RU2259840C2 - Medicinal remedy of adaptogenic activity - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: the suggested medicinal remedy of adaptogenic activity upon plant origin is being a 40%-alcoholic extract of plant raw material containing leather Bergenia (rhizomes and roots) sweet flag (rhizomes), rosewort (rhizomes with roots), safflower-like leuzea (rhizomes and roots), pentaphyllous bush (sprouts), elecampane (rhizomes and roots), great nettle (leaves), calendula (flowers), Ural's licorice (roots), sea buckthorn (fruit), dog rose (fruit), cardamom (fruit), black pepper (fruit), redhaw hawthorn (fruit), nutmeg (fruit), parsley (roots), ginger (roots) at degree of reduction of 1-3 mm in leaves and sprouts, and 0.5-2 mm in fruit, 103 mm in roots and rhizomes taken at certain ratio in weight portions. Moreover, extract should be obtained at raw material : extracting agent ratio being 1:15 and at 18-20 C. The remedy obtained is of high adaptogenic action and nontoxic.

EFFECT: higher efficiency.

1 ex, 8 tbl

Description

The invention relates to the field of pharmacy and for the production of a drug having adaptogenic activity.

In the practice of traditional medicine, multicomponent drugs are used with great success, including on average from 3 to 5 ingredients. It is believed that their high pharmacotherapeutic efficacy is due to the harmonious combination of biologically active substances contained in the original types of plant materials.

Currently, there are various approaches to the preparation of complex complex drugs. The first of these involves the achievement of summation or mutual reinforcement of the positive properties of the combinations used; another approach is aimed at weakening the negative effect or weakening the side property of one of the components, and the third approach is mainly based on the empirical method or theoretically it is expected that the therapeutic and prophylactic efficacy of the combination of ingredients used will increase. The greatest recognition and confirmation in clinical practice was received by the theory of composing combined drugs proposed by Professor A. N. Kuprin. (1956) (Kudrin AN About the rational compilation of medicinal compositions // Materials of the 17th scientific conference. Ryazan Medical Institute named after I.P. Pavlov. - Ryazan, 1956. - P.24-29). Its essence lies in the simultaneous use of drugs from three main groups aimed at eliminating (weakening) the causes of the disease, reducing pathogenetic changes and strengthening (mobilizing) the protective, compensatory and adaptive mechanisms of the body. In accordance with this, "the use of various substances acting selectively on the main links of the pathogenetic process within the corresponding physiological and biochemical systems" is necessary. According to this principle, a number of complex preparations (analeptic mixture, etc.) have been developed and are widely used in clinical practice.

A known method of obtaining funds with adaptogenic activity, including extraction of the roots of Eleutherococcus with ethanol solution (Brekhman II, Eleutherococcus root - a new stimulating and tonic. - L., - 1960, - 182 S.). The disadvantage of this method is the low yield of extractive substances, as well as insufficient pharmacological activity. The yield of extractives is 6%.

Based on literature data on the study of the chemical composition, pharmacological action of medicinal plants, as well as on the experience of composing medicinal formulations in Tibetan medicine, we have developed a comprehensive herbal remedy consisting of 17 medicinal plants, along with well-known tonic plants, the collection includes plants containing a large number vitamins, and plants with a wide range of pharmacological properties. According to the literature on the chemical composition of the plants used, it is known that the proposed composition of plant materials contains essential oils, carbohydrates, vitamins, carotene, organic acids, triterpenoids, coumarins, flavonoids, as well as other valuable biologically active substances.

The technical result of the invention is the expansion of the range of drugs with adaptogenic activity due to the use of widespread plant materials having a reliable and secure raw material base, increasing the yield of extractive substances and increasing pharmacological activity due to the multicomponent nature of the drug.

