - 0.2 g and excipients - the rest. The drug exhibits diuretic, choleretic and hepatoprotective effects in the treatment of chronic nephritis, diseases of the liver and gall bladder.

The drug “Lespenephril" is known (Solvay Pharma, France), (Compendium 2006 - Medicines / Edited by V.N. Kovalenko, A.P. Viktorov. - K .: Morion, 2006. - V. 1. - C. 771). The preparation in the form of an oral solution in 100 ml contains active substances of plant origin - tincture of lespedesa of the cephalopod 15 ml, anise essence 0.25 ml, excipients: ethyl alcohol 62 ml, water - the rest. Lespenephril has a diuretic, hypoazotemic effect and is used in the treatment of only chronic renal failure sufficiency.

Known drug "Kanefron N" (Bionorica, Germany), (Compendium 2006 - Pharmaceuticals / Edited by V.N. Kovalenko, A.P. Viktorov. - K .: Morion, 2006. - V.1 - S.609 -610). The preparation in the form of a water-alcohol extract in 100 g drops contains 29 g of a water-alcohol extract made from 59% ethanol from medicinal plants - centaury grass 0.6 g, lovage root 0.6 g, leaves rosemary 0.6 g and purified water - the rest is anti-inflammatory, antispasmodic, diuretic, vasodilator and antibacterial Serial action: Under the influence of the drug, the excretion of uric acid salts and urine pH increase, which prevents the formation and growth of calculi in the urinary tract.The drug is used in basic therapy or as part of complex treatment for chronic and acute infections of the bladder and kidneys, in particular pregnant women; with chronic glomerulonephritis, interstitial nephritis; for the prevention of the formation of urinary calculi, in particular after their removal.

It should be noted that when using the drug "Kanefron N" allergic reactions are possible.

Known drug "Cytoflavin", (EA Patent No. 1099, IPC: A61K 31/708, A61P 39/00, A61K 31/194, A61K 31/455, A61K 31/675, 2000) containing active and auxiliary substances. in the form of a solution for injection contains the active composition of natural metabolites and coenzymes in solution: succinic acid 9.5-10.5%, riboxin 1.9-2.15%, nicotinamide 0.95-1.05%, riboflavin-5- sodium mononucleotide 0.19-0.21%, sodium hydroxide 3.3-3.7%, m-methylglucamine 15.7-17.3% and water for injection - the rest.The drug has a cytoprotective effect in the treatment of liver and kidney diseases acute and myocardial infarction, cerebral ischemia, hypoxic stroke, coronary insufficiency and coronary heart disease.

Known drug "Blemaren" (Esparma, Germany) (Compendium 2006 - Pharmaceuticals / Edited by V.N. Kovalenko, A.P. Viktorov. - K .: Morion, 2006. - T.1. - S. L212) containing active and auxiliary substances: 1 effervescent tablet contains 1197.0 mg anhydrous citric acid, 835.5 mg anhydrous trisodium citrate, 967.5 mg potassium bicarbonate and excipients 100 g of Flemaren granules contain anhydrous citric acid 39.90 g, trisodium citrate anhydrous 27.85 g, potassium hydrogen carbonate 32.25 g. By establishing the optimal value The urine pH of the drug creates favorable conditions for stopping the growth and dissolution of uric acid and mixed calculi.The indications for the use of the Blemaren drug are litholysis of uric acid calculi in the urinary tract and prevention of their primary and re-formation; litholysis of mixed uric oxalate calculi; metaphylaxis of calcium oxalate re-formation of new stones and growth of residual fragments); alkalization of urine during cytostatic therapy during the use of uricosuric preparations, in the treatment of patients with cystine calculi, as well as in renal canal acidosis with phosphate lithiasis. Blemaren is also used as an adjuvant in the treatment of hyperuricemia with xanthine oxidase inhibitors (for example, with gout), as an adjuvant in the combination of symptomatic therapy for late porphyria of the skin.

