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

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

 

The invention relates to the field of medicine.

Preparation Mexidol (2-ethyl-6-methyl-3-oxypyridine succinate) is currently widely used in medical practice in Russia as anti-ischemic, neuroprotective and nootropic, anxiolytic drug. The mechanism of action of Mexidol is an inhibitor of free radical processes, reduces FLOOR, increases the activity of the endogenous antioxidant system, stabilize biological membranes, causes conformational changes in the protein components of the membrane and modulates the functioning of benzodiazepine and GABA receptors (Djumaev K.M., Voronina T.A., Smirnov L.D. Antioxidants in the prevention and treatment of pathologies of the Central nervous system. Disdata of biomedical chemistry RAMS, 1995, 271 S. Voronina T.A. Mexidol: basic drugs is got with the effects and mechanism of action. "Farmateka", 2009, CH, No. 6, p.1-4).

Earlier in the experiment and the clinic was established that Mexidol in substance, tablets, capsules has antihypoxic, neuroprotective and nootropic, anxiolytic, anticonvulsant, anti-alcohol effect (Voronina T.A. Antioxidant Mexidol: basic drugs is got with the effects and mechanism of action. Psychopharmacol. Biolargo, 2001, vol. 1, No. 1, pp.2-12; Voronina T.A., Smirnov, L.D., A. Aliyev. and other Dependence between the chemical structure of the anticonvulsant activity of derivatives of 3-oksipiridina. Pharmacology and Toxicology, 1987, No. 1, pp. 27-30; Avakian GN. et al. Experimental and clinical epileptology. Chapter in monograph "Epilepsy", under the General editorship N.G. Neznanov, 2010 - St. Petersburg, s-242; Djumaev K.M., Voronina T.A., Smirnov LD - Antioxidants in the prevention and treatment of pathologies of the Central nervous system. - Publishing house of Institute of biomedical chemistry RAMS, 1995). However, these effects occur only after 40-60 minutes after administration of Mexidol inside, and to achieve a stable effect required coursework introduction of the drug. In addition, Mexidol with the inside does not have an antidepressant effect.

The result of the present invention is the creation of Mexidol in the form of orally-of desintegrating tablets (RDT) for sublingual use, having excellent from Mexidol in other dosage forms range of pharmacological effects and capable emergency relief of anxiety, fear, depression, memory disorders, hypoxic and ischemic conditions and alcohol, as well as methods of 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 a sublingual form, the pharmaceutical composition comprising as acting is the first substance 6-methyl-2-ethyl-3-hydroxypyridine and/or its pharmaceutically-acceptable salt, made in the form of orally-desenterraremos tablets, as well as the use of such compositions as a stimulant anorectic, antidepressant, anxiolytic, nootropic, antihypoxic, anti-ischemic and anti-alcohol funds.

The invention is illustrated in schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg" (Fig.1.), figure 2 shows the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl, Fig.3 shows the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl, Fig.4, showing microscopy substance etilmetilgidroksipiridina succinate, 5. Showing microscopy crushed substance etilmetilgidroksipiridina succinate, Fig.6, showing the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl, Fig.7 schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg", 8, reflecting the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl, Fig.9 schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg, figure 10, shows the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl, Fig.11 schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg - Fig.12 shows the kinetics of release of succinate etilmetilgidroksipiridina in 0.1 M HCl, Fig.13 schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg, 14, reflecting the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl, 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 50 mg and 16, showing the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl.

In the application disclosed Mexidol OTD (oral-getintegervalue tablets for sublingual application, which has a wider range of pharmacological effects, because unlike Mexidol in tablets and capsules, in exchange application stimulant (activating) and anorectic effect and has the ability of quick emergency (after 5-10 minutes) relief of anxiety, fear, depression, memory disorders, hypoxic and ischemic conditions and alcohol, while Mexidol with the inside (intragastric) tablets and capsules (in higher doses) only takes effect after 60 minutes and in the exchange application.

OTD tablets can be produced by various pharmaceutically acceptable ways. The most simple and widely used way to obtain tablets include basically the production stage, as the preparation of the tablet mass and tableting.

Tablet weight can be prepared by different methods. Often uses the following methods of cooking tablet mass:

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

dry granulation (compacting);

- direct pressing.

In our invention pills drug "Mexidol ODT" have been produced using different methods of obtaining the tablet mass and with different content etilmetilgidroksipiridina succinate or another pharmaceutically acceptable salt.

One of the most common methods of producing a tablet mass of agents with high dosages is wet and dry granulation. Using these methods, you can get the tablet mass with a high content of active substances and homogeneous particle size distribution. Tablet mass, obtained by the above methods is not subject to delamination during tabletroute, which allows to obtain a homogeneous mass and the content of active substance pills.

The following examples confirm the possibility of obtaining OTD tablets "Mexidol" with defined characteristics.

Example 1

Direct pressing.

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

Table 1
no p/nName ingredientsFunctional purpose ingredientsmgin %To boot, g
1.Etilmetilgidroksipiridina succinateThe active ingredient125,012,5375,0
2.Mannitol (Mannogem™ EZ Spray Dried Mannitol, SPI Pharma)Inert filler615,061,51845,0
3.Crosspovidone (Polyplasdone® XL-10, ISP Pharmaceuticals)Cage mill200,020,0600,0
4.Flavouring powder "Grapes" (Aromsa)Ar is ministor 15,01,545,0
5.Sodium saccharinateSweetener10,01,030,0
6.Colloidal silicon dioxide (Aerosil-200 W Pharma, Degussa)Moving5,00,515,0
7.Sodium stearyl fumarate (PRUV®, JRS PHARMA)Grease30,03,090,0
Together tablet:1000,0100,03000,0

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

Table 2
No.Name of indicatorValue
1.Bulk density, g/cm30,550
2.The density after compaction, g/cm30,663
3.Index Carr, %of 17.0
4.The ratio of Haussner1,21

Table 3
No.Name of indicatorValue
1.Description of pillTablet form oblong, with lenticular surface
2.Tablet size, mm9×21
3.The average height of the tablets mm6,6
4.Weight tablets mg10000
5.The resistance of tablets to crushing (average value), N60,0
6.Destruction,60
7.The loss of mass during isternia (test "Abrasion"), %0,5

Was to study the dissolution kinetics of the drug "Mexidol ODT tablets 125 mg"

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

Test conditions "Dissolution":

Device type:device "ERWEKA DT 700"
Equipment:the device with a blade stirrer
Volume environment dissolution:1000 ml
Speed:50 rpm
The time of dissolution:45 min
Time of sampling:after 5, 10, 15, 25, 35 and 45 min
Environment dissolution:0.1 M solution of hydrochloric acid
The temperature of dissolution:(37,0±0,5)°C
Sampling:Automatic
The number of pills in the test:12 pills
Analysis method:spectrophotometric method.

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

Table 4
No.Time minRelease, the average value %RSD, %
1.530,87,8
2.1049,63,6
3.1567,72,9
4.2583,12,6
5.3592,42,5
6.4598,42,5

The obtained tablets (ODT) gave significant improvement in dissolution kinetics compared to commercial batches of the drug "Mexidol, tablets, film coated liner 125 mg (see Fig.3, where the number of 1 - tablets drug "Mexidol ODT tablets 125 mg, number 2 tablets of the drug "Mexidol, tablets, film coated liner 125 mg"commercial series). However, the obtained dissolution rate was not sufficient to obtain a product with high bioavailability. After analyzing the data obtained, it was concluded that one reason for the low dissolution rate of the tablets is the large size of the particles of the substance - see Fig.4, where the average particle size of the substance etilmetilgidroksipiridina succinate was 400-1500 mm. To solve this problem it was proposed to grind the particles of the substance to the particle size less than 10 μm by using a planetary ball mill PM 400 MA, the firm "Retsch". The crushed substance using electrostatic forces were glomerulus in particle size between 200 and 600 μm (see Fig.5), which also did not give significant results obtained by dissolving this substance in composition and scheme of example 1 tablets "Mexidol ODT tablets, 125 mg (see Fig.6, the number of 1 - tablet preparation is the "Mexidol ODT, tablets of 125 mg", unground substance, the number of 2 tablets of the drug "Mexidol ODT tablets 125 mg, crushed substance). To reduce electrostatic forces was proposed method of co-grinding with one of the excipients. After selection of the various auxiliary substances, their correlation with the active ingredient and mode of co-grinding, the best results were obtained by co-grinding substance with crosspovidone in the ratio 2:1 respectively.

Example 2

The composition and ratio of the ingredients of pills 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" presented on Fig.7.