The technical result is achieved by the fact that the claimed drug is a 40% alcohol extract of a crushed plant mixture of the following composition (wt. Parts):

Frankincense (rhizomes and roots) 4.0 Air marsh (rhizome) 10.0 Rhodiola rosea (rhizomes and roots) 10.0 Safrole-shaped leuzea (rhizomes with roots) 10.0 Five-leaved shrubbery (shoots) 4.0 Elecampane tall (rhizomes and roots) 10.0 Stinging nettle (leaf) 10.0 Calendula officinalis (flowers) 8.0 Ural licorice (roots) 8.0 Buckthorn buckthorn (squeezed fruits, dry) 4.0 Rosehip (fruits) 10.0 Cardamom (fruits) 2.0 Black pepper (fruits) 1,0 Hawthorn blood red (fruit) 3.0 Nutmeg (fruits) 2.0 Parsley (roots) 2.0 Ginger (roots) 2.0

and is characterized as a tool with pronounced adaptogenic activity.

For each type of raw material, depending on the anatomical features and the degree of grinding of plant material, the dynamics of the extraction of flavonoids and extractive substances was studied. The collection is divided into 3 fractions: 1 - leaves, 2 - roots and rhizomes, 3 - fruits. The raw materials were crushed to the following particle sizes: 0.5-1 mm, 2-3 mm, 5-7 mm, 7-10 mm. The grinding of the raw materials included in this composition was carried out according to the requirements of GFHI, t.1, p.266 (State Pharmacopoeia of the USSR: Issue 1. General methods of analysis. 11th ed., Add. - Moscow, 1987, - 336 p. ) The optimal degree of grinding was established for leaves and shoots 1-3 mm, fruits 0.5-1 mm and for roots and rhizomes 1-3 mm (table 1) (Biologically active additives in preventive and clinical medicine: Materials of a scientific and practical conference (18 -19 September 2003) .- Ulan-Ude: Publishing House of the BSC SB RAS, 2003. - C.100-101).

Table 1
The effect of the degree of grinding of the components of the drug on the output of the sum of flavonoids and extractive substances The degree of grinding fractions of the collection The amount of flavonoids in terms of rutin,% Extractive substances,% Leaves, flowers 0.5-1 mm 1,020 37.06 2-3 mm 1,025 37.03 5-7 mm 0.599 35.45 7-10 mm 0.468 35.09 Fruit 0.5-1 mm 0.614 38.15 2-3 mm 0.344 34.61 5-7 mm 0.238 28.11 7-10 mm 0.193 24.31 Roots and Rhizomes
0.5-1 mm 0.332 36.09 2-3 mm 0.322 37.92 5-7 mm 0.230 37.49 7-10 mm 0.187 35.23

To obtain herbal remedies, a dosage form was chosen - liquid extract (elixir).

The water absorption coefficient of the resulting mixture of medicinal plants is 1.2.

The determination of the yield of extractives in all these experiments was carried out according to the same methodology given in the Global Fund XI (1987).

The crushed air-dry raw materials (fine weighed) were poured with a solution of ethanol with water (in various concentrations), closed with a cork and insisted for a certain time with periodic stirring. The extract was filtered through a dry paper filter into a dry flask. 25 ml of the filtrate was transferred to a pre-dried at a temperature of 100-105 ° C to constant weight and accurately weighed porcelain cup and evaporated to dryness in a water bath. The cup with the residue was dried at a temperature of 100-105 ° C to constant weight and weighed. The content of extractives in percent on absolutely dry raw materials was calculated by the formula

, где

where

m is the mass of dry residue, in g

m is the mass of raw materials, in g

in - loss in mass during drying of raw materials, in%.

To select the concentration of the extractant, the processes of extraction of the total collection were studied. We have studied the yield of the sum of extractive substances using 10, 20, 30, 40, 50, 60, 70, and 96% ethanol. It was found that the maximum yield of extractive substances was obtained by extraction of raw materials with 20-50% ethanol solution (optimal 40%). The research results are shown in table 2.

table 2
The dependence of the output of the sum of extractive substances on the concentration of the extractant No. The concentration of extractant,% The output of the amount of extractives on offer. application% The output of the amount of extractive substances according to the prototype,% 1 10 14.72 - 2 twenty 15.63 3 thirty 19.10 4.90 4 40 22.55 6.00 5 fifty 22.56 6.15 6 60 22.15 6.10 7 70 21.00 8 96 17.82

The optimal ratio of raw materials and extractant, which corresponds to 1:15. A further increase in the ratio is impractical due to a slight increase in the yield of active substances, as well as in connection with an increase in the consumption of extractant. The results are presented in table 3.

