RU2704126C2 - Pharmaceutical composition based on chlorobenzoylaminoadamantane, which increases physical performance in high and low temperatures - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: present invention refers to pharmaceutical industry, namely a pharmaceutical composition possessing actoprotective and thermoprotective activity. Pharmaceutical composition possessing actoprotective and thermoprotective activity in the form of tablets contains in certain proportions a therapeutically effective amount of chlorobenzoylaminoadamantane and pharmaceutically acceptable additives - polyvinylpyrrolidone 25000, tween 80, kleptose, microcrystalline cellulose, lactose, sodium croscarmellose, magnesium stearate (embodiments).

EFFECT: pharmaceutical composition described above possesses pronounced actoprotector and thermal-protector activity, is nontoxic, without side effects, convenient and stable.

3 cl, 3 dwg, 5 tbl, 7 ex

Description

FIELD OF THE INVENTION

The invention relates to medicine, in particular to pharmacology and pharmacy, in particular to a pharmaceutical composition containing as an active substance an effective amount of a known compound 2- (p-chlorobenzoyl) aminoadamantane [RF patent No. 1646256] - chlodantan, and can be used primarily in special fields of medicine (sports, military, marine, aerospace, etc.) to increase the body's performance under extreme exposure to high and low temperatures as a drug with actoprotector and thermoprotective activity.

State of the art

The search, creation and implementation of highly effective drugs that can maintain physical performance under extreme exposure to high and low temperatures seems to be an urgent task, since at the present stage, special-purpose drugs with such activity are practically absent.

There is information about the possibility of using or the effectiveness of drugs that increase physical performance in hypo- and hyperthermia [Bobkov Yu.G. "Pharmacological regulation of maladaptation states" M., 1986, 160 s; Kozlov N.B. “Hyperthermia: biochemical principles of pathogenesis, prevention and treatment” // Voronezh, 1990, 104 s; Vasilyeva P.P. Bulletin of the Smolensk Medical Academy. 2000. No3. S. 95-96; Sedov A.V., Goncharov S.F., G.G. Onishchenko et al. Human protection in emergency situations. M., "Reinfor." 2002.S. 115-169; Ilyina I.V., Samoilov N.N., Parfenov E.A. Saratov Journal of Medical Scientific Research. 2007.Vol. 3, No. 1. from. 103-104]. For this purpose, it is proposed to use the benzimidazole derivative etomerzole [Bobkov Yu.G., Vinogradov V.M., Katkov V.F. and other Pharmacological correction of fatigue. M, Medicine, 1984. 207 s], 2-piperazino piperazino-1- (thietanyl-3) benzimidazole dihydrochloride [RF Patent No. 2210370 (13) C1]; derivatives of methyl-benzyl substituted 3-hydroxypyridine [Vasilyeva P.P. Bulletin of the Smolensk Medical Academy. 2000. No3. S. 95-96]; physiologically compatible antioxidants - derivatives of ascorbic acid [Ilyina IV, Samoilov NN, Parfenov EA Saratov Journal of Medical Scientific Research. 2007.Vol. 3, No. 1. from. 103-104]. However, the benzimidazole derivative bemitil has the greatest clinical efficacy [A. Muravyov The effect of heat training and boehmil on the adaptation of animals and humans in high ambient temperatures. Dis. Cand. honey. sciences. SPb., 1997, 135 s] and a derivative of the aminoadamantane drug, Ladasten (syn. Bromantanum) [Morozov IS, Kleimenova. N.N. The effect of bromantane on the physical performance of laboratory animals // Experiment. and clinic. pharmacology. 1998.V. 61, No. 6. S. 51-53].

The compound 2- (p-chlorobenzoyl) aminoadamantane - chlodantane is known, which, like Ladasten, also refers to aminoadamantane derivatives. Chlodantan belongs to biologically active chemical compounds, has a higher adaptive activity than compounds of the specified class and is low toxic [Ivanova IA, Morozov IS, Lukicheva TA Actoprotective and adaptogenic properties of adamantane derivatives (review) // Chem. Zh., 2001. T. 35 (5), 3-6]. It is known that 2- (p-chlorobenzoyl) aminoadamantane and a number of derivatives of the 1st 2-aminoadamantane close to it in chemical structure under extreme conditions increase the body's resistance to extreme environmental factors and have immunostimulating activity [RF patent No. 1646256].

