EA038471B1 - Liquid pharmaceutical composition for preparation of solution for local and topical application (embodiments) and method for its production - Google Patents

Abstract

The invention relates to the field of medicine, in particular, to an antimicrobial medicine product in the form of concentrated solution of nitrofural which is intended for preparation of a solution for local and topical application which has an antimicrobial effect. The composition contains an active ingredient nitrofural, a solvent (PEG-400), a co-solvent (DMSO, ethanol, propylene glycol, water), a nonionic surfactant and/or an anticrystallizer. The method of production comprises solution of the active ingredient in the solvent and/or a mixture of the solvent and the co-solvent with addition of nonionic surfactant or an anticrystallizer, if required. An antimicrobial medicine product produced using this method is applied in case of festering wounds, bed sores, small skin lesions, including racomas, scratch marks, cracks, cuts; inflammatory infections of oral cavity and throat including angina, stomatitis, gingivitis or tonsillitis. The cfoncentrated solution of nitrofural is stable during storage for 2 years and is soluble in water at room temperature either instantly or within 5 min depending on the composition.

Description

The invention relates to medicine, namely to an antimicrobial drug in the form of a concentrate for preparing a solution for local and external use.

Currently, the pharmaceutical industry of the Russian Federation produces nitrofural (semicarbazone 5-nitrofurfural, or 2 - [(5-nitrofuran-2-yl) methylene] diazinecarboxamide, or furacilin) in the following dosage forms: ointment for local and external use, sponge, solution ( water and alcohol) for local and external use, tablets (including effervescent) for the preparation of a solution for local and external use [State Register of Medicines, URL: http://grls.rosminzdrav.ru/GRLS.aspx?ReqNumber=&MnnR = Nitrofural & orderType = desc & pageNum = 1].

Nitrofural is active against gram-positive and gram-negative bacteria: intestinal, dysentery bacillus, paratyphoid, salmonella, Vibrio cholerae, lamblia, Trichomonas, staphylococcus, large viruses, gas gangrene pathogens (Staphylococcus spp., Streigcoccus spp. spp., Shigella boydii spp., Shigella sonnei spp., Escherichia coli, Clostridium perfringens, Salmonella spp., etc.); can be used as a photosensitizer for antimicrobial photodynamic therapy [RF patent No. 2497518, publ. 11/10/2013]; effective in the resistance of microorganisms to other antimicrobial agents and antibiotics.

Nitrofural is practically insoluble in chloroform (1: 27000) and benzene (1: 43500); very slightly soluble in water (1: 4200 at pH 6.0-6.5 and temperature 20 ° C); slightly soluble in ethanol (1: 590), propylene glycol (1: 350), acetone (1: 415); slightly soluble in polyethylene glycol (1:86); soluble in dimethylformamide (1:15), dimethyl sulfoxide and alkaline solutions [International Agency for Research on Cancer IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 50. Pharmaceutical Drugs, WHO-IARC, 1990, p. 415, ISBN 9283212509].

Low solubility in water at therapeutic concentrations limits the convenience of using nitrofural, including in a hospital setting.

From the prior art [RF patent No. 2360673, publ. 11/10/2013] there is a known method of preparing furacilin solutions for external, local and intracavitary use as an antimicrobial agent, when a concentrated solution of furacilin on purified water in a ratio of 1: 500-1: 400 was prepared by boiling at 100 ° C. The resulting concentrate was diluted with purified water or isotonic sodium chloride solution to the desired concentration within the solubility of furacilin 1: 10000-1: 1000. Also, a clarifying filtration of the resulting solution was carried out through a filter with a separation limit of 1 μm. The disadvantage of this method is the impossibility of storing the original concentrate (which could ensure the convenience of storage and transportation), since when cooled to a temperature of 20-25 ° C, the solubility of nitrofural in water significantly decreases, which leads to the rapid crystallization of part of the nitrofural from the solution.

Among the promising dosage forms that provide high stability and acceptable solubility of nitrofural in water when preparing a ready-to-use solution [I.I. Krasnyuk (Jr.), O. I. Stepanova, A.V. Belyatskaya, I.I. Krasnyuk, L.A. King. Prospects for obtaining dosage forms based on solid dispersions of furacilin // Development and registration of drugs. - 2015. - No. 2. - P. 72-78], there is no drug in the form of a concentrate for solution preparation.

The prior art also known tablets for the preparation of a solution for local and external use, including effervescent [RF patent No. 2533261] or obtained using melt extrusion technology [G.I. Nikulina, et al. Furacilin release from solid dispersions // Pharmaceutical Chemistry Journal, 2013, Vol. 46, No. 12, p. 745-749]. Despite a significant increase in the rate of dissolution of nitrofural in comparison with the preparation in the form of tablets based on sodium chloride and nitrofural, the proposed modifications do not provide instant dissolution, and also do not guarantee the absence of a precipitate of undissolved nitrofural.