Table 5
no p/nName ingredientsFunctional purpose ingredientsmgin %To boot, g
1.Etilmetilgidroksipiridina succinateThe active ingredient125,012,5375,0
2.Mannitol (Mannogem™ EZ Spray Dried Mannitol, SPI Pharma)Inert filler615,061,51845,0
3.Crosspovidone (Polyplasdone® XL-10, ISP Pharmaceuticals)Cage mill200,020,0600,0
4.Flavouring powder "Grapes" (Aromsa)Flavor15,01,545,0
5.Sodium saccharinateSweetener10,01,030,0
6.Colloidal silicon dioxide (Aerosil-200 W Pharma, Degussa)Moving5,00,515,0
7.Sodium stearyl fumarate (PRUV®, JRS PHARMA)Grease30,0 3,090,0
Together tablet:1000,0100,03000,0

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

Table 6
No.Name of indicatorValue
1.Bulk density, g/cm30,510
2.The density after compaction, g/cm30,620
3.Index Carr, %17,7
4.The ratio of Haussner1,21

Table 7
no Name of indicatorValue
1.Description of pillTablet form oblong, with lenticular surface
2.Tablet size, mm9×21
3.The average height of the tablets mm6,6
4.Weight tablets mg1000,0
5.The resistance of tablets to crushing (average value), N60,0
6.Destruction,48
7.The loss of mass during isternia (test "Abrasion"), %0,5

Was to study the dissolution kinetics of the drug "Mexidol ODT tablets 125 mg.

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

Test conditions "Dissolution":

Device type:device "ERWEKA DT 700"
Equipment:the device with a blade stirrer
Volume environment dissolution:1000 ml
Speed:50 rpm
The time of dissolution:45 min
Time of sampling:after 5, 10, 15,25, 35 and 45 min
Environment dissolution:0.1 M solution of hydrochloric acid
Sampling:Automatic
The number of pills in the test:12 pills
Analysis method:spectrophotometric method

The results of studies of the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCI presented in table 8 and figure 8, number 2.

Table 8
No.Time minRelease, the average value %RSD, %
1.5 78,98,8
2.1088,64,6
3.1594,83,2
4.2598,82,2
5.3599,72,1
6.4599,81,9

Example 3

For best results, release of the active substance from the dosage form has been proposed another method of producing microparticles of the substance etilmetilgidroksipiridina succinate.

The method consists in the application of the active substance etilmetilgidroksipiridina succinate from the solution through the nozzles to the medium (crosspovidone) in the installation of fluidized bed Unilab-5 DJ company "Huttlin".

The composition and ratio of the ingredients of pills 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/nName ingredientsThe functional purpose of the ingredients.mgin %To boot, g
1.Etilmetilgidroksipiridina succinateThe active ingredient125,012,5375,0
2.Mannitol (Mannogem™ EZ Spray Dried Mannitol, SPI Pharma)Inert filler615,061,51845,0
3.Crosspovidone (Polyplasdone® XL-10, ISP Pharmaceuticals)Cage mill200,020,0600,0
4.Flavouring powder "Grapes" (Aromsa)Flavor15,01,545,0
5.Intothree the saccharinate Sweetener10,01,030,0
6.Colloidal silicon dioxide (Aerosil-200 W Pharma, Degussa)Moving5,00,515,0
7.Sodium stearyl fumarate (PRUV®, JRS PHARMA)Grease30,03,090,0
Together tablet:1000,0100,03000,0

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

Table 10
No.Name of indicatorValue
1. Bulk density, g/cm30,550
2.The density after compaction, g/cm30,670
3.Index Carr, %17,9
4.The ratio of Haussner1,22

Table 11
No.Name of indicatorValue
1.Description of pillTablet form oblong, with lenticular surface
2.Tablet size, mm9×21
3.The average height of the tablets mm6,6
4.Weight tablets mg1000,0
5.The resistance of tablets to crushing (average value), N55,0
6. Destruction,35
7.The loss of mass during isternia (test "Abrasion"), %0,5

Was to study the dissolution kinetics of the drug "Mexidol ODT tablets 125 mg"

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

Test conditions "Dissolution":

Device type:device "ERWEKA DT 700"
Equipment:the device with a blade stirrer
Volume environment dissolution:1000 ml
Speed:50 rpm
The time of dissolution:45 min
Time of sampling:after 5, 10, 15, 25, 35 and 45 min
Environment dissolution:0.1 M solution of hydrochloric acid
The temperature of dissolution:(37,0±0,5)°C
Sampling:Automatic
12 pills
Analysis method:spectrophotometric method

The results of studies of the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl are presented in table and 10, number 3 (tablets drug "Mexidol ODT tablets 125 mg of microparticles of the substance obtained by the application of the active substance from the solution through the nozzles to the medium (crosspovidone) in the installation of fluidized bed Unilab-5 DJ company "Huttlin"); Bank 1 illustrates tablets drug "Mexidol ODT tablets 125 mg, unground substance, the number of 2 tablets of the drug "Mexidol ODT tablets 125 mg, co-powdered substance with crosspovidone in the ratio 2:1 respectively.

Table 12
N9Time minRelease, the average value %RSD, %
1.599,94,3
2.10100,14,6
3.15100,03,2
4.25100,02,2
5.35100,12,1
6.45100,11,9

Conclusion: the tablets obtained by the proposed methods of obtaining microparticles of active substance by a sputtering method from a solution in the installation of fluidized bed company "Huttlin" had a very high rate of release of etilmetilgidroksipiridina succinate, which in turn, prevedello to higher bioavailability of the drug "Mexidol ODT compared with a commercial preparation of Mexidol.

The following examples illustrate obtaining samples of tablets with different excipients and with different content of active substance. All tablets had a high rate of release of the active substance and pharmaceutical form, due to the proposed technological method of producing microparticles etilmetilgidroksipiridina succinate in the installation of the fluidized bed.

Example 4

The composition and soothes is the ingredients of the tablets of the drug "Mexidol ODT, tablets of 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/nName ingredientsFunctional purpose ingredientsmgin %To boot, g
1.Etilmetilgidroksipiridina succinateThe active ingredient125,012,5375,0
2.Ludiflash®, BASF (D-Mannitol Crospovidone (Kollidon® CL-SF, Polyvinyl acetate (Kollicoat SR 30D) Povidone (Kollidon 30))Multifunctional filler752,575,252257,5
3.Crosspovidone (Polyplasdone® XL-10, ISP Pharmaceuticals)Cage mill62,56,25187,5
4. Flavouring powder "Grapes" (Aromsa)Flavor15,01,545,0
5.Sodium saccharinateSweetener10,01,030,0
6.Colloidal silicon dioxide (Aerosil-200 W Pharma, Degussa)Moving5,00,515,0
7.Sodium stearyl fumarate (PRUV®, JRS PHARMA)Grease30,03,090,0
Together tablet:1000,0100,03000,0

Physico-technological characteristics of the tablet mass drug "Mexidol ODT tablets 125 mg and physico-chemical and pharmaco-technological characteristics of the tablets "Mexidol ODT tablets 125 mg" presents tables 14 and 15 corresponding the O.

Table 14
No.Name of indicatorValue
1.Bulk density, g/cm3worn : 0.505
2.The density after compaction, g/cm30,604
3.Index Carr, %16,3
4.The ratio of Haussner1,20

Table 15
No.Name of indicatorValue
1.Description of pillTablet form oblong, with lenticular surface
2.Tablet size, mm9×21
3The average height of the tablets mm6,7
4.Weight tablets mg1000,0
5.The resistance of tablets to crushing (average value), N65,0
6.Destruction,40
7.The loss of mass during isternia (test "Abrasion"), %0,4

Was to study the dissolution kinetics of the drug "Mexidol ODT tablets 125 mg.

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

Test conditions "Dissolution":

Device type:device "ERWEKA DT 700"
Equipment:the device with a blade stirrer
Volume environment dissolution:1000 ml
Speed:50 rpm
The time of dissolution:45 min
Time of sampling:after 5, 10, 15, 25, 35 and 45 min
Environment dissolution: 0.1 M solution of hydrochloric acid
The temperature of dissolution:(37,0±0,5)°C
Sampling:automatic
The number of pills in the test:12 pills
Analysis method:spectrophotometric method

The results of studies of the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M LMI presented in table 16 and figure 12.

Table 16
No.Time minRelease, the average value %RSD, %
1.598,88,6
2.1099,84,1
3.1599,72,1
4.2599,9,3
5.35101,12,4
6.45100,51,9

Example 5

The composition and ratio of the ingredients of pills of the drug "Mexidol ODT tablets 125 mg are presented in table 17, a Schematic description of the production of tablets of the drug "Mexidol ODT tablets 125 mg are presented in figure 13.

