RU2548785C2 - Medication, possessing venomotor and anticoagulant action (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutics and represents a medication, possessing venomotor and anticoagulant action, which includes a dry extract of vine leaves, a base, preservatives, solvents, and is characterised by the fact that it additionally contains heparin in the form of a pharmaceutically acceptable salt, as the base it contains a hydrophilic gel-generating agent, as the solvents it contains purified water, propyleneglycol, ethyl alcohol rectified 95%, as the preservatives it contains nipagin, nipasol, with the following component ratio, wt %: dry extract of vine leaves with the content of the sum of flavonoides counter per rutin no less than 8% - 0.1-30.0; heparin in the form of a pharmaceutically acceptable salt - 100-1000 Units, hydrophilic gel-generating agent - 0.2-20.0; nipagin - 0.01-0.2; nipasol - 0.01-0.2, propyleneglycol - 3.0-70.0; ethyl alcohol rectified 95% - 3.0-70.0; purified water - the remaining part.

EFFECT: invention provides the creation of the medication in the form of a gel with good absorption, fast soaking, storage stability and acceptable organoleptic properties.

4 cl, 8 ex

Description

The invention relates to medicine, in particular to medicines containing active ingredients, namely to medicines exhibiting venotonic and anticoagulant effects, and methods for their preparation. The invention can be used for the prevention and treatment of edema-pain syndrome and microcirculatory trophic disorders caused by venous insufficiency of the lower extremities (varicose veins, acute and chronic thrombophlebitis, post-thrombophlebitis syndrome, chronic lymphostasis), as well as soft tissue injuries (hematomas, dislocations stretching).

The creation and implementation of new and effective drugs of domestic production is one of the priority areas of pharmaceutical science. In recent years, there has been a tendency to develop new complex drugs for the treatment of socially significant diseases, which allows to expand the spectrum of pharmacological activity of these drugs. Vein diseases of the extremities are a common vascular pathology, the social significance of which is due to the spread of the disease in 15-20% of the adult population, 40% of which are between the ages of 40 and 50. Studies conducted by various European research centers show that chronic venous insufficiency among women is 25-33%, among men - 10-20%.

For the treatment of venous insufficiency, basic and adjuvant (anti-inflammatory, antibacterial, antihistamines and other groups) drugs are used. Venotonic and venosclerosing agents, aticoagulants, and platelet disintegrants are distinguished among the basic ones. Of particular interest are venotonic agents, among which the “Troxevasin” preparations in the form of capsules and gel containing a synthetic analogue of the natural flutonoid rutin - troxerutin, “Antistax” in capsules containing flavonoids of dry grape leaf extract, “Venitan” in the form of a gel and cream are distinguished. containing horse chestnut extract, Detralex in the form of tablets containing the micronized flavonoid fraction and other drugs.

The substance “Dry leaf grape extract” (VLES) is obtained from the leaves of a cultivated plant Vinograda L. cultivar (Vitis Vinifera L.), Vitaceae family, using purified water as an extractant. The raw materials for extracts from grapes can be various parts of the vine (seeds, fruits, leaves, ridges), however, these parts are not uniform in the content of polyphenolic compounds, seeds are about 2178.8, in the skin of the berry 374.6, in the pulp of the berry 23, 8, and in leaves 351.6 mg / g GAE (gallic acid equivalent - gallic acid equivalent) [Pastrana-Bonilla E., Akoh, C.S., Sellappan, S., Krewer, G. Phenolic content and antioxidant capacity of muscadine grapes \\ J. Agric. Food Chem. - 2003. - 51. - pp. 5497-4503].

Dry grape leaf extract contains the sum of flavonoids, among which are quercetin-glucuronide, isocvercetrin, rutin, kempferol and others, anthocyanins and resveratrol, which have anti-inflammatory and decongestant effects in the complex. The effectiveness of the use of dry grape leaf extract for oral use was proven in 2004 during a double-blind, placebo-controlled clinical study of the drug “Antistax” (capsules) (Per. No. P No. 015635/01 of 03.23.2009) [Kiesewetter H., at al. Efficacy of Orally Administered Extract of Red Vine Leaf AS 195 (folia vitis vinferae) in Chronic Venous Insufficiency. \\ Arzneimittel-Forschiing Drug Research.-2000. - No. 50. - pp. 109-117]. However, the use of flavonoid-containing substances is relevant not only in the composition of solid dosage forms, but also in the composition of application forms (ointments and gels). So, on the basis of flavonoid-containing raw materials, for example, homeopathic ointments and gels with tincture of calendula, tincture of witch hazel, gel “Uronefron” containing polyextract, and others are produced. Currently, dry grape leaf extract is used in the production of such cosmetic cosmetics as Antistax gel (Beringer Ingelheim), Venocorset gel (Evalar), Foot gel with red grape leaf extract (LCN), but medicines registered in Russia, with a dry extract of grape leaves in the form of a soft dosage form at the moment no.