Table 3
The output of the sum of flavonoids and extractive substances depending on the ratio of raw materials: extractant Raw Material: Extractant Ratio The output of the amount of flavonoids in terms of routine standard,% The output of the sum of extractive substances,% 1:10 0.98 19.67 1:12 1.31 20.11 1:15 1,58 22.55 1:18 1,57 22.58 1:20 1,57 22.60

The influence of the extraction method on the yield of the sum of flavonoids and extractive substances is investigated, the possibility of obtaining an elixir (liquid extract) by the methods of maceration, fractional maceration and percolation is studied. The research results are presented in table 4.

Table 4
The influence of the method of producing elixir on the output of the sum of flavonoids and extractive substances Indicator Method of extraction Maceration Remaceration (fractional maceration) Percolation The output of the amount of flavonoids,% 0.98 1.27 1,58 The yield of extractives,% 20.31 20.89 22.55

Concrete example

Shredded and sifted rhizomes of calamus swamp - 10.0; rhizomes and roots of elecampane high - 10.0; rhizomes and roots of Rhodiola rosea - 10.0; rhizomes with the roots of a safrole-shaped leuzea - 10.0; ginger roots - 2.0; parsley roots - 2.0; Ural licorice roots - 8.0; rhizomes with the roots of a thick badger berry - 4.0; cardamom seeds - 2.0; black pepper fruits - 1.0; nutmeg fruits - 2.0; fruits of sea buckthorn - 4.0 and rose hips - 10.0; shoots of a five-leaved shrub - 4.0; the fruits of hawthorn blood red - 3.0; dioecious nettle grass - 10.0; calendula officinalis flowers - 8.0 are mixed, sieved, extraction is carried out at room temperature. The ratio of raw material to extractant is 1:15, taking into account the coefficient of water absorption (k = 1.2).

First, the raw materials are loaded into the percolator and moistened, pouring with extractant (40% alcohol) to the “mirror”, left for 24 hours. After one day, the first discharge of the finished product is obtained.

Percolation is carried out at a speed of 1 / 48-1 / 24 of the used percolator volume for 1 hour. In this case, the speed of the extractant supplied from the measuring unit should be equal to the speed of the removed extract. The tap is closed at the percolator and the extractant is continuously fed to the feed at a predetermined speed. The process is carried out until the extract of the required volume is obtained, after which the receiver is replaced, and percolated until the raw materials are exhausted. The obtained secondary extract is used to obtain a new batch of product.

The extract obtained after extraction is purified by settling in the cold at a temperature not exceeding 10 ° C for 2 days. The settled liquid is drained from above or using a centrifugal pump. After settling, the liquid extract is passed through a filter apparatus or a triple layer of gauze with cotton wool, stretched over a funnel, into the collector. After filtration and analysis, the finished product is fed to packaging. The yield of extractives is 20%.

Determination of acute toxicity of an adaptogenic agent

The experiments were carried out on mice of the CBA line of both sexes weighing 18-20 g. The acute toxicity of the adaptogenic agent was determined by the method of Kerber (Belenky ML Elements of a quantitative assessment of the pharmacological effect. - L., - 1963, - 148 pp.) With its single intragastric and intraperitoneal administration in the form of a dealcoholized * aqueous solution in volumes from 1.0 to 395.0 ml / kg of animal weight. (* Note: before experiments, in order to exclude the influence of ethanol, the adaptogenic agent was dealcoholized on a rotary evaporator at 37 ° C to 1/10 of the initial volume and the resulting volume was brought to the original volume with distilled water. The resulting aqueous-alcohol solution was re-evaporated on a rotary evaporator, and the residue was adjusted to a predetermined volume with distilled water).

Animals of the control groups received an equivolume amount of distilled water. As a prototype, liquid eleutherococcus extract was used. Observation of the animals was carried out for 14 days from the date of administration of the test drug. Throughout the entire period of the experiment, the general condition and behavior of animals was observed, visible signs of intoxication and the number of dead animals were recorded with examination of internal organs and histological examination of vital organs during the death of animals.

