RU2276992C2 - Pharmaceutical composition possessing with nootropic effect - Google Patents

Abstract

FIELD: medicine, pharmacy, pharmaceutical industry.

SUBSTANCE: invention proposes a pharmaceutical composition used as a nootropic agent. The nootropic agent represents the condensed extract from the plant Atragene sibirica (family Ranunculaceae) prepared by condensing the liquid alcoholic extract from plant the Atragene sibirica under vacuum at temperature 50°C up to the moisture content 25%, and filling agents comprising lactose, microcrystalline cellulose, polyplazdon XL-10, potato starch, aerosil, magnesium stearate chosen in the definite ratio of components. Agent possesses the effective nootropic effect.

EFFECT: valuable medicinal property of pharmaceutical composition.

2 cl, 7 tbl, 4 ex

Description

The invention relates to the pharmaceutical industry and relates to medicines with nootropic activity obtained from plant materials.

Closest to the proposed is the nootropic herbal medicine Ginsana (Pharmaton, Switzerland), obtained from the white ginseng root introduced in Switzerland [1], which does not have a raw material base in Russia.

A new technical task is to expand the arsenal of methods for producing medicines from domestic plant materials with nootropic activity.

The problem is solved by a new pharmaceutical composition with nootropic activity, containing the active substance and excipients, and, as the active substance, it contains condensed extract of the Prince of Siberia (Atragene speciosa Weinm.) At a residual moisture content of 25% and excipients in the following ratio wt.%:

Extract prince thick 20.02-21.24 Milk sugar 53.54-56.86 Microcrystalline cellulose 13.39-14.21 Polyplasdone XL-10 3.03-3.21 Potato starch 2.27-2.41 Aerosil 3.79-4.03 Magnesium stearate 0.97-1.03

Also, the pharmaceutical composition may be in the form of a solid dosage form, and the pharmaceutical composition may be in the form of tablets.

The drug is a flat-cylindrical tablet with a scourge, cream color with dark spots, a specific smell and taste.

The qualitative and quantitative composition of the tablets is determined based on the pharmacological (nootropic effect) and technological (appearance, content of active ingredients, average weight, disintegration, abrasion and fracture strength, dissolution test) properties of the proposed tablet options.

The main ingredient of the drug is a thick prince extract obtained by repercolation according to N. A. Chulkov [2].

The aboveground ground part of the prince is extracted with 25% ethanol in a battery of 5 percolators with a drain interval of 1 day at a ratio of raw material to liquid extract (1: 1). The resulting liquid extract is standardized by dry solids, phenol-alcohols and heavy metals.

The liquid extract is concentrated under vacuum at a temperature of 50 ° C on a rotary evaporator IR-1M. The yield of thick extract is 13.9 ± 0.1%, moisture content up to 25%. The studies confirm that the thick prince extract shows a pronounced nootropic effect at a dose of 100 mg / kg (Table 4-6).

Excipients used for the manufacture of tableted mass with extract (milk sugar, microcrystalline cellulose, polyplasdone XL-10, Aerosil, magnesium stearate) are widely used as target additives (excipients) of the pharmaceutical industry in the manufacture of tablets [2].

The technological process for producing tablets consists of the following stages:

1. Preparation of the material.

2. Mixing, granulating, drying.

3. Tableting and quality assessment of tablets.

4. Packing and packaging.

In all the prescriptions, the amount of starch, polyplasdone, aerosil, and magnesium stearate remained constant, and the ratio of only lactose and microcrystalline cellulose was changed.

Example 1 (table 1).

Stage 1 Potato starch and magnesium stearate are sieved through a vibrating sieve with nylon cloth for screens No. 38 and No. 23, respectively. Milk sugar is sifted through a sieve with a hole size of 0.5 mm - there should be no residue on the sieve.

2 stage. Sifted milk sugar, microcrystalline cellulose, polyplasdone, starch, aerosil are loaded into the mixer, mixed thoroughly and a warm, thick prince extract is introduced. Stir until the extract is evenly distributed for 15 minutes. The homogeneous moistened mass is dried for 20 minutes at a temperature of 55 ° C. After drying, the mass is passed through a granulator with a 2 mm sieve opening and magnesium stearate is dusted.

The ratio of the starting ingredients (excipients) is optimal. The mass has good flowability, compressibility and is precisely dosed.

