RU2527342C2 - Sublingual form of 6-methyl-2-ethyl-3-hydroxypyridine and using it as agent possessing stimulating, anorectic, antidepressant, anxiolytic, antihypoxic, antiamnestic (nootropic), and antialcohol activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is described is using a pharmaceutical composition in the form of an orally disintegrated tablet containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as an active substance and crospovidone as a disintegrating agent in ratio 2:1 respectively, as a motor stimulating and anorectic agent.

EFFECT: preparing motor stimulating and anorectic agent.

16 dwg, 34 tbl, 13 ex

Description

The invention relates to the field of medicine.

Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) is currently widely used in Russian medical practice as an anti-ischemic, neuroprotective, nootropic, anxiolytic agent. According to the mechanism of action, Mexidol is an inhibitor of free radical processes, reduces lipid peroxidation, increases the activity of the endogenous antioxidant system, stabilizes biological membranes, causes conformational changes in the protein components of the membrane and modulates the functioning of the benzodiazepine and GABA receptors (Dumayev K.M., Voronina T.A., Smirnov L.D. Antioxidants in the prevention and treatment of CNS pathologies.Published.Institute of Biomedical Chemistry RAMS, 1995, 271 pp. Voronina TA Meksidol: the main neuropsychotropic effects and m mechanism of action. "Farmateka", 2009, t.180, №6, s.1-4).

Earlier in the experiment and the clinic, it was found that mexidol in the substance, tablets, capsules has antihypoxic, neuroprotective, nootropic, anxiolytic, anticonvulsant, anti-alcoholic effects (Voronina T.A.Mexidol antioxidant: the main neuropsychotropic effects and mechanism of action. Psychopharmacol. Biol. , 2001, vol. 1, No. 1, pp. 2-12; Voronina T.A., Smirnov L.D., Aliev A.N. et al. The relationship between the chemical structure and anticonvulsant activity of 3-hydroxypyridine derivatives. Toxicology, 1987, No. 1, pp. 27-30; G. Avakyan et al. Experimental and Clinical Epileptology, Chapter in the collective monograph Epilepsy, edited by N. G. Neznanov, 2010 - St. Petersburg, pp. 215-242; K. Dumayev, Voronina T.A., Smirnov L.D. - Antioxidants in the prevention and treatment of CNS pathologies. - Publishing house of the Institute of Biomedical Chemistry RAMS, 1995). However, these effects occur only 40-60 minutes after the introduction of Mexidol inside, and in order to achieve a stable effect, a course administration of the drug is required. In addition, mexidol when administered orally does not have an antidepressant effect.

The result of the present invention is the creation of Mexidol in the form of oral disintegrating tablets (ODT) for sublingual use, having a spectrum of pharmacological effects different from Mexidol in other dosage forms and having the ability to urgently stop anxiety, fear, depression, memory impairment, hypoxic and ischemic conditions and alcohol intoxication, as well as methods for the production of Mexidol in such a dosage form. Thus, the subject of the present invention is the use of 6-methyl-2-ethyl-3-hydroxypyridine and / or its pharmaceutically acceptable salt in sublingual form, a pharmaceutical composition containing as active ingredient 6-methyl-2-ethyl-3-hydroxypyridine and / or its pharmaceutically acceptable salt, made in the form of an oral disintegration tablet, as well as the use of such a composition as a stimulant, anorexigenic, antidepressant, anxiolytic, nootropic, antihypoxic, antiischemic and anti thial alcohol.

The invention is illustrated by a schematic description of the production of tablets of the drug “Mexidol ODT, 125 mg tablets” (Fig. 1.), Fig. 2, showing the kinetics of the release of ethyl methylhydroxypyridine succinate in 0.1 M HCl, Fig. 3, showing the kinetics of the release of ethyl methyl hydroxypyridine succinate at 0 , 1 M HCl, Fig. 4, showing the microscopy of the substance of ethyl methylhydroxypyridine succinate, Fig. 5. Reflecting the microscopy of the ground substance of ethyl methyl hydroxypyridine succinate, Fig. 6, showing the kinetics of the release of ethyl methyl hydroxypyridine succinate in 0.1 M HCl, Fig. 7 with a schematic description of the production of tablets of the drug “Mexidol ODT, 125 mg tablets”, Fig. 8, showing the kinetics of release of hydroxydroxy ethyl succinate in 0.1 M HCl, Fig. 9 with a schematic description of the production of Mexidol ODT tablets, 125 mg tablets, Fig. 10, showing the kinetics of the release of ethylmethylhydroxypyridine succinate in 0.1 M HCl, Fig. 11 with a schematic description of the production of tablets of the drug “Mexidol ODT, 125 mg tablets” - Fig. 12, showing the kinetics of the release of ethyl methylhydroxypyridine succinate in 0.1 M HCl, Fig. 13 with a schematic description of the production of tablets of the drug “Mexidol ODT tablets of 125 mg ", Fig. 14, showing the kinetics of the release of ethylmethylhydroxypyridine succinate in 0.1 M HCl, Fig. 15 with a schematic description of the production of tablets of the drug" Mexidol ODT, tablets, 250 mg "," Mexidol ODT, tablets, 125 mg ", And the drug" Mexidol ODT, tablets of 50 mg "And Fig. 16, showing the kinetics of the release of ethylmethylhydroxypyridine succinate in 0.1 M HCl.

The application discloses Mexidol ODT (oral disintegrating tablets) for sublingual use, which has a wider range of pharmacological effects, since, unlike Mexidol in tablets and capsules, it has a stimulating (activating) and anorexigenic effect when applied on a course, and also has the ability to quickly emergency (after 5-10 minutes) relief of anxiety, fear, depression, memory impairment, hypoxic and ischemic conditions and alcohol intoxication, while mexidol when administered in utr (intragastrically) in tablets and capsules (at higher doses) only takes effect after 60 minutes and at exchange application.

ODT tablets can be produced in various pharmaceutically acceptable ways. The simplest and most widely used method for producing tablets includes such basic stages of production as the preparation of tablet mass and tabletting.

The tablet mass can be prepared by various methods. Often used the following methods of preparation of tablet mass:

- wet granulation (using a mixer with a high level of shear and fluidized bed);

- dry granulation (compaction);

- direct pressing.

In our invention, Mexidol ODT tablets were manufactured using various tablet formulation methods and with varying levels of ethyl methyl hydroxypyridine succinate or other pharmaceutically acceptable salt.

One of the most common methods for producing tablet masses of drugs with high dosages is wet and dry granulation. Using these methods, tablet masses with a high content of active substances and with a uniform particle size distribution can be obtained. The tablet masses obtained by the above methods are not susceptible to delamination during the tabletting process, which makes it possible to obtain tablets that are uniform in weight and content of active ingredient.

The following examples confirm the possibility of obtaining ODT tablets of the drug "Mexidol" with desired characteristics.

Example 1

Direct pressing.

The composition and ratio of the ingredients of the tablets of the drug "Mexidol ODT tablets 125 mg" are presented in table 1, a schematic description of the production of such tablets is presented in Fig. one.

Table 1 No. p / n Name of ingredients Functional Purpose of Ingredients in mg at % At boot, in g one. Ethyl Methyl Hydroxypyridine Succinate Active substance 125.0 12.5 375.0 2. Mannitol (Mannogem ™ EZ Spray Dried Mannitol, SPI Pharma) Inert filler 615.0 61.5 1845.0 3. Crospovidone (Polyplasdone® XL-10, ISP Pharmaceuticals) Disintegrator 200,0 20,0 600,0 four. Powder flavoring “Grapes” (Aromsa) Flavoring 15.0 1,5 45.0 5. Sodium saccharinate Sweetener 10.0 1,0 30,0 6. Colloidal silicon dioxide (Aerosil A-200 W Pharma, Degussa) Sliding 5,0 0.5 15.0 7. Sodium Stearyl Fumarate (PRUV®, JRS PHARMA) Lubricant 30,0 3.0 90.0 Together tablet: 1000,0 100.0 3000,0

Physico-technological characteristics of the tablet mass of the drug "Mexidol ODT tablets 125 mg" and physico-chemical and pharmacological and technological characteristics of the tablets of the drug "Mexidol ODT tablets 125 mg" are presented in tables 2 and 3.

table 2 No. Name of indicator Values one. Bulk density, g / cm ³ 0.550 2. Density after compaction, g / cm ³ 0.663 3. Carra Index,% 17.0 four. Gaussner Ratio 1.21

Table 3 No. Name of indicator Values one. Description of pills Long form tablets with a biconvex surface 2. Tablet size mm 9 × 21 3. Average tablet height, mm 6.6 four. Tablet weight mg 1000,0 5. The resistance of tablets to crushing (average value), N 60.0 6. Decay, s 60 7. Weight loss during abrasion (test "Abrasion"),% 0.5

The dissolution kinetics of Mexidol ODT, 125 mg tablets were studied.