Due to the fact that agents with adaptive activity require administration under extreme conditions, it is necessary to choose a convenient and stable dosage form for use in any conditions.

The basis of the invention is the creation of a new highly effective non-toxic, non-side-effect pharmaceutical composition in solid dosage form, which has act-protective and thermoprotective effects, and meets all the requirements of the State Pharmacopoeia of the XIII edition.

Disclosure of invention

The problem is solved in that the claimed composition includes a medicinal substance and a pharmaceutical carrier or solvent, and contains as the active substance a therapeutically effective amount of 2- (p-chlorobenzoyl) aminoadamantane - chlodantane - and target additives, which use kleptose, lactose, tween 80, polyvinylpyrrolidone, croscarmellose sodium and magnesium stearate in a weight ratio of 1: 2-1: 6.

As filler in the composition of this invention can be used one or more compounds capable of providing tablets of the desired mass. It is desirable to use the filler in an amount close to the lower limit of the filler weight range. Preferred excipients are kleptose, aqueous lactose or anhydrous lactose.

One or more compounds capable of facilitating the granulation of chlodantan or a mixture with one or more substances from the group of fillers into denser and larger and / or more free-flowing particles can be used as a binder in the composition of this invention. Preferred binders are polyvinylpyrrolidone with different molecular weights (most preferably used in an amount of 2-20%).

As a disintegrant capable of facilitating the dispersion of the tablet upon contact of the tablet with an aqueous medium, croscarmellose sodium (most preferably used in an amount of 1-10%) can be used in the composition of the present invention.

As a solubilizer, promoting the dissolution and complex formation of chlodantan and kleptose formed to improve the solubility of the substance, tween 80 can be used in this composition (the most preferred amount is 0.01-5%).

As a glidant in the composition of the present invention, one or more compounds can be used that can solve the problems associated with the formation of tablets, such as releasing tablets made from the composition from the molding apparatus, eliminating sticking to the surface of the upper or lower tablet forming press. Preferred glidants are fatty acids or derivatives of fatty acids such as calcium stearate (most preferably used in an amount of 0.5-2%), magnesium stearate (most preferably used in an amount of 1-2%).

Pharmaceutical compositions made in solid dosage forms contain, as active ingredient, chlorobenzoylaminoadamantane in a therapeutically effective amount, and pharmaceutically acceptable excipients suitable for use in solid pharmaceutical compositions as excipients. Pharmaceutical compositions based on chlorobenzoylaminoadamantane as adjuvants providing an adequate tablet mass may contain at least one substance selected from the group of excipients, binders, disintegrants, solubilizers and glidants.

In accordance with the present invention, the pharmaceutical compositions are in solid form, contain the following components (wt.%):

Chlorobenzoyl aminoadamantane 16.0-50.0 PVP 25000 6.0-20.0 Twin 80 0.01-5.0 Kleptose 20.0-50.0 Lactose 10,0-40,0 Croscarmellose sodium 1.0-10.0 Magnesium / Calcium Stearate 0.1-1.0

The pharmaceutical composition may be in the form of a solid dosage form, preferably in the form of a tablet containing 25.0 or 100.0 mg of active ingredient. The weight of the resulting tablet is preferably from about 100.0 mg to about 600.0 mg.

Further, the invention is illustrated by examples representing options for its implementation with the achievement of the specified technical result:

Example 1

A mixture of 100.0 g of chlorobenzoylaminoadamantane was mixed in a mixer, then 4.0 g of tween 80 were added dropwise and stirred. Chlorobenzoylaminoadamantane was micronized with tween 80 for 60-70 minutes. A portion of beta-cyclodextrin (kleptose) 50.0 g is added to the resulting mixture and stirred for 60 minutes. Prepared components of the tablet mass: microcrystalline cellulose (5.0 g), lactose (30.0 g), are weighed and loaded into the mixer for mixing. The previously obtained mixture of chlorobenzoylaminoadamantane, tween 80 and kleptose are transferred to the mixer. The mixture is stirred for 10 minutes at a blade speed of 110 rpm. After this time, the mass is moistened with ~ 60.0 g of a binder solution and mixed to evenly distribute the humidifier with the same blade rotation speed (the binder solution is poured in parts: ~ 10.0 g every 2.5 minutes of mixing). Punch the mixture through a blade granulator with a hole diameter of a cylindrical mesh of 1 mm.