Furacilin, tablets for the preparation of a solution for local and external use, 20 mg (produced by JSC PFK Renewal, instructions for use LP004683-020218) was chosen as the closest analogue. The presence of a precipitate in a solution obtained in accordance with the requirements of the instructions for use LP004683-020218 indicates that the concentration of the active substance in the ready-to-use solution is below the nominal, which, along with photodestruction, may cause a decrease in the antimicrobial activity of the drug; in addition, the presence of sediment makes this solution unsuitable without additional filtration procedures for use in the treatment of ophthalmic diseases, which can be critical when using the drug in ophthalmology.

The developed dosage form is devoid of these disadvantages, namely, it is resistant to crystallization, despite the high concentration (up to 250 mg / ml) of nitrofural in the solvent mixture, which is achieved not only by the use of pharmaceutically acceptable solvents and co-solvents (dimethyl sulfoxide, propylene glycol, ethanol, polyethylene glycol, etc.). ), but also by introducing structure-forming polymers (polyvinylpyrrolidones, block copolymers of polyethylene and polypropylene oxide, etc.), which create a spatial network that prevents the formation of crystals in a supersaturated nitrofural solution, and also makes it possible to prepare a solution for direct use with

- 1 038471 using water with a temperature of 20 to 40 ° C for a time from 0 to 5 minutes, depending on the composition.

The objective of the present invention is to develop a composition and a method for producing an antimicrobial drug in the form of a concentrate for preparing a solution for local and external use, containing nitrofural as an active substance, dissolving in water at a temperature of 20 to 40 ° C for a time from 0 to 5 minutes depending on the composition, storage-stable for at least two years.

Technical results:

increasing the stability of the nitrofural solution;

increasing the rate of preparation of a nitrofural solution for local and external use for carrying out the necessary medical procedures;

expanding the arsenal of antimicrobial drugs for local and external use.

The problem is solved, and the technical result is achieved by creating a method for producing a liquid pharmaceutical composition, which includes the following steps:

step (a) dissolving the required amount of nitrofural in a solvent or a mixture of solvent and cosolvent, optionally, step (b) adding a nonionic surfactant and / or anticrystallizer to the solution obtained in step (a), and the final step (c) filtration of the resulting concentrated solution ...

When this stage (a) dissolution is carried out with vigorous stirring for 1 to 30 minutes at a temperature of 25 to 70 ° C. Polyethylene glycol 400 (PEG-400) is used as a solvent, a substance selected from the group including water, dimethyl sulfoxide (DMSO), ethanol, propylene glycol is used as a co-solvent, a substance selected from the group is used as a nonionic surfactant (surfactant). polysorbate-80, polyoxyethylene castor oil ether and polyethylene glycol- (15) -hydroxystearate, polyvinylpyrrolidone (povidone) or a block copolymer of polyethylene oxide and polypropylene oxide is used as an anticrystallizer.

According to preferred embodiments, the specified technical result is also achieved in that the concentrated nitrofural solution obtained by the said method is intended for preparing a solution for local and external use with antimicrobial action;

the steps of the method are carried out in an inert gas atmosphere;

at stage (c) filtration, membrane filters are used;

at all stages, the components of the liquid pharmaceutical composition are protected from UV and visible light;

the concentration of nitrofural in the composition obtained by the above method is from 1 to 250 mg / ml.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for the preparation of a solution for local and external use, which has an antimicrobial effect, which is obtained by the mentioned method, and the said composition contains, wt%:

nitrofural 0.094-0.357

PEG-400 42.561-78.746 povidone 0-3.565 water up to 100.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for preparing a solution for local and external use, which has an antimicrobial effect, and the said composition contains, wt%:

nitrofural 0.094-0.357

PEG-400 42.561-78.746 povidone 0-3.565 water UP TO 100.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for the preparation of a solution for local and external use, which has an antimicrobial effect, which is obtained by the mentioned method, and the said composition contains, wt%:

- 2 038471

nitrofural PEG-400 0.096-0.358 32,500-70,815 povidone 0-3.522 DMSO 1.432-4.263

water up to 100.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for preparing a solution for local and external use, which has an antimicrobial effect, and the said composition contains, wt%:

nitrofural PEG-400 0.096-0.358 32,500-70,815 povidone 0-3.522 DMSO 1.432-4.263 water up to 100.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for the preparation of a solution for local and external use, which has an antimicrobial effect, which is obtained by the mentioned method, and the said composition contains, wt%:

nitrofural 0.179-0.623 ethanol 0-7.622 propylene glycol 0-14.854

PEG-400 up to 100.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for preparing a solution for local and external use, which has an antimicrobial effect, and the said composition contains, wt%:

