RU2704976C2 - Phlebotrophic combination pharmaceutical composition - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a combined pharmaceutical composition for treating chronic venous insufficiency, presented in a gel dosage form for external use, containing a combination of active substances in form of diosmin and troxerutin, as well as auxiliary substances from among gelling agents, antimicrobial preserving agents, penetrators, solvents, neutralizers of gelling agent and pH regulators, components of oil phase, emulsifiers and flavouring agents, easy to use and stable during long-term storage.

EFFECT: treatment of chronic venous insufficiency.

1 cl, 2 tbl, 18 dwg

Description

Technical field

The invention relates to medicine, in particular to the pharmaceutical industry, and describes a combined pharmaceutical composition for the treatment of chronic venous insufficiency, including diosmin and troxerutin.

State of the art

Venous system diseases affect about 20% of the working-age population [Fundamentals of Clinical Phlebology / Ed. Yu.L. Shevchenko, Yu.M. Stoyko, M.I. Lytkina. - M., 2005. - 312 p.]. Chronic venous insufficiency (CVI) - a disease that occurs due to difficulty in the outflow of veins from the lower extremities, associated with varicose veins or resulting from deep vein thrombosis of the lower extremities. CVI is a common disease registered in 10-15% of the adult population. [Klimova E.A. Chronic venous insufficiency and methods of its treatment. // Breast cancer. - 2009. - No. 12. - S. 828.]. Every fourth inhabitant of the globe has signs of chronic venous insufficiency [Ochanov R.G., Savelyev V.S., Shalnova S.A. and other Risk factors for chronic venous insufficiency and the possibility of its medical treatment // Ter. Arch. - 2006. - No. 78 (4). - 68-72.].

There are many factors that determine the development of CVI, the main of which are pregnancy, obesity, prolonged static stress, hormonal contraceptives, wearing squeezing clothes, the nature of nutrition, etc.

The leading place in the pathogenesis of CVI is occupied by the valve theory. Valvular insufficiency of various parts of the venous channel of the lower extremities leads to the appearance of a pathological, retrograde blood flow, which is the main factor in damage to the microvasculature [Klimova EA Chronic venous insufficiency and methods of its treatment. // Breast cancer. - 2009. - No. 12. - S. 828.].

Among the main drugs used at all stages of CVI, phlebotropic drugs are most widely used, the main pharmacological action of which is the ability to stimulate the outflow of veins from the lower extremities, affecting various pathogenetic links of venous insufficiency.

One of the main phleboprotectors is bioflavonoids, which provide a capillaroprotective effect and reduce the permeability of the vascular wall [Klimova EA Chronic venous insufficiency and methods of its treatment. // Breast cancer. - 2009. - No. 12. - S. 828.].

In clinical practice, flavonoids are used to treat hemorrhagic diathesis, capillarotoxicosis, the effects of radiation sickness, uterine, hemorrhoidal and gastrointestinal bleeding, etc. But bioflavonoids have gained the most popularity in angiology, where for many years they have been successfully used for the prevention and treatment of chronic venous diseases , as well as complications of these diseases. One of the most famous and well-studied flavonoids with high phlebotropic activity is diosmin (3 ', 5,7-trihydroxy-4'-methoxyflavone-7-ramnoglucoside). Drugs based on it have been used for 30 years to treat chronic venous insufficiency, lymphedema and hemorrhoids [Bogachev V.Yu., Golovanova OV, Kuznetsov AN, Shekoyan A.O. Bioflavonoids and their importance in angiology. Focus on diosmin. // Angiology and vascular surgery: Scientific-practical. journal - M., 1994. - 2013. - t. 19 No. 1. - S. 73-81.].

In the pharmacodynamics of the drug, the following features are distinguished:

- enhances the vasoconstrictor effect of adrenaline and norepinephrine on the venous wall;

- increases venous tone;

- reduces venous and lymphatic stasis;

- has an antiplatelet effect;

- normalizes capillary blood flow, eliminating inflammation.

