Method for preparing medicinal product possessing choleretic, anti-inflammatory activities

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a method for preparing a medicinal product possessing choleretic activity. The medicinal product possessing choleretic activity and prepared by extracting an elevated part of Lomatogonium carinthiacum in 96% ethanol twice at room temperature, them in 40% ethanol with an extractant added in an amount equal to a discharged one, twice; the filtered aqueous-alcoholic extracts are combined; the extraction cake is extracted in purified water; the aqueous extract is filtered; the aqueous residues of the aqueous-alcoholic extracts are combined with the aqueous extract, concentrated, dried in a vacuum drying cabinet to produce the dry extract in the certain environment.

EFFECT: medicinal product prepared as described above possesses the evident choleretic activity.

11 tbl, 3 ex

 

The invention relates to pharmacy and relates to a method of obtaining funds from plant material that have choleretic, anti-inflammatory activities.

Despite the growing market of drugs with proven choleretic activity today, the problem of effective and safe therapy is far from being solved due to the high tendency to chronic diseases of the hepatobiliary system. Medicinal plants of the local flora are a renewable resource for production of new drugs broad-spectrum. Known choleretic activity of decoction of lomatogonium Carinthian used for the treatment of inflammatory diseases of the liver and gallbladder [Plant resources of the USSR: Flowering plants, their chemical composition, usage: family Caprifoliaceae - Plantaginaceae. - L.: Nauka, 1990. 326 c.]. In a decoction of medicinal plants are extracted only water-soluble substances, whereas grass lomatogonium Carinthian, in addition to water-soluble, and contains hydrophobic substances - aglycones of xanthones and flavonoids [Schaufelberger D., Hostettmann K. Flavonoid glycosides and a bitter principle from Lomatogonium carinthiacum. // Phytochemistry. 1984. V. 23. N. 4. P. 787-789], which are known to possess choleretic activity [Nikolaev S. M., sambuev Z. G., Tsyrenzhapov A.V., Badaev N. In., Radnaeva L. D., Nico�Eva G. G., Miheeva N. And., Averina E. S. Choleretic effect of natural ksenonovogo glycoside liposomally the form // Siberian medical journal. - 2004. - No. 1. S. 66-68].

The purpose of this invention is to increase the yield of biologically active substances, which is provided in the sequential extraction of plant raw materials containing substances of different polarity. This object is achieved by the fact that the method involves extraction of dried and ground to a particle size of 0.5-2.0 mm aerial parts of lomatogonium Carinthian 96% ethanol twice at room temperature for 2 h (1st and 2nd extraction), in the ratio raw:extractant (1:10-12), then 40% ethanol at a temperature of 90±5°C twice in a period of 1 hour (3rd and 4th extraction), then purified water at 100°C for 1 h (5 extractions). Alcoholic extract of the 1-4th extraction is evaporated on a rotary evaporator under vacuum to remove alcohol, water remains combined with the aqueous extract of the 5th extraction, separated for removal of plant dust and ballast substances. The final product is obtained by drying a concentrated extract in a vacuum drying Cabinet. The method allows to increase the yield of biologically active substances and to obtain a product of constant composition, its choleretic and anti-inflammatory activities.

Viewland�e distinctive features allows to make a conclusion about conformity of the proposed technological solution to the criterion "novelty" and the condition of patentability "inventive step". To prove the materiality of the proposed features of the method the series of experiments, the data of which are given below.

The study of the composition of biologically active substances of lomatogonium Carinthian 10.0 g of crushed to a particle size of 0.5-2.0 mm dried aerial parts of lomatogonium Carinthian was sequentially extracted with solvents of different polarity and after extraction solvent received a separate faction. The output of the chloroform fraction is 3,21%, ethylacetate - 1,96%, butanole - 6,01%, water - 20,71%. By chromatography on a thin layer of silica gel was studied the presence of biologically active substances in fractions in the solvent systems: hexane - ethyl acetate, 7:3 (I), chloroform - benzene, 5:1 (II), chloroform (III), chloroform - methanol, 7:3 (IV), ethyl acetate - formic acid - acetic acid - water 100:11:11:26 (V), ethyl acetate - methanol - water, 70:15:8 (VI), acetone - chloroform - water, 16:4:1 (VII), 15% acetic acid (VIII), butanol - acetic acid - water, 4:1:2 (IX). For descending chromatography coumarins used impregnated with a mixture of formamide-acetone (1:1) paper. For the detection of xanthones and flavonoids used a 3% alcoholic solution of aluminum chloride, ammonia vapors, for triterpene compounds - 1% solution of vanillin in concentrated sulphuric acid, 20% solution phosphomevalonate acid, DL� iridoid compounds - 0.2% solution diazotized sulfanilate acid, 20% aqueous solution of sodium carbonate. Used samples of substances: the aglycones of xanthones: sortierten, sortieren, decussation, surgeryn, 1-hydroxy-4,6,8-trimeton-exante; the aglycones of flavonoids - luteolin, quercetin, coumarins: scopoletin, umbelliferone; iridoid - eritrocitary; glycosides of flavonoids: rutin, cynaroside; glycoside xanthones, mangiferin; triterpene compound is oleanolic acid. In table.1 the data about the detection of biologically active compounds in different fractions.