The tests were carried out in accordance with the requirements of the pharmacopeia.

Dissolution Test Conditions:

Type of device: device "ERWEKA DT 700" Equipment: paddle mixer The volume of the dissolution medium: 1000 ml Rotation frequency: 50 rpm Dissolution Time: 45 min Sampling Time: after 5, 10, 15, 25, 35 and 45 minutes Dissolution Medium: 0.1 M hydrochloric acid solution Dissolution Medium Temperature: (37.0 ± 0.5) ° С Sample selection: Auto Number of tablets per test: 12 tablets Analysis Method: spectrophotometric method.

The results of the study are presented in table. 4 and fig. 2.

Table 4 No. Time min Release, average,% RSD,% one. 5 30.8 7.8 2. 10 49.6 3.6 3. fifteen 67.7 2.9 four. 25 83.1 2.6 5. 35 92.4 2,5 6. 45 98.4 2,5

The obtained tablet form (ODT) gave a significant improvement in dissolution kinetics compared with the commercial series of the drug “Mexidol, film-coated tablets, 125 mg” (see Fig. 3, where row 1 - tablets of the drug “Mexidol ODT, tablets of 125 mg ", Row 2 - tablets of the drug" Mexidol, film-coated tablets, 125 mg ", commercial series). However, the resulting dissolution rate was not sufficient to obtain a drug with high bioavailability. After analyzing the data obtained, it was concluded that one of the reasons for the low dissolution rate of the tablets is the large particle size of the substance - see Fig. 4, where the average particle size of the substance of ethyl methylhydroxypyridine succinate was 400-1500 μm. To solve this problem, it was proposed to grind particles of the substance to a particle size of less than 10 microns using a ball planetary mill PM 400 MA, the company "Retsch". The crushed substance was agglomerated by electrostatic forces into particles with a size of 200-600 μm (see Fig. 5), which also did not give significant results when dissolving the tablets of the preparation “Mexidol ODT, tablets, 125 mg ”(see Fig. 6, row 1 - tablets of the drug“ Mexidol ODT, tablets of 125 mg ”, unmilled substance, row 2 - tablets of the drug“ Mexidol ODT, tablets of 125 mg ”, ground substance). To reduce electrostatic forces, a co-grinding method with one of the auxiliary substances was proposed. After selecting various auxiliary substances, their ratios with the active substance, as well as the co-grinding regimen, the best results were obtained by co-grinding the substance with crospovidone in a ratio of 2: 1, respectively.

Example 2

The composition and ratio of the ingredients of the tablets of the drug "Mexidol ODT tablets 125 mg" are presented in table 5, a schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg" are presented in Fig. 7.

Table 5 No. p / n Name of ingredients Functional Purpose of Ingredients in mg at % At boot, in g one. Ethyl Methyl Hydroxypyridine Succinate Active substance 125.0 12.5 375.0 2. Mannitol (Mannogem ™ EZ Spray Dried Mannitol, SPI Pharma) Inert filler 615.0 61.5 1845.0 3. Crospovidone (Polyplasdone® XL-10, ISP Pharmaceuticals) Disintegrator 200,0 20,0 600,0 four. Powder flavoring “Grapes” (Aromsa) Flavoring 15.0 1,5 45.0 5. Sodium saccharinate Sweetener 10.0 1,0 30,0 6. Colloidal silicon dioxide (Aerosil A-200 W Pharma, Degussa) Sliding 5,0 0.5 15.0 7. Sodium Stearyl Fumarate (PRUV®, JRS PHARMA) Lubricant 30,0 3.0 90.0 Together tablet: 1000,0 100.0 3000,0

Physico-technological characteristics of the tablet mass of the drug "Mexidol ODT tablets 125 mg" and physico-chemical and pharmacological and technological characteristics of the tablets of the drug "Mexidol ODT tablets 125 mg" are presented in tables 6 and 7.

Table 6 No. Name of indicator Values one. Bulk density, g / cm ³ 0.510 2. Density after compaction, g / cm ³ 0.620 3. Carra Index,% 17.7 four. Gaussner Ratio 1.21

Table 7 No. Name of indicator Values one. Description of pills Long form tablets with a biconvex surface 2. Tablet size mm 9 × 21 3. Average tablet height, mm 6.6 four. Tablet weight mg 1000,0 5. The resistance of tablets to crushing (average value), N 60.0 6. Decay, s 48 s 7. Weight loss during abrasion (test "Abrasion"),% 0.5

The dissolution kinetics of Mexidol ODT, 125 mg tablets were studied.

The tests were carried out in accordance with the requirements of the pharmacopeia.

Dissolution Test Conditions:

Type of device: device "ERWEKA DT 700" Equipment: paddle mixer The volume of the dissolution medium: 1000 ml Rotation frequency: 50 rpm Dissolution Time: 45 min Sampling Time: after 5, 10, 15.25, 35 and 45 minutes Dissolution Medium: 0.1 M hydrochloric acid solution Sample selection: Auto Number of tablets per test: 12 tablets Analysis Method: spectrophotometric method

The results of the study of the kinetics of the release of ethyl methylhydroxypyridine succinate in 0.1 M HCI are presented in Table 8 and Fig. 8, row 2.

Table 8 No. Time min Release, average,% RSD,% one. 5 78.9 8.8 2. 10 88.6 4.6 3. fifteen 94.8 3.2 four. 25 98.8 2.2 5. 35 99.7 2.1 6. 45 99.8 1.9

Example 3

To obtain the best results of the release of the active substance from the dosage form, another method was proposed for the preparation of microparticles of the substance ethyl ethyl methyl hydroxypyridine succinate.

The method consists in applying the active substance ethyl methylhydroxypyridine succinate from solution using a nozzle on a carrier (crospovidone) in a Unilab-5 DJ fluidized bed installation, manufactured by Huttlin.

The composition and ratio of the ingredients of the tablets of the drug "Mexidol ODT tablets 125 mg" are presented in table 9, a schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg" are presented in Fig. 9.

Table 9 No. p / n Name of ingredients The functional purpose of the ingredients. in mg at % At boot, in g one. Ethyl Methyl Hydroxypyridine Succinate Active substance 125.0 12.5 375.0 2. Mannitol (Mannogem ™ EZ Spray Dried Mannitol, SPI Pharma) Inert filler 615.0 61.5 1845.0 3. Crospovidone (Polyplasdone® XL-10, ISP Pharmaceuticals) Disintegrator 200,0 20,0 600,0 four. Powder flavoring “Grapes” (Aromsa) Flavoring 15.0 1,5 45.0 5. Sodium saccharinate Sweetener 10.0 1,0 30,0 6. Colloidal silicon dioxide (Aerosil A-200 W Pharma, Degussa) Sliding 5,0 0.5 15.0 7. Sodium Stearyl Fumarate (PRUV®, JRS PHARMA) Lubricant 30,0 3.0 90.0 Together tablet: 1000,0 100.0 3000,0

Physico-technological characteristics of the tablet mass of the drug "Mexidol ODT tablets 125 mg" and physico-chemical and pharmacological and technological characteristics of the tablets of the drug "Mexidol ODT tablets 125 mg" are presented in tables 10 and 11.