Table 17
no p/nName ingredientsFunctional purpose ingredientsmgin %To boot, g
1.Etilmetilgidroksipiridina succinateThe active ingredient125,012,5375,0
2.PROSOLV® ODT, JRS PHARMA (Microcrystalline Cellulose Colloidal Silicon Dioxide, Mannitol, Fructose, Crospovidone)Multifunctional filler767,5 76,752302,5
3.Crosspovidone (Polyplasdone® XL-10, ISP Pharmaceuticals)Cage mill62,56,25187,5
4.Flavouring powder "Grapes" (Aromsa)Flavor15,01,545,0
5.Sodium saccharinateSweetener10,01,030,0
6.Sodium stearyl fumarate (PRUV®, JRS PHARMA)Grease20,02,060,0
Together tablet:1000,0100,03000,0

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

Table 18
No.Name of indicatorValue
1.Bulk density, g/cm30,492
2.The density after compaction, g/cm30,593
3.Index Ara, %of 17.0
4.The ratio of Haussner1,21

Table 19
No.Name of indicatorValue
1.Description of pillTablet form oblong, with lenticular surface
2.Tablet size, mm9×21
3.The average height of the tablets mm 6,7
4.Weight tablets mg1000,0
5.The resistance of tablets to crushing (average value), N75,0
6.Destruction,35
7.The loss of mass during isternia (test "Abrasion"), %0,3

Was to study the dissolution kinetics of the drug "Mexidol ODT tablets 125 mg. The tests were carried out in accordance with the requirements of the Pharmacopoeia.

Test conditions "Dissolution":

Device type:device "ERWEKA DT 700"
Equipment:the device with a blade stirrer
Volume environment dissolution:1000 ml
Speed:50 rpm
The time of dissolution:45 min
Time of sampling:after 5, 10, 15, 25, 35 and 45 min
Among the and dissolution: 0.1 M solution of hydrochloric acid
The temperature of dissolution:(37,0±0,5)°C
Sampling:Automatic
The number of pills in the test:12 pills
Analysis method:spectrophotometric method

The results of studies of the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl are presented in table and Fig.14.

td align="center"> 2,3
Table 20
No.Time minRelease, the average value %RSD, %
1.599,84,6
2.1099,93,2
3.15100,22,5
4.25to 100.4
5.35100,32,1
6.45100,51,7

Example 6

The composition and ratio of the ingredients of pills 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 drug "Mexidol ODT tablets 50 mg" presented in Fig.15.

Table 21
no p/nName ingredientsFunctional purpose ingredientsmgmgmgin %To boot, g
1.Etilmetilgidroksipiridina succinateThe active ingredient50,0125,0250,020,83 made up 624.9
2.PROSOLV® ODT, JRS PHARMA (Microcrystalline Cellulose Colloidal Silicon Dioxide, Mannitol, Fructose, Crospovidone)Multifunctional filler154,2385,5771,064,251927,5
3.Crosspovidone (Polyplasdone® XL-10, ISP Pharmaceuticals)Cage mill25,062,5125,010,42312,6
4.Flavouring powder "Grapes" (Aromsa)Flavor3,69,018,01,545,0
5.Sodium saccharinateSweetener2,46,0to 12.01,030,0
6.Sodium stearyl fumarate (PRUV®, JRS PHARMA) Grease4,8to 12.024,02,060,0
Together tablet:240,0600,01200,0100,03000,0

Physico-technological characteristics of the tablet mass 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 tablets 100 mg and drug "Mexidol ODT tablets 50 mg" in table 23.

Table 22
No.Name of indicatorValue
1.Bulk density, g/cm30,491
2.The density after compaction, g/cm30,600
3. Index Carr, %18,2
4.The ratio of Haussner1,22

Table 23
No.Name of indicator"Mexidol ODT tablets 250 mg"Mexidol ODT tablets 125 mg"Mexidol ODT tablets 50 mg
1.Description of pillTablet form oblong, with lenticular surfaceTablet form oblong, with lenticular surfaceTablets are round shaped, biconvex second surface
2.Tablet size, mm9×217×158
3.The average height of the tablets mm6,8the 4.72,8
4.Weight tablets mg1200,0 600,0240,0
5.The resistance of tablets to crushing (average value), N68,058,038,0
6.Destruction,353333
7.The loss of mass during isternia (test "Abrasion"), %0,30,250,25

Was to study the dissolution kinetics of the drug "Mexidol ODT tablets 250 mg", "Mexidol ODT tablets 125 mg" and drug "Mexidol ODT tablets 50 mg".

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

Test conditions "Dissolution":

Device type:device "ERWEKA DT 700"
Equipment:the device with a blade stirrer
Volume environment dissolution:1000 ml
Speed:50 rpm
The time the solution is s: 45 min
Time of sampling:through 5,10,15, 25, 35 and 45 min
Environment dissolution:0.1 M solution of hydrochloric acid
The temperature of dissolution:(37,0±0,5)°C
Sampling:Automatic
The number of pills in the test:12 pills
Analysis method:spectrophotometric method

The results of studies of the kinetics of release of etilmetilgidroksipiridina succinate in 0.1 M HCl are presented in tabl and rice.

Table 24
No.Time min"Mexidol ODT tablets, 250 mg""Mexidol ODT tablets, 125 mg"Mexidol ODT tablets, 50 mg
Release, the average value %RSD,%Release, mean LVEF is a group of %RSD, %Release, the average value %RSD.%
1.598,87,699,25,899,7the 3.8
2.1099,94,299,83,299,92,2
3.15100,52,6100,12,7100,12,1
4.25100,62,3to 100.42,6100,22,5
5.35100,32,2100,32,5100,1 2,1
6.45100,52,1100,62,6100,12,1

The following examples illustrate the effectiveness of Mexidol in the form of OTD with sublingual introduction as a means to relieve anxiety, fear, depression, memory disorders, hypoxic and ischemic conditions, as well as alcohol.

Example 7

Antidepressant effect of Mexidol OTD (sublingual).

Antidepressant activity sublingual Mexidol studied using the methods of forced swimming in rats by Porsolt (Porsolt R.D., 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 in the search and study of substances with antidepressant activity both in Russia and abroad (Andreeva N. guidelines for the study of the antidepressant activity of pharmacological substances. Manual on experimental (preclinical) study of new pharmacological substances - second Edition, revised and enlarged./CH. edit RU gabriev. - M.: 2005. - S-252).

Investigations were carried out on outbred rats male age 2-2 .5 months and wt is Oh, 220-250 Animals were placed in a container of water with a diameter of 40 cm and a depth of 60 cm, so that the rat could not escape from the vessel, neither find it as a support. Water temperature was maintained at 25°C. In this situation, the animal is forced to make active swimming movements to get out or hang in the water and make minor rowing motions to maintain the snout above the water surface. An indicator of the severity depressivnopodobnogo state (depression, despair) on the test is the duration of immobility (immobilization), which was assessed visually by determining its duration within 10 minutes of observation. Substances with antidepressant activity reduces the duration of immobilization.

Mexidol OTD was administered sublingually at doses of 50 and 100 mg/kg using a special device: the tablet was placed in a special gauze package with laces, which were tied behind the ears rats for 5 minutes, during this time occurred the absorption of the drug from the oral cavity. Animals in this period were kept in a special small cells canisters to restrict movement of the animal.

As Comparators used Mexidol in substance at doses of 50 and 100 mg/kg) and amitriptyline at a dose of 10 mg/kg, which was administered orally (intragastric) in a volume of 0.2 ml per 100 g rat. Control the major animals of the same amount was injected distilled water. Evaluation of antidepressant effect was carried out after 10 and 60 minutes after administration of the substances. For each dose and each interval was used a separate group of 8 animals. Statistical processing of results was performed using the statistical package "patch BIOSTAT" for Windows. Expected average for the group and the standard errors of the parameters.

Found that sublingual Mexidol in doses of 50 and 100 mg/kg after 10 and 60 minutes after absorption in the oral cavity statistically reduces the immobilization time in the Porsolt test (table 1), indicating that its antidepressant effect. Antidepressant effect of sublingual Mexidol has dose-dependent and increases with increasing dose (table 25).

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

Amitriptyline at a dose of 10 mg/kg oral administration in 10 minutes after administration does not have antidepressant action, and after 60 minutes has antidepressant effect (table 25).

Table 25
GroupDose, mg/kgThe time interval between the introduction of the preparations and registration effect The time of immobility (immobilization) (C)
Control-10 min446,3±25,1
Control-60 min463,4±18,3
Mexidol sublingual5010 minand 364.8±38,22*
Mexidol sublingual5060 min341,65±34,25*
Mexidol sublingual10010 min338,43±28,16*
Mexidol sublingual10060 min323,51±42,74*
Mexidol in substance5010 min452,86±43,11*
Mexidol in substance5060 min438,81±35,83
Mexidol in substance 10010 min420,66±24,41
Mexidol in substance10060 min468,54±25,19
Amitriptyline1010 min414,85±35,51
Amitriptyline1060 min311,56±22,73
* - the difference with the control group significantly at P<0,05.