In the chloroform fraction of the extract triterpene compound is oleanolic acid with Rf- 0,25 (III), 3 coumarin substances, 2 of which are identified with authentic samples as scopoletin Rf- 0,25 (II) 0,76 (impregnated BH, (III), 0,60 (VIII), 0,45 (IX) and umbelliferone with Rf- 0,40 (II) 0,42 (impregnated BH, (III), 0,58 (VIII), of 0.91 (IX). Of flavonoid aglycones in chloroform fraction dominates luteolin with RfTo 0.9 (V). In ethylacetate fraction detected xantanovy glycoside of mangiferin with Rf- 0,30 (IV) 0,35 (VIII), 0,25 (IX), identified with the authentic sample. Chromatographic analysis showed that the substances that define the choleretic effect of grass lomatogonium Carinthian have different polarity, and for them and�desire you must use a different extractants concentration.

For the quantitative determination Kantorovich of aglycones of 3.0 g of raw material (fine suspension) three times was extracted with 30 ml of 96% ethanol at room temperature for 2 hours, filtered in a volumetric flask with a capacity of 100 ml, was brought alcohol to the mark (solution A). 1 ml of extract was suirable on a column of polyamide (2.0 g sorbent mass) 25 ml of 96% ethanol. Column (diameter 1.5 cm) previously washed with distilled water and 96% ethanol. Measured optical density with spectrophotometer at a wavelength of 328 nm amid 96% ethanol, passed through a polyamide column. As the standard sample used alcoholic solution sortierten passed through a column of polyamide. The content Kantorovich of aglycones (%) was calculated by the formula

X=DC5025100100Dom(100w),

where D is the optical density of the test solution;

C - concentration of the solution sortierten, g/ml

Dooptical density of the solution sortierten;

m - hitch raw material or extract, g;

w - moisture content of raw material or extract, %.

Preparation of standard RA�down sortierten: 0.050 g (a precisely weighed) dried at 60°C of the substance was dissolved in 200 ml of 96% ethanol. 1 ml of the solution is eluted on a column of polyamide 25 ml of 96% ethanol.

For the determination of triterpene saponins 10 ml of solution A is evaporated to remove alcohol, water balance flow water to the mark in a volumetric test tube with a capacity of 10 ml, treated with chloroform in a separatory funnel 3-4 times before fining solution of 10 ml. Chloroform extract were combined, the solvent was distilled off on a rotary evaporator, the dry residue was dissolved in 10 ml of concentrated sulfuric acid in a volumetric test tube with a capacity of 10 ml. Then the extract was incubated at 70°C for 1 hour. After cooling, the solution was adjusted to the mark with sulphuric acid (solution B). To measure optical density of 1 ml of solution B was placed in a measuring tube with a capacity of 10 ml, was adjusted to the mark with sulphuric acid and spectrophotometrically at 310 nm in a cell with thickness of the absorbing layer of 10 mm. Solution comparison - concentrated sulfuric acid.

The content of triterpene compounds in the collection in terms of oleanolic acid was calculated by the formula

X=DCoVoV1100DomV2(100w)/mfrac> ,

where D is the optical density of the test solution;

Vo- the volume of the extractant, ml;

V1- analytical volume of solution, ml;

Cois the concentration of the solution oleanolic acid;

Do- the optical density of the oleanolic acid

m is the mass of raw material or extract, g;

V2- volume of sample taken for analysis, ml;

w is the loss in weight of the raw material or extract, %.

Preparation of solution the oleanolic acid. 0.01 g (accurate linkage) the oleanolic acid was dissolved in 50 ml of 96% ethyl alcohol. An analytical sample (from 0.1 to 1.0 ml) of the alcohol solution oleanolic acid was dried to dryness in a porcelain dish, the dry residue was dissolved in 10 ml conc. sulfuric acid, thermostating at 70°C for 3 h. the solution was spectrophotometrically at 310 nm in a cell with thickness of the absorbing layer of 10 mm. Solution comparison - concentrated sulfuric acid.