Table 10 No. Name of indicator Values one. Bulk density, g / cm ³ 0.550 2. Density after compaction, g / cm ³ 0.670 3. Carra Index,% 17.9 four. Gaussner Ratio 1.22

Table 11 No. Name of indicator Values one. Description of pills Long form tablets with a biconvex surface 2. Tablet size mm 9 × 21 3. Average tablet height, mm 6.6 four. Tablet weight mg 1000,0 5. The resistance of tablets to crushing (average value), N 55.0 6. Decay, s 35 s 7. Weight loss during abrasion (test "Abrasion"),% 0.5

The dissolution kinetics of Mexidol ODT, 125 mg tablets were studied.

The tests were carried out in accordance with the requirements of the pharmacopeia.

Dissolution Test Conditions:

Type of device: device "ERWEKA DT 700" Equipment: paddle mixer The volume of the dissolution medium: 1000 ml Rotation frequency: 50 rpm Dissolution Time: 45 min Sampling Time: after 5, 10, 15, 25, 35 and 45 minutes Dissolution Medium: 0.1 M hydrochloric acid solution Dissolution Medium Temperature: (37.0 ± 0.5) ° С Sample selection: Auto Number of tablets per test: 12 tablets Analysis Method: spectrophotometric method

The results of the study of the kinetics of the release of ethyl methylhydroxypyridine succinate in 0.1 M HCl are presented in Table 12 and Fig. 10, row 3 (tablets of the drug “Mexidol ODT, 125 mg tablets”, microparticles of the substance obtained by applying the active substance from the solution using a nozzle on the carrier (crospovidone) in the installation of the fluidized bed Unilab-5 DJ, the company "Huttlin"); row 1 illustrates Mexidol ODT tablets, 125 mg tablets, unmilled substance, row 2 illustrates Mexidol ODT tablets, 125 mg tablets, co-ground substance with crospovidone in a 2: 1 ratio, respectively.

Table 12 N9 Time min Release, average,% RSD,% one. 5 99.9 4.3 2. 10 100.1 4.6 3. fifteen 100.0 3.2 four. 25 100.0 2.2 5. 35 100.1 2.1 6. 45 100.1 1.9

Conclusion: tablets obtained by the proposed technology for the preparation of microparticles of the active substance by spraying from a solution in a Huttlin fluid bed setup had a very high release rate of ethyl methylhydroxypyridine succinate, which in turn led to a higher bioavailability of Mexidol ODT compared to commercial Mexidol drug.

The following examples also illustrate the preparation of tablet samples with different excipients and with different contents of the active substance. All tablets had a high rate of release of the active substance and dosage form, which is due to the proposed technological method for producing microparticles of ethylmethylhydroxypyridine succinate in a fluidized bed installation.

Example 4

The composition and ratio of the ingredients of the tablets of the drug "Mexidol ODT tablets 125 mg" are presented in table 13, a schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg" is presented in Fig. 11.

Table 13 No. p / n Name of ingredients Functional Purpose of Ingredients in mg at % At boot, in g one. Ethyl Methyl Hydroxypyridine Succinate Active substance 125.0 12.5 375.0 2. Ludiflash®, BASF (D-Mannitol Crospovidone (Kollidon® CL-SF, Polyvinyl acetate (Kollicoat SR 30D) Povidone (Kollidon 30)) Multifunctional filler 752.5 75.25 2257.5 3. Crospovidone (Polyplasdone® XL-10, ISP Pharmaceuticals) Disintegrator 62.5 6.25 187.5 four. Powder flavoring “Grapes” (Aromsa) Flavoring 15.0 1,5 45.0 5. Sodium saccharinate Sweetener 10.0 1,0 30,0 6. Colloidal silicon dioxide (Aerosil A-200 W Pharma, Degussa) Sliding 5,0 0.5 15.0 7. Sodium Stearyl Fumarate (PRUV®, JRS PHARMA) Lubricant 30,0 3.0 90.0 Together tablet: 1000,0 100.0 3000,0

Physico-technological characteristics of the tablet mass of the drug "Mexidol ODT tablets 125 mg" and physico-chemical and pharmacological and technological characteristics of the tablets "Mexidol ODT tablets 125 mg" are presented in tables 14 and 15, respectively.

Table 14 No. Name of indicator Values one. Bulk density, g / cm ³ 0.505 2. Density after compaction, g / cm ³ 0.604 3. Carra Index,% 16.3 four. Gaussner Ratio 1.20

Table 15 No. Name of indicator Values one. Description of pills Long form tablets with a biconvex surface 2. Tablet size mm 9 × 21 3 Average tablet height, mm 6.7 four. Tablet weight mg 1000,0 5. The resistance of tablets to crushing (average value), N 65.0 6. Decay, s 40 7. Weight loss during abrasion (test "Abrasion"),% 0.4

The dissolution kinetics of Mexidol ODT, 125 mg tablets were studied.

The tests were carried out in accordance with the requirements of the pharmacopeia.

Dissolution Test Conditions:

Type of device: device "ERWEKA DT 700" Equipment: paddle mixer The volume of the dissolution medium: 1000 ml Rotation frequency: 50 rpm Dissolution Time: 45 min Sampling Time: after 5, 10, 15, 25, 35 and 45 minutes Dissolution Medium: 0.1 M hydrochloric acid solution Dissolution Medium Temperature: (37.0 ± 0.5) ° С Sample selection: auto Number of tablets per test: 12 tablets Analysis Method: spectrophotometric method

The results of the study of the kinetics of the release of ethylmethylhydroxypyridine succinate in 0.1 M HCd are presented in Table 16 and Figure 12.

Table 16 No. Time min Release, average,% RSD,% one. 5 98.8 8.6 2. 10 99.8 4.1 3. fifteen 99.7 2.1 four. 25 99.9 2,3 5. 35 101.1 2,4 6. 45 100.5 1.9

Example 5

The composition and ratio of the ingredients of the tablets of the drug "Mexidol ODT tablets of 125 mg" are presented in table 17, A schematic description of the production of tablets of the drug "Mexidol ODT tablets of 125 mg" is presented in Fig. 13.

Table 17 No. p / n Name of ingredients Functional Purpose of Ingredients in mg at % At boot, in g one. Ethyl Methyl Hydroxypyridine Succinate Active substance 125.0 12.5 375.0 2. PROSOLV® ODT, JRS PHARMA (Microcrystalline Cellulose Colloidal Silicon Dioxide, Mannitol, Fructose, Crospovidone) Multifunctional filler 767.5 76.75 2302.5 3. Crospovidone (Polyplasdone® XL-10, ISP Pharmaceuticals) Disintegrator 62.5 6.25 187.5 four. Powder flavoring “Grapes” (Aromsa) Flavoring 15.0 1,5 45.0 5. Sodium saccharinate Sweetener 10.0 1,0 30,0 6. Sodium Stearyl Fumarate (PRUV®, JRS PHARMA) Lubricant 20,0 2.0 60.0 Together tablet: 1000,0 100.0 3000,0

Physico-technological characteristics of the tablet mass of the drug "Mexidol ODT, tablets of 125 mg" are presented in table 18, physico-chemical and pharmaco-technological characteristics of the tablets of the drug "Mexidol ODT, tablets of 125 mg" are shown in table 19.

Table 18 No. Name of indicator Values one. Bulk density, g / cm ³ 0.492 2. Density after compaction, g / cm ³ 0.593 3. Index _ara,% 17.0 four. Gaussner Ratio 1.21

Table 19 No. Name of indicator Values one. Description of pills Long form tablets with a biconvex surface 2. Tablet size mm 9 × 21 3. Average tablet height, mm 6.7 four. Tablet weight mg 1000,0 5. The resistance of tablets to crushing (average value), N 75.0 6. Decay, s 35 7. Weight loss during abrasion (test "Abrasion"),% 0.3

The dissolution kinetics of Mexidol ODT, 125 mg tablets were studied. The tests were carried out in accordance with the requirements of the pharmacopeia.