It was found that intragastric and intraperitoneal administration of an adaptogenic agent in volumes of 1.0-395 ml / kg did not cause the death of animals during the entire observation period. In addition, in mice treated with the test drug, there were no visible signs of intoxication; behavioral reactions and general condition did not differ from that in animals of the control group; the animals of the experimental groups remained active, took good food, their stool was normal during the entire observation period.

The data obtained allow us to attribute the adaptogenic agent to the group of practically non-toxic substances according to the classification of K. Sidorov. (1973) (KK Sidorov On the classification of toxicity of poisons with parenteral administration methods. - In the book: Toxicology of new industrial chemicals. - M., - 1973, - p. 47-51).

Acute toxicity of the extract of Eleutherococcus liquid (DL ₅₀ ) with intraperitoneal administration is 10-30 g / kg (Brekhman I.I. Root of Eleutherococcus is a new stimulating and tonic agent. - L., 1960, - 182 p.).

The effect of adaptogenic agents on the overall physical endurance of mice

The experiments were carried out on mice of the CBA line of both sexes weighing 18–20 g. The total physical endurance was determined by the generally accepted method by the duration of the animals swimming in the pool until they were completely tired. The animals of the experimental group were intragastrically injected with a dealcoholized aqueous solution of an adaptogenic agent once in a volume of 1.0 ml / 100 g, corresponding to 2.5; 5.0; 10.0 ml / kg of tincture, 1 hour before testing; and also repeatedly - in the same volume of an aqueous solution, corresponding to 5.0 ml / kg of tincture, within 7 days before testing (1 time per day 30 minutes before feeding). Animals of the control group received an equivolume amount of distilled water. Eleutherococcus extract was used as a dealcoholized aqueous solution in a volume of 5 ml / kg. 1 hour after the administration of the test substance, the total physical endurance was determined by swimming the animals with 7% weight until complete fatigue, the criterion of which was the 10-second immersion of the animal under water.

Statistical processing of the obtained data was carried out by the generally accepted method using the Wilcoxon-Mann-Whitney U-test (Sergienko, Bondareva, 2000). Differences were considered significant with a probability of 95% (P <0.05). The data obtained are shown in tables 5-6.

Table 5
The effect of the drug on overall physical endurance with a single administration №№ pp Groups of animals Volume
funds, ml / kg n Duration of swimming, min 1 Control - 10 4.6 ± 0.42 2 Adaptogenic agent 2,5 8 5.2 ± 0.30 3 h 5,0 8 6.4 ± 0.40 * 4 h 10.0 8 6.7 ± 0.35 * 5 Eleutherococcus 5,0 8 6.5 ± 0.52 * Note: * - hereinafter, the significance of differences compared with the data of animals of the control group at P <0.05; n is the number of animals in the group.

As follows from the data given in table. 5, a single administration of an adaptogenic agent in a volume of 2.5 ml / kg does not have a statistically significant effect on the duration of swimming of mice, while its administration in a volume of 5.0 ml / kg was accompanied by an increase in the overall physical endurance of animals by an average of 40% compared with mice of the control group. An increase in the volume of the test substance to 10.0 ml / kg had a similar actoprotective effect: the duration of swimming increased by 46% compared with the control. At the same time, the effectiveness of the adaptogenic agent in volumes of 5.0 and 10.0 ml / kg was close to that of the extract of Eleutherococcus.

Table 6
The effect of the drug on overall physical endurance with repeated administration №№ pp Groups of animals The volume of alcohol tincture, ml / kg n Duration of swimming, min 1 Control - 8 5.5 ± 0.45 2 Adaptogenic agent 5,0 8 10.7 ± 0.35 * 3 Eleutherococcus 5,0 8 8.5 ± 0.28 *

As follows from the data given in table 6, the actoprotective activity of the adaptogenic agent increases with its repeated administration, as evidenced by an increase in the duration of swimming of mice of the experimental group by 95% compared with the data of animals of the control group. At the same time, the effectiveness of the adaptogenic agent exceeded that of the eleutherococcus extract.