For the determination of water-soluble polysaccharides meal of raw material after extraction in 96 and 40% alcohol was extracted with purified water in a boiling water bath for 2 h, the extract was filtered, 10 ml of the filtrate was evaporated to 2 ml, was added 6 ml of 96% alcohol, the solution was left in the fridge for 2-3 hours, the precipitated polysaccharides were filtered on a dried and weighed filter paper, dried in a drying Cabinet dostojnoj mass. The content of polysaccharides was determined gravimetrically.

To extract lipophilic substances (carotenoids, aglycones of flavonoids and xanthones, triterpene compounds, etc.) extraction were 96% ethyl alcohol at room temperature, sredneplodnyh substances (phenolic glycosides and triterpene substances) - 40-60% ethanol and hydrophilic substances - water-purified. In table.2 shows the data for the definition of optimum conditions of extraction of raw materials lomatogonium Carinthian for the extraction of substances of different polarity. Set, the third extraction was 96% and 40% ethyl alcohol for 2 h, the output of xanthones and flavonoids is not appreciably increased, i.e. for the extraction of lipophilic and sredneplodnyh enough connections 2-fold extraction. The study of the dependence of release of designated substances on the ratio of raw material and extractant, resulting in the optimal ratio for extraction 96-40% alcohol (1:10-12) (Table.2).

Grinding of raw material of 0.5-2.0 mm accelerates the process of diffusion to the extraction of substances that provides the most complete release of biologically valuable compounds. The yield of flavonoids medium polarity increases with increasing temperature of extraction, and the optimal selected temperature at 90±5°C (tab.2), whereas to extract lipophil�'s substances selected room temperature to avoid the destruction of thermolabile substances (carotenoids).

Studied, the duration and frequency of extraction 96 and 40% ethanol and found that in a double extraction in 96% ethanol for 2 h, extracted the main quantity of lipophilic substances, with double extraction with 40% ethanol for 1 hour sredneplodnyh substances, and a single extraction with water at 100°C sufficient to recover the remaining meal of water-soluble polysaccharides. The method of obtaining the extract using the optimum extraction parameters are given in examples 1-3.

Example 1. 0.1 kg D. C. lomatogonium Carinthian, ground to a particle size of 0.5 mm, is loaded into an extraction apparatus, pour 1.0 l of 96% ethanol, extracted with constant stirring for 2 h, the extract was filtered into a collection, repeat the extraction under the same conditions, adding alcohol in an amount equal to the slit, the extract filtered. The meal was extracted with 1.0 l of 40% alcohol for 1 h at a temperature of 90±5°C, the extract was filtered. The extraction is repeated under the same conditions, adding an extractant in an amount equal to the slit, the filtered alcoholic extract combine. Meal after alcohol extraction is extracted at a temperature of 100°C 1,0 l purified water for 1 h with constant stirring, the aqueous extract was filtered. Hydroalcoholic extract 1-4-th extraction is evaporated on a rotary esprital� under vacuum to remove alcohol, their water balances combined with the aqueous extract of the 5th extraction, separated for removal of dust and vegetable ballast substances, concentrated to 1/5 of the original volume, and dried in a vacuum drying Cabinet at a temperature of 40-60°C for 8 h. Get 53,0 g extract dry with a moisture content of 3.8%, the yield was 53% by weight of raw materials.

Example 2. 0.1 kg D. C. lomatogonium Carinthian, crushed to a particle size of 1.0 mm, is loaded into an extraction apparatus, pour 1.2 liters of 96% ethanol, extracted with constant stirring for 2 h, the extract was filtered into a collection, repeat the extraction under the same conditions, adding alcohol in an amount equal to the slit, the extract filtered. The meal was extracted with 40% alcohol at a temperature of 90±5°C for 1 h, the extract was filtered. The extraction is repeated under the same conditions, adding an extractant in an amount equal to the slit, the filtered alcoholic extract combine. Meal after alcohol extraction is extracted at a temperature of 100°C 1.2 l of purified water for 2 h with constant stirring, the aqueous extract was filtered. Hydroalcoholic extract 1-4-th extraction is evaporated on a rotary evaporator under vacuum to remove alcohol, water remains combined with the aqueous extract of the 5th extraction, separated for removal of dust and vegetable ballast substances, conc�¼ to 1/5 the original volume, and dried in a vacuum drying Cabinet at a temperature of 40-60°C for 8 h. Get 49,0 g extract dry with a moisture content of 4.0%, the yield of 49% by weight of raw materials.

