EA009521B1 - Composition having hepatoprotective activity and normalizing metabolic processes - Google Patents

Abstract

The proposed invention relates to medicine, in particular, to preparing a pharmaceutical composition based on phospholipid having hepatoprotective activity and normalizing metabolic processes and can be used in manufacturing a medicament in the form of tablets, granules, capsules, pellets solutions for injections, syrop, suspensions.The composition comprises phospholipid both of vegetable and animal origin, essential amino acid, in particular, methionine or thrionine, and a filler, at summed content of the phospholipid and amino acid 15-80% and their mass ratio 2:1.The proposed pharmaceutical composition has an apparent hepatoprotective activity and permits to normalize lipid, protein and carbohydrate metabolisms, as well as to broaden medicaments range for the treatment of liver diseases using different medicament forms.

Description

The present invention relates to medicine, and relates to the creation of a pharmaceutical composition based on phospholipid, with hepatoprotective activity and normalizing metabolic processes, and can be used in the manufacture of medicines in the form of tablets, granules, pellets, capsules, injectable solutions, syrup, suspensions.

According to the World Health Organization, over the past 20 years, there has been a clear tendency in the world to increase the number of liver diseases. Only in the CIS countries annually from 500 thousand to 1 million people suffering from one or another liver pathology are registered. In this regard, an important problem is the search for new highly effective and at the same time safe means of hepatoprotective action.

Among them, the most promising are agents of natural origin, for example phospholipids.

The well-known drug "Essentiale® N" ["Medicines in Russia", reference Vidal, ed. 8. - M., "AstraPharmService", 2002, p. B-733], containing essential phospholipids. The drug is available in the form of capsules and injections, with its use, liver function and enzymatic activity of liver cells are improved.

However, it does not normalize metabolic processes in the body to a sufficient degree.

Known drug "Essliver® Forte" ["Medicines in Russia", Vidal, ed. 8. - M., "AstraFarmService", 2002, p. B-733], containing essential phospholipids and vitamins.

However, vitamins can lead to a deterioration in the tolerance of essential phospholipids, which reduces the effectiveness of the drug.

Closest to the claimed composition in technical essence and the achieved result is a pharmaceutical composition protected by RF patent No. 2133122 ["A composition having the ability to repair biological membranes", cl. A 61 K 31/685, A 61 K 35/78, publ. 1999.07.20, patent holder: Research Institute of Biomedical Chemistry RAMS], which is selected as a prototype for both independent claims.

The known composition contains phospholipids, glycyrrhizic acid or its salts and excipients with a total content of phospholipids and glycyrrhizic acid or its salt of 280 wt.% And the mass ratio of phospholipids and glycyrrhizic acid or its salt is not more than 4: 1.

The pharmaceutical composition described in the patent has hepatoprotective activity and normalizes fat metabolism; therefore, it is used to treat and prevent acute and chronic liver diseases, and restore liver function during intoxication.

However, this agent has insufficient hepatoprotective activity and, as a result, affects the normalization of only fat metabolism, without affecting protein and carbohydrate metabolism in the body.

The problem solved by the invention is the creation of an effective pharmaceutical composition based on phospholipid, which has a pronounced hepatoprotective activity and allows to normalize fat, protein and carbohydrate metabolism, as well as expanding the arsenal of drugs for the treatment of liver diseases in the form of various dosage forms.

The technical result from the use of the present invention is to increase the therapeutic efficacy of the drug by increasing its hepatoprotective activity and the ability to normalize both fat and protein and carbohydrate metabolism in the body.

The specified technical result is achieved by the proposed pharmaceutical composition having hepatoprotective activity and normalizing metabolic processes, and containing phospholipid of both plant and animal origin, an essential amino acid and a filler, with a total phospholipid and amino acid content of 15-80 wt.% And their mass ratio of 2 :one.

Preferably, α-amino-γ-methylthiobutyric acid (methionine) or α-amino-b-hydroxybutyric acid (threonine) is used as an essential amino acid.

Preferably, a plant-derived phospholipid obtained, for example, from soybeans, is used as the phospholipid.

Preferably, a phospholipid of animal origin obtained, for example, from egg yolk is used as the phospholipid.

Preferably, a phospholipid with a phosphatidylcholine content of 73-79 wt.% Is used as a phospholipid of plant or animal origin.

Preferably, a pharmaceutically acceptable excipient is used as the excipient, which makes it possible to obtain tablets, or granules, or pellets.

Preferably, the proposed composition is made in the form of tablets, or granules, or pellets, coated with a polymer-based shell.

Preferably, the mass of the shell relative to the mass of the core is, wt.%: For tablets 5-10, for pellets - 12-20, for granules - 30-45.

Preferably, a quantity of pellets or granules can be placed in a pharmaceutically acceptable capsule for oral administration.

- 1 009521

Preferably, the capsule is filled with pellets or granules in such an amount that the content of the active substance in them is equivalent to a therapeutic dose.

Preferably, vegetable oil, such as soybean, is used as a filler.

Preferably, the pharmaceutical composition containing vegetable oil as a filler can be placed in an oral capsule in such an amount that the content of active ingredients in it is equivalent to a therapeutic dose.

Preferably, a pharmaceutically acceptable excipient is used as an excipient to provide an injection solution.

Preferably, a pharmaceutical excipient is used as an excipient, allowing syrup to be obtained.

Preferably, a pharmaceutical excipient is used as the excipient, which makes it possible to obtain a suspension.

Introduction to the proposed pharmaceutical composition of both phospholipid and an essential amino acid with a total phospholipid and amino acid content of 15-80% and their mass ratio of 2: 1 allows you to get a composition with pronounced hepatoprotective activity and allows you to simultaneously stabilize both fat and protein and carbohydrate metabolism in the body .

The pharmacological action of essential amino acids is based on their role in the metabolic processes of the body, in particular protein metabolism.

Phospholipid, being one of the main components of cell membranes, has hepatoprotective activity. This is due to its function in maintaining and restoring the normal composition of cell membranes.

The pronounced hepatoprotective activity of the proposed composition is achieved by achieving a synergistic effect, which is due to the fact that the essential amino acid, in particular methionine and threonine, produces endogenous choline synthesis in the body, which, in turn, is involved both in the biosynthesis of endogenous phospholipids and in increasing efficiency maintaining and restoring the normal composition of the liver cell membranes by exogenous phospholipids administered.

Along with the fact that the amino acid normalizes protein metabolism, normalization of liver function entails additional stabilization of protein metabolism, as well as stabilization of fat metabolism due to the production of bile and stabilization of carbohydrate metabolism by regulating the total concentration of glucose in the blood.

The ratio of the components in the proposed composition is selected experimentally and is optimal, which allows to obtain a technical result corresponding to the task.

