RU1779379C - Method for producing bile-expelling preparation - Google Patents

Abstract

The invention relates to medicine, in particular to the pharmaceutical industry, and relates to a method for producing a preparation of choleretic action. The aim is to increase the yield and simplify the technology. The essence of the invention consists in extracting lily of the valley grass with 80% ethanol, evaporating the extract by treating it with a mixture of a halogenated hydrocarbon with ethanol, diluting with water to a ratio of 1.2-2.4 vegetable to raw materials to water, purification by extraction with butanol at a phase ratio of 1.0.6-0 , 8, washing the butanol extract with water and evaporating. The positive effect is to increase the yield from 0.4% of the prototype to 2.2-2.4% by weight of plant material 5 table. (L C

Description

The invention relates to the medical industry and relates to a method for producing a medicament of choleretic action from lily of the valley containing a purified amount of flavonoids.

Known methods for producing choleretic drugs from Far Eastern lily of the valley.

The closest is the method for the preparation of choleretic drug Convaflavin, implemented at the VNIIKhTLS pilot plant (experimental industrial production schedule for Convaflavin. Approved 3.10.80).

According to this method, dry powdered plant material is extracted with 80% ethanol, the extract is evaporated to an aqueous residue and treated with a 8: 2 chloroform-alcohol mixture. Water phase

separated, evaporated, mixed with a polyamide sorbent and applied to a chromatographic column filled with a polyamide sorbent and distilled water. After application to the column, the accompanying substances are eluted with distilled water, and when a positive sample appears on the flavonoids, the active substances are desorbed with an ethanol-aqueous mixture, the eluates are evaporated, dried and ground. The yield of dry product according to the regulations is 0.4% by weight of dry plant raw materials, the content of the total flavonoids is 17-29%

The disadvantages of this method are the low yield of the finished product due to the large losses at the stages of purification and separation on a polyamide sorbent and the complexity of the technology, which requires a lot of time, energy raw materials

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ABOUT

The aim of the proposed invention is to increase the yield of the finished product and simplify the technology.

The goal is achieved in that the aqueous extraction after treatment with a mixture of a halogenated hydrocarbon with ethanol is evaporated to remove impurities of the extractants, diluted with water to a volume ratio of 1: (2-2.4) to the mass of plant material and the amount of active substances is extracted with butanol at a ratio phases 1: (0.6-0.8), and the butanol extraction is washed with water.

The proposed method is as follows.

The dry ground grass of lily of the valley was extracted with 80% ethanol, the extract was evaporated to an aqueous residue and treated with a mixture of a halogenated hydrocarbon with ethanol. The aqueous phase is separated, evaporated to remove the extractants, diluted with water to a volume ratio of 1: (2-2.4) to the weight of the extracted plant material and treated with butanol with a total phase ratio of 1: (0.6-0.8). The butanol extracts are separated, washed with water, evaporated, dried and ground. The dry product yield of 2.2-2.4% by weight of dry plant material, the flavonoid content in the preparation is 22-27%.

PRI me R 1. 100 g of dry chopped lily of the valley grass is extracted with 80% ethanol, the extract is evaporated to a water residue of 50 l and treated 3 times with an equal volume of 3: 1 methylene chloride-ethanol mixture. The aqueous phase is separated, evaporated to remove the extracting agent, diluted with water to 200 L and treated with butanol with a total phase ratio of 1: 0.6. The butanol extracts are separated, combined and washed with 120 L of water. The aqueous layer was separated, and the washed butanol extract was evaporated, dried and ground. The dry product yield of 2.2 kg, i.e. 2.2% by weight of dry plant material.

Example 2.100 kg of dry chopped lily of the valley grass is extracted with 80% ethanol, the extract is evaporated to a water residue of 50 l and treated 3 times with an equal volume of a mixture of methylene chloride - ethanol 3: 1. - The aqueous phase is separated, evaporated to remove the extractant, diluted with water up to 220 l and treated with butanol with a total phase ratio of 1: 0.7. The butanol extracts are separated, combined and washed with 140 L of water. The aqueous layer was separated, and the washed butanol extract was evaporated, dried and ground. The yield of dry product is 2.3 kg, i.e. 2.3% by weight of dry plant material.

PRI me R 3. 100 kg of dry chopped lily of the valley grass is extracted with 80% ethanol, the extract is evaporated to a water residue of 50 l and treated 3 times with equal

the volume of the mixture is methylene chloride - ethanol 3: 1. The aqueous phase is separated, evaporated to remove the extractant, diluted with water to 240 L and treated with butanol with a total phase ratio of 1: 0.8. The butanol extracts are separated, combined and washed with 150 L of water. The aqueous layer was separated, and the washed butanol extract was evaporated, dried and ground. The yield of dry product is 2.3 kg, i.e. 2.4% of dry weight

5 vegetable raw materials.

The ratio of the aqueous and alcohol phases during liquid extraction of active substances is determined based on the data in Table 1.

0 From the data table. 1 it follows that the optimal ratio of aqueous and alcohol phases during liquid extraction of the active ingredients of the drug is 1: (0.6-0.8), since these ratios give

5 highest yields of dry product. A ratio above 1: 0.8 practically does not increase the yield of the product, and when the ratio is below 1: 0.6, the yield decreases sharply. According to the requirements of normative technical documentation, the preparation should not contain cardiac glycosides. To this end, a dilution of the initial aqueous solution is carried out before liquid extraction, and the resulting butanol treatment 5 is washed with water. The ratios for the dilution of the aqueous solution are given in Table. 2, from which it follows that the optimal dilution of the prominent solution in relation

0 to the weight of the extracted vegetable material is 1: (2-2.4).