In addition, the drug inhibits the synthesis of endothelial adhesion molecules (ICAMj, VCAMj), thromboxane A2 (TxA2) and prostaglandin E2 and F2 (PGE2, PGF2), which eliminates the migration of leukocytes into venous capillaries and surrounding tissues, as well as “sticking” of platelets and white blood cells to the walls of blood vessels. As a result, the permeability of the vascular wall decreases, its strength increases, and the rheological properties of the blood improve. By normalizing cholesterol metabolism, Diosmin prevents the formation of sclerotic plaques, and also improves the elasticity of venous and lymphatic vessels [Diosmin / Alternative Medicine Review. - 2004. - Vol. 9, No. 3. - P. 308-311.].

Also widely known and well-established angioprotector is troxerutin - a semi-synthetic bioflavonoid of the benzopyron series (a mixture of 3 ', 4' and 7 (β-hydroxyethyl) rutosides). Troxerutin has P-vitamin activity, shows pronounced angioprotective properties; reduces vascular tissue permeability and fragility of capillaries, helps to normalize microcirculation and tissue trophism, reduces stagnation in veins and paravenous tissues, has anti-edematous and anti-inflammatory effects. Improves peripheral blood circulation, especially microcirculation and tissue trophism [Handbook "Compendium 2013 - drugs" / ed. V.N. Kovalenko - K .: Morion, 2013 .-- 2360 p.].

The most preferred dosage form when choosing drugs for the treatment of CVI, are topical preparations in the form of gels, ointments and creams. This is due to their higher bioavailability when used, as well as a decrease in side effects and harmful effects on internal organs as when taking oral dosage forms. In addition, the oral administration of phlebotropic drugs during pregnancy is undesirable (the appointment is justified when the benefits of their use exceed the potential negative reactions). Also, their use is not recommended for breastfeeding.

Of particular interest among soft dosage forms for topical application are gels on RAP bases (sparsely crosslinked acrylic polymers). Gels on such bases when applied to the skin form thin, smooth films, more fully evenly release medicinal substances, providing a lasting effect, spread well on the skin surface, have a cooling effect, are non-toxic, do not have irritating effects, are well removed by water, and do not contaminate clothes.

On the pharmaceutical market of Russia, diosmin preparations are quite widely represented, containing both a mono base of the active substance and a combination of diosmin with various active pharmaceutical substances.

So, for example, the following drugs registered in the Russian Federation are known:

- “Venolek” in the dosage form of film-coated tablets containing diosmin in a dosage of 500 mg, manufactured by Canonfarm Production CJSC (Russia), registration certificate No. LSR-006551/09 of 08/17/2009;

- "Flebodia 600" in the dosage form of film-coated tablets containing 600 mg diosmin, manufactured by Innoter Laboratory (France), registration certificate P N016081 / 01 of 11/18/2009;

- "Detralex" in the dosage form of film-coated tablets containing a combination of diosmin in a dosage of 450 mg and hesperidin in a dosage of 50 mg, manufactured by Servier Laboratory (France), registration certificate P N011469 / 01 dated 06/26/2009;

- “Phlebofa” in the dosage form of tablets containing 600 mg of diosmin, manufactured by Atoll LLC (Russia), registration certificate No. LP-002517 of 07/01/2014, and others.

Known preparations of diosmin (including in the form of combinations) are presented on the domestic market only in the form of solid dosage forms. Soft forms in the form of gels, ointments and creams, from the prior art could not be identified.

Also, in the domestic market, mono and combined preparations in the dosage form of gels containing troxerutin are widely represented:

- “Troxerutin Vramed” in a gel dosage form for external use of 2%, manufactured by Sopharma JSC (Bulgaria), registration certificate P N011640 / 01 of 09/26/2011;

- Troxerutin Vetprom in the dosage form of gel for external use 2%, manufactured by VetProm AD (Bulgaria), registration certificate LS-001490 of July 15, 2011;

- “Troxevasin” in a gel dosage form for external use of 2%, manufactured by “Balkanfarm-Troyan” AD (Bulgaria), registration certificate P N012713 / 02 of 08/15/2008;

- "Troxerutin" in a gel dosage form for external use of 2%, manufactured by Atoll LLC (Russia), registration certificate LS-000487 of 03/01/2011;

- “Venolife”, containing a combination of sodium heparin, dexpanthenol and troxerutin in gel dosage form for external use, manufactured by CFC OJSC “Akrikhin” (Russia), registration certificate LS-001377 dated 03/10/2006, and others.

