Pharmaceutical composition eliciting hepatoprotective effect and medicinal agent

FIELD: medicine, pharmacy.

SUBSTANCE: invention concerns a pharmaceutical composition eliciting hepatoprotective effect. The base of pharmaceutical composition comprises adducts of orotic acid with amino acids or amines as an active substance. The composition comprises effective amount of active substance and special additives in the following ratio of active substance and special additives, wt.-%: active substance, 0.05-40.0; special additives, 60.0-99.95. As special additives the composition comprises starch, mixture of vitamins, lactose, aerosil, talc, stearates, polyvinylpyrrolidone, solid confectionary fat, Tween-80, polyethylene glycol, glycerol, citric acid, benzoic acid, sodium benzoate, correcting dye-substances. Compositions are made as tablets, capsules, lozenges, suppositories, syrups. Also, invention proposes a medicinal agent comprising above said pharmaceutical composition. Invention provides high pharmaco-therapeutical effect with fitness period 2 years, not less.

EFFECT: improved and valuable pharmaceutical properties of composition.

9 cl, 6 tbl, 8 ex

 

The invention relates to medicine, in particular to medicines that can be used for the prevention and treatment of acute and chronic hepatitis, fatty infiltration and cirrhosis, acute and chronic poisoning of the liver.

There are various compositions that have a hepatoprotective effect. The main active components known medicines are different amino acid, orotic acid and its derivatives, essential phospholipids extracted from soybean seeds, medicines based on herbs, milk Thistle, some vitamins /1, 2/.

Currently in the Russian Federation in medical practice as a hepatoprotective funds used Essentiale, zelibor, potassium orotate, legalon, Heptral, i.e. the Arsenal of drugs hepatoprotective, truly causal action is very limited. Some drugs have side effects, sometimes ineffective and mostly foreign production /2, 3/.

Recently we have identified a number of potential new hepatoprotection /4/ in a series of adducts orotovoy acid with amino acids or amines with high hepatoprotective effect. In-depth pharmacological and Toxicological studies of these compounds confirmed their high hepatoprotective effect, superior to some of the applied medical is Oh practice hepatoprotectors, low toxicity, lack of side effects. All this makes feasible the development of various dosage forms-based adducts orotovoy acid with amino acids or amines and the creation of medicines - hepatoprotectors with improved properties.

As you know, dosage forms typically comprise the active agent and pharmaceutically acceptable auxiliary substances, that can significantly affect the speed and completeness of the suction dosage forms, ensure accurate dosing of the drug, give it optimal mass and volume, not only provide bioavailability of the drug, but also contribute to the successful implementation of the technological process of manufacturing legform. The use of the particular drug excipients as the target additives require pre biopharmaceutical experimental research.

The aim of the invention is to expand the Arsenal of effective hepatoprotective drugs which are able to protect the liver is the main organ of humans and animals, providing detoxification of the body and the functioning of the various systems.

The basis of the claimed invention is the task through a combination of adducts orotovoy acid with amino acids or amines with targeted supplements to create RA is personal dosage form new hepatoprotectors, eligible Gasfurnace RF XI edition, providing a high pharmacological effect, having a shelf life of not less than 2 years.

This problem is solved by the creation of the pharmaceutical compositions containing as active principle an effective amount of adducts orotovoy acid with amino acids or amines of General formula I

X-CH-(CH2)n-Z, where X=H, COOH, COOAlk;

Z=H, COOH, NH2, CONH2n=0-5

and targeted supplements.

The ratio of the active agent and the target additives is, wt.%:

the active principle of 0.05-40,0

targeted supplements 60,0-99,95

As the target additives, the use of starch, a mixture of vitamins, lactose, Aerosil, talc, salts of stearic acid, polyvinylpyrrolidone, solid confectionery fat, tween-80, polyethylene glycol, glycerin, citric acid, benzoic acid, sodium benzoate, correcting substance, a dye, in the following ratio, wt.%:

starch 0-46

the mixture of vitamins 0-23

lactose 0-40

Aerosil 0-10

talc 0-3,0

salt of stearic acid 0-1,0

polyvinylpyrrolidone 0-4,5

solid confectionery fat 0-99,94

tween-80 0-0,01

the glycol 0-99,95

propylene glycol 0-40,0

citric acid 0-0,3

benzoic acid or sodium

benzoate 0-0,15

correcting substances 0-40

cu is Khabibullina 0-0,002

The presence of solid dosage forms of the indicated amounts of starch and Aerosil provides increased speed of release and the completeness of absorption of the active agent increases raspadaemost and dissolution legform, but also creates conditions for the penetration of water and digestive juices in the pill or pills. Starch is preferable to use potato or corn. The presence of salts of stearic acid provides the effect of slip required at the stage of pressing tablets. As the salts are useful stearate or calcium.