The effect of adaptogenic agents on the speed endurance of mice

The experiments were carried out on mice of the CBA line of both sexes weighing 18-20 g. Speed endurance was determined by the generally accepted method of forced running of animals in a 10-track treadmill equipped with an electric stimulator (70 V) (Savichev G.D. Improved treadmill for rats // Biologically active substances of the flora and fauna of the Far East and the Pacific Ocean. - Vladivostok, - 1971, - p. 67-69). The animals of the experimental group were intragastrically injected with a dealcoholized aqueous solution of an adaptogenic agent once in a volume of 1.0 ml / 100 g, corresponding to 2.5; 5.0; 10.0 ml / kg of tincture, 1 hour before testing; and also repeatedly - in the same volume of an aqueous solution corresponding to 5.0 ml / kg of tincture, within 7 days before testing (1 time per day 30 minutes before feeding). Animals of the control group received an equivolume amount of distilled water. Eleutherococcus extract was used in the form of a dealcoholized aqueous solution in a volume of 5 ml / kg. High-speed physical endurance was determined 1 hour after the administration of the test substance by the duration of the run of the animals until complete fatigue at a treadmill web speed of 40 m / min. The criterion of complete fatigue was considered to be the animal staying on the treadmill electric grid for 10 seconds. The data obtained are shown in table 7.

Table 7
The effect of the drug on the speed endurance of mice №№ pp Groups of animals n Running time, min Single introduction Multiple introduction 1 Control 12 6.0 ± 0.8 5.8 ± 0.5 2 Adaptogenic Remedy 10 10.2 ± 1.1 * 13.7 ± 0.8 * 3 Eleutherococcus 10 8.9 ± 0.9 10.5 ± 0.6

As follows from the table, a single administration of an adaptogenic agent to animals of the experimental group is accompanied by an increase in the running time of animals by an average of 70% compared with the data of mice in the control group. Repeated administration of the test agent had a more pronounced actoprotective effect, as evidenced by an increase in the speed physical endurance of mice of the experimental group by more than two times in comparison with the data of animals in the control group. At the same time, the actoprotective activity of the adaptogenic agent exceeded that of the eleutherococcus extract.

The effect of adaptogenic agents on resistance to hypobaric hypoxia

The experiments were carried out on mice of the CBA line of both sexes weighing 18-20 g. Acute hypobaric hypoxia was reproduced according to the generally accepted technique in a pressure chamber at atmospheric pressure 198.8 mm Hg, partial oxygen pressure 50 mm Hg, which corresponds to a "rise" animals to a height of 10,000 m above sea level. The animals were "lifted" at a speed of 20 m / min to a height of 6000 m, at this altitude, in order to adapt the animals, the "rise" was stopped for 2 minutes, then the "rise" was continued at the same speed to a height of 10,000 m. The animals were resistant to hypobaric hypoxia estimated by life expectancy at an altitude of 10,000 m.

The animals of the experimental group were intragastrically injected with a dealcoholized aqueous solution of adaptogenic agent in a volume of 1 ml / 100 g, corresponding to 5.0 ml of tincture, once 1 hour before testing, and also repeatedly in the same volume preliminarily for 7 days (1 time per day for 30 minutes before feeding). Animals of the control group received an equivolume amount of distilled water. As a prototype, we used a dealcoholized solution of Eleutherococcus in a similar volume of an aqueous solution corresponding to 5.0 ml of extract. The data obtained are shown in table 8.

Table 8
The effect of the drug on the life expectancy of mice in acute hypobaric hypoxia №№ pp Groups of animals n Life span, min Single introduction Multiple introduction 1 Control 8 240.5 ± 20.0 226.5 ± 23.8 2 Adaptogenic agent 8 286.6 ± 18.3 * 410.5 ± 38.5 * 3 Eleutherococcus 8 245.2 ± 20.7 320.5 ± 15.4 *

As follows from the data given in table 8, a single administration of an adaptogenic agent in the indicated volume is accompanied by an increase in the life expectancy of mice by hypobaric hypoxia by an average of 20% compared with data from animals in the control group. With repeated administration of the test drug, a more pronounced antihypoxic effect was noted, as evidenced by an almost twofold increase in the life expectancy of mice of the experimental group compared with the data of animals in the control group. Moreover, the antihypoxic activity of the adaptogenic agent was superior to that of the eleutherococcus extract.