nitrofural 0.179-0.623 ethanol 0-7.622 propylene glycol 0-14.854

PEG-400 up to 100.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for the preparation of a solution for local and external use, which has an antimicrobial effect, which is obtained by the mentioned method, and the said composition contains, wt%:

nitrofural 0.265-2.182

DMSO 7.073-27.923

PEG-400 up to 100.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for preparing a solution for local and external use, which has an antimicrobial effect, and the said composition contains, wt%:

nitrofural 0.265-2.182

DMSO 7.073-27.923

PEG-400 up to 100.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for the preparation of a solution for local and external use, which has an antimicrobial effect, which is obtained by the mentioned method, and the said composition contains, wt%:

nitrofural 4.464 - 17.841 nonionic surfactant 26.786 - 32.471

DMSO 49.688 - 68.750.

According to preferred embodiments, the specified technical result is also achieved in that the nonionic surfactant used is a substance selected from the group including polysorbate-80, polyoxyethylene castor oil ether and polyethylene glycol (15) hydroxystearate.

The problem is also solved, and the technical result is achieved by creating a liquid pharmaceutical composition for preparing a solution for local and external use, which has an antimicrobial effect, and the said composition contains, wt%:

nitrofural 4.464 - 17.841 nonionic surfactant 26.786 - 32.471

DMSO 49.688 - 68.750.

- 3 038471

According to preferred embodiments, the specified technical result is also achieved in that a substance selected from the group consisting of polysorbate-80, polyoxyethylene castor oil ether and polyethylene glycol (15) hydroxystearate is used as the nonionic surfactant.

The above compositions can be obtained by the above method.

The problem is also solved, and the technical result is achieved by creating a solution for local and external use with an antimicrobial effect, which is prepared by adding the required amount of purified water or isotonic solution to one of the above-mentioned liquid pharmaceutical compositions.

The composition of the liquid pharmaceutical composition is theoretically justified. All components that make up the liquid pharmaceutical composition are approved for use in the composition of antimicrobial agents for local and external use. The achievement of technical results is facilitated by a balanced combination of ingredients and their mutual influence on each other.

The advantages of the present invention are that, in comparison with the inventions known in this field of technology:

a new, previously unknown for the pharmaceutical substance nitrofural, dosage form is proposed, which makes it possible to obtain a drug for direct use in the form of a solution for local and external use;

an original composition was developed, which is a solution of nitrofural and excipients;

a technology for obtaining a liquid pharmaceutical composition of nitrofural has been developed;

a new preparation method has been developed that allows to obtain a solution for local and external use without the formation of a precipitate by dissolving a weighed amount of nitrofural, necessary to achieve a concentration of up to 250 mg / ml, in water with a temperature of 20 to 40 ° C for a time from several seconds to 5 minutes ( depending on the composition), allowing it to be used immediately after preparation; there is no need to dissolve a tablet (including an effervescent one) with constant stirring in 100 ml of boiling water and then cooling the solution to a temperature that allows it to be used;

developed an antimicrobial drug in the form of a concentrate for the preparation of a solution based on solvents and co-solvents that are safe for use in pharmaceutical technology (polyethylene glycol, propylene glycol, ethanol, dimethyl sulfoxide), which are infinitely miscible with water and provide high solubility of nitrofural.

In a preferred embodiment of the invention, the dissolution of the active substance in a solvent or cosolvent or in a mixture of solvent and cosolvent is carried out at a temperature of 20 to 70 ° C under conditions of complete protection from ultraviolet (UV) and visible light, adding a nonionic surfactant or an anti-crystallizer (if necessary) and subsequent filtration.

In a preferred embodiment of the invention, a liquid pharmaceutical composition of nitrofural is prepared as follows. The required weight of a sample of the PEG-400 substance is weighed on a scale into a 2 L glass calibrated beaker. A weighed portion of the nitrofural substance is loaded, a magnetic anchor is placed and installed on a magnetic stirrer with heating, the solution is stirred at a speed of 300 rpm. In order to increase the dissolution rate, it is allowed to heat the suspension not higher than 70 ° C until complete dissolution, but not more than 30 minutes; after stopping heating, stirring is continued for 10 minutes. The degree of dissolution is visually assessed. After stirring, a sample of polyvinylpyrrolidone, previously dissolved in 100 ml of water, is loaded. Bring to the mark with 1 L of water, stir for 30 minutes (if necessary in an inert nitrogen atmosphere), cool to 25 ° C and re-bring to the mark with water.

A slightly viscous yellow solution is obtained. Sampling is carried out to determine the indicators. Quantitative content. If the sample does not correspond in terms of the quantitative content, then correction is possible with the help of an additional required amount of nitrofural or water. If the sample corresponds to the indicator Quantitative content, the solution is transferred to the next stage.