Granulate is dried in an oven at a temperature of 45 ° ± 5 ° C to a residual moisture content of 2.0-3.0%. The dried mass of granules is ground in a granulator (for example, Erweka (Germany)) with a pore size of 1.0-1.5 mm. A mass of dry granulate was dusted with croscarmellose sodium 3.0 g and calcium stearate, in an amount of 2.0 g (1.0 wt.%). The granulate obtained is tabletted. The resulting tablets containing 0.10 g of chlorobenzoylaminoadamantane, where the average tablet weight is 0.200 g, meet the requirements of the State Pharmacopoeia.

Example 2

300.0 g of a mixture of chlorobenzoylaminoadamantane is mixed in a mixer, then 12.0 g of tween 80 are added dropwise and stirred. Chlorobenzoylaminoadamantane is mixed with tween 80 for 60-70 minutes. A portion of beta-cyclodextrin (kleptose) 600.0 g is added to the resulting mixture and stirred for 60 minutes. Prepared components of the tablet mass: microcrystalline cellulose (30.00 g), lactose monohydrate (138.0 g), weighed and loaded into the mixer for mixing. The previously obtained mixture of chlorobenzoylaminoadamantane, tween 80 and kleptose are transferred to the mixer. The mixture is stirred for 10 minutes at a blade speed of 110 rpm. After this time, the mass is moistened with ~ 360.0 g of PVP 25000 solution (20%) and mixed to evenly distribute the humidifier with the same rotational speed of the blades (binder solution is poured in parts: ~ 30.0 g every 2.5 minutes mixing). Punch the mixture through a blade granulator with a hole diameter of a cylindrical mesh of 1 mm.

Granulate is dried in an oven at a temperature of 45 ° ± 5 ° C to a residual moisture content of 2.0-3.0%. The dried mass of granules is ground in a granulator manufactured by Erweka (Germany) with a pore size of 1.0-1.5 mm. A mass of dry granulate was dusted with croscarmellose sodium 36.0 g and magnesium stearate in an amount of 12.0 g (1.0 wt.%). The granulate obtained is tabletted. The resulting tablets, with a chlorobenzoylaminoadamantane content of 0.10 g, an average tablet weight of 0.400 g, meet the requirements of the State Pharmacopoeia.

Example 3

A mixture of 500.0 g of chlorobenzoylaminoadamantane is mixed in a mixer, then 20.0 g of tween 80 are added dropwise and stirred. Chlorobenzoylaminoadamantane is twinned with tween 80 for 60-70 minutes. A portion of beta-cyclodextrin (kleptose) 669.00 g is added to the resulting mixture and stirred for 60 minutes. Prepared tablet mass components: microcrystalline cellulose (750.0 g), lactose (500.0 g), are weighed and loaded into a mixer for mixing. The previously obtained mixture of chlorobenzoylaminoadamantane, tween 80 and kleptose are transferred to the mixer. The mixture is stirred for 10 minutes at a blade speed of 110 rpm. After this time, the mass is moistened with ~ 900.0 g of PVP 25000 (20%) binder solution and mixed to evenly distribute the humidifier with the same speed of rotation of the blades (binder solution is poured in parts: ~ 10.0 g every 2, 5 minutes of mixing). Punch the mixture through a blade granulator with a hole diameter of a cylindrical mesh of 1 mm.

Granulate is dried in an oven at a temperature of 45 ° ± 5 ° C to a residual moisture content of 2.0-3.0%. The dried mass of granules is ground in a granulator manufactured by Erweka (Germany) with a pore size of 1.0-1.5 mm. A mass of dry granulate was dusted with croscarmellose sodium 90.0 g and magnesium stearate, in an amount of 30.0 g (1.0 wt.%). The granulate obtained is tabletted. The resulting tablets, with a content of chlorobenzoylaminoadamantane 0.10 g, an average tablet weight of 0.600 g, meet the requirements of the State Pharmacopoeia.