Example 3. 0.05 kg D. C. lomatogonium Carinthian, crushed to a particle size of 2.0 mm was charged into the extraction apparatus, pour 0.6 liters of 96% ethanol, extracted with constant stirring for 2 h, the extract was filtered into a collection, repeat the extraction under the same conditions, adding alcohol in an amount equal to the slit, the extract filtered. The meal was extracted with 0,50 liters of 40% alcohol at a temperature of 90±5°C for 1 h, the extract was filtered. The extraction is repeated under the same conditions, adding an extractant in an amount equal to the slit, the filtered alcoholic extract combine. Meal after alcohol extraction was extracted with 0.60 l of purified water at 100°C for 1 h with constant stirring, the aqueous extract was filtered. Hydroalcoholic extract 1-4-th extraction is evaporated on a rotary evaporator under vacuum to remove alcohol, water remains combined with the aqueous extract of the 5th extraction, separated for removal of dust and vegetable ballast substances, concentrated to 1/5 of the original volume, and dried in a vacuum drying Cabinet at a temperature of 40-60°C for 8 h. Get is 24.05 g extract dry with a moisture content of 3.5%, out - of 48.1% from masisira.

In the obtained extracts determine the content of carotenoids in terms of β - carotene, flavonoids - in terms of luteolin, coumarins - in terms of scopoletin, polyphenols - in terms of tannin, ascorbic acid described in the literature methods (Tab.3).

In the obtained extracts contain substances of different polarity: carotenoids, xanthones, triterpenoid saponins (lipophilic substances), flavonoids, polyphenols (srednepolny), ascorbic acid, polysaccharides (hydrophilic substances).

The definition of the choleretic activity of the dry extract lomatogonium Carinthian. Experiments to determine choleretic activity of dry extract lomatogonium conducted on 36 white Wistar rats of both sexes weighing 170-200 g. in acute experiments by the standard technique [Skakun N. P., Oleinik A. N. Comparative effects of atropine and metacin on exocrine function of the liver // Farmakol. and toxicol. - 1967. - Vol. 30, No. 3. - P. 334-337]. Rats were anesthetized by intraperitoneal injection of 1% solution of barbamyl in a volume of 0.8 ml/100 g weight of the animal. Extract lomatogonium was injected into the duodenum of animals with a syringe at doses of 50, 100 and 200 mg/kg in aqueous solution. Bile is obtained by means of a polyethylene cannula inserted into the common bile duct through each�th hour for 4 consecutive hours. The degree choleretic activity of the test extract was judged by the rate of secretion and the total amount of bile, as well as the content in the bile of its main ingredients: bilirubin [Skakun N. P. Neurohumoral mechanism choleretic action of insulin // Problems of endocrinology. - 1956. - No. 6. - P. 75-78], bile acids and cholesterol [V. P. Miroshnichenko, L. L. Gromashevsky, M. G. Kasatkin, etc. determining the content of bile acids and cholesterol in bile // Laboratory work. - 1978. - No. 3. - P. 149-153]. Statistical data processing was performed using U-Mann-Whitney test [Sergienko V. I., Bondareva I. B. Mathematical statistics in clinical trials. - M., 2000. 263 p.].

The results are shown in tables 4 and 5.

Table 4 shows that the extract lomatogonium has choleretic activity. In particular, with the introduction of the extract to rats at a dose of 50 mg/kg the rate of bile secretion was increased by 27 and 30.8% compared to the same indicator of the control (1 to 2 hours after administration). When you increase the dose up to 100 mg/kg the rate of bile secretion was higher than the control at 1.5 times (50%). With the introduction of the extract at a dose of 200 mg/kg and 38.5% and 21% respectively after 1 and 2 hours after its introduction. The total number of selected bile had risen from 22 to 29%. This choleretic �eacce remained at a high level throughout the period of experiment. In addition, the dry extract of lomatogonium stimulated the synthesis and secretion of bile acids, the total concentration of which, in particular, at the dose of 100 mg/kg was higher than that in rats of the control group 40% (tab.5).

In addition, the extract lomatogonium contributed to the excretion of bilirubin and cholesterol in the bile. At the same time with the introduction of the drug to rats comparison of flamin the rate of bile secretion was increased by 27; 29.5 23% on 2-4 hours of experience respectively. In this case the total bile acid content was higher than the control only 12%. On the excretion of cholesterol and bilirubin with bile flamin had no significant influence. Thus, the extract lomatogonium Carinthian on choleretic activity superior to the reference drug - flamin.