To eliminate the shortcomings of existing solid dosage forms, as well as for the convenience of their use by patients, the authors of the present invention proposed the creation of a combined drug in the form of a gel containing diosmin and troxerutin.

In the domestic market, drugs containing a combination of diosmin and troxerutin are not represented. Also, mild dosage forms containing diosmin are not registered in Russia. From the prior art, similar preparations and dosage forms could not be identified.

The objective of the present invention is to expand the arsenal of effective and convenient to use phlebotropic drugs of domestic production.

The technical result of the invention is the creation of a phlebotropic combined pharmaceutical composition in the form of a gel for external use (Diosmin + Troxerutin gel for external use) containing a therapeutically effective amount of diosmin and troxerutin, convenient for use and stable during long-term storage.

Disclosure of invention

The authors of the present invention, experimentally selected the composition of the drug Diosmin + Troxerutin gel for external use, in accordance with the claimed technical result.

Based on the purpose of the invention and the properties of the dosage form, the authors set the following main objectives of the study:

- develop a rational composition of the drug, taking into account the properties of diosmin, troxerutin and excipients, while developing the composition taking into account the biomedical requirements for drugs for the local treatment of venous diseases, for which:

- the drug should contain diosmin at a concentration of 2% and troxerutin at a concentration of 2%;

- the drug should have an indifferent (non-interacting with medicinal substances) gel base, which makes it possible to easily and evenly apply the drug to the surface of the body and not irritating to the skin.

- investigate the microbiological characteristics of the drug and establish their compliance with modern pharmacopoeial standards.

1. Development and justification of the rational composition of the drug Diosmin + Troxerutin gel for external use.

1.1. The choice of active substances and their content.

The active substances for the drug under development were chosen diosmin and troxerutin. The substances of diosmin and troxerutin are described in the European Pharmacopoeia and in the British Pharmacopoeia [Diosmin. - European Pharmacopoeia 8.0. - P. 2072-2073 .; Diosmin. - British Pharmacopoeia 2015. - V. I. - P. 771 .; Troxerutin. - European Pharmacopoeia 8.0. - P. 3488-3489 .; Troxerutin. - British Pharmacopoeia 2015.- V. II. - P. 1118.], the substance of diosmin is described, also in the US Pharmacopoeia [Diosmin. - USP 36 - NF 31, V. I. - P. 1417-1418.]. Dosage forms of diosmin and troxerutin are not described in leading pharmacopoeias.

For inclusion in the composition of the drug, the substances of diosmin and troxerutin were selected that meet the requirements of the European Pharmacopoeia.

In FIG. 1 shows a micrograph of a diosmin substance manufactured by Chengdu Hawk Bio-Engineering Co. Ltd. (China), FIG. 2

- micrograph of the substance troxerutin manufactured by Sichuan Xieli Pharmaceutical Co. Ltd. ”(China).

As seen in FIG. 1, the substance of diosmin is microcrystalline; the bulk of the particles has a size in the range of 10 microns or less; the powder contains no particles larger than 20 microns.

The particle size in the substance of diosmin is important, since diosmin is introduced into the composition of the drug in the form of a suspension.

As seen in FIG. 2, the bulk of the particles in the substance of troxerutin has a size in the range of 10 μm or less, the powder does not contain particles larger than 50 μm.

Since troxerutin is introduced into the composition of the drug in the form of a solution, the particle size in the substance of troxerutin is not a critical factor.

Diosmin is introduced into the composition of the drug at a concentration of 2% in the form of a suspension in propylene glycol.

Troxerutin is introduced into the composition in the form of an aqueous solution at a concentration of 2%.

1.2. Selection of excipients

To obtain a technical result, the authors of the present invention had to choose a qualitative and quantitative composition of excipients in such a way as to obtain oleogel (hydrophobic gel), in which diosmin will be in the form of a suspension, and troxerutin in the form of a solution. In addition, it was necessary to select an antimicrobial preservative in a concentration that ensured the effectiveness of the antimicrobial preservative effect at the level of the criteria established in the European Pharmacopoeia. It was also necessary to choose the composition of penetrators, ensuring proper diffusion of the active substances.