Thus, sublingual Mexidol after absorption in the oral cavity has a clear statistically significant antidepressant effects in the baseline test of behavioral despair in the Porsolt. Antidepressant effect sublinguales Mexidol has been developing for 10 minutes after the injection and increases with increasing dose. Mexidol in substance when intragastric introduction does not have antidepressant action. Amitriptyline has antidepressant effect in the hours after injection and has not had his 10 minutes after the injection.

Example 8

The study of the anxiolytic actions of Mexidol OTD (sublingual).

Investigation of the anxiolytic activity was is conducted in accordance with the Methodological guidance on the study of the activity of substances, possessing anxiolytic activity (compilers Voronina T.A. and Seredenin S.B.)set forth in the "Manual on experimental (preclinical) study of new pharmacological substances" (Federal service on surveillance in healthcare and social development, Federal state institution scientific center of expertise of medical application, ed. Medicine, Ed. RU Gabriel, Moscow, 2005). Used methodology elevated cross maze by 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 outbred mice-males weighing 23-25, Methodology elevated cross maze (PC) is based on the natural fear of being in open areas and falls from a height and skill preferences rodents dark burrows (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). Elevated plus maze (PC) consists of cross diverging from the Central site right angle 4 sleeves: two opposite, open, without walls and two closed, dark. Central ground floor and open sleeves transparent, while the floor and walls closed sleeves painted in a dark color. The sleeves are of the size of the market a width of 5 cm and a length of 20 m, the wall height of 14 cm, the Central area of 5×5 cm, PC, raised above the ground on 100 see Immediately before the beginning of the experiment the animals kept (from 3 to 5 min) in the dark cells. Then the animal was placed in the PCL to the Central site, head to the open sleeve and within 3 minutes was recorded during the stay of the animals in the open arms, number of entries into the open arm and the number of defecation boluses. Anxiolytic effect of the drug was estimated by the change of these parameters.

Mexidol was administered sublingually at a dose of 100 mg/kg using a special device: the tablet was placed in a special gauze package with laces, which were tied behind the ears of the mouse for 5 minutes, during this time occurred the absorption of the drug from the oral cavity. Animals in this period were kept in a special small cells canisters to restrict movement of the animal. Mexidol in substance at a dose of 100 mg/kg was administered orally (intragastric) in a volume of 0.01 ml per 10 g of mouse. Control animals received the same volume was injected distilled water. Evaluation of the anxiolytic effect was carried out after 10 and 60 minutes after administration of the substances. For each dose and each interval was used a separate group of 8 animals. Statistical processing of results was performed using the article is tistichesky packages "patch BIOSTAT" for Windows. Expected average for the group and the standard errors of the parameters.

Animals of the control group when placed in the PCL, there was an increase in the number of defecations and quick care of animals in closed arms of the maze, where they spent more time (table 26).

Mexidol sublingual dose of 100 mg/kg after 10 and 60 minutes after administration was significantly reduced number of bowel movements, increased the number of entries into the open arms of the maze and the time spent there (table 26), which indicates the presence of a distinct anxiolytic actions.

Mexidol in substance at a dose of 100 mg/kg over 10 minutes after oral administration (oral) not have anxiolytic action, and after 60 minutes under his influence there was reliable anksioliticheskii effect on all indicators (table 26).

Thus, sublingual Mexidol after absorption in the oral cavity has a clear statistically significant anxiolytic effect in the baseline test elevated cross maze by Pellow. Anxiolytic effect sublinguales Mexidol has been developing for 10 minutes after the injection. Mexidol in substance when intragastric introduction possesses anxiolytic effect through hours after injection and has not had his 10 minutes after the injection.

Table 26
Group, dose, Time after introductionThe number of bolesTime in open arms (s)The number of entries into the open sleeve (C)
Control after 10 min3,1±0,5181,4±7,187,6±1,1
The control after 60 min2,4±0,3278,3±8,516,9±1,9
Mexidol sublingu. 100 mg/kg in 10 min1,04±0,12*of 45.7±8,6*11,2±1,2
Mexidol sublingu. 100 mg/kg over 60 min1,2±0,11*43,3±9,13*10,5±0,7*
Mexidol substanz. 100 mg/kg in 10 min2,7±0,8679,4±10,68,1±1,4
Mexidol substanz. 100 mg/kg over 60 min1,4±0,09*48,5±6,16*11,1±0,7*
*- p<0.05 truth is ity differences on the criterion of Mann-Whitney in comparison with the control group

Example 9

Antihypoxic effect of Mexidol OTD (sublingual).

The study was carried out on outbred adult mice-males weighing 23-28, Experiments were performed using 2 tests: normobaric hypoxia with hypercapnia ("jar" hypoxia) and hypobaric hypoxia, which are the most frequently used assessment methods antihypoxic activity of substances (Lukyanova L.D., hazura CENTURIES, Pastushenkov " L.V., Urumov O.Y, Lesnaya group E.V. Methodical recommendations on the study of drugs, of the proposed clinical study as a antihypoxic means, Moscow, (published by the Pharmacological Committee of the Ministry of health, USSR), 1990, 18 C.).

According to the method normobaric hypoxia with hypercapnia mice of the same weight (range not more than 2 g per group) were placed on one animal in hermetically sealed cans with a volume of 200 cm3. Recorded survival time (standby time) of animals in hypoxia.

Hypobaric hypoxia was created in a flow-exhaust chamber with the absorber CO2. Mice raised on height of 11000 m (198,7-185 mm Hg) with a speed of 25-50 m/s. In the hyperbaric chamber at the same time put 2 mice, one of which was the control, and the other is experienced with the substance.

Mexidol was administered sublingually in dose is 100 mg/kg using a special device: the tablet was placed in a special gauze package with laces, which were tied behind the ears of the mouse for 5 minutes, during this time occurred the absorption of the drug from the oral cavity. Animals in this period were kept in a special small cells canisters to restrict movement of the animal. Mexidol in substance at a dose of 100 mg/kg was administered orally (intragastric) in a volume of 0.01 ml per 10 g of mouse. Control animals received the same volume was injected distilled water. Assessment antihypoxic effect exerted through 10 and 60 minutes after administration of the substances. For each dose and each interval was used a separate group of 10 animals. Statistical processing of results was performed using the statistical package "patch BIOSTAT" for Windows. Expected average for the group and the standard errors of the parameters.

3.1. The study antihypoxic action of sublingual Mexidol in the test normobaric hypoxia with hypercapnia.

Control animals placed in normobaric hypoxia with hypercapnia, die on average within 15 minutes (table 27).

Mexidol sublingual dose of 100 mg/kg after 10 and 60 minutes after administration significantly increased the lifespan of mice in conditions of normobaric hypoxia (table 27), which indicates the presence of a distinct antihypoxic action.

Mexidol in the substantive is in a dose of 100 mg/kg over 10 minutes after oral administration (oral) did not antihypoxic action and after 60 minutes under his influence there was reliable antihypoxic effect (table 27).

Table 27
Group, dose, timeLife expectancy min
Control after 10 min14,2±0,24
The control after 60 min15,11±0,32
Mexidol sublingual 100 mg/kg in 10 min17,07±0,21*
Mexidol sublingual 100 mg/kg over 60 min18,12±0,23*
Mexidol substance 100 mg/kg in 10 min13,82±0,71
Mexidol substance 100 mg/kg over 60 minto 18.01±0,54*
*- p<0.05, the significance of differences on the criterion of Mann-Whitney compared with the control group

3.2. The study antihypoxic action of sublingual Mexidol in hypobaric hypoxia.

Control animals are placed in conditions of hypobaric hypoxia on the height of 11000 m, die on average within 1 minute. None of the 10 we shall not survive the exposure of animals for 3 minutes at an altitude of 11000 feet (Table 28).

Mexidol sublingual doses of 10 and 100 mg/kg as 10 minutes, and 60 minutes after administration significantly increased the lifespan of mice in hypobaric hypoxia (table 28), which indicates the presence of a distinct antihypoxic action.

Mexidol in substance at a dose of 100 mg/kg 10 minutes after the injection had no antihypoxic action, and in 60 minutes after oral administration (oral) provided reliable antihypoxic effect (table 28).

