Substance lipovitan e, a potent antioxidant, and vitamin complex

 

(57) Abstract:

The invention relates to medicine, namely to the pharmaceutical industry, to create substance "Lipovitan E, vitamin complex. The invention lies in the fact that the proposed substance contains alpha-tocopherol acetate and phospholipids or phosphatides. Also offered in pill form vitamin complex, including substance "Lipovitan E" and additionally magnesium basic carbonate, microcrystalline cellulose, potato starch, calcium stearinovokisly. The invention provides improved antioxidant activity and can be used in the prevention of oxidative damage to cells and tissues caused by various exogenous factors. 2 S. and 3 C.p. f-crystals, 1 Il.

The invention relates to the field of pharmaceutical industry, namely the creation of a vitamin complex.

Known alpha-tocopherol acetate, which is used in medical practice in the form of a solution and capsules /M. D. Mashkovsky "Drugs", Ed. Medicine M., 1985, so 2, S. 37-38/.

The technical task of the present invention is to expand the range of domestic vitamin PR the Xia group of inventions, United General inventive.

The substance, called "Lipovitan E contains alpha-tocopherol acetate, phospholipids or phosphatides in the following ratio of ingredients, in mg/g:

Alpha-tocopherol acetate - 10-90

Phospholipids or phosphatides - 20-180

In addition, a vitamin complex, including substance containing alpha-tocopherol acetate, phospholipids or phosphatides. Vitamin complex is a preformed shape and further comprises magnesium basic carbonate, potato starch, calcium stearinovokisly and microcrystalline cellulose in the following ratio of components in g per 1 tablet weight of 0.3 to 0.5:

Alpha-tocopherol acetate - 0,0017-0,015

Phospholipids or phosphatides - 0,003-0,030

Magnesium carbonate basic - 0,04-0,10

Microcrystalline cellulose - 0,02-0,10

Potato starch - 0,004-0,05

Calcium stearinovokisly - 0,002-0,01

Vitamin complex optionally contains butylacetamide in the number 0,00003.

Vitamin complex contains phosphatides sunflower seeds or soy phospholipids or sunflower, and as a sorbent sorbitol and/or sugar and/or salt ovarennost sorbent use sorbitol or sugar, salt cookbook, xylitol food, mannitol, sugar of milk (lactose), a mixture of the above sorbents.

The estimated amount of the sorbent distribute a layer of 0.2-0.3 cm on the metal tray and dried at a temperature of 50-20oC for 5 hours. The residual humidity of the dry sorbent should not exceed 4-6%.

Dry sorbent milled to obtain a particle size of 5-20 μm. Next, the calculated quantity of phospholipids, Tocopheryl acetate, chloroform, and optionally butylacetate stirred for 30 minutes. In the resulting coarse powder of the drug "Lipovitan E" add sorbent and stirred at a pressure of 0.1 atmospheres and a temperature of 40-50oC. the mixing Process continued for 5 hours. Then the powder is dried for 5 hours.

The resulting substance "Lipovitan E" tabletirujut. While magnesium basic carbonate and starch is sifted through a sieve with the hole diameter of 0.5 mm Calcium stearinovokisly sieved through a sieve with the hole diameter of 0.3 mm Sifted potato starch spread a thin layer of enameled tray and dried in a vacuum drying Cabinet at a temperature of 60oC and a residual pressure of 1 ATM. Within 5-6 hours.

Kernel-tablets "Lipovitan E" is pressed in a tablet press with a biconcave punches with a diameter of 9.0 or 10.0 mm Average weight of kernel (0,28 0,03) ,

The study of biological activity "Lipovitan E". The study of biological effect of Lipovitan E" included:

a) identification of the antioxidant activity of the drug in the in vitro experiments on the culture of alveolar macrophages in rats;

b) comparing the biological activity "of Lipovitan E (at a dose of 0.5 mg/kg and 0.01 mg/kg) vitamin E) and oil solution of vitamin E (at a dose of 0.5 mg/kg) with the introduction of drugs per os daily for 14 days;

C) elucidation of the mechanisms of the antioxidant effect of Lipovitan E" by studying intracellular calcium signaling system.

A) Antioxidant activity "Lipovitan E".

"Lipovitan E" was made in a test tube culture of alveolar macrophages directly after stimulation of cells with peptide preparation FMLP. It is known that the response of macrophages to this peptide is accompanied by release into extracellular space swab products was estimated using Lomonosovskiy chemoluminescence, given the peak (maximum luminosity, mV) and time to reach peak (min.)

In control experiments (without adding to the incubation medium "Lipovitan E) stimulation of macrophages with FMLP resulted in (already in the first minute of observation) to increase the production of free radicals in 2-2,5 times. Enhanced chemiluminescence method (as a consequence of continued production of free radicals) were maintained for up to 10 min of observation.

After the introduction in the environment of incubation of alveolar macrophages "Lipovitan E (1.0 mg) was decreasing production of radicals by 42% (peak-chemoluminescence), but after 3 min again increased chemoluminescence to the level of the control (without "Lipovitan E"). Introduction in the incubation medium 2 mg "Lipovitan E" increased latent period (before the growth of production of radicals of up to 6 minutes And, finally, the addition of 4 mg of Lipovitan E" were able to completely suppress oxidant activity of macrophages in response to exogenous stimulus (FMLP), moreover, was observed even suppression of spontaneous free radical production. The reaction is continued in the form of experience, when 4 mg of Lipovitan E" was introduced into the incubation medium before stimulation of macrophages FMLP.