As excipients were selected:

- an antimicrobial preservative selected from methyl parahydroxybenzoate, propyl parahydroxybenzoate, benzalkonium chloride, gasoline alcohol, sodium benzoate;

- penetrator selected from diethylene glycol monoethyl ether;

a gelling agent selected from a carbomer homopolymer, such as Carbopol® 934, Carbopol® 980, Carbopol® Ultrez 10, Carbopol® Ultrez 21, and the like;

- a gellant neutralizer and a pH regulator selected from trometamol, triethanolamine, sodium hydroxide;

- a solvent selected from among hydrophilic solvents, such as propylene glycol, water, glycerol, ethyl alcohol, polyethylene glycol, and combinations thereof;

- an oil phase component selected from isopropyl myristate, isopropyl palmitate, squalane, dimethicone, simethicone;

an emulsifier selected from the macrogol glycerol hydroxystearate, polyoxyethylene steatate, macrogol cetostearyl ether, etc .;

- odor flavor selected from levomenthol, essential oils of lavender, neurolea, pine, etc.

When choosing excipients, the authors of the present invention solved the following main tasks:

1) selection of the composition of the gelling agent in such a way as to ensure a gel-like consistency of the drug;

2) selection of qualitative and quantitative composition of penetrators;

3) selection of the composition of emulsifiers, providing a minimum particle size of the dispersed phase;

4) selection of the composition of the oil phase, providing a softening effect of the gel on the skin;

5) selection of the composition of the flavor;

6) based on the results of microbiological studies, the selection of the composition of antimicrobial preservatives that ensure the proper effectiveness of the antimicrobial preservative effect.

As a gelling agent, a carbomer homopolymer, for example type C (Carbopol® 980), which is an analogue of polyacrylic acid [Carbomer Homopolymer, can be used, preferably, but not necessarily, in the composition of the developed product. - USP 36 - NF 31, V. I. - P. 1933-1935.] And is a polymer of acrylic acid cross-linked with allyl pentaerythritol esters, with a high molecular weight.

As an alkaline agent, when added to the dispersion of a gelling agent (for example carbomer), gelation occurs, preferably, but not necessarily, trometamol can be used. This alkaline agent, unlike traditional amine thickeners, does not have a locally irritating effect and is not toxic, which makes it possible to use it even in injection preparations (for example, Trisamine solution for injection). Tromethamol prevents the reduction of rheoparameters of gels based on carbomers under the influence of UV radiation. Also, the use of trometamol as a neutralizer of carbomers is indicated when gels contain significant quantities of hydrophilic solvents [Formulating Hydroalcoholic Gels with Carbopol® Polymers // Lubrizol: Technical Data Sheet (TDS-255), September 3, 2009. - 7 pp.]. In addition, the choice of alkaline agent seems to be critical since its use in the composition directly affects the pH level, which in turn determines the stability of the drug and its rheological properties.

For the developed product, the pH limits were initially set from 5.5 to 6.5 (the median was taken from the average normal pH values of human skin, which range from 4.0 to 7.0). Because carbomer-based gel reoparameters are dependent on its concentration and pH [Handbook of Pharmaceutical Excipients: Sixth Edition / Ed. by Raymond With Rowe, Paul J Sheskey and Marian E Quinn. - Washington / London: Pharmaceutical Press and American Pharmacists Association, 2009. - 917 p.], Rheological studies of gel samples were carried out depending on the concentration of carbomer at a constant pH (6.2 ± 0.2) and on the concentration of trometamol, which is pH corrector (at constant carbomer concentration).

The results of studies of the effect of the concentration of carbomer 980 on the rheological properties of the gels are presented in FIG. 3-4. In FIG. 3 shows rheograms of gels at a temperature of 25 ° C, and in FIG. 4 shows the dependence of the structural viscosity of the gels on the concentration of carbomer 980.

With an increase in the concentration of the gelling agent from 0.10% to 1.25% at the same pH, the structural viscosity of the gels increases almost linearly (Fig. 4). With an increase in the concentration of the gelling agent from 1.25% to 1.50%, the structural viscosity changes slightly.