Evaluation of the effect of dry extract lomatogonium Carinthian on zheleobrazovatel and biliary liver function in experimental hepatitis. Experimental hepatitis reproduced on white Wistar rats of both sexes weighing 170-200 g by intragastric administration of tetracycline hydrochloride in a dose of 1.0 g/kg 1 time per day for 7 days [Nikolaev S. M. Herbal medicines for the damage to the hepatobiliary system. Novosibirsk, 1992. - 155 p.]. Rats of the experimental group, along with the introduction of tetracy�Lina, drove peros dry extract of lomatogonium dose of 0.1 g/kg in aqueous solution, 1 time per day, during the whole experience. A separate group of rats as the comparison drug was injected cars at a dose of 0.05 g/kg for a similar scheme. Animals of the control group on the background of administration of tetracycline was administered equivolume amount of purified water in a similar mode. The interval between doses of tetracycline hydrochloride and drugs, as well as water in the respective groups of animals was 4-5 hours. Investigations were carried out on 14 and 26 days since the start of the experiment. Liver function was assessed by the rate of secretion and the total amount allocated to the bile of anesthetized rats, as well as the content in the bile of its main ingredients: bilirubin, bile acids and cholesterol [V. P. Miroshnichenko, L. L. Gromashevsky, M. G. Kasatkin, etc. determining the content of bile acids and cholesterol in bile // Laboratory work. - 1978. - No. 3. - P. 149-153]. In the serum was determined the content of cholesterol, triacylglycerides, alkaline phosphatase activity and protein concentration [Laboratory methods in the clinic: the manual / V. V. Menshikov, L. N. Delektorskaya, R. P. Zolotnitskaya and others - M., 1987. - 368 p.].

It is established that the introduction of animals of tetracycline in high doses inhibits the functional state of the liver. Comparison �providers of choleric reactions in intact rats and control groups reflected the cholestatic effects of tetracycline, that was manifested in the decrease in the rate of secretion of bile and concentration of bile acids and bilirubin (table.6, 7), as well as in increase of level of cholesterol, triacylglycerides and alkaline phosphatase activity in the serum of animals (tab.8).

Course introduction animals dry extract lomatogonium at the dose were characterized by a pronounced therapeutic effect on the course of hepatitis. Rats treated with the specified extract, on the 14th day of observation the rate of bile secretion was higher than in rats of the control group by 25.4; 27,3; 26,4 and 35.6% respectively for 1-4 hours of experience (table.6). The total number of selected bile in animals of this group exceeded the control by 23.6%. For biochemical analysis of bile found that the dry extract of lomatogonium limits violations holinoliticheskoy liver function, as evidenced by maintaining the concentration of Khalatov in bile. Against this background, the content of bilirubin in bile was higher than the control by 18.5% and cholesterol - 37.5% (tab.7).

On the 26th day of the experiment rats treated with the extract lomatogonium, remained positive dynamics choleretic response. The rate of bile secretion was increased by 13.4%, and holatov in bile was higher than the control at 16.8%, holes�Erin - 13.9%. Under the influence of the specified extract the content of bilirubin in bile exceeded 1.3 times such rats of the control group, who continued decrease in the level of bilirubin in bile (table.7). On the 14th day of the experiment rats treated with extract of dry lomatogonium, lowering cholesterol and triacylglycerides and alkaline phosphatase activity in serum was 15.3; 18.9% and 45,6%, and 26 days - 19.2; 18,1 and 39.9%, respectively, compared to control (table.8).

Thus, the results of these studies indicate that therapeutic use of the extract dry lomatogonium Carinthian inhibits the negative effect of tetracycline hydrochloride on zheleobrazovatel and biliary liver function when tetracycline hepatitis. About antiholetsaticeski the influence of dry extract lomatogonium also shows a decrease in the content of products of lipid metabolism in the serum.

Determination of anti-inflammatory activity of the extract of dry lomatogonium Carinthian conducted using the models of aseptic inflammation, allowing to estimate its influence on the main stage of the inflammatory process: exudation, alteration and regeneration.

Antiexudative activity of the extract of�Regaleali on the model of acute aseptic inflammation of the hind limbs of rats with application of the phlogogenic agent is formalin. Playback of acute aseptic inflammation of the limb was performed by the method of J. V. Strelnikova [Manual on experimental (preclinical) study of new pharmacological substances. - M., 2005. 832 p.]. The extract at a dose of 0.1 g/kg as a single solution (experimental group) and distilled water in an equivolume amount (control group) was injected intraperitoneally 3 hours before supplanting the introduction of rats into the right hind paw of 0.1 ml of 3% formalin solution, and then through 5 and 18 h after that. After 24 h after injection of formalin evaluated antiexudative activity of the extract ecometrics method. The data obtained are given in table.9.