The mixture of vitamins as special additives to the active beginning contributes to the intensification of the processes of cellular metabolism and metabolism, redox processes, regeneration of cells, lipid metabolism, which should have a positive influence on the course of treatment of liver diseases of various etiologies. From vitamins, it is preferable to use thiamine chloride or bromide, Riboflavin, pyridoxine hydrochloride, cyanocobalamin, folic acid, nicotinamide, tocopherol acetate, ascorbic acid, rutin.

As suppozitornoj bases in the manufacture of rectal suppositories, as we established, it is preferable to use solid confectionery fat with the addition of 1% tween-80 or polyethylene glycol, which provide the provide the maximum release of the active agent from the candles. In the preparation of syrups as correcting substances it is advisable to use sorbitol, xylitol, lactose, glucose, saccharin, aspartame, fruit flavouring essences or ready fruit syrups.

The pharmaceutical compositions can be in the form of powder (capsules, tablets, pills, tablets, film shell, suppositories (rectal suppositories), syrups.

The claimed ratio of components was found experimentally to be optimal and can achieve a technical result that is appropriate to the task: all pharmaceutical compositions meet the requirements of Gosfarmakapei XI edition, have a shelf life of not less than 2 years and provide a high pharmacological effect of the active principle.

One of the ways to obtain solid dosage forms is the manufacture of tablets by wet granulation, which includes the following steps: mixing powders, hydrating, mixing, granulation, drying, dusting, pressing /5/. Suppositories (rectal suppository) were prepared by the conventional technology method of pouring, and the quality of the candles were conducted according to the requirements of Gosfarmakapei XI ed. The choice of the optimal lipophilic suppozitornoj bases was carried out on results of release of the active agent from suppositories method Rav is ovesna dialysis through a semipermeable membrane. Pills and powder in capsules claimed pharmacological compositions were known in this field of technology.

Hepatoprotective properties offer medicines installed for the first time.

Evaluation of hepatoprotective activity proposed dosage forms was performed in models of acute and chronic active hepatitis in rats in a dose range of 5-25 mg/kg of the compounds of formula I after intragastric administration of tested samples and Comparators.

The following methods were used and the model and obtained the following results of a study of hepatoprotective effect of the claimed dosage forms of the compounds I, which are listed below.

Liver function was assessed using biochemical methods of analysis of blood serum and liver, as well as morphometric methods for the study of the liver tissue.

The study of hepatoprotective effect of the drugs was performed on models minisinoo hepatitis in rats (similar vnutrieritrocitarna cholestasis), on the model of hepatitis in rats caused by poisoning by carbon tetrachloride (similar chemically induced toxic hepatitis), on the model of chronic ethanol hepatitis (similar to alcohol poisoning liver), on the model paracetamolo hepatitis (similar mathematicallearning cholestasis) and on other models. Below are the results of the study drugs held on the first two of these models.

1. Biochemical methods of analysis of blood serum and liver.

The activity of aspartate aminotransferase (AST) and alanine aminotransferase (Alt) in serum were determined by the method Ritman, Frankel, alkaline phosphatase (alkaline phosphatase) - method Bessey, Brock, the content of total protein by Lowry /6/. Cholesterol (LDL) in the blood serum was determined by the method ilca /6/, cholesterol high density lipoprotein (HDL cholesterol) was assessed in the supernatant after heparin-manganese precipitation lipoprotein (LDL) and very low (VLDL) density /7/. Lipid composition of liver triglycerides (TG), free cholesterol (AU), free fatty acid (nezhk), phospholipids (PD), cholesterol esters (EH) was determined by thin layer chromatography /8, 9/ after extraction of the total lipids by the method of Folch modification /10/. The results are presented as percentage of allocation fractions.

Determination of total cholesterol in liver tissue was carried out according to the method /11/.

2. Morphometric research methods tissue and liver.

Obtained at necropsy, tissue samples of liver were fixed in 10% solution of neutral formalin, embedded in paraffin by standard methods, cooked slices of a thickness of 7 microns, the sections were stained with hematoxylin and eosin /12, 13/. Gettoproperty evaluated visas is real, and morphometry was performed, determining the total number of hepatocytes (G); damaged hepatocytes (GHG)emissions; sinusoidal; Central veins; triads; cells of the reticuloendothelial endofline system (RES) in % of the total number of listelements on a fixed area of the slice. On histological preparations was assessed as a score from 0 to $ 2 the degree of alteration of the liver tissue /14/. The main attention was paid to the degree of fat and protein degeneration of hepatocytes, the degree of disturbance of the beam patterns, the state of the terminal vascular bed of the liver, the activity of the inflammatory process parenchyma (the degree of infiltration of lymphoid elements).

3. Model minisinoo hepatitis in rats.

Chlorpromazine was administered intragastrically (W/W) once daily for 4 days at a dose of 50 mg/kg in a solution of starch mucus. The contents of the capsules 1A in doses of 5 and 15 mg/kg and capsules Essentiale in a dose of 100 mg/kg was administered/W solution of starch mucus daily for 8 days. Compound 1a - lysine orotate, 1B - β-alanine.