Filtration of the process solution is carried out in a laminar flow cabinet using a laboratory filter unit and a peristaltic pump through a nylon or polyethersulfone membrane filter or through a polypropylene membrane filter into a sterile glass beaker. The finished product is bottled in a laminar flow cabinet in dark glass bottles.

In another preferred embodiment of the invention, a liquid pharmaceutical composition of nitrofural is prepared as follows. A portion of PEG-400 was transferred into a calibrated glass beaker, then a sample of nitrofural was added to the beaker and stirred on a magnetic stirrer with heating at a speed of about 300 rpm. In order to increase the dissolution rate, the mixture was heated, but not exceeding 70 ° C. Stirring was carried out until complete dissolution (no more than 30 min, the degree of dissolution was assessed visually). Then the heating was turned off and stirred for another

- 4 038471

5-15 minutes After stirring, the resulting solution was brought to the mark and stirred for 1530 minutes. The solution was cooled to room temperature and re-brought to the mark with PEG-400. Filtration of the process solution was carried out in a laminar flow cabinet using a laboratory filter unit and a peristaltic pump through a nylon or polyethersulfone membrane filter or through a polypropylene membrane filter into a sterile glass beaker. The finished product was filled in a laminar flow cabinet into dark glass vials.

In another preferred embodiment of the invention, a liquid pharmaceutical composition of nitrofural is prepared as follows. A weighed portion of nitrofural was placed in a volume-calibrated dish with a magnetic stirrer, DMSO was poured in and stirred until the nitrofural was completely dissolved; if necessary, the solution was heated to a temperature not higher than 50 ° C, then a known amount of PEG-400 was added. The calculated amount of polyvinylpyrrolidone, previously dissolved in a third of the calculated volume of water, was added. The volume was brought to the nominal with water, the solution was cooled and re-brought to the nominal with water. The resulting solution was filtered in a laminar flow cabinet through a polypropylene membrane filter into a sterile glass beaker. The finished product was filled in a laminar flow cabinet into dark glass vials.

In another preferred embodiment of the invention, a liquid pharmaceutical composition of nitrofural is prepared as follows. A weighed portion of polyethylene glycol 400 (approximately 70% of the total volume) was placed in a calibrated dish, and a weighed portion of nitrofural was added (to accelerate dissolution, heating is allowed no higher than 70 ° C). A sample of absolute ethyl alcohol or propylene glycol was added to the resulting solution at room temperature, mixed and brought to the nominal volume with polyethylene glycol 400, then stirred for another 5 min.

Next, filtration was carried out through a polypropylene filter and poured into dark glass vials.

In another preferred embodiment of the invention, a liquid pharmaceutical composition of nitrofural is prepared as follows. A weighed portion of nitrofural was placed in a volume-calibrated dish with a magnetic stirrer, DMSO was added and stirred until the nitrofural was completely dissolved; if necessary, the solution was heated to a temperature of no higher than 50 ° C. By adding PEG-400, the volume was brought to the nominal. Filtration was carried out through a polypropylene membrane filter. The finished product was filled into dark glass vials.

In another preferred embodiment of the invention, a liquid pharmaceutical composition of nitrofural is prepared as follows. A weighed portion of nitrofural was placed in a volume-calibrated dish with a magnetic stirrer, a weighed portion of 2/3 of the required volume of DMSO was poured in and stirred until the nitrofural was completely dissolved; if necessary, the solution was heated to a temperature of no higher than 50 ° C. A calculated amount of a nonionic surfactant was added: polysorbate-80 (Tween 80), or polyoxyethylene castor oil ether (Kolliphor EL), or polyethylene glycol (15) hydroxystearate (Kolliphor HS 15) and stirred until complete dissolution. The volume was brought to the nominal DMSO, the solution was cooled and re-brought to the nominal by the addition of DMSO. The resulting solution was poured into dropper bottles made of low pressure polyethylene with a volume of 5-10 ml.

The following are examples of implementation of the invention with reference to the accompanying figures.

FIG. 1 shows the change in the content of impurities during storage of the solution obtained in paragraph 2 of Example 9 (accelerated storage 40 ° C, 6 months storage is equivalent to 2 years at 25 ° C).

FIG. 2 shows the change in the content of impurities during storage of the solution obtained in paragraph 2 of Example 9 (stress conditions 60 ° C, 38 days of storage are equivalent to 2.5 years at 25 ° C).

FIG. 3 shows the change in the content of impurities of a nitrofural solution with a concentration of 0.2 mg / ml in a 9% aqueous solution of sodium chloride during storage for 7 months at a temperature of 25 ° C (model of a commercial drug Furacilin, solution for local and external use, 0, 02%).

Examples of implementation of the invention

Example 1. Preparation of a liquid pharmaceutical composition of nitrofural.