A pharmaceutically acceptable excipient for the manufacture of tablets, or granules, or pellets may consist, for example, of starch, talc, calcium stearate, lactose, polyvinylpyrrolidone.

A pharmaceutically acceptable excipient for the manufacture of injection solutions may consist, for example, of water and polyvinylpyrrolidone.

A pharmaceutically acceptable excipient for syrup may be comprised, for example, of carbohydrate, thickener, and fruit extract.

As a carbohydrate, for example, sugar or sweeteners suitable for diabetics can be used.

As a sweetener, for example, sorbitol can be used.

As a thickener, for example, sodium alginate can be used.

As a fruit food extract, for example, an extract from apple fruits can be used.

A pharmaceutically acceptable excipient for preparing a suspension may consist, for example, of water, a preservative, and a fruit food extract.

As a preservative, for example, sodium metabisulfite can be used.

A method of obtaining the proposed composition in the form of tablets

The calculated amount of phospholipid and amino acid is mixed with a total content of 15-80 wt.% And their mass ratio 2: 1, the necessary amount of a pharmaceutically acceptable excipient is added to obtain a tablet mass containing, for example, starch, talc, calcium stearate, lactose, polyvinylpyrrolidone, and mix. From the resulting mass, kernels are formed into tablets. On the core of the tablets may be coated, comprising 5-10 wt.% By weight of the core.

A method of obtaining the proposed composition in the form of granules or pellets

The calculated amount of phospholipid and amino acids is mixed with a total content of 15-80 wt.% And their mass ratio 2: 1, the necessary amount of a pharmaceutically acceptable excipient containing, for example, starch, talc, calcium stearate, lactose is added, and the resulting mixture is moistened, for example, with polyvinylpyrrolidone . Pellets or granules are obtained from the resulting mass, the resulting cores are calibrated and dried. On the core of the pellets or granules can be coated, for example, on the basis of a polymer, comprising 12-20 wt. % by weight of the pellet core and 30-45 wt.% by weight of the pellet core. The resulting pellets or granules can be placed in gastro-soluble capsules, for example made of gelatin, in such an amount that the content of active substances in them is equivalent to a therapeutic dose.

- 2 009521

A method of obtaining the proposed composition in the form of a mixture for encapsulation

The estimated amount of prepared powders of phospholipid and amino acids with a total content of 15-80 wt.% And their mass ratio of 2: 1 is mixed with a pharmaceutically acceptable excipient, for example soybean oil. The resulting mixture is placed in gastro-soluble capsules, for example, made of gelatin, in such an amount that the content of active substances in them is equivalent to a therapeutic dose.

A method of obtaining the proposed composition in the form of a solution for injection

The calculated amount of phospholipid and amino acid powders with a total content of 15-80 wt.% And their mass ratio 2: 1 is mixed, a pharmaceutically acceptable excipient, for example, consisting of water and polyvinylpyrrolidone, is added and mixed. The resulting solution is filtered, Packed in ampoules and sterilized.

A method of obtaining the proposed composition in the form of syrup

To a pre-prepared pharmaceutically acceptable excipient, consisting, for example, of sugar syrup, a thickener and a fruit food supplement, add the calculated amount of phospholipid and amino acid powders with a total content of 15-80 wt.% And their mass ratio 2: 1. The resulting mixture is stirred and Packed in bottles.

A method of obtaining the proposed composition in the form of a suspension

The calculated amount of phospholipid and amino acid powders with a total content of 15-80 wt.% And their mass ratio of 2: 1 is mixed, a pharmaceutically acceptable excipient consisting, for example, of water, sodium metabisulfite, a fruit food supplement is added, mixed and Packed in bottles.

In the described methods for producing the proposed composition as a phospholipid used phospholipid that meets the requirements of IP; as an amino acid - a-amino-y-methylthiobutyric acid (methionine), which meets the requirements of FS 42-2787-99, and α-amino-b-hydroxybutyric acid (threonine), which meets the requirements of υδΡ27-ΝΕ22.

The following are specific examples of the manufacture of the proposed composition in the form of tablets. Example 1

10.0 g (10%) of soybean phospholipid and 5.0 g (5%) of methionine are mixed, 26.8 g (26.8%) of starch, 1.0 g (1%) of talc, 0.5 g are added. (0.5%) calcium stearate, 53.7 g (53.7%) of lactose and 3.0 g (3%) of polyvinylpyrrolidone. The result is a tablet with a total content of phospholipid and methionine 15% at a mass ratio of 2: 1.

Example 2

53.3 g (53.3%) of soy phospholipid and 26.7 g (26.7%) of methionine are mixed, 5.2 g (5.2%) of starch are added, 1.0 g (1%) of talc, 0.5 g (0.5%) of calcium stearate, 10.3 g (10.3%) of lactose and 3.0 g (3%) of polyvinylpyrrolidone. The resulting mixture was tabletted. The result is a tablet with a total content of phospholipid and methionine 80% at a mass ratio of 2: 1.

Example 3

Carried out, as example 1, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 4

Carried out, as example 2, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 5

Carried out, as example 1, only as an amino acid composition contains threonine.

Example 6

Carried out, as example 2, only as an amino acid composition contains threonine.

Example 7

Carried out, as example 3, only as an amino acid composition contains threonine.

Example 8

Carried out, as example 4, only as an amino acid composition contains threonine. Example 9

Is carried out, as example 1, only a tablet weighing 1 g is coated with a polymer shell. The mass of the shell is 0.05 g (5%) of the mass of the core.

Example 10

Is carried out, as example 1, only a tablet weighing 1 g is coated with a polymer shell. The mass of the shell is 0.1 g (10%) of the mass of the core.

Example 11

It is carried out, as example 2, only a tablet weighing 1 g is coated with a polymer shell. The mass of the shell is 0.05 g (5%) of the mass of the core.

Example 12

It is carried out, as example 2, only a tablet weighing 1 g is coated with a polymer shell. At

- 3 009521 the shell mass is 0.1 g (10%) of the mass of the core.

Example 13

Is carried out, as example 3, only a tablet weighing 1, the mass of the shell is 0.05 g (5%) of the mass of the core.

Example 14

Is carried out, as example 3, only a tablet weighing 1, the mass of the shell is 0.1 g (10%) of the mass of the core.

Example 15

Is carried out, as example 4, only a tablet weighing 1, the mass of the shell is 0.05 g (5%) by weight of the core.

Example 16

Is carried out, as example 4, only a tablet weighing 1, the mass of the shell is 0.1 g (10%) of the mass of the core.

Example 17

Is carried out, as example 5, only a tablet weighing 1, the mass of the shell is 0.05 g (5%) of the mass of the core.

Example 18

Is carried out, as example 5, only a tablet weighing 1, the mass of the shell is 0.1 g (10%) of the mass of the core.