Sources of information

1. Belenky M.L. Elements of a quantitative assessment of the pharmacological effect. - L., 1963, - 148 p.

2. Biologically active additives in preventive and clinical medicine: Materials of the scientific-practical conference (September 18-19, 2003). - Ulan-Ude: Publishing House of the BSC SB RAS, 2003, - p.100-101.

3. Brekhman I.I. Eleutherococcus root is a new stimulant and tonic. - L., 1960, - 182 p.

4. The State Pharmacopoeia of the USSR: issue 1. General methods of analysis. 11th ed. - Moscow, 1987, - 336 p.

5. Kudrin A.N. On the rational preparation of medicinal compositions // Materials of the 17th scientific conference. Ryazan Medical Institute. Pavlova. - Ryazan, 1956, p.24-29.

6. Makarov V.G. To the mechanism of action of natural adaptogens / V.G. Makarov, V.E. Ryzhenkov // Pharmacy in the XXI century: innovations and traditions: Mater. Int. conf. - St. Petersburg, 1999, p.176-177.

7. Maksyutina N.P. et al. Search for anti-inflammatory drugs and immunomodulators among plant polyphenols, terpenoids and polysaccharides / Tez. doc. 4 All-Union. Congress of Pharmacists, Nov. 18-20, 1986, Kazan, p. 428-429.

8. Nikolaev S.M., Dashiev D.B., Batorova S.M. General principles for compiling multicomponent drugs in Tibetan medicine / S.M. Nikolaev // Pharmacy. - 1988. - No. 2. - S. 51-54.

9. Plants for us. Reference publication / K.F. Blinova, V.V. Vandyshev, M.N. Komarova and others; Ed. G.P. Yakovleva and K.F. Blinova. - St. Petersburg: Textbook, 1996, - 654 p.

10. Herbal medicines / Ed. N.P. Maksyutina et al. - Kiev: Health, 1985, - 200 p.

11. Savichev G.D. Improved treadmill for rats // Biologically active substances of flora and fauna of the Far East and the Pacific Ocean. - Vladivostok, - 1971, - p. 67-69.

12. Sergienko V.I., Bondareva I.B. Mathematical statistics in clinical studies. M., - 2000, - 236 s.

13. Sidorov K.K. On the classification of toxicity of poisons with parenteral routes of administration. - In the book: Toxicology of new industrial chemicals. - M., - 1973, - p. 47-51.

14. Shantanova L.N., Ivanova I.K. The effect of the herbal complex means "Tanton" on physical performance // Thesis. doc. 8 Russian. nat. Congress "Man and medicine", April 8-12. 2002 - M., 2002, - p.619-62.

Claims (1)

A drug with adaptogenic activity, which is a 40% alcoholic extract of plant materials, characterized in that the plant material for extraction contains sweet frankincense (rhizomes and roots), calamus marsh (rhizomes), Rhodiola rosea (rhizomes with roots), and levius safflower-like (rhizomes with roots), shrubs five-leaved (shoots), elecampane high (rhizomes and roots), dioecious nettle (leaves), medicinal calendula (flowers), Ural licorice (roots), buckthorn buckthorn (fruits), rosehip (p) lodas), cardamom (fruits), black pepper (fruits), blood-red hawthorn (fruits), nutmeg (fruits), parsley (roots), ginger (roots) with a degree of grinding of leaves and shoots 1-3 mm, fruits 0.5 -1 mm, roots and rhizomes 1-3 mm in the following ratio of components, wt.h: Frankincense (rhizomes and roots) 4.0 Air marsh (rhizomes) 10.0 Rhodiola rosea (rhizomes with roots) 10.0 Safflower Leuzea (rhizomes with roots) 10.0 Five-leaved shrubbery (shoots) 4.0 Elecampane tall (rhizomes and roots) 10.0 Stinging nettle (leaves) 10.0 Calendula officinalis (flowers) 8.0 Ural licorice (roots) 8.0 Buckthorn buckthorn (fruits) 4.0 Rosehip (fruits) 10.0 Cardamom (fruits) 2.0 Black pepper (fruits) 1,0 Blood-red hawthorn (fruits) 3.0 Nutmeg (fruits) 2.0 Parsley (roots) 2.0 Ginger (roots) 2.0 while the extract was obtained at a ratio of raw materials and extractant 1:15 and a temperature of 18-20 ° C.