6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone-base stable aqueous-oily composition and method for its preparing

FIELD: pharmacy, chemical technology, medicine.

SUBSTANCE: invention proposes a composition that comprises 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone as an active component, antioxidant, non-ionogenic surface-active substance, preserving agent, lipid-soluble stabilizing agent of emulsion, water-soluble stabilizing of emulsion and water. Method for preparing the indicated composition involves mixing the definite amounts of non-ionogenic surface-active substance with antioxidant, heating to temperature 40-120°C, dissolving the necessary amounts of lipid-soluble stabilizing agent of emulsion and 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone are dissolved in the prepared solution. The prepared mixture is added at intensive stirring to the mixed solution of water-soluble stabilizing agent of emulsion and preserving agent in water preliminary heated to temperature 30-100°C. Invention provides improving bioavailability and increasing storage time of the composition. Proposed composition is used in prophylaxis and treatment of different diseases and for recreating the working ability.

EFFECT: improved preparing method, valuable medicinal properties of composition.

2 cl, 1 tbl, 5 ex

 

The invention relates to chemistry and medicine and can be used in medicine for the prevention and treatment of various diseases, as well as for recovery.

It is known that 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone (ubiquinone, coenzyme Q10) is used for prevention and treatment of several diseases of the cardiovascular and nervous systems, as well as diseases associated with impaired mitochondrial energy and the formation of free radicals, in particular: coronary heart disease, heart failure, atherosclerosis, myocardial infarction, hypertension, hypercholesterolemia, cardiomyopathy, myocardial protection during surgical interventions, obesity, diabetes, periodontal disease, chronic fatigue syndrome and fatigue, migraine, age-related macular degeneration, asthenozoospermia, the Friedrich ataxia, Parkinson's disease, restoring health. [Littarru GP, Tiano L. Clinical aspects of coenzyme Q10: an update. Curr Opin Clin Nutr Metab Care. 2005 Nov; 8(6): 641-6.]

Known composition based on 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone (ubiquinone or Winona)containing 7.5 wt.% Winona in terms of 100% substance, 0,0135 wt.% butylacetyl and 92,4865 wt.% refined sunflower oil (Mashkovsky PPM Medicines. 12th ed., part 2, M.: Medicine, 1993, s. Temporary Pharmacopeia. VFS 42-1851-88 "Maintain the s Winona 0.015 g").

Butylacetyl in this composition acts as an antioxidant. Use as a solvent of the oil in this case it is necessary, as ubiquinone in water-soluble. However, it is known that the bioavailability of the active substance from the oil solution is worse than from aqueous solutions.

The present invention is a composition based on 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone for the prevention and treatment of various diseases and/or recovery.

The technical result that can be obtained by use of the above compositions and method of reception is to reduce the size of the fatty phase of the emulsion (composition), improving the bioavailability and the reaction activity of the compound of the composition - 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone, while increasing stability and increase shelf life of the composition.

The problem is solved proposed composition comprising 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone, nonionic surfactants, antioxidants, preservatives, fat-soluble emulsion stabilizer, water-soluble stabilizer emulsion and water in the following ratio, wt.%:

6-decaprenyl-2,3-dimatix is-
5-methyl-1,4-benzoquinone0,20-10,00
Nonionic surface-
the active ingredient1,00-30,00
Antioxidant0,05-4,00
Preservative0,05-1,00
Fat-soluble
the emulsion stabilizer0,05-2,00
Water soluble
the emulsion stabilizer0,05-1,00
Waterrest

It is also proposed a method of obtaining a specified composition, which is that a certain amount of nonionic surfactant and antioxidant are mixed, heated to 40-120°C, dissolved in the obtained solution the required number of fat-soluble emulsion stabilizer and 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone and the resulting mixture with intensive stirring and poured into a preheated up to 30-100°With a mixed solution of water-soluble emulsion stabilizer and preservative in the water.

The active ingredient in the proposed composition is a 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone (ubiquinone) is a coenzyme that plays an important role in the bioenergetics of the cell Bo is esista prokaryotes and all eukaryotes. The main function of this substance is the transfer of electrons and protons from various substrates for cytochromes during cellular respiration and oxidative phosphorylation.