Example 19

Is carried out, as example 6, only a tablet weighing 1, the mass of the shell is 0.05 g (5%) by weight of the core.

Example 20

Is carried out, as example 6, only a tablet weighing 1, the mass of the shell is 0.1 g (10%) of the mass of the core.

Example 21

Is carried out, as example 7, only a tablet weighing 1, the mass of the shell is 0.05 g (5%) by weight of the core.

Example 22

Is carried out, as example 7, only a tablet weighing 1, the mass of the shell is 0.1 g (10%) of the mass of the core.

Example 23

Is carried out, as example 8, only a tablet weighing 1, the mass of the shell is 0.05 g (5%) by weight of the core.

Example 24

Is carried out, as example 8, only a tablet weighing 1, the mass of the shell is 0.1 g (10%) of the mass of the core.

The following are specific examples of the manufacture of the proposed composition in the form of granules and pellets. Example 25

10.0 g (10%) of soy phospholipid and 5.0 g (5%) of methionine are mixed, 26.8 g (26.8%) of starch are added, 1.0 g (1%) of talc, 0.5 g (0.5%) calcium stearate and 53.7 g (53.7%) of lactose. The resulting mixture was moistened with 3.0 g (3%) of polyvinylpyrrolidone. From the obtained mass of the obtained mass, pellets or granules are obtained which are calibrated and dried. The result is granules or pellets with a total content of phospholipid and methionine of 15% at a mass ratio of 2: 1.

Example 26

53.3 g (53.3%) of soy phospholipid and 26.7 g (26.7%) of methionine are mixed, 5.2 g (5.2%) of starch are added, 1.0 g (1%) of talc, 0.5 g (0.5%) of calcium stearate, 10.3 g (10.3%) of lactose. The resulting mixture was moistened with 3.0 g (3%) of polyvinylpyrrolidone. From the obtained mass of the obtained mass, pellets or granules are obtained which are calibrated and dried. The result is a tablet with a total content of phospholipid and methionine 80% at a mass ratio of 2: 1.

Example 27

As example 25 is carried out, only as a phospholipid does the composition contain an egg yolk phospholipid.

Example 28

Carried out, as example 26, only as a phospholipid composition contains a phospholipid from egg yolk.

coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. When coated with a polymer shell. At

Example 29

Carried out, as example 25, only as an amino acid composition contains threonine. Example 30

Carried out, as example 26, only as an amino acid composition contains threonine.

Example 31

Carried out, as example 25, only as an amino acid composition contains threonine.

- 4 009521

Example 32

Carried out, as example 26, only as an amino acid composition contains threonine. Example 33

Is carried out, as example 25, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.225 g (30%) of the mass of the core.

Example 34

Is carried out, as example 25, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.338 g (45%) of the mass of the core.

Example 35

It is carried out, as example 26, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.225 g (30%) of the mass of the core.

Example 36

It is carried out, as example 26, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.338 g (45%) of the mass of the core.

Example 37

It is carried out, as example 27, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.225 g (30%) of the mass of the core.

Example 38

It is carried out, as example 27, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.338 g (45%) of the mass of the core.

Example 39

It is carried out, as example 28, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.225 g (30%) of the mass of the core.

Example 40

It is carried out, as example 28, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.338 g (45%) of the mass of the core.

Example 41

Is carried out, as example 29, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.225 g (30%) of the mass of the core.

Example 42

Is carried out, as example 29, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.338 g (45%) of the mass of the core.

Example 43

Is carried out, as example 30, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.225 g (30%) of the mass of the core.

Example 44

Is carried out, as example 30, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.338 g (45%) of the mass of the core.

Example 45

Is carried out, as example 31, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.225 g (30%) of the mass of the core.

Example 46

Is carried out, as example 31, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.338 g (45%) of the mass of the core.

Example 47

Is carried out, as example 32, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.225 g (30%) of the mass of the core.

Example 48

Is carried out, as example 32, only a granule weighing 0.75 mm is coated with a polymer shell. The mass of the shell is 0.338 g (45%) of the mass of the core.

Example 49

It is carried out, as example 25, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.18 g (12%) of the mass of the core.

Example 50

It is carried out, as example 25, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.3 g (20%) of the mass of the core.

Example 51

Is carried out, as example 26, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.18 g (12%) of the mass of the core.

Example 52

Is carried out, as example 26, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.3 g (20%) of the mass of the core.

- 5 009521

Example 53

It is carried out, as example 27, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.18 g (12%) of the mass of the core.

Example 54

It is carried out, as example 27, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.3 g (20%) of the mass of the core.

Example 55

It is carried out, as example 28, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.18 g (12%) of the mass of the core.

Example 56

It is carried out, as example 28, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.3 g (20%) of the mass of the core.

Example 57

It is carried out, as example 29, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.18 g (12%) of the mass of the core.

Example 58

It is carried out, as example 29, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.3 g (20%) of the mass of the core.

Example 59

It is carried out, as example 30, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.18 g (12%) of the mass of the core.

Example 60

It is carried out, as example 30, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.3 g (20%) of the mass of the core.

Example 61

Is carried out, as example 31, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.18 g (12%) of the mass of the core.

Example 62

Is carried out, as example 31, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.3 g (20%) of the mass of the core.

Example 63

It is carried out, as example 32, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.18 g (12%) of the mass of the core.

Example 64

It is carried out, as example 32, only pellets weighing 1.5 mm are coated with a polymer shell. The mass of the shell is 0.3 g (20%) of the mass of the core.

Examples of the manufacture of the proposed composition for encapsulation

Example 65

10.0 g (10%) of soybean phospholipid and 5.0 g (5%) of methionine are mixed with 85.0 g (85%) of soybean oil. The result is a mixture with a total content of phospholipid and methionine 15% at a mass ratio of 2: 1. The mixture is encapsulated.

Example 66

53.3 g (53.3%) of soybean phospholipid, 26.7 g (26.7%) of methionine, are mixed with 20.0 g (20%) of soybean oil. The result is a mixture with a total content of phospholipid and methionine 80% at a mass ratio of 2: 1. The mixture is encapsulated.

Example 67

Carried out, as example 65, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 68

Carried out, as example 66, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 69

Carried out, as example 65, only as an amino acid composition contains threonine.

Example 70

Carried out, as example 66, only as an amino acid composition contains threonine.

Example 71

Carried out, as example 67, only as an amino acid composition contains threonine. Example 72

Carried out, as example 68, only as an amino acid composition contains threonine. Examples of the manufacture of the proposed composition in the form of a solution for injection

Example 73

Take 10.0 g (10%) of the phospholipid from soy, 5.0 g (5%) of methionine, 3 g (3%) of polyvinylpyrrolidone and

- 6 009521

72.0 g (72%) of water for injection. In this case, a solution is obtained with a total content of phospholipid and methionine of 15% at a mass ratio of 2: 1.