Also, for the treatment of venous diseases at certain stages, agents containing heparin, which has an anticoagulant effect, are used. Heparin-containing agents differ in dosages of heparin - from 100 Units / g (Heparinoid Lechiva) to 1000 Units / g (Lyoton 1000), and may also contain a combination of heparin and natural compounds, for example, Venolife in the form of a gel contains a combination of heparin and a synthetic analogue of the rutin flavonoid - troxerutin, the Essaven gel contains a combination of heparin and escin, the Venitan Forte gel also contains a combination of amorphous heparin and β-Escin. At the present stage of development of pharmaceutical science, it is considered advisable to use new substances, as well as combinations of already used substances for the treatment of socially significant diseases. In connection with the fact that the dry extract obtained from grape leaves contains a complex of pharmacologically active flavonoids of natural origin, the therapeutic effect of which has been proven in the oral dosage form, it is advisable to create a new drug in the form of a gel based on heparin and a dry extract of grape leaves as an analogue of Venolife gel, which, in turn, contains not a natural, but a synthetic analogue of the rutin flavonoid.

In the prior art, helium ointment is known having venotonic effect (RU 2367464) of the following composition

Liquid leaf extract 12.5 red grape Glycyrrhetic acid 5,0 Salicylic acid 4.0 Allantoin 2.0 Isopropanol 350,0 Propylene glycol 50,0 Carboxyvinyl polymer 20,0 Triethanolamine Enough Purified water Enough

Analyzing the description of the patent, it should be understood that the authors paid attention to the therapeutic effect of the combined use of red grape leaf extract and anti-inflammatory agent. It should be noted that the therapeutic effect is closely related to the preservation of the necessary properties of active substances, which depends on the choice of excipients. In addition, the applicability of the gel depends on its consumer organoleptic properties.

An object of the present invention is to provide a medicine based on a complex of flavonoids contained in a dry extract of grape leaves and heparin in the form of sodium or potassium salt, in the form of a gel, with good absorption, rapid absorption, and storage stability. For the implementation of the invention can be used any dry extract from grape leaves that meets the requirements of pharmaceutical quality.

The technical result obtained by using the invention is achieved by creating a new combination of heparin substances in the form of a pharmaceutically acceptable salt and a dry extract of grape leaves in a soft dosage form, as well as the method for its preparation.

The presented problem is solved by the fact that a gel based on a complex of substances of heparin and flavonoids contained in a dry extract of grape leaves is proposed, it also contains a gel-forming agent (rare cross-linked acrylic polymers (Arespol, Mars, Sakap (Russia), Karbopol) (USA) and others or a combination thereof), cellulose derivatives (hydroxypropyl methyl cellulose, hydroxyethyl cellulose and others or a combination thereof), alginic acid derivatives (alginates), xanthan derivatives and other hydrophilic gelling agents, as well as their combination), stvoriteli and absorption promoters (propylene glycol, ethyl alcohol, dimethylsulfoxide, and others, or a combination thereof), preservatives (Nipagin, Nipasol, and other preservatives, or combination thereof), water purified in the following ratio, wt.%:

Grape leaf extract dry containing the amount of flavonoids in terms of routine, at least 8% 0.1-30.0 Heparin as a pharmaceutically acceptable salt 100-1000 units Hydrophilic gelling agent 0.2-20.0 Nipagin 0.01-0.2 Nipazole 0.01-0.2 Propylene glycol 3.0-70.0 Rectified ethyl alcohol 95% 3.0-70.0 Purified water Rest

In the finished dosage form, purified water obtained by distillation, ion exchange, reverse osmosis, or a combination of these methods or by another method and corresponding to the requirements of FS 42-2619-97 “Purified water” is used.