Another function of this substance - antioxidant protection of low-density lipoproteins and cell membranes from the damaging effects of free radicals. Both of these functions are important in the prevention and treatment of various diseases and/or restoration of health.

When the content of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone (ubiquinone) in the composition of more than 10.00 wt.% the resulting system is unstable. From the composition after 2-3 weeks of storage precipitation of complex composition, which does not allow to use the composition as a therapeutic agent. The reduction in the content of ubiquinone less of 0.20 wt.% it is impractical, because the proposed composition is highly diluted, which complicates its use.

Nonionic surface-active agent (surfactant) in the proposed composition necessary for dissolution of the active ingredient is 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone and as an emulsifier to obtain a stable emulsion in water. As the nonionic surfactant in the composition can be used Cremophor RH-40, tween-20, tween-60, tween-80 and other similar properties of the surface the surface-active substances, as well as mixtures thereof.

Cremophor RH-40 (Cremofor RH-40) is a nonionic surface-active agent (surfactant)produced by the interaction of 45 moles of ethylene oxide with 1 mole of hydrogenated castor oil (polyoxyl 40 hydrogenomonas castor oil or castor oil polyoxyl hydrogenomonas). The main component of cremophor is glycerol polyethylene glycol oxystearate, which together with the glycerol polyglycidyl ether fatty acids forming the hydrophobic part of the product. The hydrophilic portion of the product includes glycols and glycuronidase.

Tween-20, tween-60, tween-80 are nonionic surfactants obtained by the interaction of sorbitan (esters of anhydromannitol and fatty acids with ethylene oxide. The main components are twin ethoxylated esters of pentaerythritol lauric, stearic or oleic acids with a degree of tarifitsirovana 1,50-1,65 and degree of oksietilirovannye 20.

When the content of nonionic surfactants in the compositions more 30.00 wt.% the resulting system is unstable: the composition of the layers, i.e. the fat and water phases are separated. It is not possible to use the proposed composition. The decrease in the amount of nonionic surfactant to concentrations less than 1 wt.% causes of the composition after 1-2 weeks of storage in the fall precipitate of complex composition and further stratify the composition. This leads to the inability to use the proposed composition.

The antioxidant in the composition required in order to prevent oxidation of the active substance. As an antioxidant in this composition you can use alpha-tocopherol, alpha-tocopherol acetate and alpha-tocopherol succinate. You can also use other antioxidants, such as butylacetyl, butylacetamide and other

When the content of the antioxidant in the composition above 4,00 wt.% the composition becomes unstable. It layers, which leads to the impossibility of its use. When you reduce the amount of antioxidant to concentrations less than 0.05 wt.% the active ingredient is 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone is oxidized within 2-3 weeks, making the composition unsuitable for use.

Preservatives are necessary to protect the proposed composition from microbial growth during storage. As use preservatives sorbic, cinnamic or benzoic acid, or their sodium or potassium salts, as well as other, similar properties of the substance.

When the content of preservative above 1 wt.% composition of 3-4 weeks falls white flocculent precipitate, which makes it impossible to use. The decrease in the amount of preservative to concentrat is th less than 0.05 wt.% causes that this component is not enough to protect the composition from microbial growth during storage. The result is that after 2-3 months of storage of the composition does not meet the requirements for microbiological purity, which makes it unsuitable for use.

Fat-soluble emulsion stabilizer in the proposed composition needed to stabilize the resulting emulsion. This component is a fatty phase. As fat-soluble emulsion stabilizer can be used ascorbicacid, ascorbyl palmitate, sarbatorile, sorbitanoleat, servicemanagement and other similar properties of the substance.

When the content of fat-soluble emulsion stabilizer above 2.00 wt.% composition stratified. From her almost immediately precipitation, making it impossible for her to use. When you reduce the amount of fat-soluble emulsion stabilizer to concentrations less than 0.05 wt.% the resulting emulsion is unstable. There is clouding of the composition associated with enlargement of the particle size of the fatty phase, and after 1-2 weeks - stratification of the obtained product, which makes it impossible for her to use.