Also known is the medicinal product Fitolizin (Herbapol, Poland), (Compendium 2006 - Medicinal Products / Edited by V.N. Kovalenko, A.P. Viktorov. - K .: Morion, 2006. - V. 2. - C. L1487), containing active substances of plant origin and excipients. The preparation in the form of a paste is used to prepare a suspension. 100 g of paste contains 67.2 g of condensed extract obtained from plant collection: wheatgrass rhizomes, onion husks, birch leaves, fenugreek seeds, parsley root, goldenrod grass, horsetail herb, Lubis root weaving, herbs of the mountaineer bird and auxiliary substances: sage essential oil - 1.0 g, pine essential oil - 0.2 g, peppermint essential oil - 0.5 g, orange essential oil - 0.15 g. The drug is used to treat infectious and inflammatory diseases of the kidneys, renal pelvis, of the ureters, as well as for the prevention and treatment of urolithiasis.The known agent does not allow to sufficiently increase the level of its specific activity, to reduce or eliminate negative side effects, which does not provide a positive integrated effect on the soil and the urinary system.

The basis of the present invention is the task of creating such an agent for the treatment and prevention of diseases of the kidneys and urinary system, in which with the introduction of new components would ensure an increase in the level and expansion of the spectrum of specific activity with a positive complex effect on the kidneys and urinary system.

The problem is achieved in that the agent for the treatment and prevention of diseases of the kidneys and urinary system, containing active substances of plant origin and auxiliary substances, according to the invention additionally contains active substances in the form of a buffer complex of sodium succinate, potassium succinate and magnesium succinate, selected in ratios 2 , 3: 2.9: 1.0, a thick or dry extract of a mixture of astragalus syrup, birch leaves and linden flowers was selected as the active substances of plant origin, zyatye in a ratio of 6.0: 3.0: 1.0, and as auxiliaries selected preservatives, sweetening components, food flavors, solvents, thickening agent and purified water, wherein the components are taken in such ratios,%:

Buffer complex sodium succinate, potassium succinate, magnesium succinate 2.9-17.3, Thick or dry extract of the mixture Astragalus amnioticus birch leaves linden flowers 1-15,

Excipients

preservatives 0.01-2.00, sweetening components 0.005-60.0 food flavorings 0.001-1.0 solvents 1.0-95.0 thickener 0.05-5.0 purified water rest

The additional introduction of a buffer complex of sodium succinate, potassium succinate and magnesium succinate into the agent for the treatment and prevention of diseases of the kidneys and urinary system, the choice of the extract of a mixture of astragalus syrup, birch leaves and linden flowers with the declared quantitative composition of all components as the plant active substances allows to reduce negative side effects and provides an increase in the level and expansion of the spectrum of specific activity with a positive integrated effect on ki and urinary system.

A buffer complex of sodium succinate, potassium succinate and magnesium succinate was obtained by the interaction of succinic acid with magnesium oxide, sodium hydroxide and potassium hydroxide, which helps maintain the colloidal composition of urine. A wide spectrum of pharmacological activity of succinic acid is known, which is a natural metabolite of the body, but there is no data on the effect of succinic acid salts on the colloidal composition of urine.

The claimed remedy for the treatment and prevention of diseases of the kidneys and urinary system has a name proposed by the authors - "Flarosuccin".

In the claimed agent, methyl parahydroxybenzoate and propyl parahydroxybenzoate, potassium sorbitol, sorbic acid, sodium benzoate and the like can be used as preservatives.

Sodium saccharin, sorbitol, maltitol, sodium cyclamate or sucrose are used as sweetening components.

As food flavorings, vanilla-creamy fragrances with the smell of strawberries, raspberries, cherries, bananas or caramels are used.

As solvents, glycerin, propylene glycol or ethyl alcohol are used, and purified water is also used.

As thickeners, xanthan gum or alkyl cellulose such as methyl cellulose, or hydroxyalkyl cellulose, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxyalkyl alkyl cellulose, such as hydroxyalkyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose or carboxyl cellulose, cellulose cellulose, carboxymethyl cellulose, carboxymethyl cellulose, cellulose cellulose, carboxymethyl cellulose, cellulose cellulose, cellulose cellulose, cellulose like sodium carboxymethyl cellulose, or carboxyalkyl cellulose such as carboxy methylcellulose, or carboxyalkyl cellulose esters, or starches, or pectins, such as sodium carboxymethylamylopectin, or chitin derivatives, such as chitosan, or whether, oligo- and polysaccharides, such as trehalose, cyclodextrins and their derivatives, alginic acid, its salts with alkali metals and ammonium salt, carrageenan, galactomannans, tragacanth, agar-agar, polyacrylic acids and their salts; polymethacrylic acids, their salts and esters, methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone or its copolymers, or polyalkylene oxide, such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

Examples of carrying out the invention.