Dry leaf grape extract is characterized by a total flavonoid content in terms of rutin of at least 8%.

If necessary, the drug may contain a neutralizing (alkaline) agent (triethanolamine, trolamine, sodium hydroxide or others) in an amount of 0.2-2.0 wt.%. antioxidants (disodium edetate, sodium metabisulfite, butyloxytoluene and others and their combination) in an amount of 0.01-5.0 wt.%, essential oils in an amount of 0.01-5.0 wt.%.

The proposed drug as a hydrophilic gelling agent may contain rare crosslinked acrylic polymers (RAP). RAPs are polymers of acrylic acid containing carboxyl groups, in appearance they are white powders capable of swelling in an aqueous medium with the formation of dispersions. Such brands as Arespol, Mars, Sakap (Russia), Karbopol (USA) and others can be used as RAP.

It is known that flavonoids are highly active compounds with, among other things, antioxidant activity. Being antioxidants, flavonoids are capable of oxidation and under the influence of external factors, such as temperature, light and humidity, they hydrolyze or oxidize [Bei Jiang, James T. Lyies, Kurt A. Reynertson, Fredi Kronenberg and Edward J. Kennelly Stability Evaluation of Selected Polyphenols, J. Agric. Food Chem., 2008, 56 (20), pp. 9510-9519]. The literature describes methods for stabilizing flavonoids in mixtures, cosmetic and dermatological preparations using various antioxidants: butyloxytoluene (ionol) [Patent EP 0998899 A1 “Verwendung von Butylhydroxytiluol zur stabilizationemng von flavonen, flavononen bzw. Flavononoiden, synergistische gemische aus flavonen, flavaninen bzw. Flavonoiden und Butylhydroxytiluol sowie kosmetische und dermatologische zubereitungen mit einem gehaly an solchen gemischen ”], surface-active citric acid esters [Patent EP 1000 603 B1“ Use of surface-active citric acis esters for stabilization flavones, flavanides and syrup and dermatological preparations containing them ”], benzophenone derivatives [Patent US 2009/0130035 A1“ Stabilized preparation composed phenolic compounds and benzophenones ”], compounds containing SH groups [Patent WO 2009/030151 A9“ Stabilized anthocyanin compositins ”]; stabilization of flavonoids in aqueous extracts using sodium metabisulfite and ethylene diamine tetraacetic acid (EDTA) is described [M.V. Gavrilin, T.A. Shatalova, A.Yu. Ayrapetova, L.A. Michichnik, O.V. Michnik, L. I. Karpenya. The study of ways to stabilize water extracts from chamomile, calendula, yarrow flowers. // Bulletin of the Samara Scientific Center of the Russian Academy of Sciences. - 2010. - T. 12, No. 1 (8). - c. 2019-2022].

In order to obtain a storage-stable drug with a combination of dry leaf extract of grapes containing a complex of flavonoids and heparin, the introduction of antioxidants is desirable. The claimed composition may contain various antioxidants, such as butyloxytoluene, sodium metabisulfite, sodium edetate ethylenediaminetetraacetic acid, and others, as well as combinations thereof.

So, the antioxidant butyloxytoluene (BOT) is a white powder with a yellowish tint, soluble in oils and alcohols. Lipophilic solvents such as ethyl alcohol, diethylene glycol monoethyl ether, castor oil, liquid paraffin, medium chain triglycerides and others or their combinations in the amount of 0.1-20.0 mass% can be used to introduce an antioxidant.

To correct the smell of the drug can also be used essential oils, such as essential oil of needles, spruce, lemon, sage and others, as well as their combination.

In another aspect, the invention also relates to variants of a method for producing a medicament.

The first variant of the method includes the steps of:

a) the dissolution of nipagin and nipazole in rectified ethyl alcohol 95%;

b) the addition of propylene glycol and purified water;

c) the preparation of leaves of dry and heparin extract in the form of a pharmaceutically acceptable salt in separate containers of aqueous solutions of grapes;

g) mixing the solutions obtained in steps b) and c), and adding a hydrophilic gelling agent;

e) homogenization.

In step c), if necessary, an antioxidant solution is further prepared.

At least one essential oil may be added before homogenization to correct odor.