At a carbomer concentration of 0.10%, the gel has a flow type close to Newtonian. With an increase in carbomer concentration, both the structural viscosity and the lower yield strength of the gels increase. At a concentration of Carbopol® 980 0.50%, the gel has a plastic type of flow with small lower (pH) and extrapolated (PE) yield strengths (Fig. 3). With an increase in the concentration of Carbopol® 980 (at the same pH), the lower and extrapolated gel yield limits increase, and at a gel-forming concentration of 0.75%, the gel exhibits significant thixotropic properties, as evidenced by the hysteresis loop in the rheogram (Fig. 3).

Gel samples with a Carbopol® 980 0.25% carbomer concentration have low structural viscosity, which does not provide the necessary gelation, structural viscosity is not high enough, resulting in poor extrusion from tubes: gels are poured out, not squeezed out.

The carbomer provides the optimal gel consistency at a concentration of 0.50%. At this concentration, the gel is easily squeezed out of the tubes, spreads well on the skin, and is easily rubbed. At a carbomer concentration of 1% or higher, gels are less distributed on the skin, leaving a sticky film on it after rubbing.

Thus, for a diosmin gel and troxerutin gel having a pH (6.2 ± 0.2), the content of Carbopol® 980 carbomer should be in the range of 0.45 to 0.55%, optimally 0.50%.

The reoparameters of gel bases and gels based on carbomer depend primarily on pH, which is regulated by an alkaline agent. To select the optimal concentration of the neutralizer, the reoparameters and pH of the diosmin and troxerutin gels were determined at a selected carbomer concentration of 0.50%, depending on the content of the neutralizing agent, trometamol in the present composition, and pH. In FIG. 5 shows the dependence of the structural viscosity of the gels on the pH, FIG. 6 - from the concentration of trometamol, and in FIG. 7 shows rheograms of these gels at a temperature of 25 ° C.

As can be seen from the data presented in FIG. 5-6, 0.5% carbomer dispersion has an acidic environment (pH = 3.73) and low structural viscosity. The type of flow of this dispersion is close to Newtonian (Fig. 7).

With the addition of trometamol, the carboxyl groups of the carbomer are neutralized and the organization of its polymer molecules is changed [Neutralizing Carbopol® and Pemulen ™ Polymers in Aqueous and Hydroalcoholic Systems // Lubrizol: Technical Data Sheet (TDS-237), September 16, 2009. - 3 p.] as a result of which the pH rises and the structural viscosity of the gels sharply increases (Fig. 5-6). At pH = 4.5, the gel acquires a plastic type of flow with pronounced lower (Rn) and extrapolated (Re) yield strengths (Fig. 7). With an increase in the concentration of trometamol and an increase in pH, the lower yield stress increases (Fig. 7).

As the concentration of trometamol increases, the pH of the gels rises. The structural viscosity of the gels also increases with an increase in the concentration of trometamol and an increase in pH, however, there are fractures in the graphs of the dependence of the structural viscosity on the concentration of trometamol and pH, after which the structural viscosity changes little (Fig. 5-6), which is associated with the neutralization of all carboxyl groups in the molecules carbomer. As can be seen from the graphs shown in FIG. 5, in the case of gels containing 0.5% Carbopol® 980, with a further increase in pH from 7 to 8, the structural viscosity of the gels slightly decreases.

As can be seen from the data presented in FIG. 8, the increase in pH from the concentration of trometamol has an almost linear dependence within the concentration of trometamol from 0.1% to 0.6%. The necessary pH ranges from 5.5 to 6.5 are provided at trometamol concentrations from 0.25% to 0.47%. An optimal pH of 6.25 gels containing 0.50% carbomer provides a trometamol concentration of 0.425%.

As a dispersed medium (solvent), it is preferable, but not necessary, to use: diethylene glycol monoethyl ether, propylene glycol, as well as purified water. The authors of the present invention as an example, a dispersion medium represented by a mixed solvent was used.