Water-soluble emulsion stabilizer in the proposed composition needed to stabilize the resulting emulsion. This component is in the aqueous phase./p>

As water-soluble emulsion stabilizers use citric, tartaric, succinic, ethylenediaminetetraacetic acid or their sodium or potassium salts, as well as other, similar properties of the substance.

When the content of water-soluble stabilizer emulsion above 1.00 wt.% composition stratified. From her almost immediately precipitation, making it impossible for her to use. When you reduce the amount of water-soluble stabilizer emulsion to concentrations less than 0.05 wt.% the resulting emulsion layers, making it impossible for her to use.

The method of obtaining the proposed composition is that a certain amount of nonionic surfactant and antioxidant are mixed, heated to 40-120°C, dissolved in the obtained solution the required number of fat-soluble emulsion stabilizer and 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone.

By dissolving the active substance at temperatures above 120°6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone, as the results of chemical analysis, is very rapidly oxidized, resulting in the use of the proposed composition is impossible. By dissolving the active substance at temperatures below 40°the duration of the process of obtaining the solution jirgas worimi components increases, which also leads to oxidation of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone and, consequently, inability to use, the proposed composition.

Further the mixture with vigorous stirring and poured into a preheated up to 30-100°With a mixed solution of water-soluble emulsion stabilizer and preservative in the water.

Heating the aqueous solution of water-soluble emulsion stabilizer and preservative to temperatures above 100°impractical because of the increased cost of production of the target product. The increased costs associated with the need to increase the pressure in the reactor and isolate it from the environment. When the temperature of an aqueous solution of water-soluble emulsion stabilizer and preservative below 30°With the resulting emulsion is characterized by relatively large particles of fat phase (>10 μm). This leads to instability of the resulting system and, consequently, the stratification proposed composition, making it impossible for her to use.

The resulting water-in-oil emulsion is poured into sterile bottles of dark glass and hermetically sealed. Keep the composition at room temperature in the dark place.

Biological experiments were performed on rabbits male weighing 2.0 to 2.5 kg To obtain reliable results in parallel the x series of experiments were used at least five rabbits. Determining the time of occurrence of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone (ubiquinone) in the blood was performed in vivo by oral administration of the composition with subsequent sampling of plasma from the ear. In all cases, the amount of active substance was of 0.03,

For a known composition (Mashkovsky PPM Medicines. 12th ed., part 2, M.: Medicine, 1993, s) the time of appearance of ubiquinone in the blood of rabbits - 31±5 min (the song was introduced in the form of oil solution without the gelatinous shell).

From the table it is seen that the time of appearance of ubiquinone in the blood of rabbits obtained for compositions significantly less. This confirms the improvement of the bioavailability of the active substance.

The possibility of implementation of the present invention is illustrated by the following examples, but is not limited to them.

Example 1.

10 g of nonionic surface-active substances (surfactants) tween-60 and 0.5 g of antioxidant - butylacetyl mixed, heated to 40°C, dissolved in the resulting solution, 0.5 g of fat-soluble stabilizer emulsion - ascorbinsaeure and 2.0 g of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone. In 986 g of distilled water dissolve 0.5 g of preservative - cinnamic acid and 0.5 g of water-soluble stabilizer emulsion - tartaric acid. The prepared aqueous solution is heated on the temperature 30° With him, with vigorous stirring, poured previously obtained solution of fat-soluble components in the nonionic surfactant.

The resulting water-in-oil emulsion is poured into 20 ml in bottles of dark glass, hermetically sealed and placed in a dark place for storage. Periodically, after 3 months of this series are selected based on 3 bottles and expose them to chemical, physico-chemical and microscopic analysis.

According to the chemical and physico-chemical methods of analysis of the concentration of the components, the pH of the emulsion and its density at the time of observation during the 27 months remained unchanged within the error of measurements (5-10%).

According to the results of microscopic analysis of the average particle diameter of the fatty phase 0,08±0.02 mm.

In biological experiments on rabbits it is shown that for this composition the appearance of ubiquinone in the blood of rabbits is 18±3 min,

Example 2.