Table 28
Group, dose, timeLife expectancy min
The control after 60 min1,12±0,26
Mexidol sublingual 100 mg/kg in 10 min2,14±0,07*
Mexidol sublingual 100 mg/kg over 60 min2,01±0,06*
Mexidol substance, 100 mg/kg in 10 min1,45±0,19
Mexidol substance, 100 mg/kg over 60 min2,18±0,15*
*- p<0.05 validity of the distinctions of what s on the criterion of Mann-Whitney compared with the control group

Thus, Mexidol sublingual after absorption in the oral cavity has a distinct antihypoxic effect in tests of hypobaric hypoxia with hypercapnia in the containment and hypobaric hypoxia. Antihypoxic effect of Mexidol sublingualis develops in 10 minutes after injection. Mexidol in substance when intragastric introduction has antihypoxic effect one hour after injection and has not had his 10 minutes after the injection.

Example 10

Antiamnesic (nootropic) effect of Mexidol OTD (sublingual Mexidol) in the test scopolamine amnesia in rats.

The study was carried out on outbred adult rats male weighing 250-280 g Study antiamnesic activity was conducted in accordance with the Methodological guidance on the study of the activity of substances with neuroprotective activity (Voronina T.A., Ostrovskaya RU, 2005), outlined in the "Manual on experimental (preclinical) study of new pharmacological substances" (Federal service on surveillance in healthcare and social development, Federal state institution scientific center of expertise of medical application, ed. Medicine, ed Ruhara, Moscow, 2005, s-320). The study antiamnesic action prevodilac is using the methods of scopolamine amnesia conditioned reflex of passive avoidance in a certified installation "Lafayette Instrument Co (USA) in rats. The unit is a dark chamber with a size of 400×400×400 mm with electrode floors. The dark chamber is connected through a square guillotine door 60×60 mm with hinged platform size 250×70 mm Hinged platform lit by the lamp of 60 W, located at a height of 400 mm Dark chamber is located on a laboratory bench, and the platform hanging above the floor at a height of 800 mm, a Rat was placed at the brightly lit platform tail to open the guillotine door leading into a dark chamber. Due to mink reflex after finding the entrance to the dark compartment of the camera rat passed into the dark compartment. Then carried out the training, which consisted in the fact that when the rat was in the dark compartment, the hole was closed and put the animal inevitable electrobalance irritation after sex (5 strokes, strength training current of 0.45 mA, the duration of each pulse was 1, and the interval between successive pulses - 2). After receiving painful stimulation (training) rat jumped out from the dark compartment on the lighted platform. Thus, the animal was trained in a dark cell, she gets pain and remembers this. The rat was removed from the platform and placed in a normal cell. For more CPAR amnesia animals were injected with scopolamine (1.0 mg/kg intraperitoneally) 30 minutes before training. Test portions is of a trained and amnesia was performed 24 h after training, what the rat was again placed on the platform by the tail to the hole and record the latent period of entry of the animal into the dark compartment and then, within 180 s, the number of animals not coming in a dark dangerous compartment and remained lit on the hanging platform (rats, remembered the situation).

Mexidol sublingual was administered at a dose of 100 mg/kg using a special device: the tablet was placed in a special gauze package with laces, which were tied behind the ears rats for 5 minutes, during this time occurred the absorption of the drug from the oral cavity. Animals in this period were kept in a special small cells canisters to restrict movement of the animal. Mexidol in substance at a dose of 100 mg/kg was administered orally (intragastric) in a volume of 0.01 ml per 10 g of mouse. Control animals received the same volume was injected distilled water.

Mexidol sublingual or Mexidol in substance was administered twice: once for 30 minutes before scopolamine (before training) and for the second time in 30 minutes to play passive avoidance reaction (24 hours after training).

Statistical processing of results was performed using the statistical package "patch BIOSTAT" for Windows. Expected average for the group and the standard errors of the parameters.

Table 29
SubstanceTesting passive avoidance reaction in 24 hours
The latent time of sunset in a dark chamber, secondsThe number is not coming in a dark chamber of animals %
Passive control, distil. waterto 132.8±14,380%
Active control, scopolamine 1 mg/kg, VSL.62,14±18,54*20%*
Mexidol sublingual 100 mg/kg106,7±18,4#50%#
Mexidol substance, 100 mg/kgto 98.6±17,3#60%#
- P<0.05 to relatively passive control.
# P<0,05 - relative to the active control.

Found that scopolamine significantly shortens the duration of the latent period of time in a dark chamber when playing passive avoidance reaction and significantly reduces the number of animals, not coming into the dark compartment of the camera during playback, i.e. remembering of applied there before the aversive stimulus. The data obtained St detailstwo disappearance antimouse action of scopolamine (table 29).

Mexidol sublingual dose of 100 mg/kg over 60 minutes after administration was significantly increased latency time of entering the dark chamber and the percentage of animals not coming in a dark chamber (table 29), which indicates the presence of his antiamnesic activity.

Mexidol in substance at a dose of 100 mg/kg over 60 minutes after oral administration (oral) provided reliable antiamnesic effect (table 29).

Example 11. The study of the effect of Mexidol OTD (sublingual Mexidol) caused by ethanol neurological deficit caused by ethanol.

The experiments were carried out on outbred adult rats male (weighing 250-270 g) using the technique of "Rat Rota-Rod (Ugo Basile, Italy), which is widely used in the study of pharmacological substances that can potentially cause neurological deficit, because animals with neurological deficits are not held on a rotating rod. The apparatus consists of a rotating drum with a diameter of 6 cm, divided 5 disks (49 cm in diameter) into 4 equal parts by 87 mm Reel automatically spins. Before testing conducted procedure of familiarization of intact rats with installation. To this end, animals were placed on a drum rotating at a minimum speed of 4-5 rotations per minute. After 2-3 training sessions within 2 minutes the animals are acclimatized to the conditions of installation Roda-Rod and 2-3 hours is ready for testing. Animals were tested at a constant high speed rotation of the rod 10 revolutions per minute. The maximum test time was 3 minutes.

Ethanol was administered at a dose of 2 g/kg (25% solution) intraperitoneally and then after 10 minutes was introduced Mexidol sublingual or Mexidol in substance and in 30 minutes was carried out by testing.

Mexidol sublingual was administered at a dose of 100 mg/kg using a special device: the tablet was placed in a special gauze package with laces, which were tied behind the ears rats for 5 minutes, during this time occurred the absorption of the drug from the oral cavity. Animals in this period were kept in a special small cells canisters to restrict movement of the animal. Mexidol in substance at a dose of 100 mg/kg was administered orally (intragastric) in a volume of 0.01 ml to 10 GOSA mouse. Control animals received the same volume was injected distilled water. Assessment of the effect was carried out in 30 minutes after administration of the substances.

Found that sublingual Mexidol in the dose of 100 mg/kg and Mexidol in substance at a dose of 100 mg/kg single administration, by themselves, do not cause neurological deficits (table 30).

Ethanol (2 g/kg b/W) significantly reduces the retention time of rats on a rotating rod, which indicates disorder in animals coordination and expressed nevrologicheskom deficit (table 30).

Table 30
Group substanceThe retention time on the rod, S.
Control intact, dieted131,45±11,82
Mexidol sublingual (100 mg/kg)143,41±21,11
Mexidol in substance (100 mg/kg)to 133.5±19,66
Ethanol (2 g/kg/b)18,19±4,91#
Mexidol sublingual (100 mg/kg)+Ethanol74,61±21,14*
Mexidol in substance (100 mg/kg)+Ethanol63,15±17,14*
# - p<0.05, the significance of differences by t-criterion of student in relation to the group of intact animals;
* - p<0.05, the significance of differences by t-criterion of student in relation to the group of animals treated with Ethanol.

Mexidol sublingual dose of 100 mg/kg, as well as Mexidol in substance at a dose of 100 mg/kg, administered to the rats that received ethanol significantly increased the retention time of the animals on the rotating rod compared on the Yu-control with the introduction of a single ethanol (table 30).

The ability to resolve neurological disorders caused by ethanol in the test of the rotating rod, sublingual Mexidol has similar effectiveness with Mexidol in substance.

Example 11

Actions of Mexidol OTD (sublingual Mexidol) on amnesia induced by ethanol.

The study was performed on outbred adult rats male weighing 250-280 g Study antiamnesic activity was conducted in accordance with the Methodological guidance on the study of the activity of substances with neuroprotective activity (Voronina T.A., Ostrovskaya RU, 2005) set out in the "Manual on experimental (preclinical) study of new pharmacological substances" (Federal service on surveillance in healthcare and social development, Federal state institution scientific center of expertise of medical application, ed. Medicine, ed Ruhara, Moscow, 2005, s-320). The study was conducted using the methods of amnesia conditioned reflex of passive avoidance in a certified installation "Lafayette Instrument Co (USA) in rats. The unit is a dark chamber with a size of 400×400×400 mm with electrode floors. The dark chamber is connected through a square guillotine door 60×60 mm with hinged platform size 250×70 mm Hinged platform illuminated by the lamp 6 watt, located at a height of 400 mm Dark chamber is located on a laboratory bench, and the platform hanging above the floor at a height of 800 mm, a Rat was placed at the brightly lit platform tail to open the guillotine door leading into a dark chamber. Due to mink reflex after finding the entrance to the dark compartment of the camera rat passed into the dark compartment. Then carried out the training, which consisted in the fact that when the rat was in the dark compartment, the hole was closed and put the animal inevitable electrobalance irritation after sex (5 strokes, strength training current of 0.45 mA, the duration of each pulse was 1, and the interval between successive pulses - 2). After receiving painful stimulation (training) rat jumped out from the dark compartment on the lighted platform. Thus, the animal was trained in a dark cell, she gets pain and remembers this. The rat was removed from the platform and placed in a normal cell.