4. Model sharp tetrachlormethane hepatitis in rats.

Carbon tetrachloride was administered to the animals subcutaneously once daily for 4 days at a dose of 0.4 ml of 50% solution in liquid paraffin to 100 g of animal body weight /15/. Pills 1B in a dose of 5 and 25 mg/kg and Essentiale at a dose of 160 mg/kg was administered/W solution of starch mucus daily for 20 days.

5. P the results of the study of hepatoprotective effect of capsules 1A model minisinoo hepatitis in rats.

Biochemical study of blood serum of experimental animals on the model minisinoo hepatitis showed that the level of transaminases increased on average 2 times and decreased de Ritis coefficient 1.4 times increased by 17% level of total serum cholesterol, slightly decreased the proportion of HDL cholesterol (6%) and 57% increased haemoglobin rate (CAT) (see table 1).

The study of the lipid composition of the liver on the model minisinoo hepatitis compared with the control animals showed a decrease in total cholesterol in the liver by 32%, and total lipids 39%, indicating that the phenomena intrahepatic cholestasis with disorders of cholesterol synthesis. The increase in the ratio FL/TG (52%) and NAS/Tg (113%) confirmed the reduction of TG. The ratio AH/SH remained unchanged. About the decrease of the relative content of fluorescence in the liver was demonstrated by the decrease of the ratio of PL/CX (19%), however this reduction was not significant.

According to the histological analysis of the toxic dose of chlorpromazine caused disturbance of the beam patterns on the periphery of the liver lobules. Fine-grained protein degeneration of hepatocytes in the Central parts of the liver lobules was growing to the periphery, passing into the balloon. Fatty degeneration was absent. Sinusoids were often narrowed Central venous endothelium was damaged is Yong, there has been a considerable narrowing of blood vessels triads, especially the portal vein endothelium of peripheral vessels were thickened and triads often looked overgrown, met karyolysis and necrosis of hepatocytes near the portal fields, lymphoid infiltration was increased near triad. The endothelium of the bile capillaries was broken. Index of liver damage (FEP) was equal to 1.0± $ 0,12 (table 2).

Capsules 1A was applied in two doses: 5 and 25 mg/kg Application 1A at a dose of 5 mg/kg positive influence on biochemical parameters of blood serum: decreased levels of transaminases (Alat 1.7 times, AST 1.4 times). However, total cholesterol and HDL-cholesterol serum drug changed slightly, reducing its only 7 per cent compared with the model for the first indicator and increasing by 8% for the second. However, these minor changes of indicators has led to a positive change CAT, decreasing it by 26% in comparison with the model.

Increasing doses of 1A to 25 mg/kg increased positive hepatoprotective effect of the drug: the level of Alt and AST decreased in 2 and 1.6 times, respectively, de Ritis coefficient increased by 24%. HDL-C increased by 10%, total cholesterol decreased by 11%. Indicators CAT was close to the corresponding values of the control group. Introduction 1A has had a positive impact on lipid metabolism and is histostructure liver. 1A as in the dose of 5 and 25 mg/kg increased reduced chlorpromazine values of total cholesterol and lipids of the liver tissue in an average of 15-20%. The ratio FL/TG increased by 21%and 37%, respectively, and nezhk/TG decreased by 5%and 18%. 1a reduced the hydrolysis AH, so the ratio AH/SH restored to normal. 1A, in addition, when applied at a dose of 25 mg/kg increasedthe ratio PL/CX.

Morphometric studies have shown that the application of 1A at a dose of 5 mg/kg beam structure is saved in the centre of the hepatic lobules, on the periphery violated, the hepatocytes in the center of the lobules are undamaged, at the periphery, there were very significant fine-grained protein degeneration, fatty degeneration was absent. Sinusoids within normal limits, vessels mostly extended, especially the Central vein. Slightly increased infiltration. FEPwas equal to 0.60±0,05 USD, which is evidence of the positive effects of the drug.

With the introduction of 1A at a dose of 25 mg/kg showed a clear beam structure in the center and the periphery. Hepatocytes evenly colored, had no damage, vessels and sinusoids were within the normal range, there were only traces of fine-grained protein malnutrition on the periphery of the lobules, fatty degeneration was not. Infiltration is negligible. FEPwas 0.30±0,05 $

So about the time, according to biochemical and morphological studies on the model minisinoo hepatitis was observed in high dose dependent hepatoprotective effect of compound 1A. With increasing doses 1A effect increased. The greatest effect is observed in capsules 1A at a dose of 25 mg/kg

6. The results of the study of hepatoprotective effect of compound 1B model tetrachlormethane hepatitis in rats.

The results showed that after 4 injections rats CCI4on the 20th day in the serum of experimental animals increased level of Alt in 2,3 times, ASAT - 1.8% and 22% of total cholesterol, low (7%) decreased HDL cholesterol compared with the control group of animals (see table 3). De Ritis coefficient decreased by 25%, and CAT increased by 72%. Liver damage by carbon tetrachloride was accompanied by an increase of the content in the liver tissue total cholesterol and total lipids in average 1.4 times, the relative share of triglycerides and a decrease in fluorescence, SH and OH, that was manifested by the decrease of the ratio FL/TG (2.1 times), nezhk/TG (2.3 times), PL/CX (9%) and EH/SH (26%).