Example 1

Composition per 100 ml, g:

Buffer complex from:

sodium succinate 3.25 potassium succinate 4.00 magnesium succinate 1.40

Dry extract mixture

Astragalus amnioticus 1.80 birch leaves 0.90 linden flowers 0.30

Excipients:

sorbitol 20.00 maltitol 30.00 methyl parahydroxybenzoate 0.18 propyl parahydroxybenzoate 0.02 xanthan gum 0.30 glycerol 5.00 sodium saccharin 0.04 vanilla cream flavor 0.10 propylene glycol 2.00 purified water rest

Production technology.

With reactor 1, 1 liter of purified water is charged with succinic acid, magnesium oxide, sodium hydroxide and potassium hydroxide with stirring, with stirring. In the process of preparing the buffer complex, a salt formation reaction takes place: sodium succinate, potassium succinate, magnesium succinate. Propylene glycol and preservatives (methyl parahydroxybenzoate, propyl parahydroxybenzoate) are loaded into reactor No. 2, and stirred until a solution is obtained. Glycerin and xanthan gum are loaded into reactor No. 3, mixed until a homogeneous mass is obtained. In the reactor No. 1 with a buffer complex of salts, a dry extract is loaded, previously obtained from Astragalus syrup, birch leaves and linden flowers in a ratio of 6.0: 3.0: 1.0 and mixed until dissolved. Auxiliary substances are loaded into reactor No. 1 with a mixture of active substances: sweetening components (sorbitol, maltitol, sodium saccharin) and contents of reactor No. 3. The resulting blend is mixed until a homogeneous mass is obtained (30-40 minutes) and then auxiliary substances from reactor No. 2 are introduced into this reactor, flavors and purified water to a predetermined volume are mixed until a homogeneous mass is obtained. The resulting syrup is poured and packaged.

Example 2

Composition per 100 ml, g:

Buffer complex from:

sodium succinate 1,625 potassium succinate 2.00 magnesium succinate 0.70

Thick extract of the mixture;

astragalus 6.0 birch leaves 3.0 linden flowers 1,0

Excipients:

sucrose 30.00 methyl parahydroxybenzoate 0.15 propyl parahydroxybenzoate 0,03 hydroxyethyl cellulose 0.35 glycerol 2.0 sodium cyclomat 0.05 flavor raspberry 0.05 ethyl alcohol 96% 1.00 water is purified rest.

Production technology.

With reactor 1, 1 liter of purified water is charged with succinic acid, magnesium carbonate, sodium carbonate and potassium carbonate with stirring. In the process of preparing the buffer complex, a salt formation reaction takes place: sodium succinate, potassium succinate, magnesium succinate. Ethyl alcohol and preservatives (methyl parahydroxybenzoate, propyl parahydroxybenzoate) are loaded into reactor No. 2, and stirred until a solution is obtained. Glycerin and hydroxyethyl cellulose are loaded into reactor No. 3, mixed until a homogeneous mass is obtained. In the reactor No. 1 with a buffer complex of salts, a thick extract is loaded containing sickle astragalus, birch leaves and linden flowers in a ratio of 6.0: 3.0: 1.0 and mixed until dissolved. Sweetening components (sucrose, sodium cyclamate) are loaded into reactor No. 1 with a mixture of active substances, the contents of reactor No. 3 are introduced and mixed until a homogeneous mass is obtained (60-90 minutes). The contents of reactor No. 2, flavor, are introduced into the resulting solution, and mixed until a homogeneous mass is obtained. The resulting syrup is packaged.

Example 3

Composition per 100 ml, g:

Buffer complex from:

sodium succinate 4,875 potassium succinate 6.0 magnesium succinate 2.1

Thick extract of the mixture:

astragalus 3.0 birch leaves 1,50 linden flowers 0.50

Excipients:

sucrose 40,0 sodium benzoate 0.1 potassium sorbate 0.1 caramel flavor 0.15 ethyl alcohol 96% 10.00 purified water rest

Production technology.