The second option relates to a method for producing a medicinal product containing RAP. To obtain a gel based on RAP, a stage of neutralization of the carboxyl group of the polymer with an alkaline agent is necessary, resulting in crosslinking and gel formation. As an alkaline or neutralizing agent, trometamol, triethanolamine, sodium hydroxide solution and others can act.

The phenolic compounds (anthocyanins) of the grape extract, as well as RAP, have acidic properties and are able to react with a neutralizing (alkaline) agent during the preparation of the RAP-based gel, which manifests itself in a color change of the compounds from red-burgundy to olive green, and the finished product changes color. The principle technology for the preparation of the gel consists in selecting a sequence of stages for preparing the gel and introducing the components, as well as controlling the amount of neutralizing agent and the pH of the dispersion of the RAP gel, which is equivalent to 6.8, and the pH of the finished product.

A method of obtaining a medicinal product according to the second embodiment includes:

a) the dissolution of nipagin and nipazole in rectified ethyl alcohol 95%;

b) the addition of propylene glycol;

c) adding purified rare-crosslinked acrylic polymer to water to obtain a dispersion;

g) adding to the dispersion the solution obtained in step b);

d) adding a neutralizing agent to form a gel with a pH of 6.8;

f) the preparation in separate containers of aqueous solutions of grapes of leaves of the extract of dry and heparin in the form of a pharmaceutically acceptable salt;

g) mixing the gel with the solutions obtained in step e);

h) homogenization.

In step e), if necessary, an antioxidant solution is further prepared.

At least one essential oil may be added before homogenization.

The possibility of implementing the invention is confirmed by examples.

Example 1

40.0 kg of purified water is loaded into the homogenizer tank, and a rare cross-linked acrylic polymer is added. In this example, carbopol is used in an amount of 1.7 kg. Stirred until a homogeneous suspension of the polymer. A solution of preservatives is prepared in a separate container: 10.0 kg of rectified ethyl alcohol, 0.08 kg of nipagin, 0.02 kg of nipazole are loaded into the container, stirred until dissolved, 15.0 kg of propylene glycol are added. A solution of preservatives is added to the resulting dispersion of the crosslinked acrylic polymer with stirring. To obtain the gel, the polymer dispersion is neutralized to a pH of 6.8 with an alkaline agent of triethanolamine in an amount of 1.87 kg. Solutions are prepared in separate containers: 3.0 kg of grape extract is dissolved in 15.0 kg of purified water, 0.25 kg of heparin (which corresponds to 300 U / g of the product with a substance activity of 120 U / mg) is dissolved in 13.08 kg of purified water . Solutions of the active components are added to the obtained polymer gel with stirring until a uniform gel is obtained. In appearance, the gel is a homogeneous mass of red-brown in color with a specific smell.

The final product has the following composition, wt.%

Grape leaf extract dry 3.0 Heparin 300 units Rare cross-linked acrylic polymer - Carbopol 1.7 Triethanolamine 1.87 Nipagin 0.08 Nipazole 0.02 Propylene glycol 15.0 Rectified ethyl alcohol 95% 10.0 Purified water Rest

Example 2

It differs from example 1 in the composition of the gel and the technology of its preparation.

10.0 kg of rectified ethyl alcohol are loaded into the homogenizer tank and 0.02 kg of nipagin and 0.08 kg of nipazole are dissolved with stirring. Solutions are prepared in separate containers: 3.0 kg of grape extract is dissolved in 15.0 kg of purified water, 0.25 kg of heparin (which corresponds to 300 U / g of the product with a substance activity of 120 U / mg) is dissolved in 13.65 kg of purified water . 15.0 kg of propylene glycol and 40.0 kg of purified water are loaded into the homogenizer, solutions of the active components prepared in separate production tanks with stirring. Then, 3.0 kg of the hydroxyethyl cellulose derivative cellulose is charged and homogenized until a uniform gel is formed. In appearance, the gel is a homogeneous mass of red-brown in color with a specific smell.

The final product has the following composition, wt.%

Grape leaf extract dry 3.0 Heparin as a pharmaceutically acceptable salt 300 units Hydroxyethyl cellulose 3.0 Nipagin 0.08 Nipazole 0.02 Propylene glycol 15.0 Rectified ethyl alcohol 95% 10.0 Purified water Rest

Example 3

It differs from example 2 in the composition of the gel and the technology of its preparation.