The pharmacological effect of the claimed composition has been studied in animal experiments and is demonstrated by the following examples:

Example 4. The study of the effect of the pharmaceutical composition based on 2- (p-chlorobenzoyl) aminoadamantane and reference drugs on the performance of animals in hyperthermia.

The experiments were performed on non-linear male mice weighing 18-20 g contained in the vivarium in accordance with the rules of laboratory practice (GLP) and regulatory documents - Decree of the Chief State Sanitary Doctor of the Russian Federation of August 29, 2014 N 51 "On approval of SP 2.2.1.3218-14 "Sanitary and epidemiological requirements for the design, equipment and maintenance of experimental biological clinics (vivariums)" (Registered in the Ministry of Justice of Russia on October 31, 2014 No. 34547 and Order of the Ministry of Health and Social Development of the Russian Federation of August 23, 2010 No. 708n “On approval of the Laboratory Practice Rules”.

The performance of animals was assessed on a LE8700 Tredmill control V20 / 09/10 treadmill Panab Harvard apparatus (Spain) with a treadmill speed of 15 m / min. The criterion for assessing the tolerance of physical activity is the duration of the animals running on the treadmill until they are completely tired, as evidenced by the coup of the animal on its back / side or its stay on the fixed part of the treadmill for more than 10 seconds. Using the above program, the distance traveled (m) was calculated.

Before the start of each experiment, the treadmill was placed in a Binder MKF115 climatic chamber (Germany), in which a constant temperature level of + 40 ° С was maintained. The temperature control, in addition to the standard camera thermometer, was carried out by digital thermometers Testo 622 (Germany), located on the front and rear walls of the camera, and a temperature sensor TR-75M (Russia), located directly above the treadmill.

Before the start of each series of experiments, animals were adapted to work on a treadmill for 4 days. For this purpose, they were placed daily in a treadmill for 20 minutes at a treadmill speed of 15 m / min. One day after the last training, animals were included in the main experiment.

As reference preparations, the most effective known actoprotectors were used - bemitil and ladasten preparations.

The inventive composition and reference preparations bemitil and Ladasten were administered once an hour before the start of the experiment per os (intranasally) as a suspension in a starchy suspension weighing 10 ml / kg. Animals of the control groups received per os the same volume of starch suspension. The dose of the claimed composition was calculated according to the content of the active substance - compound 2- (p-chlorobenzoyl) aminoadamantane.

The results were processed statistically. The normality of the data distribution was checked using the Shapiro-Wilk test, the homogeneity of the variances using the Barlett test. If the distribution of data corresponds to the normal law and the dispersion is homogeneous, the statistical significance of the differences was determined using the Student criterion (when comparing 2 samples) or one-way analysis of variance with further processing by the multiple Dannet comparison method (in the case of 3 or more samples, the criterion is one-sided ) Otherwise, the Mann-Whitney test (2 samples) or a nonparametric Kruskal-Wallis analysis of variance with further processing using the Dann multiple-comparison method (3 or more samples) was used. The data are described in the case of a normal distribution using arithmetic means and their standard errors, otherwise the medians and the lower and upper quartiles are given. The critical significance level is α = 0.05.

It was shown that under normothermy conditions (+ 20 ° С) the duration of running of the animals (n = 10) to complete fatigue was 112.83 ± 16.06 minutes (Table 1). At the same time, the distance covered was 1663.00 ± 302.73 m.

Under conditions of hyperthermia (+ 40 ° C), the performance of mice (n = 18) decreases sharply, as evidenced by a statistically significant decrease in running duration compared to normothermia (p≤0.05) - 27.69 ± 1.31 min and 112, respectively , 83 ± 16.06 min. The same applies to the distance covered - 425.79 ± 25.03 m and 1663.00 ± 302.73 m, respectively (see Table 1).

* - p≤0.005 compared to normothermia

It was shown that bemitil (50 mg / kg; n = 8) under conditions of hyperthermia (+ 40 ° C) leads to a statistically significant increase in the running time of animals, statistically significant (p≈0.0214) - 41.66 ± 2, respectively. 76 min and 27.69 ± 1.31 min. The same applies to the distance covered - 613.33 ± 41.84 m and 425.79 ± 25.03 m, respectively (see Table 2).