B) Biological effect duration is getnewname long (within two weeks) oral application "Lipovitan E in doses of 0.01 and 0.5 mg/kg (corresponding to 1 and 6 capsules of the drug an adult body weight of 60 kg) revealed no any toxic manifestations of the effects of the drug. Animals remained good appetite, normal function of the gastrointestinal tract and diuresis. During visual analysis at autopsy, there has been no macroscopic changes in the lungs, heart, liver, kidney, adrenal gland and other organs. Parameters biometrics (pulmonary coefficient, heart and adrenal indices) did not differ from those in intact animals. A similar pattern was observed in the group of animals treated oil solution of alpha-tocopherol at a dose of 0.5 mg/kg

they bronchoalveolar lavagno liquid (the total number of cells and differential composition) in all investigated groups corresponded to the norm.

In the study of the culture of alveolar macrophages isolated from lavagno fluid of rats treated for 14 days "Lipovitan E" in a dose of 0.5 mg/kg, showing that the response to exogenous stimulation wore deferred character: peak chemoluminescence there were 4-5 minutes (not 1, as in the control) and had a smaller amplitude. Over the next minutes of observation remained elevated production of free radicals. Alveolar macrophages of animals treated "Lipovitan E" in a dose of 0.01 mg/kg, was characterized by higher the temperature is and the 1st min, but by 3-4 min of observation, the level of production of free radicals returned to the original. After two weeks the rats of oil solution of vitamin E (0.5 mg/kg) in the response of alveolar macrophages to the stimulator of oxidative explosion was unable to identify any pattern: the response was unstable, unidirectional. The values of spontaneous oxidative activity of the cells also had a large range (from 1.8 to 8.0 mV). The lack of regular changes in the functional activity of macrophages of rats treated with oil solution of alpha-tocopherol, may be due to poor absorption of the drug in the intestinal tract and associated significant individual differences in the doses of alpha-tocopherol, really affecting the cells of the body in each case. "Lipovitan E" does not have this drawback due to acquired when dissolved in biological fluids liposomal form, providing good absorbability of the drug.

C) Influence of "Lipovitan E" on the formation of calcium signaling in peritoneal macrophages in rats.

Direct action "Lipovitan E studied in peritoneal macrophages stained flu. the via 3-5 seconds after entering into the incubation medium "Lipovitan E (at a concentration of vitamin E is 5.0 μg/ml) is small (up to 200 nm) and short (15-20 C) increasing the intracellular concentration of ions of Ca2+. This indicates a very rapid penetration of the drug into cells, at least in their plasma membrane, which is the receptor zone of formation of the Ca signal. In terms Beccalli environment (elimination of ions of Ca2+from the incubation medium of macrophages) were observed the same changes in intracellular ion concentrations of Ca2+that suggests that celebrated the rise of the concentration of free calcium in the cell is associated with mobilization of ions of Ca2+from endocellular depots, and not with the entrance of calcium from the external environment. A similar response was recorded when using a higher concentration of "Lipovitan E" (to 12.8 µg/ml, Fig. 1A, b).

It should be noted that the same effect was provided, and liposomes containing vitamin E (Fig. in). On the basis of this observation we can conclude that the observed effect is determined, most likely, unsaturated fatty acids present in the phospholipids liposomes and are known to cause mobilization of ions of Ca2+2+from the cytoplasm and maintaining the constancy of the concentration of ions of Ca2+inside the cell. The latter is extremely important for the implementation of the ions of calcium, their functions secondary mediator in the running and regulation of critical physiological reactions of the cell.

Thus, studies have shown:

a) the absence of toxic manifestations of the drug "Lipovitan E" in a dose of 0.5 mg/kg daily for 14 days;

b) reliable significant antioxidant effect of Lipovitan E", manifested in the decreased production of free radicals alveolar macrophages in response to exogenous stimulator;

C) formation of a specific antioxidant reserve of macrophages with long-term use "Lipovitan E", which is reflected in the lagged reaction of the oxidant blast on exogenous stimulator and less symptoms of this reaction. This effect is not observed when using oil solution of vitamin E;

g) increasing the antioxidant potential of cells reduces the risk of secondary tissue damage by free radicals while maintaining the normal absorptive capacity of macrophages (phagocytic number of 36.5 2.2 percent, phagocytic index 3, is her least in the surface of the plasma membrane. On this basis, we can assume that there is a rapid binding molecules of alpha-tocopherol with membrane structures, increasing its antioxidant efficiency and antioxidant potential of cells;

(e) the use of "Lipovitan E" may be important in the prevention of oxidative damage to cells and tissues caused by various factors.

1. Substance with antioxidant activity, including alpha-tocopherol acetate, phospholipids or phosphatides in the following ratio of ingredients, mg/g:

Alpha-tocopherol acetate - 10 - 90

Phospholipids or phosphatides - 20 - 180

2. Vitamin complex containing substance, including alpha-tocopherol acetate, phospholipids or phosphatides, characterized by the fact that he is a preformed shape, wherein it additionally contains magnesium basic carbonate, potato starch, calcium stearinovokisly and microcrystalline cellulose in the following ratio of components, g per 1 tablet weight of 0.3 to 0.5:

Alpha-tocopherol - 0,0017 - 0,015

Phospholipids or phosphatides - 0,003 - 0,030

Magnesium carbonate basic - 0,04 - 0,10

Microcrystalline the hydrated complex of p. 2, characterized in that it further comprises butiloksianizol in the number 0,000034,

4. Vitamin complex under item 2 or 3, characterized in that it contains phosphatides sunflower seeds, or phospholipids, soybean, or sunflower seeds.

5. Vitamin complex according to any one of paragraphs.2 to 4, characterized in that the sorbent it contains sorbitol, and/or sugar and/or salt cookbook, and/or xylitol food, and/or mannitol and/or lactose.

 

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