Dissolution Test Conditions:

Type of device: device "ERWEKA DT 700" Equipment: paddle mixer The volume of the dissolution medium: 1000 ml Rotation frequency: 50 rpm Dissolution Time: 45 min Sampling Time: after 5, 10, 15, 25, 35 and 45 minutes Dissolution Medium: 0.1 M hydrochloric acid solution Dissolution Medium Temperature: (37.0 ± 0.5) ° С Sample selection: Auto Number of tablets per test: 12 tablets Analysis Method: spectrophotometric method

The results of the study of the kinetics of the release of ethylmethylhydroxypyridine succinate in 0.1 M HCl are presented in Table 20 and Fig. 14.

Table 20 No. Time min Release, average,% RSD,% one. 5 99.8 4.6 2. 10 99.9 3.2 3. fifteen 100,2 2,5 four. 25 100,4 2,3 5. 35 100.3 2.1 6. 45 100.5 1.7

Example 6

The composition and ratio of the ingredients of the tablets of the drug "Mexidol ODT tablets 250 mg", "Mexidol ODT tablets 125 mg" and "Mexidol ODT tablets 50 mg" are presented in table 21, a schematic description of the production of tablets of the drug "Mexidol ODT tablets 250 mg "," Mexidol ODT tablets 125 mg "and the drug" Mexidol ODT tablets 50 mg "is shown in Fig. 15.

Table 21 No. p / n Name of ingredients Functional Purpose of Ingredients in mg in mg in mg at % At boot, in g one. Ethyl Methyl Hydroxypyridine Succinate Active substance 50,0 125.0 250,0 20.83 624.9 2. PROSOLV® ODT, JRS PHARMA (Microcrystalline Cellulose Colloidal Silicon Dioxide, Mannitol, Fructose, Crospovidone) Multifunctional filler 154.2 385.5 771.0 64.25 1927.5 3. Crospovidone (Polyplasdone® XL-10, ISP Pharmaceuticals) Disintegrator 25.0 62.5 125.0 10.42 312.6 four. Powder flavoring “Grapes” (Aromsa) Flavoring 3.6 9.0 18.0 1,5 45.0 5. Sodium saccharinate Sweetener 2,4 6.0 12.0 1,0 30,0 6. Sodium Stearyl Fumarate (PRUV®, JRS PHARMA) Lubricant 4.8 12.0 24.0 2.0 60.0 Together tablet: 240.0 600,0 1,200.0 100.0 3000,0

Physico-technological characteristics of the tablet mass of the drug "Mexidol ODT tablets 250 mg", "Mexidol ODT tablets 125 mg" and "Mexidol ODT tablets 50 mg" are presented in table 22, physico-chemical and pharmaco-technological characteristics of the tablets " Mexidol ODT, 100 mg tablets "and Mexidol ODT tablets 50 mg" are shown in table 23.

Table 22 No. Name of indicator Values one. Bulk density, g / cm ³ 0.491 2. Density after compaction, g / cm ³ 0,600 3. Carra Index,% 18.2 four. Gaussner Ratio 1.22

Table 23 No. Name of indicator "Mexidol ODT, 250 mg tablets" "Mexidol ODT, 125 mg tablets" "Mexidol ODT, 50 mg tablets" one. Description of pills Long form tablets with a biconvex surface Long form tablets with a biconvex surface Round tablets with a biconvex surface 2. Tablet size mm 9 × 21 7 × 15 8 3. Average tablet height, mm 6.8 4.7 2,8 four. Tablet weight mg 1,200.0 600,0 240.0 5. The resistance of tablets to crushing (average value), N 68.0 58.0 38,0 6. Decay, s 35 33 33 7. Weight loss during abrasion (test "Abrasion"),% 0.3 0.25 0.25

The dissolution kinetics of Mexidol ODT, 250 mg tablets, Mexidol ODT, 125 mg tablets, and Mexidol ODT, 50 mg tablets were studied.

The tests were carried out in accordance with the requirements of the pharmacopeia.

Dissolution Test Conditions:

Type of device: device "ERWEKA DT 700" Equipment: paddle mixer The volume of the dissolution medium: 1000 ml Rotation frequency: 50 rpm Dissolution Time: 45 min Sampling Time: after 5,10,15, 25, 35 and 45 minutes Dissolution Medium: 0.1 M hydrochloric acid solution Dissolution Medium Temperature: (37.0 ± 0.5) ° С Sample selection: Auto Number of tablets per test: 12 tablets Analysis Method: spectrophotometric method

The results of the study of the kinetics of the release of ethyl methylhydroxypyridine succinate in 0.1 M HCl are presented in Table 24 and Fig.

Table 24 No. Time min "Mexidol ODT, tablets, 250 mg" "Mexidol ODT, tablets, 125 mg" "Mexidol ODT, tablets, 50 mg" Release, average,% RSD,% Release, average,% RSD,% Release, average,% RSD.% one. 5 98.8 7.6 99,2 5.8 99.7 3.8 2. 10 99.9 4.2 99.8 3.2 99.9 2.2 3. fifteen 100.5 2.6 100.1 2.7 100.1 2.1 four. 25 100.6 2,3 100,4 2.6 100,2 2,5 5. 35 100.3 2.2 100.3 2,5 100.1 2.1 6. 45 100.5 2.1 100.6 2.6 100.1 2.1

The following examples confirm the efficacy of mexidol in the form of ODT for sublingual administration as a means of stopping anxiety, fear, depression, memory impairment, hypoxic and ischemic conditions, as well as intoxication.

Example 7

The antidepressant effect of mexidol ODT (sublingual).

The antidepressant activity of sublingual mexidol was studied using the Porsolt method of forced swimming in rats (Porsolt RD, Anton G., Blavet N. et al. Behavioral despair in rats: a new model sensitive to antidepressant treatment // Europ. J. Pharmacol. - 1978 - v.47. - p.379-391), which is the basic model for the search and study of substances with antidepressant activity both in Russia and abroad (NI Andreeva Methodological guidelines for the study of the antidepressant activity of pharmacological substances. Guide to experimental (preclinical) study of new pharmacological their substances - Second Edition, revised and augmented. / Ch. ed. by R.U. Khabriev. - M .: 2005. - S.244-252).

The studies were performed on white outbred male rats, 2-2.5 months old and weighing 220-250 g. Animals were placed in a vessel with water 40 cm in diameter and 60 cm deep, so that the rat could neither get out of the vessel nor find it support. The water temperature was maintained at 25 ° C. In such a situation, the animal is forced to make active swimming movements to get out or hover in the water and make minor rowing movements to maintain the muzzle above the surface of the water. An indicator of the severity of a depression-like state (depression, despair) in this test is the duration of immobility (immobilization), which was evaluated visually with a determination of its duration during 10 minutes of observation. Substances with antidepressant activity reduce the duration of immobilization.

Mexidol ODT was administered sublingually at doses of 50 and 100 mg / kg using a special device: the tablet was placed in a special gauze bag with laces that were tied behind the ears of the rat for 5 minutes, so that the drug was absorbed from the oral cavity during this time. Animals during this period were kept in special small cage-cases in order to restrict the movement of the animal.

Mexidol in the substance at doses of 50 and 100 mg / kg and amitriptyline at a dose of 10 mg / kg, which were administered orally (intragastrically) in a volume of 0.2 ml per 100 g of rat weight, were used as comparison preparations. To the control animals, distilled water was injected in the same volume. Evaluation of the antidepressant effect was carried out 10 and 60 minutes after the introduction of substances. For each dose and each interval, a separate group of 8 animals was used. Statistical processing of the results was carried out using statistical packages "BioStat" for Windows. Group averages and standard error indicators were calculated.

It was found that sublingual mexidol in doses of 50 and 100 mg / kg 10 and 60 minutes after absorption in the oral cavity statistically significantly reduces the time of immobilization in the Porsolt test (Table 1), which indicates its antidepressant effect. The antidepressant effect of sublingual mexidol is dose-dependent in nature and increases with increasing dose (table 25).

Mexidol in the substance at doses of 50 and 100 mg / kg 10 and 60 minutes after oral administration (oral) does not have an antidepressant effect (Table 25).

Amitriptyline at a dose of 10 mg / kg when administered orally 10 minutes after administration does not have an antidepressant effect, and after 60 minutes it has an antidepressant effect (Table 25).