10.0 kg of rectified ethyl alcohol are loaded into the homogenizer tank and 0.02 kg of nipagin and 0.08 kg of nipazole are dissolved with stirring. Solutions are prepared in separate containers: 3.0 kg of grape extract is dissolved in 15.0 kg of purified water, 0.25 kg of heparin (which corresponds to 300 U / g of the product with a substance activity of 120 U / mg) is dissolved in 11.65 kg of purified water . 15.0 kg of propylene glycol and 40.0 kg of purified water are loaded into the homogenizer, solutions of the active components prepared in separate production tanks with stirring. Then, 5.0 kg of alginic acid derivative (sodium alginate) are charged and homogenized until a uniform gel is formed. In appearance, the gel is a homogeneous mass of red-brown in color with a specific smell.

The final product has the following composition, wt.%

Grape leaf extract dry 3.0 Heparin as a pharmaceutically acceptable salt 300 units Sodium Alginate 5,0 Nipagin 0.08 Nipazole 0.02 Propylene glycol 15.0 Rectified ethyl alcohol 95% 10.0 Purified water Rest

Example 4

It differs from examples 1-3 by the presence of an antioxidant and production technology.

40.0 kg of purified water is loaded into the homogenizer tank, 1.7 kg of the rare cross-linked acrylic polymer carbopol, which can be brands such as Arespol, Mars, Sakap, Karbopol and others, are added and mixed to obtain a homogeneous suspension of the polymer. A solution of preservatives is prepared in a separate container: 10.0 kg of rectified ethyl alcohol, 0.08 kg of nipagin, 0.02 kg of nipazole are loaded into the container, stirred until dissolved, 15.0 kg of propylene glycol are added. A solution of preservatives is added to the resulting dispersion of the crosslinked acrylic polymer with stirring. To obtain a gel, the polymer dispersion is neutralized to a pH of 6.8 with an alkaline agent, which may be triethanolamine, trometamol, sodium hydroxide solution, and others. In this example, triethanolamine in an amount of 1.87 kg is used. Solutions of active substances are prepared in separate containers: 3.0 kg of grape extract is dissolved in 15.0 kg of purified water, 0.25 kg of heparin (which corresponds to 300 U / g of product with a substance activity of 120 U / mg) is dissolved in 10.58 kg purified water, 0.5 kg of BOT are dissolved in 2.0 kg of medium chain triglycerides when heated to 80 degrees and cooled. Solutions of the active components are added to the obtained polymer gel with stirring until a homogeneous gel is obtained, after which a BOT solution is added and mixed with a high-speed stirrer until a homogeneous gel with slight opalescence is obtained. In appearance, the gel is a homogeneous mass of red-brown in color with opalescence and with a specific smell.

The final product has the following composition, wt.%

Grape leaf extract dry 3.0 Heparin as a pharmaceutically acceptable salt 300 units Carbopol 1.7 Triethanolamine 1.87 Nipagin 0.08 Nipazole 0.02 Propylene glycol 15.0 Rectified ethyl alcohol 95% 10.0 Butyloxytoluene 0.5 Medium Chain Triglycerides 2.0 Purified water Rest

Example 5

Differs from example 4 by antioxidant and production technology. Sodium metabisulfite can be used as an antioxidant. The technology for producing the gel is as follows: 40.0 kg of purified water is loaded into the homogenizer tank, 1.7 kg of rare cross-linked acrylic polymer are added, which can be brands such as Arespol, Mars, Sakap, Karbopol " and others. In this example, carbopol is used. Mixing is performed until a homogeneous suspension of the polymer is obtained. A solution of preservatives is prepared in a separate container: 10.0 kg of rectified ethyl alcohol, 0.08 kg of nipagin, 0.02 kg of nipazole are loaded into the container, stirred until dissolved, 15.0 kg of propylene glycol are added. A preservative solution is added to the resulting carbopol dispersion with stirring. To obtain a gel, the polymer dispersion is neutralized to a pH of 6.8 with an alkaline agent, which may be triethanolamine, trometamol, sodium hydroxide solution, and others. In this example, triethanolamine in an amount of 1.87 kg is used. Solutions of active substances are prepared in separate containers: 3.0 kg of grape extract is dissolved in 15.0 kg of purified water, 0.25 kg of heparin (which corresponds to 300 U / g of product with a substance activity of 120 U / mg) is dissolved in 10.58 kg purified water, 0.2 kg of sodium metabisulfite is dissolved in 2.3 kg of purified water. To the polymer gel obtained, a solution of sodium metabisulfite is added with stirring, mixed until homogeneous, after which solutions of the active components are added and mixed until a uniform gel is obtained. In appearance, the gel is a homogeneous mass of red-brown in color with a specific smell.