Example 74

53.3 g (53.3%) of the soybean phospholipid, 26.7 g (26.7%) of methionine, 3 g (3%) of polyvinylpyrrolidone and 17.0 g (17%) of water for injection are taken. In this case, a solution is obtained with a total content of phospholipid and methionine of 80% at a mass ratio of 2: 1.

Example 75

Carried out, as example 73, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 76

Carried out, as example 74, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 77

Carried out, as example 73, only as an amino acid composition contains threonine.

Example 78

Carried out, as example 74, only as an amino acid composition contains threonine.

Example 79

Carried out, as example 75, only as an amino acid composition contains threonine.

Example 80

Carried out, as example 76, only as an amino acid composition contains threonine.

Examples of the manufacture of the proposed composition in the form of syrup

Example 81

Take 10.0 g (10%) of the soy phospholipid, 5.0 g (5%) of methionine, 1.0 g (1%) of the fruit food supplement, 71.4 g (71.4%) of sugar syrup and 12, 6 g (12.6%) of sodium alginate. The resulting mixture is stirred and packaged. In this case, a syrup is obtained with a total content of phospholipid and methionine of 15% at a mass ratio of 2: 1.

Example 82

Take 53.3 g (53.3%) of soy phospholipid, 26.7 g (26.7%) of methionine, 1.0 g (1%) of a fruit food supplement, 16.15 g (16.15%) of sugar syrup and 2.85 g (2.85%) of sodium alginate. The resulting mixture is stirred and packaged. In this case, a syrup is obtained with a total content of phospholipid and methionine of 80% at a mass ratio of 2: 1.

Example 83

Carried out, as example 81, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 84

Carried out, as example 82, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 85

Carried out, as example 81, only as an amino acid composition contains threonine.

Example 86

Carried out, as example 82, only as an amino acid composition contains threonine.

Example 87

Carried out, as example 83, only as an amino acid composition contains threonine.

Example 88

Carried out, as example 84, only as an amino acid composition contains threonine.

Example 89

Carried out, as example 81, only as a carbohydrate composition contains sorbitol syrup. Example 90

Carried out, as example 82, only as a carbohydrate composition contains sorbitol syrup.

Examples of the manufacture of the proposed composition in the form of a suspension

Example 91

Take 10.0 g (10%) of soy phospholipid, 5.0 g (5%) of methionine, 0.5 g (0.5%) of a fruit food supplement, 0.1 g (0.1%) of sodium metabisulfite and 84.4 g (84.4%) of water. The resulting mixture is stirred and packaged. In this case, a suspension is obtained with a total content of phospholipid and methionine of 15% at a mass ratio of 2: 1.

Example 92

Take 53.3 g (53.3%) of the soy phospholipid, 26.7 g (26.7%) of methionine, 0.5 g (0.5%) of the fruit food supplement, 0.1 g (0.1%) ) sodium metabisulfite and 19.4 g (19.4%) of water. The resulting mixture is stirred and packaged. In this case, a suspension is obtained with a total content of phospholipid and methionine of 80% at a mass ratio of 2: 1.

Example 93

Carry out, as example 91, only as a phospholipid, the composition contains phospholipid

- 7 009521 from the egg yolk.

Example 94

Carried out, as example 92, only as a phospholipid composition contains a phospholipid from egg yolk.

Example 95

Carried out, as example 91, only as an amino acid composition contains threonine.

Example 96

Carried out, as example 92, only as an amino acid composition contains threonine.

Example 97

Carried out, as example 93, only as an amino acid composition contains threonine. Example 98

Carried out, as example 94, only as an amino acid composition contains threonine.

Determination of phospholipid content in the proposed compositions is carried out by spectrophotometric method, of essential amino acids, in particular methionine, by direct titration.

Tests for microbiological purity of tablets, granules, pellets and capsule mass obtained in examples 1-72, the syrup obtained in examples 81-88, and suspensions obtained in examples 89-96, were carried out in accordance with the requirements of Global Fund XI and Changes No. 3, category 3B. The results obtained comply with regulatory requirements.

The sterility tests of the injection solution obtained in Example 73-80 were carried out in accordance with the requirements of Global Fund XI. The results obtained comply with regulatory requirements.

Studies have been conducted to study the effect of physical factors, such as temperature and light, on the pharmaceutical compositions described in Examples 1-96.

After conducting research, it was found that the best storage conditions are in a dry place at a temperature of no higher than 25 ° C.

In order to determine the general toxic effect and evidence of the effectiveness of the proposed pharmaceutical products, preclinical trials were conducted.

These tests were conducted at the central research laboratory of the Nizhny Novgorod State Medical Academy in December 2004.

For testing, the proposed pharmaceutical composition was presented in the form of hard gelatin capsules (TFA). The content of the components in mg per capsule is presented in the table below.

The composition of the proposed pharmaceutical composition per capsule

Phospholipids 200 mg Methionine 100 mg Soybean oil Up to 550 mg

Experimental studies were conducted in accordance with the requirements of the normative document “Guidelines for the experimental (preclinical) study of new pharmacological substances” - M., IIA “Remedium”. - 2000 and Order of the Ministry of Health of Russia dated 06/19/03 No. 267 “On approval of laboratory practice rules in the Russian Federation”.

In the experiments, we used sexually mature outbred white rats (Stolbovaya nursery, GU Scientific Center BMT RAMS). Experimental groups of animals were formed by random sampling, taking into account body weight as a determining indicator.

To assess the effectiveness of the proposed pharmaceutical composition, it was administered intragastrically in a 2% starch gel through a probe.

Given the intended course of the drug in humans, the duration of administration of the composition to animals during the experiment was 30 days.

When calculating the doses, we proceeded from the daily dose of a hard gelatin capsule: 6 capsules (2 capsules 2-3 times a day) with a total content of essential phospholipids of 1800 mg per person weighing 70 kg and taking into account the conversion factor in rats of 5.9 for essential phospholipids: 25 7-5.9 = 152 mg / kg.

Acute toxicity was determined on randomly bred white male mice weighing 20-22 g. The studied composition was administered to mice once intraperitoneally at doses of 3000, 5000, and 6000 mg / kg. Observation of the animals was carried out for 14 days.

The introduction of the composition with intraperitoneal administration at doses of 3000, 5000, and 6000 mg / kg caused a slight change in behavioral reactions in mice, manifested in the form of increased respiration, grouping of animals, and decreased motor activity. This condition of the animals lasted for 30-40 minutes, after which the behavioral reactions gradually returned to normal. The death of animals was not observed (table. 1). The introduction of large doses is technically impossible, which did not allow to determine the average lethal dose.