From the data presented in table 9, it follows that the extract lomatogonium has expressed exudative action, inhibiting the development of formalin edema by 28.1%.

To assess the impact on the phase of alteration modeling of the inflammatory process was carried out according to the method Mancina [Manual on experimental (preclinical) study of new pharmacological substances. - M., 2005. - 832 C.] by subcutaneous injection of 0.5 ml of 9% solution of acetic acid in the back with pre-cut wool. Simultaneously, the rats were intraperitoneally injected with a solution of dextran at a dose of 300 mg/kg. the First intragastric introduction�of the investigated extract at a dose of 0.1 g/kg was carried out for 1 hour before injection of acetic acid, and then every day, 1 time a day, for 25 days. Control animals received water purified in a similar way in equivolume amounts. 9, 20, 29, the day of the experiment evaluated the area of necrotic tissue planimetric method. The data obtained are given in table.10.

Course introduction extract for 25 days inhibits the action of the phlogogenic agent and stimulates the healing of ulcerated surfaces. On the 9th day of the experiment, the area of necrotic tissue in rats treated with the extract lomatogonium, as compared to that in rats of the control group decreased on 21%, respectively (difference statistically insignificant). 20 day significant decrease in the area of destruction was 31.8 per cent and 29 days - 28%, indicating that the stimulation of regeneration processes in the inflammation under the influence of the tested extract.

To study the effect on the proliferative processes, the inflammatory reaction caused by the method of Trinus et al. [Manual on experimental (preclinical) study of new pharmacological substances. - M., 2005. - 832 p.]. For this, sterile cotton balls weighing 20 mg were implanted under the skin of rats in the back under aseptic conditions. The extract was administered intragastrically in a volume of 1 times a day for 7 days. Animals of the control group enter�in equivolume amounts for a similar scheme, purified water. After 7 days removed granulomas and weighed on an analytical balance and after drying at a temperature of 70°C for 24 h to constant weight. The proliferative response was assessed by the difference between the dry weight of the granuloma and the initial mass of a cotton ball, antiexudative activity - by the difference between wet and dry mass of granulomas. The data obtained are given in table.11.

From the data presented in table.11, it follows that the dry extract of lomatogonium has no significant effect on cell proliferation on the model of "cotton granuloma" and reduces the degree of education only 15%.

Thus, the dry extract of lomatogonium Carinthian containing a water-soluble, lipophilic substance has a pronounced choleretic activities.

A means of having choleretic activity, obtained by extraction of the crushed to 0.5-2.0 mm aerial parts Lomatogonium carinthiacum 96% ethanol twice at room temperature for 2 h, in the ratio raw: extractant (1:10-12), then 40% ethanol, adding an extractant in an amount equal to the slit, at a temperature of 90±5°C twice in a period of 1 h, filtered water-alcohol extract were combined, the meal was extracted with purified water at a rate of 0.1 kg of feedstock per 1 liter of water at 100°C for 1 h, water extraction filter�Ute, combine water remains water-alcohol extraction, water extraction, concentrated, and dried in a vacuum drying Cabinet at a temperature of 40-60°C for 8 h to obtain the dry extract.



 

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3 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to method of simultaneous obtaining of two flavonoids - patuletine and its 7-O-β-D-glucopyranoside - patuletrine. Method consists in the following: milled edge petals of flower of high flavonoid sorts of tagetes patula are extracted with hexane, dried and r-extracted with chloroform, chloroform extract is concentrated, dry residue is dissolved in mixture of petroleum ether - chloroform, precipitated sediment is filtered, washed with petroleum ether and dried, obtained dry powder is dissolved in mixture chloroform - ethanol, precipitated sediment is filtered, washed with petroleum ether and dried with obtaining patuletine. Then, extraction of raw material, which remains after chloroform processing, is carried out with ethanol, alcohol extract is filtered and concentrated, after that, water residue is subjected to liquid phase extraction with ethylacetate, then, organic layer is concentrated, dry residue is dissolved in mixture chloroform - ethylacetate, precipitated sediment is filtered, washed with cooled ethylacetate, solution of hydrochloric acid in ethanol, ethanol and ethylacetate and dried, dry powder is dissolved in mixture ethylacetate-ethanol, precipitated sediment is filtered, washed with ethylacetate and dried with obtaining patuletrine.

EFFECT: method makes it possible to obtain highly pure samples of patuletine and patuletrine, as well as increase target product output.