Table 25 Group Dose mg / kg Time interval between drug administration and effect recording The time of immobility, (immobilization) (s) The control - 10 min 446.3 ± 25.1 The control - 60 min 463.4 ± 18.3 Mexidol sublingual fifty 10 min 364.8 ± 38.22 * Mexidol sublingual fifty 60 min 341.65 ± 34.25 * Mexidol sublingual one hundred 10 min 338.43 ± 28.16 * Mexidol sublingual one hundred 60 min 323.51 ± 42.74 * Mexidol in the substance fifty 10 min 452.86 ± 43.11 * Mexidol in the substance fifty 60 min 438.81 ± 35.83 Mexidol in the substance one hundred 10 min 420.66 ± 24.41 Mexidol in the substance one hundred 60 min 468.54 ± 25.19 Amitriptyline 10 10 min 414.85 ± 35.51 Amitriptyline 10 60 min 311.56 ± 22.73 * - the difference with the control group is significant at P <0.05.

Thus, sublingual mexidol after absorption in the oral cavity has a distinct statistically significant antidepressant effect in the basic Porsolt behavioral despair test. The antidepressant effect of sublingual mexidol develops within 10 minutes after administration and increases with increasing dose. Mexidol in the substance with intragastric administration does not have an antidepressant effect. Amitriptyline has an antidepressant effect one hour after administration and does not have it 10 minutes after administration.

Example 8

The study of the anxiolytic effect of mexidol ODT (sublingual).

The study of anxiolytic activity was carried out according to the Methodological guidelines for the study of the activity of substances with anxiolytic activity (compiled by T. Voronin and S.B.Seredenin), set forth in the “Guidelines for the experimental (preclinical) study of new pharmacological substances” (Federal Service for Surveillance in the field of health care and social development, Federal State Institution Scientific Center for Expertise in Medical Devices, ed. Medicine, ed. R.U. Khabriev, Moscow, 2005). We used the technique of an elevated cruciform labyrinth according to Pellow, which is widely used in the search and study of substances with anxiolytic activity both in Russia and abroad.

The experiments were carried out on white outbred male mice weighing 23-25 g. The technique of the elevated cross-shaped labyrinth (PCL) is based on the natural fear of being in open areas and falling from a height and the skill of rodents to prefer dark holes (Pellow S., Chopin P., File SE , Driley M., Validation of open-close arm entries in an elevated plus maze as a measure of anxiety in the rat., J. Neurosci. Meth., 1985, v.14, pp. 149-167). The elevated cross-shaped labyrinth (PCL) consists of 4 arms that are crosswise diverging from the central platform at a right angle: two opposite, open, without walls and two closed, dark. The central platform and the floor of the open sleeves are transparent, while the floor and walls of the closed sleeves are painted dark. The sleeves have dimensions — a width of 5 cm and a length of 20 m, a wall height of 14 cm, a central platform of 5 × 5 cm, PKL raised 100 cm above the floor. Immediately before the start of the experiment, animals are kept (from 3 to 5 minutes) for dark cells. Then the animal was placed in the PCL on the central platform, with its head facing the open sleeve, and for 3 minutes the time spent by the animals in the open arms, the number of entries into the open arms and the number of bowel movements were recorded. The anxiolytic effect of the drug was evaluated by a change in these indicators.

Mexidol was administered sublingually at a dose of 100 mg / kg using a special device: the tablet was placed in a special gauze bag with laces that were tied behind the mouse’s ears for 5 minutes, so that the drug was absorbed from the oral cavity during this time. Animals during this period were kept in special small cage-cases in order to restrict the movement of the animal. Mexidol in a substance at a dose of 100 mg / kg was administered orally (intragastrically) in a volume of 0.01 ml per 10 g of mouse weight. To the control animals, distilled water was injected in the same volume. The anxiolytic effect was evaluated 10 and 60 minutes after the administration of the substances. For each dose and each interval, a separate group of 8 animals was used. Statistical processing of the results was carried out using statistical packages "BioStat" for Windows. Group averages and standard error indicators were calculated.

In animals of the control group, when placed in PCL, an increase in the number of bowel movements and a quick departure of animals to the closed labyrinth arms was observed, where they spent more time (Table 26).

Mexidol sublingually at a dose of 100 mg / kg 10 and 60 minutes after administration significantly reduced the number of bowel movements, increased the number of visits to the open arms of the labyrinth and the time spent there (Table 26), which indicates that it has a clear anxiolytic effect.

Mexidol in the substance at a dose of 100 mg / kg 10 minutes after oral administration (oral) did not have an anxiolytic effect, and after 60 minutes, under its influence, a significant anxiotilic effect was observed for all indicators (Table 26).

Thus, sublingual mexidol after absorption in the oral cavity has a distinct statistically significant anxiolytic effect in the basic test of the elevated crosswise labyrinth according to Pellow. The anxiolytic effect of sublingual mexidol develops within 10 minutes after administration. Mexidol in a substance with intragastric administration has an anxiolytic effect one hour after administration and does not exert it 10 minutes after administration.

Table 26 Group, Dose, Time after Administration Number of boluses Open Sleeve Time (s) The number of visits in open sleeves (s) Control after 10 min 3.1 ± 0.51 81.4 ± 7.18 7.6 ± 1.1 Control after 60 minutes 2.4 ± 0.32 78.3 ± 8.51 6.9 ± 1.9 Mexidol Sublingue. 100 mg / kg after 10 minutes 1.04 ± 0.12 * 45.7 ± 8.6 * 11.2 ± 1.2 Mexidol Sublingue. 100 mg / kg after 60 minutes 1.2 ± 0.11 * 43.3 ± 9.13 * 10.5 ± 0.7 * Mexidolum substance. 100 mg / kg after 10 minutes 2.7 ± 0.86 79.4 ± 10.6 8.1 ± 1.4 Mexidolum substance. 100 mg / kg after 60 minutes 1.4 ± 0.09 * 48.5 ± 6.16 * 11.1 ± 0.7 * * - p <0.05 significance of differences according to the Mann-Whitney criterion in comparison with the control group

Example 9

Antihypoxic effect of mexidol ODT (sublingual).

The study was performed on white, purebred, adult male mice weighing 23-28 g. The experiments were carried out using 2 tests: normobaric hypoxia with hypercapnia (“canned” hypoxia) and hypobaric hypoxia, which are the most commonly used methods for assessing the antihypoxic activity of substances (Lukyanova L.D., Gatsura V.V., Pastushenkov L.V., Uryupov O.Yu., Lesnovskaya E.V. Methodical recommendations for the study of drugs proposed for clinical study as antihypoxic drugs, Moscow, (Izd. ments Pharmacological Committee of the Ministry of Health of the USSR), 1990, 18 pp.).

According to the method of normobaric hypoxia with hypercapnia of mice of the same weight (spread of no more than 2 g per group), one animal was placed in hermetically sealed jars of 200 cm ³ volume. The survival time (standby time) of animals under hypoxia was recorded.

Hypobaric hypoxia was produced in the exhaust flow-pressure chamber with an absorber of CO _2. Mice were "raised to a height" of 11,000 m (198.7-185 mm Hg) at a speed of 25-50 m / s. Two mice were simultaneously placed in the pressure chamber, one of which was the control, and the other was experimental with the introduced substance.

Mexidol was administered sublingually at a dose of 100 mg / kg using a special device: the tablet was placed in a special gauze bag with laces that were tied behind the mouse’s ears for 5 minutes, so that the drug was absorbed from the oral cavity during this time. Animals during this period were kept in special small cage-cases in order to restrict the movement of the animal. Mexidol in a substance at a dose of 100 mg / kg was administered orally (intragastrically) in a volume of 0.01 ml per 10 g of mouse weight. To the control animals, distilled water was injected in the same volume. The antihypoxic effect was evaluated 10 and 60 minutes after the administration of the substances. For each dose and each interval, a separate group of 10 animals was used. Statistical processing of the results was carried out using statistical packages "BioStat" for Windows. Group averages and standard error indicators were calculated.

3.1. Study of the antihypoxic effect of sublingual mexidol in the normobaric hypoxia test with hypercapnia.

Control animals placed in conditions of normobaric hypoxia with hypercapnia die on average within 15 minutes (Table 27).