The final product has the following composition, wt.%

Grape leaf extract dry 3.0 Heparin as a pharmaceutically acceptable salt 300 units Carbopol 1.7 Triethanolamine 1.87 Nipagin 0.08 Nipazole 0.02 Propylene glycol 15.0 Rectified ethyl alcohol 95% 10.0 Sodium metabisulfite 0.2 Purified water Rest

Example 6

It differs from example 5 by the presence of an antioxidant and production technology.

Ethylene diamine tetraacetic acid or its salt, disodium edetate, sodium edetate and others, can be used as an antioxidant. The technology for producing the gel is as follows: 40.0 kg of purified water is loaded into the homogenizer tank, 1.7 kg of rare cross-linked acrylic polymer are added, which can be brands such as Arespol, Mars, Sakap, Karbopol " and others. In this example, carbopol is used. Mixing is performed until a homogeneous suspension of the polymer is obtained. A solution of preservatives is prepared in a separate container: 10.0 kg of rectified ethyl alcohol, 0.08 kg of nipagin, 0.02 kg of nipazole are loaded into the container, stirred until dissolved, 15.0 kg of propylene glycol are added. A preservative solution is added to the resulting carbopol dispersion with stirring. To obtain a gel, the polymer dispersion is neutralized to a pH of 6.8 with an alkaline agent, which may be triethanolamine, trometamol, sodium hydroxide solution, and others. In this example, triethanolamine in an amount of 1.87 kg is used. Solutions of active substances are prepared in separate containers: 3.0 kg of grape extract is dissolved in 15.0 kg of purified water, 0.25 kg of heparin (which corresponds to 300 U / g of product with a substance activity of 120 U / mg) is dissolved in 10.58 kg purified water, 0.01 kg of disodium edetate is dissolved in 2.49 kg of purified water. To the obtained polymer gel, a solution of edetate disodium is added with stirring, mixed until uniform, then solutions of the active components are added and mixed until a uniform gel is obtained. In appearance, the gel is a homogeneous mass of red-brown in color with a specific smell.

The final product has the following composition, wt.%

Grape leaf extract dry 3.0 Heparin as a pharmaceutically acceptable salt 300 units Carbopol 1.7 Triethanolamine 87 Nipagin 0.08 Nipazole 0.02 Propylene glycol 15.0 Rectified ethyl alcohol 95% 10.0 Disodium edetate 0.01 Purified water Rest

Example 7

It differs from example 6 by the presence of an antioxidant and production technology.

As antioxidants, combinations of antioxidants BOT, sodium metabisulfite, disodium edetate with each other can be used. The technology for producing the gel is as follows: 40.0 kg of purified water is loaded into the homogenizer tank, 1.7 kg of rare cross-linked acrylic polymer are added, which can be brands such as Arespol, Mars, Sakap, Karbopol " and others. In this example, carbopol is used. Mixing is performed until a homogeneous suspension of the polymer is obtained. A solution of preservatives is prepared in a separate container: 10.0 kg of rectified ethyl alcohol, 0.08 kg of nipagin, 0.02 kg of nipazole are loaded into the container, stirred until dissolved, 15.0 kg of propylene glycol are added. A preservative solution is added to the resulting carbopol dispersion with stirring. To obtain a gel, the polymer dispersion is neutralized to a pH of 6.8 with an alkaline agent, which may be triethanolamine, trometamol, sodium hydroxide solution, and others. In this example, triethanolamine in an amount of 1.87 kg is used. Solutions of active substances are prepared in separate containers: 3.0 kg of grape extract is dissolved in 15.0 kg of purified water, 0.25 kg of heparin (which corresponds to 300 U / g of product with a substance activity of 120 U / mg) is dissolved in 10.58 kg purified water, 0.2 kg of sodium metabisulfite and 0.01 kg of disodium edetate are dissolved in 2.29 kg of purified water. To the obtained polymer gel, a solution of disodium edetate and sodium metabisulfite is added with stirring, mixed until uniform, then solutions of the active components are added and mixed until a uniform gel is obtained. In appearance, the gel is a homogeneous mass of red-brown in color with a specific smell.