4 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a method for preparing lappaconitine hydrobromide (versions) A method for preparing lappaconitine hydrobromide is implemented by extraction of Aconitum leucostomum root and herb or Aconitum septentrionale root and herb in methylene chloride in a continuous extraction apparatus that is followed by decontamination by means of flash chromatography (version 1), or extraction of a herbal raw material in a polar organic solvent followed by extract removal from the organic solvent (version 2), alkalinisation and extraction of the prepared extract in methylene chloride followed by decontamination of the extract by flash chromatography.

EFFECT: method for preparing lappaconitine hydrobromide provides simplifying the technological process, reducing its length and improving higher yield of the end product of officinal purity.

7 cl, 1 tbl, 9 ex

FIELD: food industry.

SUBSTANCE: method for production of Siberian cedar seeds liqueur (with hepatoprotective, antioxidant, antihypoxic, hypolipidemic effect) by way of maceration with ethyl alcohol usage; whole Siberian cedar seeds are loaded into the reactor, poured with 70% ethyl alcohol water solution; extraction is performed under preset conditions. The medicinal preparation with hepatoprotective, antioxidant, antihypoxic, hypolipidemic effect contains Siberian cedar seeds liqueur. Usage of the medicinal preparation as a hepatoprotective remedy.

EFFECT: liqueur has pronounced hepatoprotective, antioxidant, antihypoxic and hypolipidemic effect.

6 cl, 3 dwg, 8 tbl

FIELD: medicine.

SUBSTANCE: using a polyphenolic complex produced by extracting milled ash berry in 40% ethanol, condensing the alcohol-water extract, adding 95% ethanol, centrifuging the residue, filtering and condensing the supernatant in the certain environment, as an agent possessing anti-inflammatory action.

EFFECT: polyphenolic complex possesses pronounced anti-inflammatory action.

1 dwg, 9 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition, containing compound of formula or for prevention or treatment of diseases, associated with oxidative stress, selected from group, consisting of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke episodes), MERRF syndrome (myoclonic epilepsy with ragged red fibres) or Kearns-Sayre syndrome, arrhythmia, cardioplegia or myocardium infarction. in formula (1) na stands for 1 or 2, Aa represents 5-membered heteroaryl or heterocycle, each of which has 2 heteroatoms, selected from N, O and S, Rla represents R5a-Xa-Ba-X′a-, Ba represents direct bond, Xa and X′a independently on each other represent direct bond or -OC(O)-, R5a represents hydrogen or 6-9-membered monocyclic or condensed cyclic heterocycle or heteroaryl, each of which has from 1 to 3 heteroatoms, selected from N, O and S, and is optionally substituted with oxo or C1-C6-alkyl, R2a represents -(CR8aR9a)pa-Ya-R7a, pa stands for number from 0 or 1, Ya represents direct bond or -O-, R7a represents hydrogen or phenyl, R3a, R8a, R9a, R10a represent hydrogen, R4a represents -(CH2)pa-Da-R10a-, Da represents C5-cycloalkyl or 6-membered heterocycle, which has 1 heteroatom, selected from N, S and O. Radical values for formula (2) are give in invention formula.

EFFECT: obtaining compositions for prevention or treatment of diseases, associated with oxidative stress.

19 dwg, 5 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 9-aryl-6,8,20-trioxa-13-azapentacyclo-[11.8.0.01,10.02,7.014,19]heneicosa-9,14,16,18-tetraene-11,12,21-triones (IIa-d), which includes reacting 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones (Ia-d) with 3,4-dihydro-2H-pyran in a medium of an inert aprotic solvent, followed by separation of the end products. In general formula (I) Ar=Ph (a, d), C6H4Br-4 (b), C6H4OMe-4 (c), R=H (a-c), Cl (d).

EFFECT: obtaining 9-aryl-6,8,20-trioxa-13-azapentacyclo-[11,8,0,01,10,02,7,014,19]heneicosa-9,14,16,18-tetraene-11,12,21-triones.

2 cl, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention refers to a new compound, namely to 2-[(2-methylphenyl)imino]-9-oxo-7-phenyl-8-(3-phenyl-2-quinoxalinyl)-1,6-dioxaspiro[4,4]none-3,7-diene-3,4-dicarboxylic acid dimethyl ester of formula possessing antinociceptive activity, and a method for producing it consisting in synthesis of 4-(3-phenylquinoxalin-2-yl)-5-phenylfurane-2,3-dione, acetylene dicarboxylic acid dimethyl ester and o-methylphenylisonitrile.

EFFECT: preparing the new compound.

2 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula

,

or its pharmaceutically acceptable salt. In claimed formula each symbol has values, determined in formula of invention. Versions of formula [I] compound and particular compounds are also objects of invention. In addition, invention relates to pharmaceutical composition, ITK inhibitor and means for treatment or prevention of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and other diseases and methods of treating said diseases.