With reactor 1, 1 liter of purified water is charged with succinic acid, magnesium oxide, sodium bicarbonate and potassium carbonate with stirring. In the process of preparing the buffer complex, a salt formation reaction takes place: sodium succinate, potassium succinate, magnesium succinate. Sugar is loaded into reactor No. 2 with purified water, heated with constant stirring until completely dissolved, and cooled. In the reactor No. 1 with a buffer complex of salts, a thick extract is loaded containing sickle astragalus, birch leaves and linden flowers in a ratio of 6.0: 3.0: 1.0 and mixed until dissolved. In the reactor No. 2 with sugar syrup, the contents of the reactor No. 1, ethyl alcohol, preservatives (sodium benzoate and potassium sorbate), flavor are loaded, flavor is mixed until a homogeneous mass is obtained. The resulting syrup is packaged.

In an experiment studying the pharmacological action of syrup, it was unexpectedly found that succinic acid salts (sodium, potassium and magnesium succinate) create favorable conditions for stopping the growth and dissolution of uric acid and mixed calculi. Moreover, this combination in a lower dose exhibits a therapeutic effect similar to the Blemaren drug containing sodium citrate. As a result of a preclinical study of the drug, its therapeutic efficacy in the pathology of the kidneys and urinary system of the composition was demonstrated.

A rational selection of the active substances of the claimed drug and experimentally selected optimal ratios between them within the indicated limits provide a complex effect on various pathogenesis links of kidney and urinary tract diseases. At the same time, we studied the diuretic, anti-inflammatory, antispasmodic, litholytic effect, the normalizing effect of the drug on the filtration-reabsorption function and morphostructure of the kidneys, the ability to restore and maintain electrolyte balance at the level of physiological values in renal failure.

Next, we present the data of experimental studies indicating the pharmacological properties of the proposed drug Flarosuccin.

The effect of the buffer complex from succinate, which is part of Flarosuccin, on the pH of urine

We studied the effect of the buffer complex of Flarosuccin on the possibility of urine pH shifting towards alkaline values and the duration of retention of this effect for 4 hours. The experiments were carried out on intact white purebred sexually mature rats of both sexes in comparison with the Blemaren drug (Esparma, Germany). Intact animals were administered intragastrically with Blemaren at a daily therapeutic dose of 1.5 g / kg. The buffer complex of the drug “Flarosuccin was administered to intact animals in doses of 0.5 and 0.75 g / kg. The research results are shown in table 1.

Table 1 Comparative dynamics of the urine pH of rats with the introduction of a buffer complex of succinate and Blemaren drug (n = 6) Groups of animals Dose g / kg PH initial values Dynamics of pH in dynamics, after ... hours one % four % Buffer complex of succinate (composition according to example 1) 0.5 5.67 ± 0.31 6.75 + 0.31 * 19.05 7.33 + 0.21 * 29.3 0.75 5.6 ± 0.32 6.5 ± 0.18 * 16.07 7.3 ± 0.3 *** 30.3 Blemaren 1,5 5.75 ± 0.28 6.83 ± 0.25 * 18.5 7.00 ± 0.18 * 21.7 Note: * - probability of differences with respect to the initial values (P <0.05); ** - significance of differences up to 1 hour of observation (P <0.05); *** - significance of differences to the comparison tool (P <0.05).

From the data given in table 1, it is seen that when using a buffer complex consisting of potassium, magnesium and sodium succinate in doses of 0.5 and 0.75 g / kg (1/3 and 1/2 of the average daily dose of Blemaren ) there is a shift in the pH of urine to the alkaline side. In addition, both doses for a long time (within 4 hours) maintain the urine pH in the region of alkaline values. The introduction of these doses throughout the observation period has no significant differences from the use of the comparison drug - Blemaren.

The antispasmodic effect of Flarosuccin in a model of obstructed urination

Investigated the antispasmodic effect of the claimed drug in rats on a model of obstructed urination caused by intramuscular injection of ephedrine. As a comparison drug, the drug Fitolizin (Herbapol, Poland) was used. The animals “Flarosuccin” and the comparison drug Phytolysin were administered 30 minutes before modeling the pathology at a dose of 2.0 ml / kg. The effect of the drugs was studied by the intensity of urination. The research results are shown in table 2.