The purified water was used as a solvent of trometamol, a co-solvent (together with propylene glycol) of troxerutin and methyl parahydroxybenzoate and a carbomer swelling medium during the technological process. Propylene glycol was used as a solvent of diosmin and a co-solvent (together with purified water) of troxerutin and methyl parahydroxybenzoate; it is a solvent that provides the drug with osmotic activity. In addition, aqueous solutions of propylene glycol and diethylene glycol monoethyl ether, as a penetrator, provide proper tissue permeability for drugs, help relieve inflammation in the damaged area of the skin due to hyperosmolar action.

The concentration of propylene glycol in the composition of the preparation was from 8.0% to 12.0%, optimally 10.0%, and diethylene glycol monoethyl ether from 4% to 6%, optimally 5%.

In FIG. 9 shows the kinetics of water absorption by a gel with a selected solvent composition, characterizing its osmotic activity.

As can be seen from the data presented in FIG. 9, the drug has moderate osmotic activity, as a result of which it will not exert a drying effect on the skin [Chapter 9. Pharmaceutical development of drugs / N.A. Lyapunov, E.P. Bezuglaya, Yu.M. Stolper et al. // In the book: Analytical chemistry in the creation, standardization and quality control of medicines / Ed. V.P. St. George's. - Volume 3. Metrological and regulatory support for the creation, production and quality control of medicines. - Kharkov: Publishing House "NTMT", 2012. - S. 1419-1512].

During the first half hour, the gel absorbs about 16% of the water. Subsequently, the absorption of water by the drug occurs less intensely. By the sixth hour, the developed drug absorbs about 60% of the water.

As components of the oil phase, preferably, but not necessarily, squalane can be used in a concentration of 4.0% to 6.0%, optimally 5.0%, isopropyl myristate in a concentration of 4.0 to 6.0, optimally 5.0 % and dimethicone 100 in a concentration of from 0.3% to 2.0%, optimally 1.0%.

Squalane in chemical structure is close to triterpene alcohols. It has a softening effect on the skin and is highly stable to oxidation even at high temperatures [Squalane. - European Pharmacopoeia 8.4. - P. 4816-4819.].

Isopropyl myristate is an emollient (emollient), widely used in world practice. This substance does not oxidize during storage of the drug and, therefore, do not require additional administration of antioxidants.

In addition, another hydrophobic component, dimethicone, is included in the composition of the drug being developed, which improves the absorption of the emulgel into the skin without the whitish traces left by the emulsifier and helps to eliminate the feeling of greasy after using the drug.

The total concentration of the oil phase in the developed product ranged from 8.3% to 14%, optimally 11%.

To emulsify the oil phase and stabilize the suspension of diosmin, a nonionic surfactant, macrogol glycerol hydroxystearate 40, was included in the composition of the developed drug.

In FIG. 10 shows rheograms of gel samples containing Kolliphor RH 40 at various concentrations, FIG. 11 shows micrographs of gel samples, and FIG. 12 - dependence of the structural viscosity of these gels on the concentration of macrogol glycerol hydroxystearate 40 (Kolliphor RH 40).

An emulsifier-free gel sample was delaminated immediately after preparation. An increase in the concentration of Kolliphor RH 40 from 1.5% to 6.0% has practically no effect on the rheoparameters of the gels (Figs. 10-12). The particle size of the emulsion with an increase in the concentration of the emulsifier from 1.5% to 6.0% varies slightly, however, in the gel sample containing 4.5% Kolliphor RH 40, the particles of the oil phase are slightly smaller in comparison with the particles of the oil phase of other gel samples .

According to the results of the studies, a concentration of Kolliphor RH 40 was selected from 3.0% to 6.0%, optimally 4.50%.

As a flavoring agent for odor, it is preferable, but not necessary, to use levomenthol. Samples of gels containing 0%, 0.10%, 0.25%, 0.50%, 0.75% and 1.00% levomenthol were prepared. After that, an organoleptic evaluation of each gel was carried out and it was found that the inclusion of 0.25% to 0.75% of levomenthol in the composition of the drug provides the gel with a pleasant smell when rubbed into the skin, during the process, levomenthol easily dissolves in the oil phase. According to the results of organoleptic studies, levomenthol in a concentration of 0.25% to 0.75%, optimally 0.50%, was included in the composition of the drug.