Morphometric studies showed that CCI4evoked in rat liver disorders beam patterns in the center and on the periphery of the liver lobules. Hepatocytes in the center of the lobules affected globular fatty degeneration in the periphery of the lobules were observed the considerable proteinases. Sine wave slightly narrowed, Central vein in some areas expanded. Peripheral vessels mostly in the normal range, they stagnated blood. Infiltration is negligible. Morphometric index of liver FEPwas equal to 1.1±0,1$. (table 4).

The introduction of tablets 1B in a dose of 5 mg/kg was accompanied by a decrease in the serum levels of Alt and AST 1.4 times, de Ritis coefficient remained unchanged. Total cholesterol decreased by 13%and HDL cholesterol increased slightly (by 3%), and therefore the CAT fell by 29%. In the liver of animals under the influence 1B decreased the content of total lipids and total cholesterol by 12%on average. The ratio FL/TG and nezhk/TG, former model significantly reduced compared to control animals, when applying 1B increased 1.7 times and 1.9 times, respectively, indicating the predominance of the processes of lipolysis over the processes of lipocytes.

Pathomorphological observations testified about restoring beam patterns in the center of the slices, a significant reduction in adipose degeneration. Sinusoids were normal Central vein in some areas expanded. Peripheral vessels mostly in the normal range. Infiltration of lymphoid elements is negligible. This morphometric index of FEPdecreased as compared with the model for the 45% and was equal to 0.6± 0,05 USD.

The introduction of tablets 1B in a dose of 25 mg/kg was accompanied by a significant decrease in serum level of Alt (1.8 times) and AST (1.6 times), de Ritis coefficient increased by 9%. Total cholesterol decreased by 14%and HDL cholesterol increased slightly (4%), which led to the decrease in CAT 32%.

In the liver of animals 1B compared to the model reduced the total cholesterol and total lipids in average by 22%. Significantly reduced in the model the ratio FL/TG and nezhk/TG when applying 1B increased 1.9 and 2.1 times, respectively, the ratio of PL/CS and EH/SH - 18 and 32%. Thus, the values of lipid metabolism in the experimental group of animals treated with pills 1B in a dose of 25 mg/kg, approached those of the animals of the control group.

Pathological examination of the liver testified about restoring beam patterns in the center of the slices, a significant reduction in fat and protein malnutrition. Sinusoids, Central vein and peripheral vessels were mostly within the normal range. Lymphoid infiltration is negligible. FEPwas equal to 0.4± $ 0,03.

Thus, according to the biochemical and morphological studies of the dosage form 1B in tablet form in doses of 5 and 25 mg/kg had a high dose dependent hepatoprotective effect on the model of toxic hepatitis in rats induced by carbon tetrachloride.

We performed pharmacological studies and other proposed dosage forms of the compounds having the structure I. however, a significant (reliable) differences in the effectiveness of different legform of these compounds in various models of liver injury has not been set.

The composition and methods of manufacture of the claimed pharmaceutical compositions in the following examples.

Example 1 (the pharmaceutical composition in powder form in capsules).

To 60 g of the powder of the compound 1A was added 60 g of a mixture of vitamins (for example, 1 g thiamine bromide or chloride, 1 g of Riboflavin, 1 g pyridoxine hydrochloride, 0.01 g cyanocobalmin, 0.3 g of folic acid, 5 g of tocopherol acetate, 20 g of nicotinamide and 31.8 g of ascorbic acid), thoroughly mixed in the mixer and added 138 g of potato starch or corn, 30 g of Aerosil, 9 g of talc and 3 g of calcium stearate or magnesium. The mass was thoroughly homogenized and the resulting powder was dispersed on the capsules. Get 1 thousand capsules of 0.3 g having the following composition powder (parts by weight):

the active principle 1a - 20,0

the mixture of vitamins - 20,0

starch - 46,0

Aerosil - 10,0

talc - 3,0

calcium stearate or magnesium - 1,0

Example 2 (the pharmaceutical composition in the form of pellets).

To 60 g of the adduct orotovoy acid and gamma-aminobutyric acid (1B) gain of 26.5 g of a mixture of vitamins (e.g. the measures 2 g of thiamine chloride or bromide, 2 g of Riboflavin, 0.5 g of folic acid, 2 g of pyridoxine hydrochloride, 3 g of tocopherol acetate, 17 g nicotinamide) and mix thoroughly. Then load 185 g of lactose, 218,5 g of dry starch, 5 g of talc and 5 g of calcium stearate or magnesium. The mixture is homogenized and dragonaut in dragonator to get nokiausers pills. Get 1 thousand tablets with the following composition of ingredients in one tablet (parts by weight):

the active principle 1B - 12,0

the mixture of vitamins - 5,3

lactose - 38,0

starch - 43,7

talc - 1,0

magnesium stearate - 1,0

Example 3 (the pharmaceutical composition in the form of tablets).