The previous intragastric administration of “Flarosuccin” relieves spasm of the urinary tract, the volume of urine in comparison with the control of pathology increases by 3.7 times and does not have significant differences from indicators of intact animals. In the group of animals to which the comparison drug Phytolysin was administered at the same dose, the urine volume increased by the end of the observation period only 2.7 times.

Table 2. The effect of drugs Flarosuccin and Fitolizin on spasm of the urinary organs (n = 6) Groups of animals Urine volume in 4 hours, ml Intact control 3.63 ± 0.47 Pathology control 1.24 ± 0.18 * Pathology + Flarosuccin, 2 ml / kg (composition according to example 1) 4.45 ± 0.20 ** / *** Pathology + Flarosuccin, 2 ml / kg (composition according to example 2) 4.52 ± 0.28 ** / *** Pathology + Flarosuccin, 2 ml / kg (composition according to example 3) 4.72 ± 0.22 ** / *** Pathology + Phytolysin, 2 ml / kg 3.29 ± 0.48 ** Note: * - probability of differences with respect to intact control (P <0.05); ** - significance of differences to pathology control (P <0.05); *** - significance of differences to the comparison tool (P <0.05).

Thus, Flarosuccin has a pronounced diuretic and antispasmodic effect in a dose of 2.0 ml / kg and 1.4 times more than the comparison drug Fitolizin in these indicated effects.

In preliminary experiments, it was shown that a change in the claimed ratios of active substances worsens the therapeutic effectiveness of the drug.

The effect of Flarosuccin on the course of experimental urolithiasis. The effect of Flarosuccin on the course of experimental urolithiasis was compared with Fitolizin (Herbapol, Poland). Experimental stone formation in rats was caused by the operative introduction of a foreign body into the bladder of animals (a disk with an average weight of 30 mg). After healing of the surgical wound, the animals were injected intragastrically every day for 18 days with a lithogenic substance - 1% ethylene glycol solution. To assess the effectiveness of the drugs, urine pH and specific gravity, the mass of the disk sewn into the bladder were determined. The research results are presented in table 3.

On the model of experimental urolithiasis, flarosuccin shifts the pH of the urine towards neutral and slightly alkaline values, and also reduces its specific gravity, which is a necessary condition to prevent the formation and growth of urinary calculi (calcium oxalate and calcium carbonate). The use of Flarosuccin leads to a significant decrease in the mineral part on the disk, which was sewn into the bladder.

For all the studied parameters (urine pH, specific gravity and mass of the disk sewn into the bladder), Flarosuccin significantly exceeds the effect of the comparison drug Fitolizin, which is administered in a similar dose.

In preliminary experiments, it was shown that a change in the claimed ratios of active substances worsens the therapeutic effectiveness of the drug.

The effect of Flarosuccin on filtration and reabsorption function of the kidneys and a marker of kidney inflammation - alkaline phosphatase in experimental renal failure

Experimental renal failure in rats was modeled by daily (for 14 days) intragastric administration of a 1% aqueous solution of ethylene glycol. For animals, Flarosuccin and a comparison tool Phytolysin (Herbapol, Poland) were administered at a dose of 2 ml / kg for 14 days. The effect of Flarosuccin and Phytolysin on spontaneous diuresis in rats was judged by the volume of urine and its specific gravity. The values of glomerular filtration and tubular reabsorption, the content of urea and uric acid in the blood and urine of animals were evaluated. The anti-inflammatory activity of the drugs was judged by their effect on the content of the marker of kidney inflammation - alkaline phosphatase in the blood and urine of animals with pathology (tables 4, 5).