Table 1

Description of the composition of the liquid pharmaceutical composition

Component The amount of the component per 5 ml of solution Nitrofural, g 0.020 0.005 PEG-400, g 4.520 3.955 3.955 3.6725 3.390 4.520 2.0 Povidone K-30, g 0.1 0.1 0.15 0.2 0.1 0 0 Water ml up to 5 ml

A portion of PEG-400 was transferred into a calibrated glass beaker with a volume of 2 liters, then a sample of nitrofural was added to the beaker and stirred on a magnetic stirrer with heating at a speed of about 300 rpm. In order to increase the dissolution rate, the mixture was heated to a temperature of 45-70 ° C, but not exceeding 70 ° C. Stirring was carried out until complete dissolution (no more than 30 min, the degree of solution

- 5 038471 was assessed visually). Then the heating was turned off and the mixture was stirred for another 10 min. After stirring, a sample of K-30 povidone, previously dissolved in 100 ml of water for injection, was added to the resulting nitrofural solution, then it was brought to the mark with 1000 ml of water for injection and stirred for 30 min while bubbling the solution with nitrogen. The solution was cooled to 25 ° C and re-brought to the 1000 ml mark with water for injection.

The result was a slightly viscous yellow solution.

Samples were taken to determine the indicators Quantitative content. In case of discrepancy between the obtained solution and the indicator The quantitative content of nitrofural, the solution was corrected by adding an additional required amount of nitrofural or water. If the sample corresponded to the indicator Quantitative content, the solution was transferred to the filtration stage.

Filtration of the nitrofural solution is carried out in a laminar cabinet using a laboratory filtering unit and a peristaltic pump through a nylon or polyethersulfone membrane filter with a pore size of 0.45 μm or through a polypropylene membrane filter with a pore size of 1.2 μm into a sterile glass beaker. The finished product is bottled in a laminar flow cabinet in dark glass bottles of the 3rd hydrolytic class with a volume of 100-200 ml.

At all stages of solution preparation, the components were protected from UV and visible light.

The resulting solution has no sediment and corresponds to the specification given in table. 2.

table 2

Specification for solution for local and external use

Index Method Norm Description of Nitrofural Liquid Pharmaceutical Composition Visual Viscous liquid from yellow to brownish yellow. Description of the solution for local and external use Visual Transparent or slightly opalescent light yellow liquid. Authenticity HPLC GF RF, spectrophotometry in the UV and visible regions The retention time of the main peak in the chromatogram of the test solution should correspond to the retention time of the nitrofural peak in the chromatogram of the reference solution. The absorption spectra of the test solution and the reference solution of nitrofural, prepared for quantitative determination, in the wavelength range from 230 to 450 nm should have maxima and minimum at the same wavelengths. pH GF RF, potentiometric 4.0 to 6.0. Viscosity GF RF 90.0 to 115.0 mPa s. Density GF RF, method 1 From 1.07 to 1.17 g / cm ³ . Package content volume GF RF In accordance with the requirements. Related impurities HPLC Any single impurity - no more than 1.0%; the amount of impurities is not more than 6.0%. Microbiological purity GF RF Category 2. quantitation Spectrophotometry Not less than 3.60 mg / ml and not more than 4.40 mg / ml.

HPLC stands for high performance liquid chromatography.

GF RF - State Pharmacopoeia of the Russian Federation, XIV edition.

Example 2. Preparation of a solution for local and external use.

Table 3

Description of the composition of the liquid pharmaceutical composition

Component The amount of the component per 5 ml of solution Nitrofural, g 0.010 0.020 0.025 0.030 0.035 PEG-400, ml up to 5 ml

A portion of 1000 g of PEG-400 was transferred into a calibrated glass beaker with a volume of 2 liters, then a sample of 2.00 to 7.00 g of nitrofural was added to the beaker and stirred on a magnetic stirrer with heating at a speed of about 300 rpm. In order to increase the dissolution rate, the mixture was heated to

- 6 038471 temperatures 45-70 ° С, but not exceeding 70 ° С. Stirring was carried out until complete dissolution (no more than 30 min, the degree of dissolution was assessed visually). Then the heating was turned off and the mixture was stirred for another 10 min. After stirring, the resulting solution was brought to the mark with 1000 ml of PEG-400 and stirred for 10 minutes. The solution was cooled to 25 ° C and re-adjusted with PEG-400 to the 1000 ml mark.

Filtration of the nitrofural solution is carried out in a laminar cabinet using a laboratory filtering unit and a peristaltic pump through a nylon or polyethersulfone membrane filter with a pore size of 0.45 μm or through a polypropylene membrane filter with a pore size of 1.2 μm into a sterile glass beaker. The finished product is bottled in a laminar flow cabinet in dark glass bottles of the 3rd hydrolytic class with a volume of 100-200 ml.