Manufacturing of tablets is carried out by operations of preparation (mixing components), wetting, wet caroliniana, drying, dry granulation, grinding and powder granules, tablets, dedusting and rejection pills.

In the mixer load 62,65 g powder 1B, 58,06 g of potato starch, to 27.88 g of lactose and 3.13 g of Aerosil. After stirring the mixture of powders download 66,83 g 5tpercent starch paste (3,41 g of starch) and stirred until a uniform distribution of moisture. The resulting mass is thoroughly mixed and passed through a granulator with a hole diameter of 2 mm, the Wet granulate is dried to a residual moisture of 1.5 to 2.5%, the dried granules are passed through gr is olator hole diameter 1 mm The resulting mass optivault of 1.53 g of magnesium stearate and tabletirujut on a tablet machine. Get 150 tablets with the following composition of ingredients in one pill (parts by weight):

the active principle 1B - 40,0

starch - 39,2

magnesium stearate - 1,0

lactose - 17,8

Aerosil - 2,0

The resulting tablets have a shelf life of more than 2 years, good structural and mechanical characteristics meet all the General requirements of Gosfarmakapei XI publications (see table 5).

Example 4 (the pharmaceutical composition in the form of tablets in a film wrapper).

In the mixer load sifted powders adduct orotovoy acid and lysine (1 g) 120 g, mixture of vitamins to 75.7 g of potato starch 100 g and 2 g of Aerosil Stirred the mixture for 15 minutes, humidified with a solution of polyvinylpyrrolidone (PVP)containing 13,6 g PVP. The wetted mass is stirred and granularit, the granules are dried to a moisture content of not more than 4%. Then dry granules grind, optivault a stearate or calcium (2 g) and tabletirujut in the tabletting machine. Get kernel-tablets having the following ingredients (parts by weight):

the active principle (1) - 40,0

the mixture of vitamins - 23,3

starch - 30,8

polyvinylpyrrolidone - 4,5

Aerosil - 0,7

magnesium stearate (calcium) - 0,7

Next on kernel-tablets applied film coating prepared from a solution of acetylide is icellulse (AFC) in a mixture of acetone with 96%ethyl alcohol (containing 15 g AFC), 4 g of titanium dioxide, 2.9 g of castor oil and 3.1 g of paraffin oil. The coating weight should be 3-3,5% by weight of the total tablet.

Get 1 thousand tablets in the shell with a mass 0,325 g, which meet all the requirements of Gosfarmakapei XI ed. and have a shelf life of more than 2 years (see table 5).

Example 5 (rectal candles weighing 0.5 g).

Suppositories (rectal suppositories) are prepared according to the conventional technology, a method of pouring the mass into molds in the following ratio of ingredients (parts by weight):

the orotate D-(-)-threo-p-nitro-

phenyl-2-aminopropanol-1,3 (1D) - 0,06

solid confectionery fat (TKJ) - 99,94

47 g of lipophilic suppozitornoj bases TKJ and 3 g of active principle 1D receive 100 candles with an average weight of 0.5 g containing 60 mg 1D in every candle that meets the requirements of Gosfarmakapei XI ed. rectal candles (see table 5).

Example 6 (candle mass of 1 g).

Rectal candles prepared by the method of pouring, similar to that described in example 5, the following ratio of ingredients (parts by weight):

the active principle 1B - 0,06

TKJ - 99,93

tween-80 - 0,01

6 g of the active principle 1B, 93 g suppozitornoj bases TKJ and 1 g of tween-80 get 100 candles with a mass of 1 g, containing 60 mg of 1B according to the demands of Gosfarmakapei XI ed.

Example 7 (candle mass 4 g).

Rectal candles prepared by the method of splashing in the following ratio in which regienov (parts by weight):

the active principle 1A - 0,05

polyethylene glycol (95% PEG with Mm=1500+

+5% PEG with Mm=400) - 99,95

20 g of the active principle 1A and 380 g of PEG method of pouring receive 100 candles with a mass of 4 g containing 50 mg 1a, corresponding to the requirements of Gosfarmakapei XI ed.

Example 8 (syrup in bottles).

It heated up to 50°With a solution of 220 g of propylene glycol was added 12 g orotata guanidine (1E), 1 g of sodium benzoate and 2.4 g of citric acid (solution No. 1). In another mixer dissolve 0.2 g of menthol and 1 g of vanilla or other flavorings in 80 ml of propylene glycol (solution No. 2). In the 3rd mixer is prepared by heating an aqueous solution of 350 g of sorbitol or other sweetener (solution No. 3). Then to the cooled solution No. 1 is poured a solution of No. 3 and to the resulting mixture is added 0.001 g food coloring, such as tropeolin 0, and a solution of 1 g of saccharin in 200 ml of water (solution No. 4). Next, to the mixture is poured solution No. 2 was added 4 g of food flavouring essences, for example essences "lemon", and bring the total amount of purified water to 1 L. After stirring and filtration of solids syrup Packed in glass bottles of 100 ml Get 10 bottles of syrup.