Table 4 The effect of Flarosuccin and Phytolysin on diurnal diuresis of glomerular filtration and tubular reabsorption in experimental renal failure Groups of animals Urine Volume, ml Specific gravity Glomerular filtration, ml / min Tubular reabsorption% Intact control 6.66 ± 0.605 1.0196 ± 0.0006 0.193 ± 0.037 97.2 ± 0.34 Pathology 3.9 ± 0.3 * 1,024 ± 0,0004 * 0.034 ± 0.006 * 90.24 ± 1.5 * Pathology + Flarosuccin 2 ml / kg (composition according to example 1) 11.23 ± 1.40 * / ** 1.017 ± 0.0005 ** / *** 0.372 ± 0.040 * / ** / *** 97.70 ± 0.16 ** Pathology + Flarosuccin 2 ml / kg (composition according to example 2) 11.63 ± 1.45 * / ** 1.018 ± 0.0006 ** / *** 0.384 ± 0.044 * / ** / *** 97.86 ± 0.18 ** Pathology + Flarosuccin 2 ml / kg (composition according to example 3) 11.53 ± 1.35 * / ** 1.016 ± 0.0004 ** / *** 0.390 ± 0.038 * / ** / *** 97.76 ± 0.15 ** Pathology + Phytolysin 2 ml / kg 12.38 ± 0.8 *** 1.019 ± 0.0005 ** 0.29 ± 0.043 ** 96.64 ± 0.48 ** Note: * - significance of differences with respect to intact animals (P <0.05); ** - significance of differences with respect to pathology control (P <0.05); *** - the significance of differences with respect to the comparison tool (P <0.05).

Flarosuccin, along with a means of comparing Phytolysin in animals with experimental renal failure on day 14, not only restored diuresis, but also increased it 1.7-1.8 times in comparison with the intact control.

The action of Flarosuccin leads to an increase in glomerular filtration by 11 times (Fitolizin 8.5 times) and the normalization of tubular reabsorption in comparison with pathology control. Thus, the claimed tool increases the filtration of fluid in the glomeruli and completely restore impaired reabsorption more effectively than the reference drug, removing nitrogenous substances, in particular creatinine, from the body.

Flarosuccin normalizes the content of nitrogen metabolism products - urea and uric acid - in the blood of animals with experimental pathology and due to the restoration of glomerular filtration leads to an increase in their excretion in urine. At the same time, Flarosuccin more effectively normalizes the blood urea and urinary urea excretion, exceeding the action of Fitolizin by 30 and 34% (respectively, in blood and urine). According to the effect on the level of uric acid in the blood, Flarosuccin was also significantly more effective than the reference drug. It should be noted that the daily excretion of urea and uric acid with urine in the group of rats that received Flarosuccin exceeds intact values by 1.2 and 2 times, which indicates a decrease in uremia.

Due to the combined effect of the plant extract and the buffer complex from the salts of succinic acid included in its composition, Flarosuccin helps to reduce the inflammatory process in the kidneys. The indicated action of the agent is confirmed by the normalization of alkaline phosphatase activity both in the blood and in the urine of animals with experimental renal failure. According to the specified type of pharmacological action, the claimed product Flarosuccin has no significant differences from the means of comparison - Fitolizin.

In preliminary experiments, it was shown that a change in the claimed ratios of active substances worsens the therapeutic effectiveness of the drug.

Study of the effect of Flarosuccin on electrolyte metabolism in experimental renal failure

The effect of Flarosuccin on electrolyte metabolism in rats with experimental renal failure caused by intragastric administration of a 1% aqueous solution of ethylene glycol was evaluated. Means Flarosuccin and Phytolysin at a dose of 2 ml / kg were administered once a day for 14 days. The level of calcium and phosphorus in the blood and urine of animals was determined on the 14th day of the experiment (table 6).