60 g of nonionic surfactant tween - 80 and 10.0 g of the antioxidant alpha-tocopherol, mixed, heated to 70°C, dissolved in the resulting solution of 5.0 g of fat-soluble stabilizer emulsion sorbitrate and 15.0 g of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone. In 905 g of distilled water dissolve 3.0 g of preservative - sorbic acid and 2.0 g of water-soluble stabilizer emulsion - disodium salt ethylendiamine raucously acid. The prepared aqueous solution is heated to a temperature of 70°and to him, with vigorous stirring, poured previously obtained solution of fat-soluble components in the nonionic surfactant.

The resulting water-in-oil emulsion is poured into 20 ml in bottles of dark glass, hermetically sealed and placed in a dark place for storage. Periodically, after 3 months of this series are selected based on 3 bottles and expose them to chemical, physico-chemical and microscopic analysis.

According to the chemical and physico-chemical methods of analysis of the concentration of the components, the pH of the emulsion and its density at the time of observation during the 27 months remained unchanged within the error of measurements (5-10%).

According to the results of microscopic analysis of the average particle diameter of the fatty phase constituted 0.10±0.02 mm. According to biological studies, the time of occurrence of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone in the blood of rabbits is 16±4 minutes

Example 3.

200 g of nonionic surfactants surfactant tween-80 and 40.0 g of the antioxidant alpha-tocopherol succinate mixed, heated to 120°C, dissolved in the resulting solution of 20.0 g of fat-soluble stabilizer emulsion - sorbitanoleat and 60.0 g of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone. In 662 g of distilled water dissolve 10.0 g preservative is - potassium sorbate and 8.0 g of water-soluble emulsion stabilizer is citric acid. The prepared aqueous solution is heated to a temperature of 80°and to him, with vigorous stirring, poured previously obtained solution of fat-soluble components in the nonionic surfactant.

The resulting water-in-oil emulsion is poured into 20 ml in bottles of dark glass, hermetically sealed and placed in a dark place for storage. Periodically, after 3 months of this series are selected based on 3 bottles and expose them to chemical, physico-chemical and microscopic analysis.

According to the chemical and physico-chemical methods of analysis of the concentration of the components, the pH of the emulsion and its density at the time of observation during the 27 months remained unchanged within the error of measurements (5-10%). According to the results of microscopic analysis of the average particle diameter of the fatty phase was 0,30±0.03 micrometers.

According to biological studies, the time of occurrence of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone in the blood of rabbits is equal to 20±4 minutes

Example 4.

100.0 g of nonionic surfactant tween-20, 200 g of nonionic surfactant tween-80 and 40.0 g of the antioxidant alpha-tocopherol acetate are mixed, heated to 100°C, dissolved in the resulting solution of 20.0 g of fat-soluble stabilizer emulsion - ascorbyl palmitate and 100.0 g of 6-decaprenyl-2,3-dimethoxy-5-IU the Il-1,4-benzoquinone. In 520 g of distilled water dissolve 10.0 g of preservative - sodium benzoate and 10.0 g of water-soluble stabilizer emulsion - Ethylenediamine-tetraoxane acid. The prepared aqueous solution is heated to a temperature of 100°and to him, with vigorous stirring, poured previously obtained solution of fat-soluble components in the nonionic surfactant.

The resulting water-in-oil emulsion is poured into 20 ml in bottles of dark glass, hermetically sealed and placed in a dark place for storage. Periodically, after 3 months of this series are selected based on 3 bottles and expose them to chemical, physico-chemical and microscopic analysis.

According to the chemical and physico-chemical methods of analysis of the concentration of the components, the pH of the emulsion and its density at the time of observation during the 27 months remained unchanged within the error of measurements (5-10%). According to the results of microscopic analysis of the average particle diameter of the fatty phase was 0,40±0,08 ám.

According to biological studies, the time of occurrence of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone in the blood of rabbits is equal to 19±5 minutes

Example 5.

100.0 g of nonionic surfactant Cremophor RH-40 and 4.5 g of the antioxidant alpha-tocopherol acetate are mixed, heated to 120°C, dissolved in the resulting solution of 5.0 g of fat-soluble stabilizer emulsion of sorbitanoleat and 30.0 g of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone. In 848,5 g of distilled water dissolve 2.0 g of preservative - benzoic acid and 10.0 g of water-soluble stabilizer emulsion - succinic acid. The prepared aqueous solution is heated to a temperature of 50°and to him, with vigorous stirring, poured previously obtained solution of fat-soluble components in the nonionic surfactant.