EFFECT: claimed compounds inhibit induced T-cellular kinase (ITK).

32 cl, 86 tbl, 387 ex

FIELD: medicine.

SUBSTANCE: application of a compound of the general formula 1 or its spatial isomers as analgesic means is claimed.

EFFECT: compounds have high efficiency, low toxicity, can be applied in medicine.

4 tbl 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical industry, namely to composition for treating skin ageing. Composition for treating signs of skin ageing, increase of cytikin IL-1α secretion, contains: NF-kB inhibitor, selected from the group, consisting of substituted resorcinols, (E)-3-(4-methylphenylsulphonyl)-2-propenenitrile, tetrahydrokurkuminoids, extracts of Paulownia tomentosa wood, as well as their combinations, and anti-inflammatory compound, which is not NF-kB inhibitor. Composition for treating signs of skin ageing, increase of cytokine IL-1α, containing NF-kB inhibitor, selected from the group, consisting of substituted resorcinols, and anti-inflammatory compound (versions).

EFFECT: compositions are effective for treating signs of skin ageing.

4 cl, 9 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention aims at pharmaceutical compositions containing a number of microparticles with taste masking, containing high-/low-dose therapeutic agents, at dosage forms containing the above pharmaceutical compositions (such as orally dispersible tablets), and at methods for producing these pharmaceutical compositions and dosage forms.

EFFECT: dosage forms containing the pharmaceutical compositions according to the invention represent the improved homogenous mixtures of the high-dose and low-dose therapeutic agents, which enable controlling the release rate of the therapeutic agent from particles by various ways, as well as flexible correction of dosages when administering the combinations of the therapeutic agents, eg in pain management.

31 cl, 4 dwg, 12 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of the general formula

,

wherein R1/R2 independently represent hydrogen, (CR2)o-C3-7 cycloalkyl optionally substituted by a lower alkyl or hydroxy, or represent a lower alkyl or tetrahydropyranyl, and o represents 0 or 1; and R can be identical or different, and represent hydrogen or a lower alkyl; or R1 and R2 can form together with a N atom to which they are attached, a heterocycloalkyl group specified in a group consisting of pyrrolidinyl, piperidinyl, 3-aza-bicyclo[3.1.0]hex-3-yl or 2-aza-bicyclo[3.1.0]hex-2-yl which are optionally substituted by hydroxy; R3 represents an S-lower alkyl, lower alkyl, lower alkoxy or C3-7 cycloalkyl; R3′ represents hydrogen, a lower alkyl substituted by a halogen, lower alkyl or lower alkoxy; R4 represents a lower alkyl substituted by a halogen; X represents -O- or -CH2-; X' represents -O- or -CH2-; provided one of X or X' always represent -O- and the other represents -CH2-; or a pharmaceutically acceptable acid-additive mixture, a racemic mixture, or a respective enantiomer and/or an optical isomer.

EFFECT: compounds of the general formula (I) are good inhibitors of glycine transporter 1 (GlyT-1) and hence can be used for treating schizophrenia and other neurological conditions, including pain.

13 cl, 1 tbl, 63 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition, containing compound of formula or for prevention or treatment of diseases, associated with oxidative stress, selected from group, consisting of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke episodes), MERRF syndrome (myoclonic epilepsy with ragged red fibres) or Kearns-Sayre syndrome, arrhythmia, cardioplegia or myocardium infarction. in formula (1) na stands for 1 or 2, Aa represents 5-membered heteroaryl or heterocycle, each of which has 2 heteroatoms, selected from N, O and S, Rla represents R5a-Xa-Ba-X′a-, Ba represents direct bond, Xa and X′a independently on each other represent direct bond or -OC(O)-, R5a represents hydrogen or 6-9-membered monocyclic or condensed cyclic heterocycle or heteroaryl, each of which has from 1 to 3 heteroatoms, selected from N, O and S, and is optionally substituted with oxo or C1-C6-alkyl, R2a represents -(CR8aR9a)pa-Ya-R7a, pa stands for number from 0 or 1, Ya represents direct bond or -O-, R7a represents hydrogen or phenyl, R3a, R8a, R9a, R10a represent hydrogen, R4a represents -(CH2)pa-Da-R10a-, Da represents C5-cycloalkyl or 6-membered heterocycle, which has 1 heteroatom, selected from N, S and O. Radical values for formula (2) are give in invention formula.

EFFECT: obtaining compositions for prevention or treatment of diseases, associated with oxidative stress.

19 dwg, 5 tbl, 3 ex

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