3 stage. The resulting mass is tabletted on a Kilian tablet machine and the tablets are standardized. The tablets disintegrate in 8.0 ± 0.4 min, the fracture strength (Erweka device) is 105.8 ± 1.69 N, and the abrasion resistance is 99.49 ± 0.51%.

The drug has a pronounced nootropic activity (tab. 7-9).

4 stage. Tablets are packed in blister packs of 10 pieces.

Example 2 (table 2).

Obtaining tableted mass is carried out, as in example 1, but without the use of microcrystalline cellulose. The mass has good flowability and is well pressed, but the tablets obtained from it do not meet the requirements of regulatory documentation (ND) - not more than 15 minutes - according to disintegration (more than 20 minutes).

Example 3 (table 3).

The preparation of tablets is carried out according to the technological scheme indicated in example 1. The tabletted mass is well pressed, has good flowability, but the quality of the tablets does not meet the requirements of ND for disintegration (17 min).

When using milk sugar without microcrystalline cellulose (example 2), as well as in equal ratios 1: 1 (example 3), the disintegration of the tablets was from 20 to 17 minutes, respectively. When microcrystalline cellulose tablets are introduced into the prescription in an amount four times less than milk sugar, the disintegration of the tablets meets the requirements of ND and is 8.0 ± 0.7 min.

The authenticity of extracts and tablets is determined by thin-layer chromatography (TLC) by the qualitative reaction to phenol alcohols with vanillin-phosphorus reagent. Phenol-alcohols are characteristic of the raw materials of the prince of Siberia, which go into the extract and tablets of the prince ("Atrasinol"). Quantitative determination of phenol alcohols was carried out in a unified series of raw materials - liquid and thick extracts of the Atrasinol tablet.

Example 4 (tables 4-7).

Pharmacological studies were performed on male CBA mice with a body weight of 20-22 g. All category 1 animals (conventional linear mice) were obtained from the collection fund of the laboratory for experimental biological modeling of the Institute of Pharmacology of the Tomsk Scientific Center SB RAMS.

The experiments are carried out in the autumn-winter period. Work in the framework of experimental methods is carried out from 10 a.m. and ends by 15 p.m. Animals are kept in a vivarium on a normal feeding ration with free access to water and food (except in cases where other conditions are specified). Killing animals was carried out by an overdose of ether anesthesia.

The study of the influence of the thick extract of prince of Siberia on orienting-research behavior was evaluated using the "open field" model, and the learning ability of the conditioned reflex of passive avoidance in mice undergoing hypoxic injury was studied (Tables 4, 5). Also, for a more accurate assessment, studies were additionally performed on the effect of the drug on the course of immobilization stress (Table 6).

Approximate research behavior was studied under the conditions of the “open field” model, which is one of the most commonly used teaching methods used to judge the functional state of the central nervous system [3, 4]. The experimental setup "open field" represents a camera measuring 40 × 40 × 20 cm with a square floor and white walls. Its floor, divided into 16 squares, has in each of them a circular hole with a diameter of 3 cm. From above, the camera is illuminated by an electric incandescent lamp with a power of 100 W, located at a height of 1 m from the floor. The mouse is placed in one of the corners of the camera and within 2 minutes the number of movements from square to square (horizontal activity), the number of stands on the hind legs (vertical activity), the number of hole examinations (mink reflex), the number of washings (grooming) and the number of acts are recorded defecation by the number of fecal balls (boluses), calculate the coefficient of asymmetry of behavior in the form of the ratio of the number of horizontal movements to the total motor activity, expressed as a percentage.