The final product has the following composition, wt.%

Grape leaf extract dry 3.0 Heparin as a pharmaceutically acceptable salt 300 units Carbopol 1.7 Triethanolamine 1.87 Nipagin 0.08 Nipazole 0.02 Propylene glycol 15.0 Rectified ethyl alcohol 95% 10.0 Sodium metabisulfite 0.2 Disodium edetate 0.01 Purified water Rest

Example 8

It differs from examples 2, 5, 6 in the composition and production technology.

10.0 kg of rectified ethyl alcohol are loaded into the homogenizer tank and 0.02 kg of nipagin and 0.08 kg of nipazole are dissolved with stirring. Solutions are prepared in separate containers: 3.0 kg of grape extract is dissolved in 15.0 kg of purified water, 0.25 kg of heparin (which corresponds to 300 U / g of the product with a substance activity of 120 U / mg) is dissolved in 10.85 kg of purified water 0.2 kg of sodium metabisulfite is dissolved in 2.3 kg of purified water. 15.0 kg of propylene glycol and 40.0 kg of purified water are loaded into the homogenizer, solutions of the active components prepared in separate production tanks with stirring. Then 3.0 kg of the cellulose derivative hydroxyethyl cellulose are charged and homogenized until a uniform gel is formed. At the final stage of production, essential oils are added. In this example, 0.3 kg essential oil of needles is used. The gel is homogenized until uniform. In appearance, the gel is a homogeneous mass of red-brown in color with a slight opalescence with a specific smell.

The final product has the following composition, wt.%

Grape leaf extract dry 3.0 Heparin as a pharmaceutically acceptable salt 300 units Hydroxyethyl cellulose 3.0 Nipagin 0.08 Nipazole 0.02 Propylene glycol 15.0 Rectified ethyl alcohol 95% 10.0 Sodium metabisulfite 0.2 Needles essential oil 0.3 Purified water Rest

Thus, a gel for external use can be obtained that meets acceptable organoleptic consumer properties, which preserves the activity of active substances and their amount during storage, which can be used along with other agents with the same therapeutic effect.

Claims (4)

1. A medicinal product with venotonic and anticoagulant effects, including dry grape leaf extract, a base, preservatives, solvents, is characterized in that it additionally contains heparin in the form of a pharmaceutically acceptable salt, contains a hydrophilic gelling agent as a base, and contains purified water as a solvent, propylene glycol, rectified ethyl alcohol 95%, as preservatives - nipagin, nipazole, in the following ratio, wt.%:
Grape leaf extract dry
containing the amount of flavonoids
in terms of routine, at least 8% 0.1-30.0 Heparin as a pharmaceutically acceptable salt 100-1000 units Hydrophilic gelling agent 0.2-20.0 Nipagin 0.01-0.2 Nipazole 0.01-0.2 Propylene glycol 3.0-70.0 Rectified ethyl alcohol 95% 3.0-70.0 Purified water Rest 2. The drug according to claim 1, characterized in that it further comprises an antioxidant in an amount of 0.01-5.0 wt.%. 3. The drug according to claim 1, characterized in that it further comprises an essential oil in an amount of 0.01-5.0 wt.%. 4. A medicinal product with venotonic and anticoagulant effects, including dry leaf grapes, a base, preservatives, solvents, is characterized in that it additionally contains heparin in the form of a pharmaceutically acceptable salt and a neutralizing agent, it contains a rare cross-linked acrylic polymer as a base, as solvents contains purified water, propylene glycol, rectified ethyl alcohol 95%, as preservatives - nipagin, nipazole, in the following ratio, wt.%:
Grape leaf extract dry containing the amount of flavonoids in terms of routine, at least 8% 0.1-30.0 Heparin as a pharmaceutically acceptable salt 100-1000 units Rare cross-linked acrylic polymer 0.2-20.0 Neutralizing agent 0.2-2.0 Nipagin 0.01-0.2 Nipazole 0.01-0.2 Propylene glycol 3.0-70.0 Rectified ethyl alcohol 95% 3.0-70.0 Purified water Rest