Mexidol sublingually at a dose of 100 mg / kg 10 and 60 minutes after administration significantly increased the life expectancy of mice under conditions of normobaric hypoxia (Table 27), which indicates the presence of a distinct antihypoxic effect.

Mexidol in the substance at a dose of 100 mg / kg 10 minutes after oral administration (oral) did not exert antihypoxic effects, and after 60 minutes, a significant antihypoxic effect was observed under its influence (Table 27).

Table 27 Group, dose, time Life span, min Control after 10 min 14.2 ± 0.24 Control after 60 minutes 15.11 ± 0.32 Mexidol sublingual 100 mg / kg after 10 min 17.07 ± 0.21 * Mexidol sublingual 100 mg / kg after 60 minutes 18.12 ± 0.23 * Mexidol substance 100 mg / kg after 10 minutes 13.82 ± 0.71 Mexidol substance 100 mg / kg after 60 minutes 18.01 ± 0.54 * * - p <0.05 significance of differences according to the Mann-Whitney criterion compared with the control group

3.2. The study of the antihypoxic effect of sublingual mexidol under hypobaric hypoxia.

Control animals, "placed" in conditions of hypobaric hypoxia to a height of 11,000 m, die on average within 1 minute. None of the 10 mice survived when animals were exposed for 3 minutes at an altitude of 11,000 m (Table 28).

Mexidol sublingually at doses of 10 and 100 mg / kg both after 10 minutes and 60 minutes after administration significantly increased the life expectancy of mice under conditions of hypobaric hypoxia (Table 28), which indicates the presence of a distinct antihypoxic effect.

Mexidol in the substance at a dose of 100 mg / kg 10 minutes after administration did not exert antihypoxic effects, and 60 minutes after oral administration (orally) had a significant antihypoxic effect (Table 28).

Table 28 Group, dose, time Life span, min Control after 60 minutes 1.12 ± 0.26 Mexidol sublingually, 100 mg / kg after 10 minutes 2.14 ± 0.07 * Mexidol sublingually, 100 mg / kg after 60 minutes 2.01 ± 0.06 * Mexidol substance, 100 mg / kg after 10 minutes 1.45 ± 0.19 Mexidol substance, 100 mg / kg after 60 minutes 2.18 ± 0.15 * * - p <0.05 significance of differences according to the Mann-Whitney criterion compared with the control group

Thus, mexidol sublingually after absorption in the oral cavity has a distinct antihypoxic effect in tests of hypobaric hypoxia with hypercapnia in a hermetic volume and hypobaric hypoxia. The antihypoxic effect of mexidol sublingualno develops 10 minutes after administration. Mexidol in a substance with intragastric administration has an antihypoxic effect an hour after administration and does not exert it 10 minutes after administration.

Example 10

Antiamnestic (nootropic) effect of mexidol ODT (sublingual mexidol) in the rat scopolamine amnesia test.

The study was performed on white mongrel sexually mature male rats weighing 250-280 g. The study of antiamnestic activity was carried out according to the Methodological guidelines for the study of the activity of substances with nootropic activity (Voronina T.A., Ostrovskaya R.U., 2005) described in " Guidelines for the experimental (preclinical) study of new pharmacological substances ”(Federal Service for Supervision of Health and Social Development, Federal State Institution Scientific Center for Expertise of Means medical use, ed. Medicine, ed. R.U. Khabriev, Moscow, 2005, p. 308-320). The study of anti-amnestic action was carried out using the method of scopolamine amnesia of the conditioned reflex of passive avoidance in a certified installation "Lafayette Instrument Co" (USA) in rats. The installation is a dark chamber 400 × 400 × 400 mm in size with an electrode floor. The dark chamber is connected through a 60 × 60 mm square guillotine door to a 250 × 70 mm mounted platform. The mounted platform is illuminated by a 60 W lamp located at a height of 400 mm. A dark chamber is located on the laboratory bench, and the platform hangs above the floor at a height of 800 mm. The rat was seated on a brightly lit platform with its tail toward the open guillotine door leading into a dark chamber. Due to the mink reflex, after finding the entrance to the dark compartment of the chamber, the rat passed into the dark compartment. Then training was carried out, which consisted in the fact that when the rat was in the dark compartment, the opening was closed and the animal was treated with unavoidable electric pain stimulation through the floor (5 strokes, the strength of the training current 0.45 mA, the duration of each pulse was 1 s, the interval between consecutive pulses - 2 s). After receiving pain irritation (training), the rat jumped out of the dark compartment onto the illuminated platform. Thus, the animal was trained in the fact that in a dark chamber it receives pain irritation and remembers this. The rat was removed from the platform and placed in an ordinary cage. To obtain amnesia of passive avoidance reaction, animals were injected with scopolamine (1.0 mg / kg ip) 30 minutes before training. The test for reproducing the trained and amnesia was carried out 24 hours after the training, for which the rat was again placed on the platform with its tail to the hole and the latent period of the animal entering the dark compartment was recorded and then, for 180 s, the number of animals did not enter the dark dangerous compartment at all and remaining on the illuminated hanging platform (rats, well remembering the situation).

Mexidol was sublingually administered at a dose of 100 mg / kg using a special device: the tablet was placed in a special gauze bag with laces that were tied behind the ears of the rat for 5 minutes, so that the drug was absorbed from the oral cavity during this time. Animals during this period were kept in special small cage-cases in order to restrict the movement of the animal. Mexidol in a substance at a dose of 100 mg / kg was administered orally (intragastrically) in a volume of 0.01 ml per 10 g of mouse weight. To the control animals, distilled water was injected in the same volume.

Mexidol sublingually or Mexidol in the substance was administered twice: the first time 30 minutes before scopolamine (before training) and the second time 30 minutes before the passive avoidance reaction (24 hours after training).

Statistical processing of the results was carried out using statistical packages "BioStat" for Windows. Group averages and standard error indicators were calculated.

Table 29 Substances Passive avoidance test after 24 hours Latent time of entry into the dark chamber, seconds The number of animals not entering the dark chamber,% Passive control, distill. water 132.8 ± 14.3 80% Active control, scopolamine 1 mg / kg, vnb. 62.14 ± 18.54 * twenty%* Mexidol sublingual, 100 mg / kg 106.7 ± 18.4 # fifty%# Mexidol substance, 100 mg / kg 98.6 ± 17.3 # 60% # - P <0.05 - relative to passive control. # P <0.05 - relative to the active control.

It was found that scopolamine significantly shortens the duration of the latent period of entry into the dark chamber when reproducing passive avoidance reaction and significantly reduces the number of animals that did not enter the dark compartment of the chamber at all during reproduction, i.e. remembering the aversive stimulus applied there the day before. The data obtained indicate a pronounced amnesic effect of scopolamine (table 29).

Mexidol sublingually at a dose of 100 mg / kg 60 minutes after administration significantly increased the latent time of entry into the dark chamber and the percentage of animals that did not enter the dark chamber (Table 29), which indicates that it has an antiamnestic effect.

Mexidol in a substance at a dose of 100 mg / kg 60 minutes after oral administration (oral) also had a significant antiamnestic effect (Table 29).

Example 11. A study of the effect of mexidol ODT (sublingual mexidol) on ethanol-induced neurological deficiency caused by ethanol.

The experiments were performed on white purebred adult male rats (weight 250-270 g) using the Rat Rota-Rod method (Ugo Basile, Italy), which is widely used in the study of pharmacological substances potentially causing neurological deficit, as animals with neurological deficit not held on a rotating rod. The installation is a rotating drum with a diameter of 6 cm, divided by 5 discs (49 cm in diameter) into 4 identical parts of 87 mm each. The drum rotates automatically. Prior to testing, a procedure was introduced to familiarize intact rats with the setup. For this purpose, animals were placed on a drum rotating at a minimum speed of 4-5 rotations per minute. After 2-3 training sessions within 1-2 minutes, the animals acclimatize to the conditions of the Roda-Rod installation and after 2-3 hours are ready for testing. The animals were tested at a constant high rod rotation speed of 10 rpm. The maximum testing time was 3 minutes.