The shelf life of all developed formulations given in examples 1-8, not less than 2 years.

All of the claimed pharmaceutical compositions have high hepatotoxity the effect and therapeutic index 2-5 times greater than the number of known hepatoprotectors.

Thus, the positive effect and industrial applicability of the invention lies in the opportunities available new highly effective methods hepatoprotective drugs for the treatment of liver diseases, superior effectiveness and therapeutic breadth of some well-known in clinical practice, drugs of the same purpose.

Sources of information

1. Radbill O.S Pharmacotherapy in gastroenterology (Handbook), M, "Medicine", 1991.

2. Mashkovsky PPM Medicines, M, "Medicine", ISDthpart 1 , 2, 1993.

3. Vidal-2002 (reference). Drugs in Russia, ed. "Attraversare", SB-733.

4. Pat. Of the Russian Federation No. 2047606.

5. Technology of medicinal forms, volume 2 (edited by Laipanov) M, "Medicine", 1991, p.142.

6. Biochemical research methods in the clinic (Ed. OAS) M, 1969, s-303.

7. Titov V.N. and other lab. case, 1979, No. 1, p.36-41.

8. Velichko, LN. and other Matters. the honey. chemistry, 1980, No. 2, s-277.

9. Cats M. Technique of lipid (Per. s angl.). M., Mir, 1975, p.74.

10. Gribanov GA, Sergeev S.A. the. the honey. chemistry, 1975, t, s.

11. Watson D. Clin. Chim. Acta, 1960, No. 5, R.

12. O.V. Volkov, Eletsky J.K. Fundamentals of histology and histological techniques. M., 1982, 304 S.

13. Eliseev V.G. and other Basics of histology and histological techniques. M., 1967, 267 S.

14. Avtandil - Introduction to quantitative pathologic the massive morphology. M., 1980, 216 S.

15. Fischer A. Physiology and experimental pathology of the liver. Budapest, 1961, 216 S.

1. Pharmaceutical composition having a hepatoprotective effect, comprising as active principle derived orotovoy acid and the target additives, characterized in that as derived orotovoy acid it contains adducts orotovoy acid with amino acids or amines of General formula I

X-CH-(CH2)n-Z, where X=H, COOH, lk;

Z=H, COOH, NH2, CONH2; n=0-5

in the following ratio, wt.%:

The active principle of 0.05-40,0

Targeted supplements 60,0-99,95

2. The pharmaceutical composition according to claim 1, characterized in that as the target additives it contains components selected from the group of starch, a mixture of vitamins, lactose, Aerosil, talc, salt of stearic acid, polyvinylpyrrolidone, solid confectionery fat, tween-80, polyethylene glycol, propylene glycol, citric acid, benzoic acid or sodium benzoate, correcting agents, dye.

<> 3. The composition according to claim 1, characterized in that the starch it contains potato and/or corn starch.

4. The composition according to claim 1, characterized in that salts of stearic acid using calcium or magnesium salt of this acid.

5. The composition according to claim 1, characterized in that as a mixed use vitamins thiamine chloride or bromide, Riboflavin, pyridoxine hydrochloride, cyanocobalamin, folic acid, nicotinamide, tocopherol acetate, ascorbic acid, rutin.

6. The composition according to claim 2, characterized in that as correcting substances use sorbitol, xylitol, lactose, glucose, sucrose, aspartame or ready fruit syrup and flavoring essences.

7. The composition according to claim 1, characterized in that it is a powder, tablets, pills, capsules, suppositories, syrups.

8. Drug, possess hepatoprotective effect, comprising the pharmaceutical composition according to claim 1.

9. The drug of claim 8, wherein the adduct orotovoy acid with amino acids or amines contains as amino acid components or amine L-glutamic acid, gamma-aminobutyric acid, lysine, beta-alanine, guanidine or D-(-)-threo-p-nitrophenyl-2-aminopropane-1,3.



 

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3 tbl

FIELD: medicine, hepatology.