The increase in body weight, daily intake of dry, wet food and water in experimental animals under the influence of the proposed composition did not have statistically significant differences with the control

- 8 009521 lem (tab. 2, 3, 4, 5). The behavioral reactions of experimental animals did not differ significantly from control animals.

When exposed to the proposed composition for 30 days in the peripheral blood of rats of all experimental groups, there were no significant differences from the control of the studied parameters (erythrocytes, leukocytes, hemoglobin, reticulocytes, platelets, leukocyte formula). The data are presented in table. 6, 7.

The introduction of the proposed composition within 30 days of the experiment did not affect the state of the blood coagulation system of experimental animals, judging by the parameters of the coagulogram (table. 8).

A study of the functional state of the liver and pancreas showed that the introduction of the proposed TFA composition for 30 days did not affect the excretory, absorption and protein synthesizing function of the liver in all experimental animals (Tables 9, 10).

The lipid function of the liver and blood glucose in all experimental groups did not differ from the control (tab. 11, 12).

The proposed composition, TFA, did not have a noticeable effect on the concentration of total cholesterol in the blood serum of animals of all experimental groups (Table 13).

When studying the functional state of the kidneys, it was found that under the influence of the proposed composition - TFA - the functional state of the kidneys in all experimental animals was practically unchanged (tab. 14-20).

When studying the functional state of the cardiovascular system, it was found that after 30 days of administration of the proposed composition, TFA does not cause statistically significant changes on the part of the studied electrocardiogram parameters in experimental animals (Tables 21, 22).

A study of the state of the nervous system showed that 30 days after the start of the introduction of the proposed composition - TFA - the parameters of the main conditioned and unconditioned reflexes did not differ significantly from the control (Tables 23, 24).

After 1 month of administration of the proposed composition - TFA - indicators of total motor activity and emotional state did not significantly differ from control (table. 25).

After 30 days of administration of the proposed composition visually and during histological studies, no local irritant effect was found in any group.

During the experiment, the death of animals was not observed.

Examination of the animals showed that they are all well-fed, have the correct physique, are neat, the hairline and natural openings are clean.

During a visual examination during autopsy from the internal organs, no significant differences were found in the experimental and control rats. The organs are correctly located, there is no free fluid in the chest and abdominal cavities. No visual signs of pathology of organs and tissues were found.

Heart muscle and valves unchanged. The gleams of the trachea and large bronchi are free. The lung tissue is airy, pink in color, without signs of edema. The mucous membrane of the stomach, duodenum, small and large intestines and appendix without ulceration and hemorrhage. The capsule of the kidneys is easily removed, on the cut the cortical and medulla are clearly distinguishable. The thymus is gray-pink, not enlarged. The thyroid gland is pink in color with a clearly visible parathyroid gland. Adrenal glands unchanged. Shells of the brain are not strained, convolutions are well defined. Genitals without any abnormalities.

For pathomorphological studies, the following organs were taken from experimental animals of all groups: brain, heart, lymph nodes, spleen, thyroid and parathyroid glands, thymus, adrenal glands, pituitary gland, stomach, small and large intestines, pancreas, liver, lungs, kidneys, testes.

The determination of the relative mass of the organs of experimental animals did not reveal significant differences from the control when exposed to the proposed composition in the studied doses (table. 26).

Histological studies showed that the morphological structure of the internal organs of control animals is normal. No pathological changes were found at the injection site.

According to the results of the experiment, the proposed composition - TFA - in the studied doses did not cause significant changes in the integral indicators in experimental animals (weight gain, behavioral reactions, food, water consumption), cellular composition and parameters of peripheral blood coagulation, excretory, absorbent, protein synthesizing, the carbohydrate function of the liver, the level of cholesterol in blood serum, the functional state of the excretory, cardiovascular and nervous systems. The proposed composition - TLC - did not have a local irritant effect.

The composition in the studied doses did not cause structural disturbances in organs and tissues. Under the influence of the proposed composition at a dose of 700 mg / kg, plethora in the liver and mild hepatocyte dystrophy were noted.

- 9 009521

Table 1

The acute toxicity parameters of the proposed composition

Animal species Route of administration Dose of the drug (mg / kg) The number of dead animals in the group ϋίΐ6 Peso oi Mice in / b 3000 5000 6000 0/6 0/6 0/6 - > 6000

table 2

The increase in body weight of rats when exposed to the proposed composition (M ± t; n = 11)

Group No. Floor Dose mg / kg Body weight g Measurement days Background 10 days 20 days 30 days one 70.0 208.6 + \ - 4.2 233.2 + \ - 3.9 270.9 + \ - 5.8 285.4 + \ - 6.7 2 3 700,0 205.9 + \ - 4.5 235.5 + \ - 4.6 264.1 + \ - 3.7 281.0 + \ - 10.9 3 in the control 204.5 + \ - 4.3 241.4 + \ - 7.7 276.8 + \ - 9.8 289.5 + \ - 13.3

Table 3 The daily consumption of dry food in grams per rat when exposed to the proposed composition (M)

Group No. Floor Dose mg / kg The number of rats in the group Measurement days Background 10 days 20 days 30 days one 3 70.0 eleven 25.5 24.0 25.5 24.5 2 3 700,0 eleven 24.3 23,2 24.5 23,2 3 3 the control AND 24.5 19.5 26,4 24.1

Table 4

The daily intake of boiled food in grams per rat when exposed to the proposed composition (M)

№№ groups Floor Dose mg / kg The number of rats in the group Measurement days Background 10 days 20 days 30 days one 3 70.0 AND 23.6 24.5 24.5 23.9 2 3 700,0 eleven 24.1 25.0 23,2 24.8 3 3 the control eleven 26,4 25.5 24.1 26.1 one

Table 5

The daily water intake of rats when exposed to the proposed composition ml / 1 is alive. (M)

№№ groups Floor Dose mg / kg The number of rats in the group Measurement days Background 10 days 20 days 30 days one 3 70.0 eleven 24.0 25.5 25.5 24.6 2 about 700,0 AND 23,2 24.5 25.9 26,4 3 3 the control eleven 19.5 26,4 245 25.5 _

- 10 009521

Table 6

The condition of the peripheral blood in rats before the introduction of the proposed composition (M ± t; n = 10)