Ethanol was administered at a dose of 2 g / kg (25% solution) intraperitoneally and then, after 10 minutes, mexidol was administered sublingually or mexidol in the substance and testing was performed after 30 minutes.

Mexidol was sublingually administered at a dose of 100 mg / kg using a special device: the tablet was placed in a special gauze bag with laces that were tied behind the ears of the rat for 5 minutes, so that the drug was absorbed from the oral cavity during this time. Animals during this period were kept in special small cage-cases in order to restrict the movement of the animal. Mexidol in a substance at a dose of 100 mg / kg was administered orally (intragastrically) in a volume of 0.01 ml per 10 g of mouse weight. To the control animals, distilled water was injected in the same volume. Evaluation of the effect was carried out 30 minutes after the introduction of substances.

It was found that sublingual mexidol at a dose of 100 mg / kg and mexidol in a substance at a dose of 100 mg / kg with a single administration alone do not cause a neurological deficit (Table 30).

Ethanol (2 g / kg, ip) significantly reduces the retention time of rats on a rotating rod, which indicates an impaired coordination of movements in animals and a pronounced neurological deficit (Table 30).

Table 30 Group, substance Retention time on the rod, sec. Intact control, diet water 131.45 ± 11.82 Mexidol sublingual (100 mg / kg) 143.41 ± 21.11 Mexidol in substance (100 mg / kg) 133.5 ± 19.66 Ethanol (2 g / kg, w / w) 18.19 ± 4.91 # Mexidol sublingual (100 mg / kg) + Ethanol 74.61 ± 21.14 * Mexidol in substance (100 mg / kg) + Ethanol 63.15 ± 17.14 * # - p <0.05, the significance of differences by student t-test relative to the group of intact animals; * - p <0.05, the significance of differences by Student's t-test relative to the group of animals treated with Ethanol.

Mexidol sublingually at a dose of 100 mg / kg, as well as mexidol in a substance at a dose of 100 mg / kg, administered to rats receiving ethanol significantly increased the retention time of animals on a rotating rod compared to the control with the introduction of ethanol alone (Table 30).

By its ability to eliminate neurological disorders caused by ethanol in a rotating rod test, sublingual mexidol has a similar effectiveness with mexidol in a substance.

Example 11

The effects of mexidol ODT (sublingual mexidol) on amnesia caused by ethanol.

The study was performed on white outbred adult male rats weighing 250-280 g. The study of anti-anamnestic activity was carried out according to the Methodological guidelines for studying the activity of substances with nootropic activity (Voronina T.A., Ostrovskaya R.U., 2005) described in the "Manual on experimental (preclinical) study of new pharmacological substances ”(Federal Service for Supervision of Health and Social Development, Federal State Institution Scientific Center for Expertise of Means pocket medical applications, ed. Medicine, ed R.U.Habriev, Moscow, 2005, s.308-320). The study was conducted using the method of amnesia of the conditioned reflex of passive avoidance in a certified installation "Lafayette Instrument Co" (USA) in rats. The installation is a dark chamber 400 × 400 × 400 mm in size with an electrode floor. The dark chamber is connected through a 60 × 60 mm square guillotine door to a 250 × 70 mm mounted platform. The mounted platform is illuminated by a 60 W lamp located at a height of 400 mm. A dark chamber is located on the laboratory bench, and the platform hangs above the floor at a height of 800 mm. The rat was seated on a brightly lit platform with its tail toward the open guillotine door leading into a dark chamber. Due to the mink reflex, after finding the entrance to the dark compartment of the chamber, the rat passed into the dark compartment. Then the training was carried out, which consisted in the fact that when the rat was in the dark compartment, the hole was closed and the animal was subjected to inevitable electric pain stimulation through the floor (5 strokes, the training current was 0.45 mA, the duration of each pulse was 1 s, the interval between consecutive pulses - 2 s). After receiving pain irritation (training), the rat jumped out of the dark compartment onto the illuminated platform. Thus, the animal was trained in the fact that in a dark chamber it receives pain irritation and remembers this. The rat was removed from the platform and placed in an ordinary cage.

To obtain amnesia of passive avoidance reaction, animals were injected with ethanol at a dose of 2 mg / kg (intraperitoneally) 30 minutes before training. The test for reproducing the trained and amnesia was performed 24 hours after the training, for which the rat was again placed on the platform with its tail to the hole and the latent period of the animal entering the dark compartment was recorded and then for 180 s the number of animals that did not enter the dark dangerous compartment at all and remained on illuminated hanging platform (rats, well remembering the situation).

Mexidol was sublingually administered at a dose of 100 mg / kg using a special device: the tablet was placed in a special gauze bag with laces that were tied behind the ears of the rat for 5 minutes, so that the drug was absorbed from the oral cavity during this time. Animals during this period were kept in special small cage-cases in order to restrict the movement of the animal. Mexidol in a substance at a dose of 100 mg / kg was administered orally (intragastrically) in a volume of 0.01 ml per 10 g of mouse weight. To the control animals, distilled water was injected in the same volume.

Mexidol sublingually or Mexidol in the substance was administered twice: the first time 10 minutes after the introduction of ethanol (before training) and the second time 30 minutes before the passive avoidance reaction (24 hours after training).

It was found that ethanol significantly shortens the duration of the latent period of entry into the dark chamber during reproduction of passive avoidance reaction and significantly reduces the number of animals that did not enter the dark compartment of the chamber at all during reproduction, i.e. remembering the aversive stimulus applied there the day before. The data obtained indicate a pronounced amnesating effect of ethanol (table 31).

Mexidol sublingually at a dose of 100 mg / kg significantly increased the latent time of entry into the dark chamber and the percentage of animals that did not enter the dark chamber (Table 31), which indicates its ability to eliminate amnesia caused by ethanol.

Table 31 Substances Passive avoidance test after 24 hours Latent time of entry into the dark chamber, seconds The number of animals not entering the dark chamber,% Control, Intact animals (distillation water) 148.3 ± 16.9 90% Ethanol 2 g / kg, (vnb). 74.12 ± 10.63 * 25% * Mexidol sublingual, 100 mg / kg 97.6 ± 14.9 # 60% # Mexidol substance, 100 mg / kg 105.6 ± 11.8 # fifty%# * - P <0.05 - relative to passive control. # P <0.05 - relative to the group that received ethanol.

Mexidol in the substance at a dose of 100 mg / kg also had a significant antiamnestic effect against amnesia caused by ethanol (Table 31).

Thus, sublingual mexidol at a dose of 100 mg / kg was able to eliminate the amnesia of the conditioned passive avoidance reflex caused by ethanol and was not inferior in this activity to mexidol in a substance at a dose of 100 mg / kg.

Example 12

The activating effect of sublingual mexidol ODT (orally disintegrating tablets).

The activating effect of mexidol ODT was studied in experiments on sexually mature outbred white male mice weighing 24-30 g. The study was carried out using open field techniques and an OptoVarimex actometer (T. Voronina, SB Serendenin. Methodological guidelines for the study of anxiolytic activity of pharmacological substances, Guidelines for the experimental (preclinical) study of new pharmacological substances ”(Federal Service for Supervision of Health and Social Development, Federal State Institution deniye scientific center for the examination of means of medical use, published by Medicine, ed. R.U. Khabriev, Moscow, 2005, 253-263).

7.1. Study of the activating effect of sublingual mexidol in an open field test.

The Open Field installation is a square arena measuring 60 × 60 cm, with walls 15 cm high; the chamber floor is divided into 9 squares with sides 20 × 20 cm with 16 holes at the intersection of the joints of squares with a diameter of 4 cm. The behavior of animals in the open field technique was evaluated for 3 min, recording horizontal motor activity (the number of crossed lines), vertical motor activity (number of racks), research activity (number of holes examined when the animal lowered its head into the hole by more than half).

Mexidol ODT was administered for a long time daily for 21 days at doses of 25 and 50 mg / kg sublingually. The animals in the control group were injected with distilled water in an equivalent volume. Motor activity was recorded 30 minutes after the last administration of Mexidol.