For more CPAR amnesia animals were injected with ethanol at a dose of 2 mg/kg (intraperitoneally) 30 minutes before training. Test playback trained and amnesia was performed 24 h after training, for which the rat was again placed on the platform by the tail to the hole and record the latent period of entering an animal in a dark office and then for a 180 with the number of animals souse is not coming in a dark dangerous compartment and remained lit on the hanging platform (rat, well remembering the situation).

Mexidol sublingual was administered at a dose of 100 mg/kg using a special device: the tablet was placed in a special gauze package with laces, which were tied behind the ears rats for 5 minutes, during this time occurred the absorption of the drug from the oral cavity. Animals in this period were kept in a special small cells canisters to restrict movement of the animal. Mexidol in substance at a dose of 100 mg/kg was administered orally (intragastric) in a volume of 0.01 ml to 10, the weight of the mouse. Control animals received the same volume was injected distilled water.

Mexidol sublingual or Mexidol in substance was administered twice: once after 10 minutes after administration of ethanol (before training) and for the second time in 30 minutes to play passive avoidance reaction (24 hours after training).

It was found that ethanol significantly shortens the duration of the latent period of time in a dark chamber when playing passive avoidance reaction and significantly reduces the number of animals, not coming into the dark compartment of the camera during playback, i.e. remembering of applied there before the aversive stimulus. The data obtained indicate pronounced antimouse action of ethanol (table 31).

Mexidol sublingual dose of 100 mg/kg significantly increased the latency time of entering the dark chamber and the percentage of animals, not ushedshih in a dark chamber (table 31), that testifies to its ability to resolve the amnesia caused by ethanol.

Table 31
SubstanceTesting passive avoidance reaction in 24 hours
The latent time of sunset in a dark chamber, secondsThe number is not coming in a dark chamber of animals %
Control, Intact animals (distilled water)148,3±16,990%
Ethanol 2 g/kg (VSL).74,12±10,63*25%*
Mexidol sublingual 100 mg/kgthe 97.6±14,9#60%#
Mexidol substance, 100 mg/kg105,6±11,8#50%#
* - P<0.05 to relatively passive control.
# P<0,05 - in relation to the group that received ethanol.

Mexidol in substance at a dose of 100 mg/kg also had a reliable antiamnesic effect against amnesia induced by ethanol (table 31).

So about what atom, Mexidol sublingual dose of 100 mg/kg were able to resolve the amnesia of the conditioned reflex of passive avoidance caused by ethanol and not inferior in this activity the Mexidol in substance at a dose of 100 mg/kg

Example 12

The activating action of sublingual Mexidol OTD (orally getintegervalue tablets).

The study of the activating action of Mexidol OTD was carried out in experiments on adult outbred white mice-males weighing 24-30 hisshadowone was performed using methods of open fields and hectometre "OptoVarimex" (Voronina T.A., Seredenin S.B. guidelines for the study of anxiolytic activity of pharmacological substances, Manual on experimental (preclinical) study of new pharmacological substances" (Federal service on surveillance in healthcare and social development, Federal state institution scientific center of expertise of medical application, ed. Medicine, ed Ruhara, Moscow, 2005, 253-263).

7.1. The study of the activating action of sublingual Mexidol in the open field test.

Installing the open field is a square arena with a size of 60×60 cm, with a wall height of 15 cm; the floor of the chamber is divided into 9 squares with sides of 20×20 cm with 16 holes at the intersection of joints squares with a diameter of 4 see the Assessment on which edenia animals in terms of the methodology of the open fields was carried out for 3 min, registering horizontal locomotor activity (number of crossed lines), vertical locomotor activity (number of columns), exploratory activity (number of surveyed holes, when the beast lowered his head into the hole more than half).

Mexidol OTD was introduced a long time daily for 21 days at doses of 25 and 50 mg/kg sublingually. Animals of the control group was administered distilled water in an equivalent amount. Locomotor activity was recorded 30 minutes after the last injection of Mexidol.

It was found that after the introduction of Mexidol sublingual doses of 25 and 50 mg/kg for 21 days, there was a statistically significant increase in both horizontal and vertical locomotor activity of animals in the open field, as well as increasing the number of zaglyadyvanie in holes (table 32).

Mexidol in substance when intragastric introduction (using a special probe) at doses of 25 and 50 mg/kg for 21 days had no statistically significant effect on locomotor activity of animals in the open field (table 32).

Table 32
GroupHorizontal activityVertical active is e Peeking in the hole
Control86,8±4,1118,8±2,7115,1±1,41
Mexidol OTD, 25 mg/kg sublingual129,5±6,21*27,4±1,19*21,8±1,54*
Mexidol OTD, 50 mg/kg sublingual112,9±2,38*29,5±2,08*20±1,05*
Mexidol, 25 mg/kg intragastric90,1±5,1820,7±3,0112,4±2,58
Mexidol, 50 mg/kg intragastricfor 93.4±6,1819,9±5,0114,4±2,15
* - p≤0,005 compared with the control group, student test

7.2. The study of the activating action of sublingual Mexidol in hectometre "OptoVarimex".

Installing actometry "OptoVarimex" (Columbus instruments, USA) is a square Plexiglas arena with sides 42 x 42 cm and height 20 cm, transparent, re-sealable lid. Around the perimeter of the arena are sensitive photocells, the machine is Cesky transmitting the indices of locomotor activity of animals on the counter. Animals were placed in octomer "OptoVarimex" for 5 minutes. In automatic mode, the minutes were recorded horizontal and vertical activity of animals. The average value was determined horizontal and vertical activity of animals in the group of mice for 1 minute.

Mexidol OTD was introduced a long time for 21 days at a dose of 25 mg/kg sublingually. Mexidol in substance was introduced a long time for 21 days at a dose of 25 mg/kg intragastric (using a special probe). Animals of the control group was administered distilled water in an equivalent amount.

Locomotor activity was recorded 30 minutes after the last injection of Mexidol.

5,2±0,12
Table 33
GroupHorizontal activity of the animal per minute, a unitVertical activity of the animal per minute, a unit
Control476,27±56,154,8±0,32
Mexidol OTD 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
* - p≤0.05 compared with the control group, student test

It was found that after the introduction of Mexidol OTD sublingual dose of 25 mg/kg for 21 days, there was a statistically significant increase in both horizontal and vertical locomotor activity of animals in hectometre (table 33).

Mexidol in substance with the introduction of 21 days at a dose of 25 mg/kg intragastric (using a special probe) had no effect on locomotor activity in mice hectometre (table 33).

Thus, the results obtained when studying the effect of Mexidol OTD (sublingual, 21 days) on the behavior of mice in the open field and hectometre "OptoVarimex", showed the presence sublingual Mexidol activating action as opposed to Mexidol in substance that the activating effect on locomotor activity did not possess.

Example 13

Anorectic effect of Mexidol OTD with sublingual application.

Studies were performed on Mature white mongrel rats-females weighing 260-280 g

The first group of control rats received a standard diet:

complete feed (extruded pellets made without preservatives) LLC "MEST" (Moscow). The feed was environmentally friendly the m product balanced amino acid composition, mineral substances and vitamins, made from high-quality components.

The second group of control rats received a standard diet and additionally improved food: porridge (millet, tasteless, buckwheat beef broth with meat and sunflower oil, cheese, bread and vegetables (potatoes, cabbage, carrots). Control animals daily for 35 days received distilled water (0.2 ml) in the oral cavity.

The third group of rats received a standard diet and additionally high-calorie diet and daily was administered orally (intragastric, through a special probe) Mexidol in a dose of 50 mg/kg for 35 days.

The fourth group of rats received a standard diet and additionally high-calorie diet and daily entered Mexidol sublingual dose of 50 mg/kg for 35 days.

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

Found that with increased nutrition rats are much larger and statistically reliable gained weight, compared to animals that were on standard dry diet (table 34).