No. No. Floor Dose mg / kg Hemoglobin, G / l Red blood cells, T / L Color indicator Reticulocytes % Platelets, g / l Leiko cit, g / l Leukogram (g / l) Neutrophils Lymphocytes Monocytes Eosinophils PO Box s / i one <3 70.0 129.5 gu-3.5 7.7 + \ - 0.4 0.87 + U-0.07 29.3 + \ - 1.9 475.0 + U-34.3 14.3 + Y-0.7 0.23 + \ - 0,03 2.39 + \ - 0.26 11.3 GU-0.6 0.09 Γί- 0,03 0.2 gU-0.1 2 3 700,0 129.3 + \ - 5.7 7.5 GU-0.3 0.87 gou-0.04 30,4 + \ - 1.9 516.5 GU-27.4 13.6 + \ - 1.2 0.18 τί- Ο, 03 2.33 τί- 0.55 10.8 gu-0.9 0.15 + Y- 0.04 0.1 + U-OD 3 > 3 the control 127.4 GU-4.0 8.0 gu-0,5 0.82 t \ -0.06 30.3 + Y-1.9 555.5 + U-43.9 14.1 g \ -0.9 0.20 τί- Ο, 03 2.19 Γί- 0.28 11.5 GU-0.7 0.13 g 0.04 0.1 g

Table 7

The state of peripheral blood in rats after 30 days of administration of the proposed composition (M ± t; n = 10)

No. No. Floor Dose mg / kg Hemoglobin, g / l Red blood cells, T / L Color indicator Reticulocytes % Thrombocyte you, g / l White blood cells G / l Leukogram (g / l) Neutrophils Lymphocytes Mo- noci you Eosinophils PO Box s / i one 70.0 129.5 g \ -3.5 8.5 gU-0.5 0.80 g-0.07 21.5 g \ -1.2 475.8 g \ -35.7 12.4 + \ - 1.2 0.15 + Y- 0,03 1,67 Α- 0.33 10.4 g \ -1.0 0.02 gu 0.02 0.2 g \ -0.1 2 700,0 129.3 GU-5.7 8.9 + U-0.3 0.74 g-0.06 22.0 g \ -1.3 528.4 GU-25.4 13.4 gou-0.9 0.17 g \ - 0.02 1,62 R \ - 0.15 11.5 + U-0.8 0.01 Α- 0.01 0.1 + \ - 0.1 3 <3 the control 127.4 + \ - 4.0 8.7 g'-0.2 0.73 gu-0.03 24.0 g \ -1.0 471.2 g \ -28.6 13.5 g \ -1.0 0.20 + Y- 0,03 1.65 g \ - 0.38 11.5 g \ -0.9 0.03 g \ - 0.02 0.1 gu-0,1

Table 8

The state of blood coagulation in rats after 30 days of administration of the proposed composition (M ± t; n = 10)

№№ corpse py Floor Dose mg / kg Coagulation, sec. Clotting speed Start the end Duration for 1 min for 2 min min one -Λ ABOUT 70.0 121.0 GU- 23.9 231.0 + \ 45.9 230,0 GU-26.9 0.83 g. 0.16 0.40 GU- 0.11 0.33 G'- 0.12 2 3 700,0 127.6 GU26.0 350.6 GU 30.6 223.0 g \ -24.5 0.60 + Y- 0.08 0.42 + Y- 0.10 0.26 + Y- 0.06 3 about con troll 120.9 + Y- 17.9 300,3 GU- 24.0 179.4 GU-13.1 0.83 g \ - 0.17 0.69 R \ - 0.16 0.21 GU- 0.14

Table 9

The state of absorption and excretory function of the liver of rats after 30 days of administration of the proposed composition (M ± t; n = 10)

№№ groups Floor Dose mg / kg Retention of BSF in the blood, (%) one g 70.0 14.25 g-0.37 2 3 700,0 14.94 + U-0.26 3 <3 the control 14.42 + U-0.49

- 11 009521

Table 10

The effect of the proposed composition on the concentration of total protein in rat serum (M ± t; n = 10)

Group No. Floor Dose mg / kg Total serum protein (g / l) Before the introduction After 30 days of administration one At 70.0 86.41 +) - 2.44 88.19 +) - 1.5 2 700,0 85.48 +) - 2.39 89.48 +) - 1.67 3 in con troll 85.73 +) - 1.57 88.34 +) - 1.62

Table 11

The influence of the proposed composition on the content of total lipids in the blood serum of rats (M ± t; n = 10)

Group No. Floor Dose mg / kg Total lipids (g / l) Before the introduction After 30 days of administration one in 70.0 2.51 +) - 0.08 2.10 +) - 0.13 2 at 700,0 2.47 +) - 0.01 2.04 + \ - 0.11 3 At the control 2,52 +) - 0.08 1.94 +) - 0.12

Table 12

The influence of the proposed composition on the glucose ____________ in blood serum (M ± t; p = 10)

Group No. Floor Dose mg / kg Serum Glucose (mM / L) Before the introduction After 30 days introductions one <3 70.0 3.74 +) - 0.11 3.96 +) - 0.17 2 700,0 3.84 +) - 0.11 3.93 +) - 0.11 3 3 the control 3.84 +) - 0.10 3.70 +) - 0.11

Table 13 The effect of the proposed composition on the concentration of total cholesterol in the blood serum of rats (M ± t; n = 10)

Group No. Floor Dose mg / kg Total cholesterol (mM / L) Before the introduction After 30 days of administration one 3 70.0 1.83 +) - 0.07 1.74 +) - 0.06 2 700,0 1.79 +) - 0.08 1.73 +) - 0.09 3 at the control 1.85 +) - 0.08 1.76 +) - 0.08

- 12 009521

Table 14

Indicators of the excretory system of rats before the introduction of the proposed composition (M ± t; n = 10)

No. gr. Floor Dose mg / kg Diuresis in 18 hours, ml urine pH, units The specific gravity of urine, g / cm ³ Urea concentration, mM / L The urea content in urine, mm / 18 hours sk m to son. blood in urine one 70.0 2.21 + 1-0.22 6.7 + 1-0.1 1,041 + 1-0.002 7.12 + 1-0.20 41.13 + 1-1.09 0,092 + 1-0,011 0.24 + 1-0.02 2 Τ ' ABOUT 700,0 2.52 + 1-0.20 6.5 + 1-0.1 1,042 + 1-0.002 7.34 + 1-0.21 40.79 + 1-1.05 0.103 + 1-0.008 0.27 +1 0.01 3 con troll 2,51 + 1-0.28 6.6 + 1-0.1 1,043 + 1-0,002 7.20 + 1-0.13 40.79 + 1-0.98 0.103 + 1-0.013 0.27 + 1-0.02

Table 15

Indicators of the excretory system of rats after 30 days of administration of the proposed composition (M ± t; n = 10)