It was found that after the administration of mexidol sublingually at doses of 25 and 50 mg / kg for 21 days, a statistically significant increase in both horizontal and vertical locomotor activity of animals in the open field was observed, as well as an increase in the number of peeping in holes (Table 32).

Mexidol in the substance during intragastric administration (using a special probe) at doses of 25 and 50 mg / kg for 21 days did not have a statistically significant effect on the motor activity of animals in an open field (Table 32).

Table 32 Group Horizontal activity Vertical activity Peeping through holes The control 86.8 ± 4.11 18.8 ± 2.71 15.1 ± 1.41 Mexidol ODT, 25 mg / kg sublingually 129.5 ± 6.21 * 27.4 ± 1.19 * 21.8 ± 1.54 * Mexidol ODT, 50 mg / kg sublingually 112.9 ± 2.38 * 29.5 ± 2.08 * 20 ± 1.05 * Mexidol, 25 mg / kg intragastrically 90.1 ± 5.18 20.7 ± 3.01 12.4 ± 2.58 Mexidol, 50 mg / kg intragastrically 93.4 ± 6.18 19.9 ± 5.01 14.4 ± 2.15 * - p≤0.005 compared with the control group, student criterion

7.2. Study of the activating effect of sublingual mexidol in the OptoVarimex Actometer.

The installation of the OptoVarimex Actometer (Columbus instrument, USA) is a square Plexiglas arena with sides 42 x 42 cm and a height of 20 cm, closed with a transparent cover. Sensitive photocells are located around the perimeter of the arena, which automatically transmit indicators of the motor activity of animals to the counter. Animals were placed in an OptoVarimex Actometer for 5 minutes. In automatic mode, horizontal and vertical activity of animals was recorded per minute. The average index of horizontal and vertical activity of animals was calculated for a group of mice per 1 minute.

Mexidol ODT was administered continuously for 21 days at a dose of 25 mg / kg sublingually. Mexidol in the substance was administered continuously for 21 days at a dose of 25 mg / kg intragastrically (using a special probe). The animals in the control group were injected with distilled water in an equivalent volume.

Motor activity was recorded 30 minutes after the last administration of Mexidol.

Table 33 Group The horizontal activity of the animal per minute, units The vertical activity of the animal per minute, units The control 476.27 ± 56.15 4.8 ± 0.32 Mexidol ODT 25 mg / kg (sublingual, 21 days) 524.15 ± 21.24 * 6.14 ± 0.18 * Mexidol substance 25 mg / kg (intragastric, 21 days) 491.92 ± 34.31 5.2 ± 0.12 * - p≤0.05 compared with the control group, student criterion

It was found that after the administration of mexidol ODT sublingually at a dose of 25 mg / kg for 21 days, a statistically significant increase in both horizontal and vertical motor activity of animals in the actometer was observed (Table 33).

Mexidol in the substance when administered for 21 days at a dose of 25 mg / kg intragastrically (using a special probe) did not affect the motor activity of mice in the actometer (Table 33).

Thus, the results obtained by studying the effect of mexidol ODT (sublingually, 21 days) on the behavior of mice in an open field and OptoVarimex actometer revealed the presence of an activating effect on sublingual mexidol in contrast to mexidol in a substance that did not have an activating effect on motor activity .

Example 13

Anorexigenic effect of mexidol ODT with sublingual administration.

The studies were performed on sexually mature white outbred rats-females weighing 260-280 g.

The first group of control rats received standard food:

complete feed (extruded granules made without the use of preservatives) MEST LLC (Moscow). Compound feed was an environmentally friendly product balanced in amino acid composition, minerals and vitamins, made from high-quality components.

The second group of control rats received standard nutrition and additionally enhanced nutrition: porridge (millet, hercules, buckwheat on meat broth with meat and sunflower oil, cottage cheese, bread and vegetables (potatoes, cabbage, carrots). Control animals received distilled daily for 35 days. water (0.2 ml) into the oral cavity.

The third group of rats received standard nutrition and additionally enhanced nutrition, and they were daily injected (intragastrally, through a special probe) with mexidol at a dose of 50 mg / kg for 35 days.

The fourth group of rats received standard nutrition and additionally enhanced nutrition, and they were daily administered mexidol sublingually at a dose of 50 mg / kg for 35 days.

Weight measurement was performed 7 and 35 days after the introduction of Mexidol or distilled water.

It was found that with enhanced nutrition, rats significantly more and statistically significantly gained weight, compared with animals that were on standard dry food (Table 34).

Mexidol at a dose of 50 mg / kg when administered orally (intragastrically, using a special probe) daily for 35 days to rats receiving enhanced nutrition did not statistically significantly change the weight of animals compared to control (rats receiving enhanced nutrition) (Table 34) .

Mexidol ODT at a dose of 50 mg / kg when administered sublingually daily for 14 days to rats receiving enhanced nutrition statistically significantly reduced the weight gain of animals compared to control (rats receiving enhanced nutrition) (Table 34).

Table 34 Groups Before the experiment 14 days after the introduction of substances 35 days after the introduction of substances Control (dist.water). The weight of rats in g without nutrition 272.7 ± 10.8 287.6 ± 14.7 305.4 ± 13.9 Control, (dist.voda). Weight gain in rats without nutrition 14.9 ± 2.1 32.7 ± 4.1 Control, (dist.water) Weight of rats in g with enhanced nutrition 260.6 ± 12.1 306.7 ± 10.3 332.3 ± 7.1 ^∧

Control, (diet water) Weight gain in g in rats with enhanced nutrition 46.1 ± 6.4 ^∧ 71.71 ± 6.8 ^∧ Mexidol 50 mg / kg orally in rats with enhanced nutrition. Weight rats in 278.7 ± 14.8 319.8 ± 15.7 340.9 ± 15.1 Mexidol 50 mg / kg orally in rats with enhanced nutrition. Weight gain in g. 41.1 ± 8.4 62.2 ± 9.4 Mexidol 50 mg / kg sublingually in rats with enhanced nutrition. Weight rats in 268.7 ± 10.8 280.1 ± 8.7 * # 302.3 ± 8.2 * # Mexidol 50 mg / kg sublingually in rats with enhanced nutrition. Weight gain in g. 11.4 ± 2.4 * # 33.6 ± 4.8 * # ^∧ - p≤0.05 compared with the control group without enhanced nutrition. * - p≤0.05 compared with the control group receiving enhanced nutrition. # - p≤0.05 compared with the group receiving enhanced nutrition and mexidol inside (intragastric).

Mexidol ODT at a dose of 50 mg / kg when administered sublingually daily for 35 days to rats receiving enhanced nutrition statistically significantly reduced the weight gain of animals compared to control (rats receiving enhanced nutrition) (Table 34).

Weight reduction under the influence of mexidol, administered sublingually, was more pronounced with the introduction of mexidol for 35 days compared with its use for 14 days (table 34).

The data obtained indicate that mexidol ODT at a dose of 50 mg / kg with daily sublingual administration for 14 and, especially, 35 days to rats receiving enhanced nutrition, statistically significantly reduces the weight gain of animals, while mexidol (50 mg / kg) when administered intragastrically for 35 days does not affect weight gain.

Thus, mexidol ODT with sublingual long-term use has anorexigenic effect in contrast to mexidol when administered orally, which does not have such an effect.

In summary, pharmacological studies have shown that mexidol ODT (sublingual mexidol), after absorption in the oral cavity, has a distinct activating (stimulating) and anorexigenic effect in contrast to mexidol, which is administered intragastrically (in tablets or substances), which does not have these effects. Mexidol ODT with sublingual administration also has anxiolytic, antihypoxic, antiamnestic, antidepressant and anti-alcoholic effects and is not inferior to mexidol in the substance and tablets when administered orally (intragastrically). The effects of sublingual mexidol are manifested both after 10 minutes and 60 minutes after its administration. Mexidol in a substance with intragastric administration has effects one hour after administration and does not exert it 10 minutes after administration.

Claims (1)

The use of a pharmaceutical composition in the form of an orally disintegrating tablet containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as an active ingredient and crospovidone in a 2: 1 ratio, respectively, as a motor stimulant and anorexigenic agent as a disintegrant.

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