Hypoxic trauma was studied under conditions of hermetic hypoxia. For a more detailed assessment of the effect of hypoxic injury in mice, we studied not only survival under conditions of hypoxia, but also evaluated the functional state of the central nervous system by the state of orientational research behavior and memory by reproducing the conditioned passive avoidance reflex (passive avoidance reaction), which is produced immediately before hypoxic exposure, as described below. Hermetic volume hypoxia was modeled by placing mice previously selected by weight (g) in a 250 ml hermetically sealed chamber. The mice were kept until a convulsive seizure occurred, after which the animals were removed from the chamber, allowed to sit for 1 h, and then they studied the tentative research behavior in the "open field". The technique of the conditioned reflex of passive avoidance [3, 5] is based on the suppression of the innate reflex of preference for dark space in rodents. The experimental setup is a camera consisting of two compartments - large (light) and small (dark). The animal is placed in the light compartment and after a while it goes into the dark one, after which the hole connecting the two compartments is closed with a door and the electric compartment is supplied with pulses of 50 ms duration, frequency 5 Hz and amplitude, onto the floor of the dark compartment, which is a grid of parallel alternating electrodes 50 mA After 20 seconds, the door is opened and the animal can jump out into the bright compartment with the usual floor. As a result of the described procedure, a conditioned reflex of avoiding dark space was developed in animals. To develop a reflex, the animal was placed in the corner of the chamber of the bright compartment, opposite from the entrance, and was observed for 3 min. The time of the first entry into the dark compartment (latent time of entry), the total time spent in the dark compartment, and the number of animals with a developed reflex were recorded. A preserved reflex was considered if the animal had never visited the dark compartment during 3 minutes of observation. If the latent time of approach exceeded 150 s, this was considered a sign of the presence of a reflex. Reflex was checked 24 and 48 hours after hypoxic exposure.

Immobilization stress was created by suspending animals by the neck fold for 22 hours [6]. After this time, the mice were removed and 15 minutes after the stress, they studied the orientational research behavior in the “open field”, recorded the emotional response by the method of Brady and Nauta [7], determined the number of leukocytes in peripheral blood, after which the animals were killed and determined the mass of the spleen, thymus, adrenal glands, the number of ulcers on the gastric mucosa was calculated and the weight coefficients of organs were calculated in terms of 20 g of body weight. Then, according to the method of Yu.I. Dobryakov [6], the severity of stress in points was determined. When assessing behavioral indicators, we used a point scale similar to that adopted in the method of Yu.I. Dobryakov in our modification [8].

Preparations and extracts were introduced into the stomach with a probe in the form of a solution or suspension in purified water 5 times for 5 days (5th time 1 hour before testing). Piracetam (Nootropil, Chieh-Polfa Group) at a dose of 400 mg / kg was used as reference preparations as a reference drug for nootropic activity.

The obtained experimental data were statistically processed using the Fisher parametric criterion and the nonparametric Wilcoxon criterion [9, 10].

The results of the study are given in table 4-7.

As the data in tables 4 and 5 show, a thick prince extract in all doses almost equally improves these behavioral indicators when registering 1 hour after a hypoxic injury. When tested 24 hours after hypoxic exposure, the thick prince extract restores the reproducibility of the reflex in approximately the same way in all doses studied from 75 to 92%.

When conducting studies on the effect on the behavior and condition of internal organs during acute immobilization stress, a thick prince extract had a positive effect on the behavior of animals undergoing stress. This was expressed in the activation of behavior, normalization of changes in the coefficient of asymmetry of behavior and emotional response, altered by stress. A decrease in leukocytosis and the number of ulcers in the stomach was also noted (Table 6). At the same time, the effect of the prince extract is superior in nootropic activity (preservation of orientational research behavior in the open field and the conditioned reflex of passive avoidance after hypoxic injury) to the Ginsana reference preparation and corresponds with a slight advantage to the piracetam effect. In the conditions of this technique, the optimal dose is 100 mg / kg. The thick prince extract and tablets based on it do not differ in pharmacological activity.

Thus, the thick prince extract and tablets based on it (Tables 7, 8) exhibit a pronounced nootropic effect at a dose of 100 mg / kg, which is included in the tablets. Since excipients, such as aerosil, magnesium stearate, are insoluble in water, the tablets are administered to animals in the form of a suspension, which does not interfere with the absorption of active substances in the gastrointestinal tract.

Literature

1. Chinna C. Current clinical aspects of ginseng research // Osterreichische Apoteker - Zeitung. - 1992. - B.19, No. 46. - S.377-381.

2. Ivanova A.A. Technology of dosage forms. - M .: Medicine, 1991. - 4.2. - S.134-220).

3. Buresh Ya. Methods and basic experiments on the study of the brain and behavior / Ya. Buresh, O. Bureshova, J.P. Houston - M .: Higher school, 1991. - 398 p.

4. Walsh R.N. The open - field test: a critical review / R.N. Walsh, R.A. Cummins // Psychol. Bull. - 1976. - V.83. - P. 482-504.