An increase in the dose of the drug to 100 mg / kg was not accompanied by an increase in its active and thermoprotective activity (see table. 2). For example, when using the drug at a dose of 50 mg / kg, the running time of animals (n = 9) was 41.66 ± 2.76 minutes, and at a dose of 100 mg / kg - 40.62 ± 5.01 minutes.

Thus, bemitil in doses of 50 and 100 mg / kg, administered per os an hour before the start of the experiment, under conditions of hyperthermia, exhibits act- and thermoprotective activity, increasing the running time of animals by an average of 50%. The distance traveled increases in a similar way.

Ladasten at a dose of 20 mg / kg (n = 10) under conditions of hyperthermia (± 40 ° C) does not show acto and thermoprotective activity. So, for example, the running duration against the background of the drug 36.69 ± 3.37 minutes does not statistically significantly differ (p≈0.1954) from that registered in the control - 27.69 ± 1.31 minutes (Table 2).

p is indicated with respect to control.

An increase in the dose of the drug to 50 mg / kg leads to the realization of its active and thermoprotective activity. Thus, under conditions of hyperthermia (+ 40 ° C), the running time of animals receiving Ladasten was statistically significantly (p≈0,0009) higher than in the control — 44.67 ± 3.62 min and 27.69 ± 1, respectively. 31 minutes The distance traveled compared to the control increased by approximately 55% (Table 2).

Thus, the reference preparation of lastasten at a dose of 50 mg / kg under conditions of hyperthermia exhibits significant acto-and thermoprotective activity comparable to that known for the reference preparation of bemitil (50 mg / kg).

It is shown that the claimed composition in conditions of hyperthermia (+ 40 ° C) exhibits pronounced acto-and thermoprotective activity, 35-40% higher than that of the reference drugs. So, for example, if in the control series of experiments the running duration is 27.69 ± 1.31 min, then in animals treated with the claimed composition (25 mg / kg; n = 9) - 56.23 ± 5.36 (Table 2 ) The difference is statistically significant (p <0.0001). Moreover, the distance traveled was also significantly (p <0.0001) greater - respectively 425.79 ± 25.03 m in the control and 832.95 ± 80.28 m in animals receiving the claimed composition.

An increase in the dose of the claimed compound to 50 mg / kg under conditions of hyperthermia is accompanied by a decrease in its active and thermoprotective activity, and when using the claimed composition at a dose of 10 mg / kg, its specific activity is not realized (Table 2).

Thus, as follows from the above data, the claimed composition under conditions of hyperthermia exhibits pronounced acto-and thermoprotective activity, significantly superior to that of the standard drugs - bemitil and Ladasten and can be used to increase the body's performance under extreme exposure to high temperatures.

Example 5. The study of the effect of the pharmaceutical composition based on 2- (p-chlorobenzoyl) aminoadamantane and the reference preparation on the performance of animals in hypothermia.

The experimental procedure (except for the temperature in the climatic chamber), the scheme and method of administration of the studied drugs, as well as statistical processing of the results are similar to those in Example 4. The experiments were carried out in the Binder MKF115 climate chamber (Germany), in which a constant temperature level of -5 ° was maintained FROM. As a reference drug used drug Ladasten.

In control experiments, it was shown that under hypothermia (-5 ° C), as well as hyperthermia, the performance of mice (n = 15) decreases sharply (Table 3). Thus, the running time of animals under hypothermia was 42.15 ± 4.27 minutes, while under normothermia it was 112.83 ± 16.06 minutes (p≤0.05), and the length of the distance covered by animals was 585.45 ± 61.67 m and 1663.00 ± 302.73 m, respectively (p≤0.05).

* - p≤0.005 compared to normothermia

Ladasten (20 mg / kg; n = 10) under hypothermia (-5 ° C) does not show acto and thermoprotective activity. So, for example, the running duration against the background of the drug does not statistically significantly differ (p≈0.995) from that recorded in the control — 38.59 ± 3.40 min and 42.15 ± 4.27 min, respectively (Table 4).