Table 6 The effect of Flarosuccin and Phytolysin on the content of calcium and phosphorus in the blood and urine of rats with experimental renal failure Groups of animals Calcium Phosphorus blood mmol / l urine, mmol / day blood mmol / l urine, mmol / day Intact control 2.71 ± 0.029 181.99 ± 20.48 2.73 ± 0.08 241.3 ± 39.05 Pathology 1.72 ± 0.109 * 42.86 ± 6.03 * 3.3 ± 0.066 * 62.35 ± 9.29 * Pathology + Flarosuccin 2 ml / kg (composition according to example 1) 2.48 ± 0.158 ** / *** 181.74 ± 15.80 ** 2.86 ± 0.080 ** 305.44 ± 25.34 ** Pathology + Flarosuccin 2 ml / kg (composition according to example 2) 2.52 ± 0.164 ** / *** 183.82 ± 16.72 ** 2.76 ± 0.085 ** 301.33 ± 26.47 ** Pathology + Flarosuccin 2 ml / kg (composition according to example 3) 2.54 ± 0.170 ** / *** 185.69 ± 16.47 ** 2.80 ± 0.076 ** 304.72 ± 24.72 ** Pathology + Phytolysin 2 ml / kg 1.78 ± 0.043 * 187.61 ± 23.07 ** 2.96 ± 0.13 ** 329.26 ± 32.67 ** Note: * - significance of differences with respect to intact animals (P <0.05); ** - significance of differences with respect to pathology control (P <0.05); *** - the significance of differences with respect to the comparison tool (P <0.05).

Flarosuccin retained the concentration of phosphorus and calcium in the blood of animals and regulated their excretion in urine, which was impaired in experimental renal failure. Flarosuccin significantly exceeded the means of comparison Phytolysin in its effect on electrolyte metabolism. The normalizing effect of Flarosuccin on calcium-phosphorus homeostasis contributed to the dissolution and elimination of both calcium-oxalate and calcium-phosphate calculi.

In preliminary experiments, it was shown that a change in the claimed ratios of active substances worsens the therapeutic effectiveness of the drug.

Study of the effect of Flarosuccin on the course of experimental renal failure in childhood

We studied the effect of Flarosuccin on experimental renal failure in sexually immature rats with a single intramuscular injection of 50% glycerol solution at a dose of 10 ml / kg in comparison with Canefron N (Bionorika, Germany).

Flarosuccin in doses of 2.0 g / kg and 3.2 g / kg showed a diuretic effect, increasing diuresis in rat pups against the background of water load, and also shifted the urine pH to neutral values. According to the diuretic effect, Flarosuccin at a dose of 2.0 g / kg significantly exceeded the effect of the comparison agent Kanefron N, which was administered in a larger dose, and, in contrast to the latter, contributed to a shift in the pH of the urine towards neutral values. This pharmacological effect is necessary for loosening and subsequent excretion of calcium-oxalate and calcium-phosphate calculi (table 7).

Table 7 Comparative study of the effect of Flarosuccin and Kanefron N on induced diuresis in immature rat pups Groups of animals Urine Volume, ml Specific gravity pH Glomerular filtration ml / min Tubular reabsorption% Intact control 5.0 ± 0.72 1.02 ± 0.001 5.71 ± 0.26 0.16 ± 0.035 96.7 ± 0.76 Pathology 2.13 ± 0.54 * 1,024 ± 0,001 * 7.5 ± 0.34 * 0.03 ± 0.01 * 93.86 ± 0.86 * Pathology + Flarosuccin 2 ml / kg (composition according to example 1) 7.25 ± 0.54 * / ** / *** 1.019 ± 0.001 ** 6.0 ± 0.19 ** / *** 0.15 ± 0.022 ** / *** 96.9 ± 0.4 ** Pathology + Flarosuccin 3.2 ml / kg (composition according to example 2) 6.06 ± 0.42 ** / *** 1,022 ± 0,001 6.63 ± 0.25 * / *** / *** 0.206 ± 0.023 ** / *** 97.64 ± 0.21 ** Pathology + Kanefron N 1 ml / kg 2.25 ± 0.31 * 1,021 ± 0,003 7.7 ± 0.3 * 0.052 ± 0.015 * 94.18 ± 1.4 Note: * - significance of differences with respect to intact animals (P <0.05); ** - significance of differences with respect to pathology control (P <0.05); *** - the significance of differences with respect to the comparison tool (P <0.05).