As an antimicrobial preservative, preferably, but not necessarily, methyl parahydroxybenzoate in a concentration of 0.2% can be used.

In accordance with the requirements of the RF GF of the XIII edition in locally applied drugs (category 2), the logarithm of reducing the number of viable bacterial cells after 14 days should be at least 2, from 14 to 28 days the number of viable bacterial cells should not increase. The number of viable fungal cells should not increase after 14 and 28 days compared with the initial level. This criterion is significantly less stringent than the criterion given in OFS.1.2.4.0011.15 of the State Pharmacopoeia of the Russian Federation (State Pharmacopoeia of the XIII edition) and EF 8.

In accordance with the requirements of OFS.1.2.4.0011.15 of the State Pharmacopoeia of the Russian Federation (GF RF of the XIII edition) and EF 8 in medicines for cutaneous use (criterion A), the logarithm of reducing the number of viable bacteria cells after 2 days should be at least 2, after 7 days - at least 3, in the future, the number of viable bacterial cells should not increase. The logarithm of reducing the number of viable fungal cells after 14 days should be at least 2, in the future, the number of viable fungal cells should not increase.

In order to ensure the high quality of the drug and prevent the multiplication of microorganisms in it during storage and use, when evaluating the effectiveness of the antimicrobial preservative effect in the studied medicinal product, the authors of the present invention were guided by the criteria given in OFS.1.2.4.0011.15 of the State Pharmacopoeia of the Russian Federation (GF RF XIII edition) and EF 8.

The results of experimental studies are shown in table 1.

From the data presented in table 1 it can be seen that inoculated samples show rapid death or a decrease in the number of viable cells of test microorganisms. The logarithm of the decrease in the number of viable S. aureus cells in the initial seeding was 0.86, after 2 days - 3.08, after 7 and 14 days - 4.56, after 28 days no viable cells of this test microorganism were found. The logarithm of the decrease in the number of viable P. aeruginosa cells in the initial seeding was 2.04, after 2 days 4.47, after 7 days and no viable P. aeruginosa cells were found after subsequent seeding. The logarithm of the decrease in the number of viable E. coli cells in the initial plating was 1.69, after 2 days and during subsequent plating no viable cells of this test microorganism were detected. The logarithm of the decrease in the number of viable C. albicans cells in the initial plating was 0.13, after 2 days and subsequent plating no viable C. albicans cells were detected. The logarithm of reducing the number of viable cells of A. brasiliensis (niger) in the initial seeding was 0.18, after 2 days - 0.25, after 7 days - 3.52, after 14 and 28 days no viable cells of this test microorganism were found.

Such effectiveness of antimicrobial preservatives meets the requirements of criterion A EF 8 (5.1.3) for medicines for cutaneous use and significantly exceeds the requirements of the article "Determining the effectiveness of antimicrobial preservatives" OFS.1.2.4.0011.15 of the State Pharmacopoeia of the Russian Federation of the XIII edition to category 2 medicines .

According to the results of studies, methyl parahydroxybenzoate at a concentration of 0.20% was introduced into the composition of the drug Diosmin + Troxerutin gel for external use as a preservative.

Thus, the authors of the present invention managed to create a phlebotropic combined pharmaceutical composition in the form of a gel for external use containing diosmin in an amount of 2% (2 g / 100 g) and troxerutin in an amount of 2% (2 g / 100 g), as well as auxiliary substances suitable for use and stable during long-term storage.

Table 2 shows the most preferred content of the components in the developed preparation Diosmin + Troxerutin gel for external use.

In one of the embodiments of the implementation of the technical result as an example, the composition of the developed phlebotropic combined pharmaceutical composition is as follows:

The compatibility of active and excipients has been proven by HPLC and spectrophotometry in the UV and visible regions. In FIG. 13-15 show chromatograms of a standard solution, a test solution of a preparation, and a placebo of a preparation under conditions of quantitative determination of diosmin. In FIG. 16 shows the spectra of a standard solution, a test solution of a preparation, and a placebo of a preparation under conditions of quantitative determination of troxerutin.