Similar results were obtained with the use of the drug at a dose of 50 mg / kg. So, the running time of animals against the background of the use of the drug in this dose is 34.44 ± 5.37 minutes, and the distance covered is 486.28 ± 83.79 m, while in the control, 42.15 ± 4.27 minutes and 585.45 ± 61.67 m (Table 4). The difference with control is not statistically significant.

It is shown that the claimed composition in conditions of hypothermia (-40 ° C) exhibits pronounced acto-and thermoprotective activity. So, for example, if in the control series of experiments the running duration is 42.15 ± 4.27 minutes, then in animals treated with the claimed composition (25 mg / kg; n = 9) - 63.45 ± 5.48 (Table 4 ) The difference is statistically significant (p <0.0063). Moreover, the distance traveled was also significantly (p <0.0055) greater — 585.45 ± 61.67 m in the control, respectively, and 913.29 ± 54.21 m in animals treated with the claimed composition.

"P" is indicated with respect to control

An analysis of the results indicates that the claimed composition at a dose of 25 mg / kg (per os, one hour before the start of the experiment) under hypothermia has a pronounced acto-and thermoprotective effect, in contrast to the reference drug, lastasten, which was ineffective in the conditions of this experiment .

Thus, as follows from the obtained data, the claimed pharmaceutical composition based on 2- (p-chlorobenzoyl) aminoadamantane (25 mg / kg) under conditions of hypothermia exhibits pronounced acto- and thermoprotective activity and can be used to increase the body’s performance under extreme exposure to low temperatures.

Example 6. The study of the effect of the pharmaceutical composition based on 2- (p-chlorobenzoyl) aminoadamantane and the reference drug on the emergency adaptation of animals in hyperthermia.

The experiments were performed on outbred male mice weighing 20-25 g. By random sampling the main group was formed, receiving the test composition (n = 18), the control group (n = 12) and the group of animals that received the reference preparation bemitil (n = 18). The inventive pharmaceutical composition (tablet mass) and bemitil were administered an hour before the experiment at a dose of 25 and 100 mg / kg, respectively, per os in a starch suspension in a volume of 10 ml / kg. Animals of the control group received per os the same volume of starch suspension. The dose of the claimed composition was calculated by the content of the active substance, the compound 2- (p-chlorobenzoyl) aminoadamantane. An hour after the introduction of the studied substances, the animals were placed in a climatic chamber with a temperature of + 40 ° C. The criterion for evaluating the target effectiveness was the total death of animals for each hour and the entire observation period. According to the data obtained, survival curves were constructed. The statistical significance of the differences between the curves was determined by the Gehan-Wilcoxon test taking into account the multiplicity of comparisons.

As follows from the data obtained, the inventive composition increased the life expectancy of animals in the climatic chamber at a temperature of + 40 ° C. So, if in the control group the average life expectancy of animals was 162.5 ± 20.1 minutes, then in animals treated with the claimed composition -225.0 ± 69.2 minutes. From the constructed survival curve (Fig. 1) it follows that the difference is statistically significant (p = 0.01). The reference preparation bemitil in the conditions of this experiment does not affect the survival of animals - accordingly, the control is 162.5 ± 20.1 minutes, bemitil is 165.0 ± 37.5 minutes.

Thus, the claimed composition, in contrast to the reference drug bemitil in the conditions of this experiment, statistically significantly increases the survival of animals.

Example 7. A study of the effect of a pharmaceutical composition based on 2- (p-chlorobenzoyl) aminoadamantane and a reference preparation on the coordination of movements of animals that have been under conditions of hypothermia for a long time.

The experiments were performed on outbred male mice weighing 20-25 g. The impact of the claimed composition and the reference preparation of sydnocarb on the coordination of movements of small laboratory animals was assessed using the standard Rotating Rod technique using the Rota-Rod / RS instrument (Panlab Harvard Apparatus , Spain). The installation is a drum 3 cm in diameter, divided by 6 discs (25 cm in diameter) into 5 identical parts. The drum can rotate in different speed modes. Under the conditions of this experiment, the initial drum speed is 5 revolutions per minute, which, in accordance with a given program, is progressively increasing to 40 rpm. Before the start of the experiment (a day before placement in the heat chamber), the animals were introduced to the installation at a drum rotation speed of 5 rpm.