At all stages of solution preparation, the components were protected from UV and visible light.

The resulting solution has no sediment and corresponds to the specification given in table. 2.

Example 3. Preparation of a liquid pharmaceutical composition of nitrofural.

Table 4

Description of the composition of the liquid pharmaceutical composition

Component The amount of the component per dose (5 ml of solution) Nitrofural, g 0.02 0.005 PEG-400, g 3.39 3.39 3.39 3.39 3.39 3.39 3.6725 3.955 1.5 Povidone K-30, g 0.1 0.2 OD 0.2 0.1 0.2 0.1 0.1 0 DMSO, g 0.08 0.08 0.16 0.16 0.24 0.24 0.08 0.08 0.16 Water ml up to 5 ml

A weighed portion of nitrofural is placed in a volume-calibrated dish with a magnetic stirrer, poured in DMSO and stirred until the nitrofural is completely dissolved, if necessary, heating the solution to a temperature not higher than 50 ° C, then add PEG-400. Add the calculated amount of polyvinylpyrrolidone K-30, previously dissolved in a third of the calculated volume of water. Bring the volume to the nominal with water, cool the solution and bring it back to the nominal with water.

Filtration of the resulting solution is carried out in a laminar flow cabinet through a polypropylene membrane filter with a pore size of 1.2 μm into a sterile glass beaker. The finished product is bottled in a laminar flow cabinet in dark glass bottles of the 3rd hydrolytic class with a volume of 100-200 ml.

When preparing a solution for direct use, one dose (5 ml) of the concentrate is dissolved in approximately 100 ml of water at a temperature of 20 ° C instantly without the need for stirring. The resulting solution has no sediment.

At all stages of solution preparation, the components were protected from UV and visible light. The resulting solution corresponds to the specification given in table. 2.

Example 4. Preparation of a liquid pharmaceutical composition of nitrofural.

Table 5

Description of the composition of the liquid pharmaceutical composition

Component The amount of the component per dose (5 ml of solution) Nitrofural, g 0.02 0.010 0.035 Ethanol (abs.), G 0.375 0 0.30 0.15 0 Propylene glycol, g 0 0.75 0.45 0.60 0.75 0.75 PEG-400, ml up to 5 ml

A weighed portion of PEG-400 (70% of the total volume) is placed in a calibrated dish, a weighed portion of nitrofural is added (to accelerate dissolution, heating is allowed no higher than 70 ° C). A sample of absolute ethyl alcohol or propylene glycol is added to the resulting solution at room temperature, mixed and brought to the nominal volume with polyethylene glycol 400, then stirred for another 5 minutes. Next, filtration is carried out through a polypropylene filter with a pore size of 1.2 μm and poured into dark glass vials of 3 hydrolytic class with a volume of 100-200 ml.

When preparing a solution for direct use, one dose (5 ml) of the concentrate is dissolved in approximately 100 ml of water at a temperature of 20 ° C instantly without the need for stirring. The resulting solution has no sediment.

At all stages of solution preparation, the components were protected from UV and visible light. The resulting solution corresponds to the specification given in table. 2.

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Example 5. Preparation of a liquid pharmaceutical composition of nitrofural.

Table 6

Description of the composition of the liquid pharmaceutical composition

Component The amount of the component per dose (1 ml of solution) Nitrofural, g 0.020 0.003 0.025 DMSO, g 0.08 0.16 0.24 0.08 0.32 PEG-400, ml up to 1 ml

A weighed portion of nitrofural is placed in a volume-calibrated dish with a magnetic stirrer, DMSO is poured in and stirred until the nitrofural is completely dissolved, if necessary, heating the solution to a temperature not exceeding 50 ° C. By adding PEG-400, the volume is brought to the nominal volume (hereinafter, the nominal volume refers to the volume of the calibrated glassware taken for the preparation of a liquid pharmaceutical composition).

Filtration is carried out through a polypropylene membrane filter with a pore size of 1.2 μm; the finished product is bottled in 50 ml hydrolytic class 3 dark glass bottles.

When preparing a solution for direct use, one dose (1 ml) of the concentrate is dissolved in 100 ml of water at a temperature of 30-40 ° C in no more than 1 minute with periodic stirring. The resulting solution has no sediment.

At all stages of solution preparation, the components were protected from UV and visible light. The resulting solution corresponds to the specification given in table. 2.

Example 6. Preparation of a liquid pharmaceutical composition of nitrofural.