As can be seen from the chromatograms shown in FIG. 13-15, the retention time of the diosmin peak in the chromatograms of the test solution coincides with the retention time of the corresponding peak in the chromatograms of the standard solution. There are no peaks in the chromatograms of the placebo solution with a retention time coinciding with the retention time of the diosmin peak in the chromatograms of the test solution and the chromatograms of the standard solution. The method for determining the quantitative content of diosmin is characterized by sufficient convergence and sufficient accuracy, and also meet the requirements for linear dependence parameters, which indicates the absence of chemical interaction between diosmin, troxerutin and excipients.

As can be seen from the spectra shown in FIG. 16-18, the ultraviolet absorption spectrum of a drug solution, like the ultraviolet absorption spectrum of a standard solution, has a maximum at a wavelength of (407 ± 2) nm in the wavelength range from 300 nm to 500 nm. The optical absorption of the placebo solution at a wavelength of 407 nm is 0.005, which corresponds to 0.70% of the optical absorption of a standard solution (0.710) obtained at the same wavelength. The methodology for determining the quantitative content of troxerutin is characterized by sufficient convergence and sufficient accuracy, and also meets the requirements for linear dependence parameters, which characterizes the absence of chemical interaction between troxerutin, diosmin and excipients.

Thus, the above results indicate the absence of a chemical interaction between diosmin, troxerutin and excipients. Their chemical compatibility is also proved by the quantitative determination of the active substances in the preparation Diosmin + Troxerutin gel for external use during storage. The results of stability studies have shown that there are no chemical interactions between diosmin, troxerutin and excipients that would not allow them to be determined qualitatively and quantitatively or lead to the departure of their quantitative content beyond the limits specified in the specification.

The inventive phlebotropic combined pharmaceutical composition can be made as follows:

A pre-weighed portion of water and a gelling agent are loaded into homogenizer No. 1, mixed until a homogeneous dispersion is obtained, then a penetrator is loaded into homogenized reactor No. 1 and mixed until a homogeneous dispersion is obtained, after which solvent and antimicrobial preservative are loaded into tank No. 1 and the mixture is mixed until a clear solution is obtained, then Troxerutin is loaded into the same container No. 1, part of the water is mixed until troxerutin is completely dissolved, then the gel-neutralizer is loaded into the container No. 2 (pH adjuster) and part of the water and mix until a clear solution is obtained, after which the oil phase component and odor flavor are loaded into the homogenizer No. 2, the mass is mixed until the odor flavor is completely dissolved, then the necessary oil components are loaded into the homogenizer No. 2 phase and mix them until a homogeneous solution. Next, the emulsifier is loaded into homogenizer reactor No. 2 and mixed until it is completely dissolved, after which part of the solvent and diosmin are loaded into tank No. 3 and the mixture is stirred until a homogeneous suspension is formed, then the previously obtained solution of the antimicrobial preservative and troxerutin is loaded into homogenizer No. 1 and mixed, after which the previously obtained oil phase is loaded into the homogenizing reactor No. 1 and mixed, then the previously obtained trometamol solution is loaded into the homogenizing reactor No. 1 and mixed, for thus, the previously obtained diosmin suspension is loaded into the homogenizing reactor No. 1 and mixed, and at the end of the process, the gel obtained is unloaded from the tube filling machine hopper and packaged in tubes.

The preparation is prepared on the basis of oleogel, with troxerutin in the preparation in the form of a solution, and diosmin in the form of a suspension.

BUT - viable cells of test microorganisms were not detected (less than 5 CFU / g for S. aureus, P. aeruginosa, E. coli, C. albicans and A. brasiliensis (niger));

NU - the number of viable cells of test microorganisms does not increase.

Claims (2)

 A phlebotropic combined pharmaceutical composition made in the form of a gel, containing a combination of active substances consisting of diosmin and troxerutin, and excipients, characterized in that troxerutin is in the form of a solution in the preparation, and diosmin is in the form of a suspension, and it contains excipients methyl parahydroxybenzoate, diethylene glycol monoethyl ether, carbomer type C hemopolymer, trometamol, propylene glycol, isopropyl myristate, squalane, macrogol glycerol hydroxystearate, dimethicone, lion Omenthol and purified water in the following ratio of components, g / 100 g:

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