A lower ratio leads to a deterioration in the quality of the product, while a higher ratio significantly reduces the yield of the product.

Cholagogue action. The choleretic effect of the drug obtained by the known and proposed technology was studied in rats of both sexes.

0 weighing 280-320 g. The animals opened the abdominal cavity under nembutal anesthesia, the bile duct was separated, a polyethylene catheter was inserted into it, through which bile flowed out a hundred and fifty. Flowing bile was recorded every hour. taken as the initial value, and time was indicated by the control hour. To reduce the effect of drugs on the bile secretion function of the liver in rats in the duodenum

after the control hour, the intestine was administered convaflavin at a dose of 80 mg / kg (the dose of convaflavin. According to our preliminary data, it causes the maximum choleretic effect in rats). The choleretic action of the drug was judged by the difference in the volume of bile excreted in each subsequent hour after the administration of the preparations, as compared to the control hour, as well as by the total amount of bile excreted by the animals in 4 hours. In addition, a control group of experiments was set up. After the control hour, animals were injected into the duodenum with 1% sodium bicarbonate solution in the same volume in which the drug was dissolved. For each series of 8-11 experiments. The results were processed statistically by the method of variation statistics. The results are shown in table.3.

After administration of drugs, bile excretion in rats is increased compared to the intact group. The maximum increase in bile secretion is observed mainly in the first two hours after the administration of drugs and is for convaflavin. obtained by known technology 30.6+ t2.86%. The proposed convaflavin technology, improving its purification, does not significantly alter the choleretic activity of the drug. After administration of all series of the drug, the total amount of bile is equally increased compared to the intact group.

The toxicity of the drug.

Convaflavin toxicity determination. obtained by the known and proposed technology, was carried out in acute experiments on mice and rats with a single administration inside at a dose that is maximum permissible in volume (10 g / kg). The data obtained are presented in table. 4.

Studies have shown that, according to toxicity, preparations obtained by different technologies do not differ from each other and belong to non-toxic substances.

A comparative characteristic of the technical and economic indicators of the known and proposed methods is presented in table. 5, from which it follows that the proposed method reduces the total number of technological operations by eliminating chromatographic separation, which, in turn, eliminates the parallel target production and standardization of the polyamide sorbent (not shown in Table 3), since it is not centrally located in the USSR produced.

The replacement of chromatography by liquid extraction with butanol can significantly increase the yield of the drug, simplify the process by reducing the number of stages and time of its implementation, as well as reduce labor costs per unit of product.

An increase in the yield is achieved due to a more complete separation by liquid extraction from an aqueous solution and a reduction in losses during the purification and separation process compared to chromatography. According to the proposed method, the process of purification and isolation of active substances is reduced to an easily reproducible technological process of liquid extraction instead of chromatography. providing for:

-use of a polyamide sorbent obtained from various feed stocks and various methods and because of this has fluctuations in the quality indicators affecting the content of the total flavonoids in the preparation and its yield;

-preparation of chromatographic columns;

-separation of the water-soluble fraction,

- desorption of active substances with ethanol.

In the absence of additional capital investments, the economic effect per 1 kg of konflavin powder. obtained by the claimed technology is 2588.7 rubles.

The economic effect per 100 thousand packs of convaflavin is 132023.7

rub.

The proposed method was tested in industrial conditions and introduced into production at the VNIIKhTLS pilot plant in 1991.

Claims (1)

SUMMARY OF THE INVENTION A method for producing a choleretic drug, comprising extracting lily of the valley grass with 80% ethanol, evaporating the extract, treating it with a mixture of a halogenated hydrocarbon with ethanol, evaporating the aqueous phase, isolating the target product and drying, characterized in that, in order to increase the yield of the target product and simplification of the technology, water extraction after processing it with a mixture of a halogenated hydrocarbon with ethanol is diluted with water to a ratio of 1: 2.0-2.4, and the isolation of the target product is carried out It is extracted with butanol at a phase ratio of 1: 0.6-0.8, followed by washing the butanol extract with water. Table 1 The dependence of the yield of the finished product and its quality on the dilution of the aqueous solution l differences statistically significant compared with the control hour, differences statistically significant compared with the intact group, table 2 Table 3 According to the prototype (according to the regulations for the production of convaflavin, excluding the targeted production of polyamide sorbent) I. Technological operations 12 3 4 5 6 7 8 10 eleven 12 Grinding vegetable raw materials Extraction 80% ethanol Evaporation of the extract Treatment with chloroform-alcohol mixture Evaporation of an aqueous solution Preparation of a mixture of an aqueous concentrate with a sorbent Preparation of a chromatographic column Column application and elution of a water soluble fraction Preparation of eluent Elution of active substances Evaporation by Eluate Drying, Grinding II. Labor costs, in n / h per 1 kg of product, 8 III. Product yield,% of the mass of plant material on average 0.42.2-2.4 IV. Total flavonoid content in% 17-2S22-2 Grinding Vegetable Extraction 80% Ethanol Evaporation of the Extract Processing chloromethylene with YOUR mixture Evaporation of an aqueous solution Rinsing butanol Drying, grinding Table4 Table3 According to the proposed method Grinding vegetable raw materials Extraction 80% ethanol Evaporation of the extract Treatment with chloromethylene-alcohol-YOUR mixture Evaporation of an aqueous solution; Liquid extraction with butanol Washing the butanol extract Evaporating the butanol extract Drying, grinding