5. Guidelines for screening and preclinical testing of antihypoxic drugs Min. Health of the USSR. - M .: 1989. - 20 p.

6. Dobryakov Yu.I. Screening method for assessing the antistress effect of drugs // Stress and adaptation: Thes. All-Union. symposium - Chisinau, 1978. - P.172.

7. Brady J.V. Subcortical mechanisms in emotional behavioral effective changes following septal forebrain lesions in albino rat / J.V. Brady, W.J. H. Nauta // J. comparative and physiol. psychol. - 1953. - V.46, No. 3. - P.339-341.

8. Suslov N.I. Pathogenetic substantiation of the psychopharmacological effects of drugs of natural origin. Diss. Doct. honey. sciences. - Tomsk, 1995 .-- 406 p.

9. Belenky M.L. Elements of a quantitative assessment of the pharmacological effect. - L .: Medicine, 1963. - P.81-147.

10. Zaitsev G.N. Mathematical statistics in experimental botany. - M .: Nauka, 1984 .-- 425 p.

Table 1 Prescription 1 Extract of prince thick (residual humidity 25%) 0.066 g 20.63% Excipients (milk sugar, 55.20% microcrystalline cellulose, 13.80% polyplasdone XL-10, potato starch, aerosil, magnesium up to 0.32 g 10.37% stearate) table 2 Prescription 2 Extract of prince thick (residual humidity 25%) 0.066 g 20.63% Excipients (milk sugar, polyplasdone XL-10, potato starch, aerosil, magnesium stearate) up to 0.32 g 79.37% Table 3 Prescription 3 Extract of prince thick (residual humidity 25%) 0.066 g 20.63% Excipients (milk sugar, 34.50% microcrystalline cellulose, 34.50% polyplasdone XL-10, potato starch, aerosil, magnesium stearate) Up to 0.32 g 10.37%

Table 4
The influence of the thick extract of the prince of Siberia in comparison with piracetam on the main indicators of orienting-exploratory behavior in the "open field" and the safety of the conditioned reflex of passive avoidance in mice after hypoxic exposure (X _cf ± m; n = 12) Observation groups, dose Total motor activity Asymmetry coefficient The proportion of animals with reflexes,% 1 hour 24 hours 1 hour 24 hours 24 hours Intact control 35 ± 4 51 ± 4 44 ± 3 50 ± 6 one hundred Hypoxic 54 ± 3 * 60 ± 2 * 90 ± 4 * 85 ± 4 * 25 * the control p <0.05 p <0.05 p <0.05 p <0.05 p <0.05 Extract 50 ± 7 56 ± 4 52 ± 5 56 ± 3 ^# 75 ^# prince, 20 mg / kg p <0.05 p <0.05 Extract 43 ± 8 48 ± 3 ^# 52 ± 4 ^# 65 ± 3 ^# 92 ^# prince, 100 mg / kg p <0.05 p <0.05 p <0.05 p <0.05 Extract 38 ± 4 49 ± 5 57 ± 5 ^# 70 ± 5 ^# 82 ^# prince, 500 mg / kg p <0.05 p <0.05 p <0.05 Extract 42 ± 6 19 ± 4 ^# 55 ± 3 ^# 49 ± 4 ^# 75 ^# prince, 2000 mg / kg p <0.05 p <0.05 p <0.05 p <0.05 Ginsana 42 ± 6 43 ± 4 * 59 ± 4 ^# 75 ± 5 83.3 ^# 100 mg / kg p <0.05 p <0.05 p <0.05 Piracetam 42 ± 6 57 ± 4 ^# 63 ± 5 ^# 47 ± 3 100 ^# 400 mg / kg p <0.05 p <0.05 p <0.05 Note: * - differences are significant with respect to intact control;
# - differences are significant with respect to hypoxic control.