No. gr. Floor Dose mg / kg Diuresis for 18 hours, ml urine pH, units The specific gravity of urine, g / cm ³ Urea concentration, mM / L The urea content in the urine, mm / 18 hours sk m in the batch. blood in urine one 51 70.0 3.19 + 1-0.41 6.9 + 1-0.1 1,041 + 1-0.002 7.13 + 1-0.19 40.87 + 1-0.72 0.130 + 1-0.016 0.31 + 1-0.03 Ί at 700,0 3.26 6.7 1,043 7.37 40.64 0.132 0.23 + 1-0.34 + 1-0.1 + 1-0.002 + 1-0.15 + 1-1.04 + 1-0.014 + 1-0.02 con 3.64 6.8 1.041 7 ΊΊ 40.40 0.148 0.32 ό troll + 1-0.50 + 1-0.1 + 1-0.002 + 1-0.17 + 1-0.76 + 1-0.021 + 1-0.03

Table 16

The state of the secretory function of the kidneys of rats after 30 days of administration of the proposed composition (M ± t; n = 10)

№№ groups Floor Dose mg / kg Excretion of phenol red mg / 2 hours one in 70.0 41.61 + \ - 2.50 2 700,0 39.45 + 1-1,44 3 3 the control 38.23 + 1-0.89

Table 17

Rat mineral metabolism prior to the introduction of the proposed composition (M ± t; n = 10)

Group No. - Floor Dose mg / kg Potassium Sodium Ν3 + / Κ + serum, mmol / l Urine serum, mmol / l Urine mm / 18 h mm / 18 h one in 70.0 6.44 + 1-0.33 0.47 + 1-0.05 165.3 + 1-4.1 0.48 + 1-0.07 25.6 / 1 2 b 700,0 6.50 + 1-0.35 0.50 + 1-0.06 161.8 + 1-4.9 0.47 + 1-0.06 24.8 / 1 3 in con troll 6.50 + 1-0.31 0.52 + 1-0.06 173.1 + 1-4.9 0.50 + 1-0.07 26.6 / 1

- 13 009521

Table 18

Rat mineral metabolism after 30 days of administration of the proposed composition (M ± t; n = 10)

№№ corpse py Floor Dose mg / kg Potassium Sodium Ma 1 / Kg ¹ serum, mmol / l Urine serum, mmol / l Urine mm / 18 h mm / 18 h one 3 70.0 6.55 +/- 0.35 0.68 +/- 0.10 186.2 +/- 6.8 0.93 +/- 0.15 28.4 / 1 2 3 700,0 6.96 +/- 0.45 0.67 +/- 0.09 187.1 +/- 8.01 0.82 +/- 0.14 26.9 / 1 3 3 the control 6.60 +/- 0.40 0.69 +/- 0.11 182.7 +/- 6.6 0.98 +/- 0.16 27.7 / 1

Table 19 Glomerular filtration of the kidneys of rats before the introduction of the proposed composition (M ± t; p = 10)

№№ corpse py Floor Dose mg / kg Diuresis in 18 hours ml Creatine concentration Nina, Creatinine clearance, ml / min μM / L mm / l in blood serum in urine one 3 70.0 2.21 +/- 0.22 69.31 +/- 2.61 10.18 +/- 0.14 0.30 = + 0.03 2 3 700,0 2,52 +/- 0.19 68.15 +/- 1.95 10.23 +/- 0.32 0.35 +/- 0.03 3 3 con troll 2,51 +/- 0.28 71.34 +/- 2.94 10.21 +/- 0.18 0.33 +/- 0.04

Table 20 Glomerular filtration of the kidneys of rats after 30 days of administration of the proposed composition (M ± t; p = 10)

Group No. Floor Dose mg / kg Diuresis in 18 hours ml Concent Creati μM / L grace Nina, mmol / l Creatinine clearance, ml / min in blood serum in urine one 3 70.0 3.19 +/- 0.41 73.37 +/- 1.99 10.41 +/- 0.10 0.43 +/- 0.06 $ 700,0 3.26 71.09 10.18 0.44 +/- 0.34 +/- 2.63 +/- 0.17 +/- 0.05 3 3 the control 3.64 +/- 0.50 73.65 +/- 2.07 10.39 +/- 0.25 0.48 +/- 0.07

Table 21

The rat ECG parameters before exposure to the proposed composition (M ± t; n = 10)

No. No. gru pp =: o E Dose mg / kg Amplitude of teeth, mv Duration of intervals, sec heart rate in minutes R to 1 8 t RC Ok 8 FROM QC one 70.0 0,098 + \ - 0.005 0.34 + \ - 0.03 0.045 + \ - 0.019 0,083 + \ - 0.006 0.041 + 4-0.001 0.019 + \ - 0.001 0.058 + 4-0.001 0.112 + 4-0.002 535.2 + 4-7.5 2 from? 700,0 0.102 + \ - 0.003 0.33 + \ - 0.02 0.015 + -0.011 0,083 + \ - 0.007 0,041 + \ - 0.001 0.018 + 4-0.001 0.054 + \ - 0.001 0.112 + 4-0.001 536.4 + \ - 3.7 3 <3 the control 0.103 + \ - 0.005 0.36 + \ - 0.03 0.046 + 4-0.038 0.084 + 4-0.005 0,040 + 4-0.001 0.018 ++ 0.001 0.056 ++ 0.002 0.111 + 4-0.002 542.4 + 4-7.0

- 14 009521

Table 22

The ECG parameters of rats after 30 days of administration of the proposed composition (M ± t; p = 10)

No. No. gruy =: o E Dose mg / kg Amplitude of teeth, mv Duration of intervals, sec heart rate in minutes R to 5; t RB FROM kk one 3 70.0 0.098 + 3-0.004 0.33 + 3-0.03 0.056 + 3-0.019 0,090 + 3-0.005 0.041 + 3-0.001 0.0197 + 3-0,0006 0,055 + 3-0,001 0.114 + 3-0.001 527.8 + 3-5.9 2 3 700,0 0,100 + 3-0.004 0.34 + 3-0.02 0.056 + 3-0.022 0.089 + 3-0.004 0,042 + 3-0.001 0.0197 + 3-0.0006 0.058 + 3-0.001 0.115 + 3-0.001 522.0 + 3-3.8 3 3 the control 0.102 + \ - 0.003 0.35 + 3-0.02 0,066 + 3-0.032 0,087 + 3-0.004 0.042 + 3-0.001 0.0196 + 3-0,0007 0.058 + 3-0.002 0.114 + 3-0.002 529.0 + 3-7.1

Table 23 Functional indicators of the state of the nervous system of rats before the introduction of the proposed composition. (M ± m; n = 11)

No. No. gru pp Floor Dose mg / kg Open field Mink reflex Intersection of squares Racks Minds vania Purges Shaking off Bowel movements 15 minutes 6-10 min in 10 min δ 70.0 69.3 + 3-8.6 18.0 <-3-2.0 3,1 L-0.8 2.9 L-0.4 2.0 + \ - 0.6 4.1 L-0.6 5,6 L-1,5 2.7 L-1,5 8.4 L-2,3 2 δ 700,0 74.3 + 3-13.9 16.9 + 3-2.5 3,7 L-0.7 3,7 L-0.7 1,2 L-0.4 4.4 L-0.7 4.6 L-1,1 2.9 L-1,5 7.5 L-2.0 3 δ the control 63.5 L-13.1 18.5 L-4.0 4.6 L-0.9 2,3 L-0.6 0.9 L-0.4 4.6 L-0.5 8.2 L-2.0 3.0 L-0.9 11.2 L-2.6