Table 7

Description of the composition of the liquid pharmaceutical composition

Component The amount of the component per dose (0.112 g of solution or about 0.08 ml) Nitrofural, g 0.0200 0.015 0.010 0.003 Polysorbat-80, g 0.0364 0.0385 0.024 0.020 DMSO, g 0.0557 0.0586 0.0781 0.0891

A weighed portion of nitrofural is placed in a volume-calibrated dish with a magnetic stirrer, a weighed portion of 2/3 of the required volume of DMSO is poured in and stirred until the nitrofural is completely dissolved, if necessary, heating the solution to a temperature not higher than 50 ° C. The calculated amount of polysorbate-80 (Tween 80) is added and stirred until complete dissolution. Bring the volume to nominal by adding DMSO, cool the solution and bring it back to nominal by adding DMSO. The resulting solution is poured into dropper bottles made of low pressure polyethylene with a volume of 5-10 ml.

When preparing a solution for direct use, one dose (4 drops, this is about 0.08 ml, or 0.112 g of the composition, which contain 5-20 mg of nitrofural) of the concentrate is dissolved in 100 ml of water at a temperature not lower than 40 ° C for 5 minutes at periodic stirring.

At all stages of solution preparation, the components were protected from UV and visible light. The resulting solution corresponds to the specification given in table. 2.

Example 7. Preparation of a liquid pharmaceutical composition of nitrofural.

Table 8

Description of the composition of the liquid pharmaceutical composition

Component The amount of the component per dose (0.112 g of solution or about 0.08 ml) Nitrofural, g 0.0200 0.015 0.010 0.005 Castor oil polyoxyethylene ether, g 0.0364 0.0385 0.024 0.020 DMSO, g 0.0557 0.0586 0.0781 0.0891

A weighed portion of nitrofural is placed in a volume-calibrated dish with a magnetic stirrer, a weighed portion of 2/3 of the required volume of DMSO is poured in and stirred until the nitrofural is completely dissolved, if necessary, heating the solution to a temperature not higher than 50 ° C. Add the calculated amount of castor oil polyoxyethylene ether (Kolliphor EL) and mix until completely dissolved. Bring the volume to the nominal DMSO, cool the solution and bring it back to the nominal DMSO. The resulting solution is poured into dropper bottles made of low pressure polyethylene with a volume of 5-10 ml.

When preparing a solution for direct use, one dose (4 drops) of the concentrate

- 8 038471 is dissolved in 100 ml of water at a temperature not lower than 40 ° C for 5 minutes with periodic stirring.

At all stages of solution preparation, the components were protected from UV and visible light. The resulting solution corresponds to the specification given in table. 2.

Example 8. Preparation of a liquid pharmaceutical composition of nitrofural.

Table 9

Description of the composition of the liquid pharmaceutical composition

Component The amount of the component per dose (0.112 g of solution or about 0.08 ml) Nitrofural, g 0.0200 0.015 0.010 0.005 Polyethylene glycol (15) -hydroxystearate, g 0.0364 0.0385 0.024 0.020 DMSO, g 0.0557 0.0586 0.0781 0.0891

A weighed portion of nitrofural is placed in a volume-calibrated dish with a magnetic stirrer, a weighed portion of 2/3 of the required volume of DMSO is poured in and stirred until the nitrofural is completely dissolved, if necessary, heating the solution to a temperature not higher than 50 ° C. Add the calculated amount of polyethylene glycol (15) -hydroxystearate (Kolliphor HS 15) and mix until completely dissolved. Bring the volume to the nominal DMSO, cool the solution and bring it back to the nominal DMSO. The resulting solution is poured into dropper bottles made of low pressure polyethylene with a volume of 5-10 ml.

When preparing a solution for direct use, one dose (4 drops) of the concentrate is dissolved in 100 ml of water at a temperature not lower than 40 ° C for 5 minutes with periodic stirring.

At all stages of solution preparation, the components were protected from UV and visible light. The resulting solution corresponds to the specification given in table. 2.

Example 9. Comparative experiments on the preparation of solutions of nitrofural for local and external use, with antimicrobial action.

1. Tablet of the drug Furacilin, tablets for the preparation of a solution for local and external use, 20 mg (manufactured by JSC PFK Renewal) (the closest analogue) was dissolved in 100 ml of purified water.

In six parallel experiments at a temperature of 20 ° C and continuous stirring, the tablet dissolved for more than 45 minutes.

In six parallel experiments at a temperature of 50 ° C and continuous stirring, the tablet dissolved for more than 25 minutes.

In six parallel experiments at a temperature of 90 ° C and continuous stirring, the tablet dissolved for more than 15 minutes.

In all cases, complete dissolution within the specified time could not be achieved; a precipitate of an undissolved drug was observed. In accordance with the instructions for medical use, the drug Furacilin, tablets for the preparation of a solution for local and external use, 20 mg is used, among other things, for the treatment of blepharitis and conjunctivitis. According to the requirements of the State Fund of the Russian Federation (XIV edition), a drug for use in ophthalmology should not contain mechanical impurities (sediment), thus, all solutions obtained from tablets selected as the closest analogue require filtration before use.