Table 5
The effect of the thick extract of prince of Siberia in comparison with piracetam on the content of leukocytes in peripheral blood and the process of ulceration in the stomach in animals undergoing immobilization stress (X _cf ± m; n = 12) Observation group, dose The number of leukocytes, g / l The number of ulcers in the stomach Points Intact control 7.2 ± 0.6 0 ° 0 0 Stressful 14.5 ± 1.9 * 2.0 ± 0.3 * 24 the control p <0.001 p <0.001 Extract 7.5 ± 1.6 # 0.9 ± 0.2 # 13 prince, 20 mg / kg p <0.001 p <0.01 Extract 5.4 ± 0.3 # 0.2 ± 0.1 # 9 prince, 100 mg / kg p <0.001 p <0.001 Extract 8.0 ± 1.0 # 0.5 ± 0.3 # eleven prince, 500 mg / kg p <0.001 p <0.05 Extract 9.0 ± 0.8 # 0.3 ± 0.2 # eleven prince, 2000 mg / kg p <0.001 p <0.001 Ginsana 9.1 ± 0.9 ^# 0.4 ± 0.2 ^# eleven 100 mg / kg p <0.001 p <0.001 Piracetam 9.1 ± 0.9 # 0.4 ± 0.2 # 10 400 mg / kg p <0.001 p <0.001 Note: * - differences are significant with respect to intact control;
# - differences are significant in relation to stress control

Table 6
The influence of tablets of the Siberian prince in comparison with piracetam on the main indicators of orientational research behavior in the "open field" and the preservation of the conditioned reflex of passive avoidance in mice after hypoxic exposure (X _cp ± m; n = 12) Observation group, dose Total motor activity Asymmetry coefficient The proportion of animals with a reflex,% 1 hour 24 hours 1 hour 24 hours 24 hours Intact control 35 ± 4 48 ± 2 44 ± 3 50 ± 6 one hundred Hypoxic 54 ± 3 * 60 ± 2 * 90 ± 4 * 85 ± 4 * 25 * the control p <0.05 p <0.05 p <0.05 p <0.05 p <0.05 Pills 50 ± 5 44 ± 4 52 ± 5 ^# 63 ± 3 ^# 90 ^# prince, 640 mg / kg p <0.05 p <0.05 p <0.05 Extract 43 ± 8 48 ± 3 ^# 52 ± 4 ^# 65 ± 3 ^# 92 ^# prince, 100 mg / kg p <0.05 p <0.05 p <0.05 p <0.05 Ginsana 42 ± 6 43 ± 4 * 59 ± 4 ^# 75 ± 5 83.3 ^# 100 mg / kg p <0.05 p <0.05 p <0.05 Piracetam 49 ± 3 57 ± 4 63 ± 5 ^# 47 ± 3 100 ^# <0.05 400 mg / kg p <0.05 Note: * - differences are significant with respect to intact control;
# - differences are significant with respect to hypoxic control.

Table 7
The effect of princely tablets in comparison with piracetam on the content of leukocytes in peripheral blood and the process of ulceration in the stomach in animals undergoing immobilization stress (X _cf ± m; n = 12) Observation group, dose The number of leukocytes, g / l The number of ulcers in the stomach Points Intact control 7.2 ± 0.6 0 ± 0 0 Stressful 14.5 ± 1.9 * 2.0 ± 0.3 * 24 the control p <0.001 p <0.001 Pills 6.5 ± 0.6 ^# 0.2 ± 0.2 ^# 9 prince, 640 mg / kg p <0.001 p <0.01 Extract 5.4 ± 0.3 ^# 0.2 ± 0.1 ^# 9 prince, 100 mg / kg p <0.001 p <0.001 Ginsana 9.1 ± 0.9 # 0.4 ± 0.2 # eleven 100 mg / kg p <0.001 p <0.001 Piracetam 9.1 ± 0.9 ^# 0.4 ± 0.2 ^# 10 400 mg / kg p <0.001 p <0.001 Note: * - differences are significant with respect to intact control;
# - differences are significant in relation to stress control

Claims (2)

1. Nootropic agent containing prince of Siberia extract, characterized in that it contains condensed prince of Siberian extract obtained by thickening liquid alcoholic extract of prince of Siberia under vacuum at a temperature of 50 ° C to a moisture content of 25%, and fillers, including milk sugar, microcrystalline cellulose, polyplasdone XL-10, potato starch, aerosil, magnesium stearate in the following ratio, wt.%: Condensed prince siberian extract 20.02-21.24 Milk sugar 53.54-56.86 Microcrystalline cellulose 13.39-14.21 Polyplasdone XL-10 3.03-3.21 Potato starch 2.27-2.41 Aerosil 3.79-4.03 Magnesium stearate 0.97-1.03 2. The composition according to claim 1, characterized in that it is made in the form of tablets.