Table 24 Functional indicators of the state of the nervous system of rats after 30 days of administration of the proposed composition (M ± t; n = 11)

No. gru 11111.1 Floor Dose mg / kg Open field Mink reflex Intersection of squares Racks Wash niya Purges Shaking off Bowel movements 1-5 min 6-10 m and n in 10 min ..BUT 70.0 46.1 L-12.4 9.5 L-2,1 3.0 L-0.8 1,5 L-0.7 0.6 L-0.5 2.2 L-0.6 2.4 L-0.7 2,3 L-0.7 4.6 L-1.2 2 700,0 43,4 L-14.9 10.4 L-3,5 3,1 L-0.7 1,5 L-0.8 1.5 + \ - 0.6 3.0 L-0.7 1,5 L-0.9 1.3 L-0.6 2.7 L-1,4 s the control 30.9 L-12.5 8.3 L-2,4 1.8 + 3-0.6 1.1 L-0.5 1.4 L-0.7 3.4 L-0.8 1.0 + \ - 0.4 1.6 L-0.7 2.6 L-0.9

Influence

Table 25 of the composition on the motor activity of rats (M ± t; n = 11)

№№ group py Floor Dose mg / kg Locomotion Bowel movements Before introduction After 30 days of administration Before introductions After 30 days of administration one 3 70.0 187.18 + 3-12.97 163.55 + 3-15.32 2.91 + 3-0.83 3.27 + 3-0.87 2 3 700,0 183.64 + 3-13,03 168.18 + 3-18,08 3.00 + 3-0.69 3.18 + 3-0.94 3 3 the control 188.18 + 3-17.43 165.27 + 3-20.06 2.36 + 3-0.96 1.82 + 3-0.92

Table 26

The relative mass of rat organs in an experiment to study the general toxic effects of the proposed composition (M ± t; n = 10)

No. No. Floor Dose mg / kg The ratio of body weight to body weight (%) Liver A heart Selka Zenka Kidney Adrenal glands Testis Thyroid Brain Mr. pituitary left great vaya left right left right one in 70.0 3.78 + 3- 0.12 0.37 + \ - 0.02 0.60 + 3- 0.05 0.37 + 3- 0.01 0.36 + 3- 0.01 0.014 + 3- 0.002 0.015 + 3- 0.002 0.522 + 3- 0.014 0.518 + 3- 0.015 0.007 + 3- 0.001 0.622 + 3-0.020 0.0035 + 3-0.0001 2 3 700,0 con troll 3.62 ΓΙΟ, 01 0.38 + 3- 0.01 0.49 ΓΙ- Ο, 04 0.39 + 3- 0.01 0.37 ΓΙ- Ο, 01 0.011 ΓΙ- Ο, 001 0.012 ΓΙ- Ο, 001 0.543 + 3- 0,025 0.538 + 3- 0,023 0.007 ΓΙ- Ο, 001 0.666 + 3-0.018 0.0036 + 3-0,0002 3 3 3.71 ΓΙ- Ο, 01 0.36 + 3- 0.01 0.50 + 3- 0.05 0.39 + 3- 0.02 0.38 _: 0.010 + 3-: ΓΙ- Ο, 01 0.001 0.011 ΓΙ- Ο, 001 0.511 + 3- 0,020 0.514 ΓΙ- Ο, 020 0.008 + 3- 0.001 0.661 + \ - 0,033 0.0036 + 3-0,0002

- 15 009521

Thus, the choice of active substances - phospholipids and amino acids, the choice of their quantitative values, the implementation of the composition in the form of tablets, or pellets, or granules, or capsules, or an injection solution, or syrup, or suspension allows us to obtain a new technical result - the creation of an effective pharmaceutical compositions with hepatoprotective activity and normalizing lipid, protein and carbohydrate metabolism.

Claims (15)

CLAIM 1. A pharmaceutical composition with hepatoprotective activity and normalizing metabolic processes, and containing a phospholipid of both vegetable and animal origin, an organic acid and a filler, characterized in that it contains an essential amino acid as an organic acid with a total content of phospholipid and amino acid 15- 80 wt.% And their mass ratio of 2: 1. 2. The pharmaceutical composition according to claim 1, characterized in that it contains a-amino-methyl-thiobutyric acid (methionine) or α-amino-in-hydroxybutyric acid (threonine) as an essential amino acid. 3. The pharmaceutical composition according to claim 1, characterized in that it contains, as a phospholipid of vegetable origin, for example, a phospholipid from soy. 4. The pharmaceutical composition according to claim 1, characterized in that it contains, as an animal phospholipid, for example, an egg yolk phospholipid. 5. The pharmaceutical composition according to PP.3-4, characterized in that the phospholipid contained in it contains 73-79 wt.% Phosphatidylcholine. 6. The pharmaceutical composition according to claim 1, characterized in that it contains a pharmaceutically acceptable excipient, allowing it to be made in the form of a tablet, or granules, or pellets. 7. The pharmaceutical composition according to claim 6, characterized in that the tablets, or granules, or pellets can be coated on the basis of the polymer. 8. The pharmaceutical composition according to claim 7, characterized in that the mass of the shell in relation to the mass of the core is, wt.%: For tablets - 5-10, for pellets - 12-20, for granules - 30-45. 9. The pharmaceutical composition according to PP.6-8, characterized in that a certain amount of pellets or granules can be placed in a pharmaceutically acceptable capsule for oral administration. 10. The pharmaceutical composition according to claim 9, characterized in that the capsule can be filled with pellets or granules in such an amount that the content of active ingredients in them is equivalent to a therapeutic dose. 11. The pharmaceutical composition according to claim 1, characterized in that it contains vegetable oil as a filler, for example soybean oil. 12. The pharmaceutical composition according to claim 11, characterized in that it can be placed in a capsule for oral administration in such a quantity that the content of active ingredients in it is equivalent to a therapeutic dose. 13. The pharmaceutical composition according to claim 1, characterized in that it contains a pharmaceutically acceptable excipient, allowing to obtain it in the form of a solution for injection. 14. The pharmaceutical composition according to claim 1, characterized in that it contains a pharmaceutically acceptable excipient, allowing it to be obtained in the form of a syrup. 15. The pharmaceutical composition according to claim 1, characterized in that it contains a pharmaceutically acceptable excipient, allowing to obtain it in the form of a suspension.