The resulting water-in-oil emulsion is poured into 20 ml in bottles of dark glass, hermetically sealed and placed in a dark place for storage. Periodically, after 3 months of this series are selected based on 3 bottles and expose them to chemical, physico-chemical and microscopic analysis.

According to the chemical and physico-chemical methods of analysis of the concentration of the components, the pH of the emulsion and its density at the time of observation during the 27 months remained unchanged within the error of measurements (5-10%). According to the results of microscopic analysis of the average particle diameter of the fatty phase amounted to 0.15±0.03 micrometers.

According to biological studies, the time of occurrence of 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone in the blood of rabbits is 17±4 minutes

Thus, the proposed composition is a stable for 27 months water-oil emulsion with a particle size of the fatty phase is less than 0.5 μm, which provides improved bioavailability compared with the WPI is a unique composition.

Table
TrackThe time of appearance of ubiquinone in the blood of rabbits (min)The average particle diameter of the fatty phase (μm)
Known composition31±5Oil solution
For example 118±30,08±0,02
For example 216±40,10±0,02
For example 320±40,30±0,03
In example 419±50,40±0,08
For example, 517±40,15±0,03

1. The composition is based on 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone, including the active ingredient, an antioxidant and a solvent, characterized in that the composition contains the solvent - non-ionic surfactant, preservative, fat-soluble emulsion stabilizer, water-soluble stabilizer emulsion and water in the following ratio, wt.%:

6-decaprenyl-2,3-dimethoxy 5-methyl-1,4-benzoquinone0,20-10,00
Nonionic surfactantAntioxidant0,05-4,00
Preservative0,05-1,00
Fat-soluble emulsion stabilizer0,05-2,00
Water-soluble stabilizer emulsion0,05-1,00
WaterRest

2. A method of obtaining a composition based on 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone, which consists in the fact that the nonionic surfactant and an antioxidant are mixed, heated to 40-120°C, dissolved in the resulting solution of fat-soluble emulsion stabilizer and 6-decaprenyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone, and the resulting mixture with intensive stirring and poured into a preheated up to 30-100°With a mixed solution of water-soluble emulsion stabilizer and preservative in the water.



 

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2 tbl

FIELD: biotechnology.

SUBSTANCE: the present innovation deals with obtaining biologically active substances of protein nature out of cereals, moreover it is necessary to isolate a stress separating protein 310 and/or protein being immunochemically similar to that as coarse and/or finely purified extract of the target product. For this purpose one should destruct cellular walls of 3-7-d-aged sprouts due to homogenization to isolate cell-free extract due to centrifuging which should be supplemented with a reagent-precipitator at the first stage under certain conditions to obtain residue followed by isolating a liquid phase which should be subjected to the second of impact with reagent-precipitator under certain conditions, then residue should be separated against a liquid phase due to centrifuging, and an obtained coarsely purified extract of target product should be separated against reagent-precipitator due to dialysis due to the impact of fine purification by gel filtration, if necessary. Moreover, one should conduct this procedure at certain temperature mode, and , if necessary, the extract of target product should be freeze dried. The suggested biologically active substance provides efficient regulation of body energy balance.

EFFECT: higher efficiency.

8 cl, 3 ex

FIELD: pharmacology.

SUBSTANCE: invention proposes use of polysorb as drug with membrane-stabilizing efficacy supplementing early known antioxidant and sorption properties of this substance.

EFFECT: enabled use of polysorb for monotherapy to treat a large number of diseases.

1 tbl

FIELD: medicine, dermatology, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to compositions used for skin care in itching dermatosis. The composition comprises essential oils of different plants, citrosept and cedar nut oil prepared by cold pressing method. Proposed composition possesses the stable effect on allergic and inflammatory processes and can be used as an accessory agent in treatment of itching dermatosis and allergic responses after hirudotherapy.

EFFECT: valuable medicinal properties of composition.

6 ex

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