SUBSTANCE: at achieving alkaline phosphatase of 580 U and more one should introduce ursodesoxycholic acid at the dosage of 15-20 mg/kg and orlistate at the dosage of 90-100 mg twice or thrice daily for patients with steatohepatitis. According to normalization of clinical and biochemical values of blood analyses it is possible to conclude upon successfulness of therapy performed. The method provides clinic-laboratory remission of the disease.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to the substituted 4-benzylaminoquinolines and their heteroanalogs of the general formula (I): P-L-G (I) wherein G means compound of the formula: G(I) wherein K means -OR(7), -NH-CH2-CH2-SO3H, -NH-CH2-CO2H wherein R(7) means hydrogen atom, CH3; R1-R6 mean independently of one another hydrogen atom, -OR(10), -R(10) being one of residues R1-R6 means a bond with L always; R(10) means hydrogen atom, (C1-C4)-alkyl; L means (C1-C15)-alkyl being one or some structural CH2-fragments can be replaced for -C≡C-, -NR(11)-, -CO-, -O- wherein R(11) means hydrogen atom; P means: or wherein A means nitrogen atom (N); B means CH; D means CH; E means CH; R16-R24 mean independently of one another hydrogen atom, F, Cl atoms, (C1-C4)-alkyl being alkyl residues can be mono- or multiple-substituted with fluorine atom, NR(25)R(26), OR(25), COR(25), COOR(25), CONR(25)R(26) being one of residues R16-R(24) means a bond with L always; R25 and R26 mean independently of one another hydrogen atom, (C1-C4)-alkyl or benzyl. Also, invention relates to their pharmaceutically acceptable salts. Also, invention relates to a method for their preparing and to a drug based on thereof for prophylaxis of supersaturation of bile with cholesterol. Invention provides preparing new compounds and a drug based on thereof that can be used for prophylaxis and treatment of patients suffering with gallstones.

EFFECT: improved preparing method, valuable medicinal properties of compounds and drugs.

10 cl, 32 ex

"antipsoriaz" cream // 2246935

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to developing medicaments in the form of ointment based on vegetable components and designed, in particular, to treat psoriasis as well as fungus diseases and can also be used in cosmetology. Psoriasis treatment cream includes water extracts of bur-marigold (Bidens tvipartita), white birch leaves (Betula alba L), greater celandine (Chelidonium majus), calendula (Calendula officanalis L), cudweed (Gnphalium uliginosum L), medical vaseline, lanolin, camphor, linseed oil, and medical solid oil at specified proportions of components.

EFFECT: increased treatment efficiency, avoided use of chemical additives, and prolonged shelf time.

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: medicine, surgical gastroenterology.

SUBSTANCE: as a curative preparation one should apply a pectin-containing powder product of table beet out of sublimated raw material. For reducing the powder before application one should apply low-mineralized low-alkaline amicrobial solution of electrochemically activated catholyte. Supernatant transparent fraction of this solution should be constantly introduced by drops into nasobiliary probe, residual fraction should be applied for peroral additional enterosorption. The method provides sanitation of biliary ducts by preventing duodenocholedochous reflux, and enterosorption that decreases portal toxemia.

EFFECT: higher efficiency of therapy.

2 cl, 1 ex

FIELD: pharmaceutical industry.

SUBSTANCE: preparation method comprises heating rock oleoresin to specified temperature, forming tape by passing through rolls, and tableting in laminar air flow using, for example, tubular knife with cutting edge sharpening radius no greater than 0.2 mm.

EFFECT: enabled tableting in absence of inert additives at any temperature and moisture characteristics of atmospheric air and enhanced therapeutical effect of rock oleoresin tablets.

2 cl, 3 tbl, 3 ex

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to pharmaceutical composition comprising atenolol as an active component and additives - starch, magnesium basic carbonate, polyvinylpyrrolidone and/or starch glycolate sodium salt, gelatin and stearate; or starch, polyvinylpyrrolidone, stearate, aerosil and microcrystalline cellulose. Composition shows improved physical-mechanical properties.

EFFECT: improved pharmaceutical properties of composition.

14 cl, 1 tbl, 5 ex

FIELD: medicine, oncology, chemical-pharmaceutical industry and technology, pharmacy.

SUBSTANCE: tablet with antitumor effect contains acceptable carrier on which the following mixture of aqueous-alcoholic tinctures is applied: bloody geranium, penny-cress, common cocklebur and European wild ginger. Tablets by mass 1 g including slipping substance contains the following amounts of indicated tinctures as measure for dry matters, g: bloody geranium, 0.015-0.020; penny-cress, 0.011-0.015; common cocklebur, 0.011-0.017, and European wild ginger, 0.024-0.036. Method for preparing tablet involves applying on carrier the mixture of aqueous-alcoholic tinctures of above indicated plants, the following drying the prepared mass, its granulating and tableting. Method for prophylaxis and treatment of oncological patients involves prescription 0.5-2 tablets with oncological designation, tree times per a day and the treatment course is determined individually based on objective data of treatment. Tablet made by claimed methods shows complex properties: it delays tumor growth and metastazing and can be recommended for treatment and prophylaxis of oncological pathology both independently and in combination with chemo-radiation therapy. Invention can be used in technology for making medicinal formulations of preparations with oncological designation and for treatment of patients with oncological pathology of different organs and body systems.

EFFECT: improved for making tablet, valuable medicinal properties of tablet.

7 cl, 4 ex

FIELD: medicine, oncology, chemical-pharmaceutical technology, pharmacology, pharmacy.