Mexidol in a dose of 50 mg/kg ingestion (intragastric, using a special probe) daily for 35 days to rats fed a high-calorie diet, statistically stovern did not change the weight of animals compared to control (rats, receiving a high-calorie diet) (table 34).

Mexidol OTD at a dose of 50 mg/kg with the introduction of sublingual daily for 14 days to rats fed a high-calorie diet, statistically significantly reduced the weight gain of the animals compared with the control group (rats fed a high-calorie diet) (table 34).

Table 34
GroupBefore the start of the experiment14 days after injection of substances35 days after injection of substances
Control (distad). The weight of rats in gbes enhanced power272,7±10,8287,6±14,7305,4±13,9
Control, (distad). Weight gain of rats in gbes enhanced power14,9±2,132,7±4,1
Control, (distad) Weight of rats in the city with enhanced nutritionreaches 260.6±12,1of 306.7±10,3332,3±7,1

Control, (dieta) weight Gain in g u cu is with power supply 46,1±6,471,71±6.8 cm
Mexidol 50 mg/kg inside rats with enhanced nutrition. The weight of rats in,278,7±14,8319,8±15,7340,9±15,1
Mexidol 50 mg/kg inside rats with enhanced nutrition. Weight gain,41,1±8,462,2±9,4
Mexidol 50 mg/kg sublingual rats with enhanced nutrition. The weight of rats in,268,7±10,8280,1±8,7*#302,3±8,2*#
Mexidol 50 mg/kg sublingual rats with enhanced nutrition. Weight gain,11,4±2,4*#33,6±4,8*#
p≤0.05 compared with the control group without power supply.
*- p≤0.05 compared with the control group fed a high-calorie diet.
# p≤0.05 compared with the group receiving the high-calorie diet and Mexidol inside (intragastric).

M is xodol OTD at a dose of 50 mg/kg with the introduction of sublingual daily for 35 days to rats, receiving a high-calorie diet, statistically significantly reduced the weight gain of the animals compared with the control group (rats fed a high-calorie diet) (table 34).

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

The data obtained indicate that Mexidol OTD at a dose of 50 mg/kg sublingually daily introduction over 14 and, particularly, 35 days to rats fed a high-calorie diet, statistically reduces the weight gain of the animals, whereas Mexidol (50 mg/kg) by intragastric introduction within 35 days does not affect the weight gain.

Thus, Mexidol OTD with sublingual long-term use has an anorectic effect in contrast to Mexidol with the inside, which therefore has no effect.

To sum up, pharmacological studies have shown that Mexidol OTD (sublingual Mexidol) after absorption in the oral cavity has a distinct activating (stimulating) and anorectic actions as opposed to Mexidol entered intragastric (tablets or substance)that these effects has not. Mexidol OTD with sublingual application oblad the et also anxiolytic, antihypoxic, antiamnesic, antidepressant and alcohol action and not inferior to these effects Mexidol in substance and tablets when administered orally (intragastric). Effects sublinguales Mexidol manifest as after 10 minutes and 60 minutes after its introduction. Mexidol in substance when intragastric introduction has effects through the hours after injection and has not had his 10 minutes after the injection.

The use of pharmaceutical compositions in the form of oral-getintegervalue tablets containing as active substance 6-methyl-2-ethyl-3-hydroxypyridine succinate and as disintegrant - crospovidon in the ratio 2:1, respectively, as stimulating locomotor activity and anorectics.



 

Same patents:

FIELD: medicine.

SUBSTANCE: for the purpose of post-surgical treatment of cerebral tumours, memantine is prescribed in a dose of 10 mg daily for 5-7 days before radiation therapy, and in a dose of 20 mg during radiation therapy 4-6 hours before the radiation session. On completing the course of radiation therapy, memantine is prescribed in patients aged up to 60 years old in a dose of 10 mg for 2-3 months daily, in patients aged 60 and older in a dose of 20 mg for 5-6 months daily.

EFFECT: method enables providing the higher patients' quality of life with a view to cancellation of glucocorticoids, ensuring higher clinical effectiveness ensured by an increase of the medullary substance to radiation.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, namely to an agent with an antidyslipidemic and analgesic effect. The method for preparing the phytocomplex with the antidyslipidemic and analgesic effect, involving: a) grinding peeled bergamot fruit to prepare an undegraded mixture, b) introducing pectinolytic enzymes into the mixture; c) reducing pulp content; d) inactivating the above enzymes added at the stage b), to prepare a degraded mixture; e) performing ultrafiltration of the degraded mixture through membranes isolating the substances having a molecular weight of over 30,000 Da, to prepare a transparent solution; f) introducing the transparent solution on a polyphenol absorption column; g) washing the polyphenol absorption column with water and increasing pH to prepare an aqueous polyphenol fraction; h) transmitting the aqueous polyphenol fraction to cationic resin to recover the phytocomplex in an aqueous phase; i) drying the phytocomplex in the aqueous phase. The phytocomplex in the aqueous phase with the antidyslipidemic and analgesic effect. The phytocomplex with the antidyslipidemic and analgesic effect. A pharmaceutical composition with the antidyslipidemic effect containing the phytocomplex, and pharmaceutically acceptable additives. A pharmaceutical composition with the analgesic effect containing the phytocomplex, and pharmaceutically acceptable additives.

EFFECT: phytocomplex described above possesses the evident antidyslipidemic and analgesic effect.

11 cl

FIELD: medicine.

SUBSTANCE: method involves preliminary intraperitoneal single administration of 5% aqueous alloxan in a dose of 15 mg/kg of body weight into a rat's body on an empty stomach. That is followed by administering afobazol under conditions of oxidative stress after observing the rat's blood glucose gain at least twice. Afobazol is administered subcutaneously in a dose of 10 mg/kg of body weight once a day for 30 days with underlying administration of L-arginine in a dose of 10 mg/kg of body weight or with underlying NG-nitroarginine methyl ester (L-NAME)-inhibitor of NOS-3 enzyme in a dose of 25 mg/kg of animal's weight.

EFFECT: method enables correcting the oxidative stress and NO-producing endothelial dysfunction accompanying vascular complications of diabetes mellitus.

1 dwg, 6 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns an antioxidant representing the amino acid glycine immobilised on the detonation-synthesised nanodiamond particles of 2-10 nm in size.

EFFECT: higher efficacy.

4 cl, 5 dwg, 7 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: improving the functional result of a low resection of rectum in the patient suffering from rectum cancer is ensured by prescribing the drug preparation Laviocard+ 1 capsule 2 times a day with food for the pre-operative radiation course, one day before the operation and for 30 postoperative days to the extent of the low resection of rectum.

EFFECT: invention enables reducing a rate and degree of defecation and continence dysfunctions following the low resection of rectum and the radiation therapy.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound for formula (1) , antioxidant, containing formula (1) compound or its salt as active ingredient, and to application of formula (1) compound or its salt for oxidant manufacturing. Invention also relates to formula (2) compound, which is intermediate for obtaining formula (1) compound.

EFFECT: formula compound, demonstrating antioxidant properties.

4 cl, 1 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a method for increasing the radioresistance in mice. The method for increasing the radioresistance in mice consisting in the fact that 20-30 min before a radiation exposure, parsley juice diluted with normal saline is introduced intramuscularly.

EFFECT: method increases the radioresistance in mice effectively.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine. A pharmaceutical formulation for the treating diseases associated with endothelial dysfunction contains an active ingredient presented by a methyl pyridine derivative - 1.0-6.0 wt %; purine - 10.0-80.0 wt % and additive agents - the rest. The active substance is presented by compounds of a group: 3 -(N,N-dimethyl carbamoyloxy)-2-ethyl-6-methylpyridinium succinate, 3-methylpyridinium succinate, 2-ethyl-6-methyl-3-hydroxypyridinium hydrochloride, 6-trichloromethyl-2-chloropyridine (nitrapyrin), 2-ethyl-6-methyl-3-hydroxypyridine succinate. Purine is presented by inosine, adenosine, hypoxanthine. The pharmaceutical formulation may be presented in the form of injections, lyophilisate, solid capsules, tablets and suppositories.

EFFECT: formulation according to the invention provides creating the stable drug dosage form which considerably exceeds the existing analogues in pharmacodynamics activity on the endothelial dysfunction and toxicological properties.

4 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to diastereomers of isobornyl compounds of the structural formula (I), where R1=H and isobornyl fragments have the configuration (1S, 2R, 4R, 1'S, 2'R, 4'R) and (1R, 2S, 4S, 1'R, 2'S, 4'S), where R1=CH3 and isobornyl fragments have the configuration (1S, 2R, 4R, 1'R, 2'S, 4'S) or the isobornyl fragments have the configuration (1S, 2R, 4R, 1'S, 2'R, 4'R) and (1R, 2S, 4S, 1'R, 2'S, 4'S).