Table 8 The effect of Flarosuccin and Kanefron N on the content of urea, uric acid and electrolytes in the urine and blood of rats with experimental renal failure Groups of animals Urine Uric acid Calcium urine Phosphorus urine urine, mmol / day blood mmol / l urine mmol / day blood mmol / l mmol / day mmol / day Intact control 301.24 ± 43.66 8.33 ± 1.45 10.77 ± 1.28 159.89 ± 12.87 77.44 ± 9.55 142.1 ± 19.2 Pathology 125.45 ± 37.86 * 14.47 ± 0.78 * 3.68 ± 1.12 * 269.73 ± 16.19 * 42.96 ± 10.8 * 64.45 ± 20.3 * Pathology + Flarosuccin 2 ml / kg (composition according to example 2) 315.19 ± 42.1 * / ** / *** 8.72 ± 0.46 ** / *** 10.1 ± 2.88 ** / *** 168.73 ± 12.52 ** 76.28 ± 9.39 ** / *** 147.24 ± 11.1 ** / *** Pathology + Flarosuccin 3.2 ml / kg (composition according to example 3) 392.54 ± 43.98 * / ** / *** 7.27 ± 0.95 ** / *** 12.76 ± 1.49 ** / *** 146.76 ± 14.41 ** 94.23 ± 14.02 ** / *** 176.36 ± 18.67 ** / *** Pathology + Kanefron N 1 ml / kg 100.18 ± 21.93 * 10.7 ± 0.52 ** 3.09 ± 0.85 ** 199.53 ± 31.03 ** 43.92 ± 8.1 * 59.27 ± 12.1 * Note: * - significance of differences with respect to intact animals (P <0.05); ** - significance of differences with respect to pathology control (P <0.05); *** - significance of differences with respect to the means of comparison (P <0.05).

Flarosuccin improved the filtration-reabsorption ability of the kidneys, normalizing nitrogen excretion function and promoting the resumption of phosphorus-calcium homeostasis. Flarosuccin exhibits a more pronounced effect with respect to the effect on all studied parameters at a dose of 2.0 g / kg, significantly exceeding the effect of the comparison drug Canefron N (table 8).

In preliminary experiments, it was shown that a change in the claimed ratios of active substances worsens the therapeutic effectiveness of the drug.

A preclinical study of the proposed tool also showed that prolonged administration of it to animals in therapeutic doses did not cause a negative effect on the functional state of their vital organs and systems.

The inventive tool did not show irritating and allergic effects, as well as negative effects on the immune system of animals. When pathomorphological examination of the internal organs of experimental animals was not detected changes due to the toxic effect of the proposed funds.

A comprehensive analysis of the data, performed on the basis of standard methods of pharmacological assessment, allows us to conclude that, in terms of the severity of the effect on the diuretic, filtration, and nitrogen excretory function of the kidneys, as well as on the effect on electrolyte metabolism, and on the antispasmodic activity, Flarosuccin significantly exceeds the comparison drugs Fitolizin and Kanefron N in experiments on sexually mature and immature animals. This favorably distinguishes Flarosuccin from well-known drugs with nephroprotective properties and allows us to characterize it as an effective nephroprotective agent that has a pharmacotherapeutic effect on various links in the pathogenesis of kidney and urinary tract diseases.

It has been established that the high pharmacotherapeutic activity of the claimed means of Flarosuccin is directly related to the synergistic effect of all its components - a plant extract and a buffer complex. Flarosuccin is also characterized as a drug that does not have side effects.

Thus, preclinical studies have confirmed that the claimed drug has a wide range and a high level of specific pharmacological activity, resulting in a complex effect on various links of the pathogenesis of kidney and urinary tract diseases while reducing treatment time.

Claims (1)

An agent for the treatment and prevention of diseases of the kidneys and urinary system containing active substances of plant origin and excipients, characterized in that it additionally contains active substances in the form of a buffer complex of sodium succinate, potassium succinate and magnesium succinate, selected in the ratio of 2.3: 2 , 9: 1,0, a thick or dry extract of a mixture of astragalus syrup, birch leaves and linden flowers, taken in a ratio of 6.0: 3.0: 1.0, was selected as the active substances of plant origin, and as a whole the preservatives, preservatives, sweeteners, food flavorings, solvents, thickener and purified water were selected, while the components are taken in ratios, in%:
Buffer complex from: sodium succinate potassium succinate magnesium succinate 2,9-17,3 Mixture extract Astragalus amnioticus birch leaves linden flowers 1-15
Excipients:
preservatives 0.01-2.00 sweetening components 0.005-60.0 food flavorings 0.001-1.0 solvents 1,0-95,0 thickener 0.05-5.0 purified water rest