SUBSTANCE: tablet eliciting the antitumor effect comprises active dose of aconite alkaloids in the amount 0.0125-0.0375 mg. Invention relates to a method for making tablet with antitumor effect. Method involves treatment suitable carrier taken in the amount corresponding to the content of alkaloids in tablet 0.0125-0.0375 mg with aconite tincture wherein amount of the total content of alkaloids is determined preliminary. Then carrier treated by such manner is dried at temperature 30-35°C, not above, granulated, granules are powdered and tableted. Also, invention relates to a method for treatment of oncological patients that involves prescription to patient 0.5-2 tablets with oncological designation being this treatment is determined individually. Invention can be used in manufacturing medicinal formulations of preparations used for treatment of patients with oncological pathology.

EFFECT: improved method for treatment and making, valuable medicinal properties of tablet.

8 cl, 2 ex

FIELD: stomatology.

SUBSTANCE: invention relates to films for in-mouth application containing cosmetic or pharmaceutical substances. Film comprises at least one water-soluble polymer such as pullulan, pharmaceutically active agent, and ion-exchange resin as taste masking agents containing divinylbenzene-crosslinked polystyrene. Preparation procedure: water-soluble ingredients are dissolved in water; water-soluble film-forming agent is mixed with one stabilizer to form film-forming mixture; the latter is combined with above aqueous solution and resulting mixture is stirred to form gel; gel is mixed with oil blend to give homogenous gel, which is poured onto support and dried to form desired film.

EFFECT: achieved good masking of agent taste and good-quality appearance.

28 cl, 7 tbl, 7 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the solid medicinal formulation comprising chondroitin sulfate. The proposed medicinal formulation comprises 250 mg of chondroitin sulfate as an active component, filling agent, binding agent, antifriction substances and can comprise a solubilizing agent additionally. Pharmaceutical composition is made as a tablet. Invention provides development of the preparation for oral administration with the less amount of active substance and with indices satisfying requirements of the State Pharmacopoeia.

EFFECT: improved and valuable properties of formulation.

8 cl, 16 tbl, 39 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: antiviral agent comprises aciclovir as an active substance and special additives wherein agent comprises potato starch, talc, stearic acid or stearates as special additives taken in the definite ratio of components. Antiviral agent is made as a tablet. Also, invention relates to a simple method for preparing an antiviral agent and invention provides rapid release of active component. Invention can be used for treatment of skin and mucosa viral diseases induced by herpes simplex virus or herpes zoster virus, and for prophylaxis of these diseases in patients with damage of the immune system.

EFFECT: improved method for preparing, valuable medicinal properties of agent.

4 cl, 1 tbl

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to producing a medicinal preparation with analgesic, antipyretic and anti-inflammatory effect. The preparation is made as a tablet comprising a core containing ibuprofen as an active substance wherein a core is covered by envelope masking taste of the preparation. Core comprises potato starch and calcium stearate as special additives, and envelope comprises sugar, magnesium basic carbonate, polyvinylpyrrolidone, aerosil, talc, titanium dioxide, gelatin, vanillin, dye acid red and bee wax. Invention provides the necessary quality and necessary therapeutic effect of tablets due to rapid release of active substance from the tablet core wherein the core decomposition is 7-8 min and that in dissolving and 92-94% of active component transfers to medium in 45 min.

EFFECT: improved method for preparing, improved and valuable medicinal and pharmaceutical properties of preparation.

4 cl, 1 tbl, 5 ex

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a solid composition eliciting with an anti-ulcer activity and to a method for its preparing. Pharmaceutical composition consists of a core containing famotidine as an active component and starch, aerosil, stearic acid salt as accessory inert substances wherein a core is covered by polymeric envelope. Core comprises glucose and stearic acid as an accessory inert substance and magnesium stearate as a stearic acid salt. Polymeric envelope comprises oxypropylmethylcellulose, propylene glycol, castor oil, talc and titanium dioxide taken in the definite ratio of all components in the composition. Method for preparing pharmaceutical composition involves preparing raw, mixing therapeutically effective amount of famotidine with glucose and starch, moistening the mixture with starch paste, granulation, drying wetted granulate, repeated granulation, powdering dry granules, tableting and applying polymeric envelope containing oxypropylmethylcellulose on prepared cores with addition of titanium dioxide, propylene glycol, castor oil and talc. Invention provides enhancement of degradability, solubility and stability in storing.

EFFECT: improved method for preparing, valuable pharmaceutical properties of composition.

3 cl, 1 ex

Floating table // 2254121

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to medicinal formulations. Tablet consists of a mixture of medicinal agents and accessory substances and made with internal cavity filled with air. Cavity can involve isolated cells and the reduced specific weight of tablet is less 1 g/cm3. Invention provides enhanced effectiveness and safety of orally ingested tableted medicinal agents and safety of dissolving process and absorption of medicinal agent in stomach.

EFFECT: improved and valuable properties of tablet.

2 cl

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

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