By random sampling, the main (n = 12) and control (n = 12) group of animals were formed, as well as the group of animals treated with the reference drug (n = 12) sydnocarb. The day after randomization, the animals were placed for seven days in a climatic chamber at a temperature of -4 ° C. The inventive composition and sydnocarb were administered per os in starch suspension in a volume of 10 ml / kg for 7 days at a dose of 25 mg / kg. Animals of the control group received per os the same volume of starch suspension. The dose of the claimed composition was calculated according to the content of the active substance - compound 2- (p-chlorobenzoyl) aminoadamantane. One hour after the last injection, rats were placed for 15 minutes in a climatic chamber at a temperature of -8 ° C. After the time spent in the climate chamber, the animals were removed from it and placed on the Rota-Rod / RS device located in the climate chamber with a temperature of -4 ° C. The criterion for evaluating the target efficiency was the retention time of animals on a rotating rod.

Statistical data processing was performed as follows. The normality of the data distribution was checked using the Shapiro-Wilk test, the homogeneity of the variances using the Leven criterion. Since the variances were inhomogeneous, the statistical significance of the differences was determined using a non-parametric analog of the Kruskal-Wallis analysis of variance with further processing by the method of multiple comparisons according to Dunn (3 or more samples). Data were described using medians and lower and upper quartiles. The critical significance level is α = 0.05.

It was shown that prolonged stay of animals under hypothermia significantly affects the coordination of their movements. So, if in the conditions of normothermia the average residence time of intact animals on a rotating rod is 127.0 (100.5 ÷ 183.0) s, then under hypothermia it decreases by 90%, respectively, from 127.0 (100.5 ÷ 183 , 0) to 11.5 (9.5 ÷ 15.5) s-p <0.0001.

A comparative study of the effect of the claimed composition (25 mg / kg, per os) and sydnocarb (25 mg / kg, per os) on the coordination of movements of animals that have been under conditions of hypothermia for a long time, indicates that the claimed composition, in contrast to the reference preparation of sydnocarb , improves coordination of movements, while sydnocarb has a negative effect on this indicator. So, if the animals receiving the claimed composition, the residence time on the rotating rod was more than 2 times higher than in the control: 24.0 (17.0 ÷ 33.0) and 11.5 (9.5 ÷ 15, respectively 5) - p = 0.04, then in animals treated with sydnocarb, the retention time on the rotating rod was statistically significantly (p = 0.04) less than in the control: 6.5 (5.0 ÷ 9, respectively 0) and 11.5 (9.5 ÷ 15.5) (Table 5).

Notes: data are presented as median, lower and upper quartiles;

* - p <0.05 compared with the control.

Thus, the obtained data indicate that the claimed composition, in contrast to the reference drug sydnocarb, improves the coordination of movements in animals that have been under conditions of hypothermia for a long time, which, most likely, is associated with its ability to increase the adaptive capabilities of the body in these conditions.

Claims (5)

1. The pharmaceutical composition having actoprotective and thermoprotective activity in the form of tablets containing a therapeutically effective amount of chlorobenzoylaminoadamantane and pharmaceutically acceptable excipients in the following ratio of ingredients, mass. %: Chlorobenzoylaminoadamantane 25.0 Polyvinylpyrrolidone 25000 (PVP 25000) 6.0 Twin 80 1,0 Kleptose 50,0 Microcrystalline cellulose 2.5 Lactose 11.5 Croscarmellose sodium 3.0 Magnesium stearate 1,0 2. A pharmaceutical composition having actoprotective and thermoprotective activity in the form of tablets containing a therapeutically effective amount of chlorobenzoylaminoadamantane and pharmaceutically acceptable excipients in the following ratio of ingredients, mass. %: Chlorobenzoylaminoadamantane 18.27 Polyvinylpyrrolidone 25000 (PVP 25000) 6.58 Twin 80 0.73 Kleptose 24.45 Microcrystalline cellulose 27.41 Lactose 18.27 Croscarmellose sodium 3.29 Magnesium stearate 1.00 3. The pharmaceutical composition according to claim 1 or 2, characterized in that the lactose contains predominantly lactose monohydrate.

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