EFFECT: high antioxidant activity.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology. What is presented is using a cell culture prepared of one or more homogenous cell lines originated from cambium Panax ginseng, or extract thereof when preparing an anti-aging cosmetic composition.

EFFECT: invention provides the effective agent for preventing or suppressing the aging ensured by the antioxidant effect of the natural materials being the ingredients of the above composition.

7 cl, 7 dwg, 20 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to the addiction pharmacology, and concerns new application of threonyl-lysyl-prolyl-arginyl-prolyl-glycyl-prolyl-diacetate (Selank) as an agent for managing alcohol abstinence syndrome (AAC). It has been stated that Selank eliminates anxiety induced by withdrawal of ethanol. Selank has been detected to recover a threshold of tactile sensation reduced in the period of alcohol withdrawal to the level observed in intact animals.

EFFECT: anxiolytic Selank can be applied as the effective agent for correction of clinical manifestations of mild and moderate alcohol abstinence syndrome with no adverse side effects.

7 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: disclosed is use of a heptapeptide of general formula Tyr-D-Ala-Phe-Gly-Tyr-X-Ser-NH2, where X is D-Pro or Dh-Pro, or Dh-D-Pro, where Dh-Pro is 3,4-dehydroproline, as an antispasmodic, anxiolytic, central anti-inflammatory or anti-alcohol agent.

EFFECT: obtaining an agent used as an antispasmodic, anxiolytic, central anti-inflammatory or anti-alcohol agent.

3 cl, 8 tbl, 26 ex

FIELD: biotechnologies.

SUBSTANCE: invention provides hemihydrate of naltrexone base that has characteristic peaks at powder X-ray diffraction pattern at the angles 2θ 7.1, 9.4, 12.7, 13.5, 14.3, 14.9, 16.9, 21.6, 22.2, 24.2, 25.6 and 27.7°. Moreover the invention pertains to the method of its obtaining as well as to the method of obtaining microspheres containing naltrexone base.

EFFECT: hemihydrate of naltrexone base with high solvability in organic solvents, simplified and cheap method for obtaining polymorph of naltrexone base, method for obtaining microspheres with reduced toxic properties and improved profile of naltrexone release.

5 cl, 2 tbl, 1 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and describes a disulphiram implant for treating the alcohol or opiate addictive patients. The implant contains disulphiram 95.0-59.0 wt %, nitrogen polymer composition 4.8-40.5 wt % and stearic acid or magnesium stearate 0.2-0.5 wt %. The nitrogen polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or salts of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone.

EFFECT: implant may be used in addictology and provides a prolonged and uniform release of disulphiram with improving incisional wound healing.

5 ex, 2 tbl

Nalmefene prodrugs // 2495042

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to ester prodrug forms of nalmefene of formula (I) wherein R1 means C6-16alkyl or C8-12alkylamino; or a pharmaceutically acceptable acid additive salt thereof. Also the invention claims the pharmaceutical compositions possessing action of an opioid receptor agonist containing a pharmaceutically acceptable salt and a therapeutically acceptable amount of the compound of formula (I).

EFFECT: invention describes the chemical methods for preparing the above compounds and using them in treating substance abuse disorders, such as abuse of alcohol and alcohol dependence, and pulse control disorders, such as compulsive gambling and shopping addiction.

14 cl, 5 ex, 1 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds, namely nalmefene prodrugs of formula (I) wherein R1 means C16-20alkyloxycarbonylC2-4alkyl, as well as to pharmaceutical compositions containing the above compounds, as well as to a method for preparing the above compounds.

EFFECT: compounds possess action of an opioid receptor antagonist and may be used for treating substance abuse disorders, wherein the above disorder represents abuse of alcohol and alcohol dependence.

8 cl, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacy, namely to an agent for treating alcoholic toxicosis. The declared agent contains an enzymatic hydrolysis product of mixed cereals and cereal grains in the relation of 1:9 to 1:25 and cereal flour, wherein the amount of cereal flour makes 1.0-20.0 wt %. As a cereal, the declared agent contains pearlbarley or oatmeal or buckwheat, and as a cereal grains - wheat or barley or corn.

EFFECT: invention provides pharmacological stimulation of the endogenous ethanol synthesis and normalisation of the carbohydrate metabolism.

7 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented methods of treating or preventing an addiction or recurrent addictive behaviour, including: alcohol, nicotine, marijuana, marijuana derivative, opioid receptor antagonist, benzodiazepine, barbiturate and psychostimulant by administering the peroxisome proliferator-activated receptor gamma (PPARγ) agonist thiazolidinedione, alone or in a combination with another therapeutic agent - an opioid receptor agonist, a mixed partial opioid receptor agonist/antagonist, an anti-depressant, an antiepileptic agent, an antiemetic agent, a corticotrophin releasing factor 1 (CRF-1) receptor antagonist, a selective serotonin 5-HT3 receptor antagonist, a 5-HT2A/2C antagonist or a cannabinoid 1 (CB1) receptor antagonist (versions), related pharmaceutical compositions with the above combinations (versions), a standard dosage form (versions) and kits (versions).

EFFECT: it is shown that the PPARγ agonist pioglitazone had no effect on amphetamine sensitisation, however it reduced opiate consumption and opiate addiction, also reduced nicotine self-administration in rats, and reduced alcohol consumption if synergistically combined with topiramate Pioglitazone reduced ethanol self-administration in rats.

33 cl, 23 dwg, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a drug preparation containing 97.0-59.5 wt % of naltrexone base, 0.5-3.0 wt % of corticosteroid specified in triamcinolone, betamethasone or dexamethasone, 2.0-37.0 wt % of a nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. The nitrogen-containing polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or a salt of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone. The drug preparation may be used in addictology for treating the alcohol- or opioid-dependent patients.

EFFECT: invention provides prolonged and uniform naltrexone release with a lower probability of the implant rejection caused by an inflammatory response.

2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical industry and deals with disulfiram-based medication, which additionally contains corticosteroid. Medicine contains 59.5-97.0 wt % of disulfiram base, 0.5-3.0 wt % of corticosteroid, 2.0-37.0 wt % of nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. Composition of nitrogen-containing polymers includes copolymer of N-vinylpyrrolidone and 2-methyl-5-vinylpyridine or salts of dissolved oligomers of hexamethylenediamine and guanidine and polyvinylpyrrolidone.

EFFECT: medication can be applied in addictology for treatment of alcohol or opiate-dependent patient.

2 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula III or to its pharmaceutically acceptable salts, in which: R1 and R2 are independently selected from group, consisting of: (a) H, (b) (C2-C6)alkyl, (c) C1-C6 alkyl, interrupted by one or more groups -O-, (d) (C0-C3)alkyl-(C3-C7)cycloalkyl and (e) (CH2)nQ, where n=1-2 and where Q stands for aromatic ring system, which has from 5 to 6 ring atoms C, and Q can be independently substituted with groups up to 3 in number, selected from halogen, on condition that R1 and R2 simultaneously do not stand for H, and each alkyl of R1 and R2 can be independently substituted with one or more groups, selected from group, consisting of halogen, hydroxy, cyano, CF3 or C1-C4 alkyl, or R1 and R2 together with carbon, to which they are attached, form 3-7-member cycloalkyl or 6-member heterocycloalkyl ring, including one oxygen atom and which in case of necessity carries C1-C4 alkyl substituent, or R1 and R2 together with carbon, to which they are connected, form 3-7-member cycloalkyl ring, substituted with R20 and R21, and R20 and R21 together with carbon or carbons, to which they are connected, form 3-7-member cycloalkyl ring; R6 stands for C1-C6 alkyl; each R7 independently stands for C1-C6 alkyl; Y stands for -O-; R4 is selected from group, consisting of: (a) (C0-C3)alkyl-(C3-C7)cycloalkyl, (b) trifluoroethyl, and (c) trifluoropropyl; Z stands for phenyl or bicyclic ring system, which has 9 ring atoms, independently selected from C, N, O and S, on condition that not more than 3 ring atoms in any single ring differs from C, and said ring system can carry to 3 substituents, independently selected from group, consisting of R6, CF3 and SR6; and R5 is selected from group, consisting of NO2, NH2, F, Cl, Br, CN, SR6, S(O)2N(R7)2 and (C1-C4)alkyl, and each alkyl can be independently substituted with one or more halogens or CF3. Invention also relates to pharmaceutical composition for treatment of neurodegenerative disorder or improvement of cognitive function, containing therapeutically effective quantity of said compound; as well as to method of treatment of neurodegenerative disorder, for instance Alzheimer's disease, or improvement of cognitive function.

EFFECT: compounds act as modulators of gamma-secretase.

31 cl, 14 tbl, 3147 ex, 1 dwg

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