2.5 ml of a liquid pharmaceutical composition of nitrofural (4 mg / ml) prepared in accordance with example 1 (0.355% nitrofural, 80.142% PEG-400, 1.773% povidone, 17.730% water) was placed in a 100 ml volumetric flask, then the volume was brought up to the mark with purified water. In six parallel experiments at a temperature of 20 ° C, the solution was obtained instantly without the need for continuous stirring. The resulting solution did not contain mechanical impurities in the form of a precipitate of undissolved active substance and did not require filtration.

3. 5 ml of a liquid pharmaceutical composition of nitrofural (4 mg / ml) prepared in accordance with example 2 (0.452% nitrofural, 99.548% PEG-400) was placed in a 100 ml volumetric flask, then the volume was brought to the mark with purified water. In six parallel experiments at a temperature of 20 ° C, the solution was obtained instantly without the need for continuous stirring. The resulting solution did not contain mechanical impurities in the form of a precipitate of undissolved active substance and did not require filtration.

4.5 ml of a liquid pharmaceutical composition of nitrofural (4 mg / ml) prepared in accordance with example 3 (0.362% nitrofural, 61.302% PEG-400, 1.808% povidone, 4.340% DMSO, 32.188% water) was placed in a volumetric flask 100 ml, then the volume was brought to the mark with isotonic sodium chloride solution. In six parallel experiments at a temperature of 20 ° C, the solution was obtained

- 9 038471 instantly without the need for continuous stirring. The resulting solution did not contain mechanical impurities in the form of a precipitate of undissolved active substance and did not require filtration.

5. 5 ml of a liquid pharmaceutical composition of nitrofural (4 mg / ml) prepared in accordance with example 4 (0.357% nitrofural, 13.381% propylene glycol, 86.262% PEG-400) was placed in a 100 ml volumetric flask, then the volume was brought to the mark isotonic sodium chloride solution. In six parallel experiments at a temperature of 20 ° C, the solution was obtained instantly without the need for continuous stirring. The resulting solution did not contain mechanical impurities in the form of a precipitate of undissolved active substance and did not require filtration.

6.1 ml of a liquid pharmaceutical composition of nitrofural (20 mg / ml) prepared in accordance with example 5 (1.743% nitrofural, 7.668% DMSO, 90.589% PEG-400) was placed in a 100 ml volumetric flask, then the volume was brought to the mark purified water. In six parallel experiments at a temperature of 30-40 ° C and no more than 1 min with periodic stirring. The resulting solution did not contain mechanical impurities in the form of a precipitate of undissolved active substance and did not require filtration.

7. 0.08 ml (4 drops) of a liquid pharmaceutical composition of nitrofural (250 mg / ml) prepared in accordance with example 6 (17.841% nitrofural, 32.471% Tween 80, 49.688% DMSO) was placed in a 100 ml volumetric flask, then the volume was brought to the mark with purified water. The specified volume of liquid pharmaceutical composition of nitrofural (4 drops) was dissolved in 100 ml of water at a temperature of about 40 ° C for 5 minutes with occasional stirring. The resulting solution did not contain mechanical impurities in the form of a precipitate of undissolved active substance and did not require filtration.

8. 0.08 ml (4 drops) of a liquid pharmaceutical composition of nitrofural (250 mg / ml) prepared in accordance with example 7 (17.841% nitrofural, 32.471% Kolliphor EL, 49.688% DMSO) was placed in a 100 ml volumetric flask, then the volume was brought to the mark with purified water. The specified volume of liquid pharmaceutical composition of nitrofural (4 drops) was dissolved in 100 ml of water at a temperature of about 40-45 ° C for 5 minutes with occasional stirring. The resulting solution did not contain mechanical impurities in the form of a precipitate of undissolved active substance and did not require filtration.

9. 0.08 ml (4 drops) of a liquid pharmaceutical composition of nitrofural 250 mg / ml) prepared in accordance with example 8 (17.841% nitrofural, 32.471% Kolliphor HS 15, 49.688% DMSO) was placed in a 100 ml volumetric flask, then the volume was brought to the mark with purified water. The specified volume of liquid pharmaceutical composition of nitrofural (4 drops) was dissolved in 100 ml of water at a temperature of about 40 ° C for 5 minutes with occasional stirring. The resulting solution did not contain mechanical impurities in the form of a precipitate of undissolved active substance and did not require filtration.

Example 10. Comparative experiments to study the stability of solutions of nitrofural for local and external use, which has antimicrobial action.

A study was conducted on the content of impurities in a solution for local and external use prepared according to paragraph 2 of Example 9 from a liquid pharmaceutical composition of nitrofural according to Example 1 (4 mg / ml nitrofural), subjected to accelerated aging (40 ° C, 6 months of storage, which is equivalent to two years at 25 ° C; Fig. 1) and exposure to stressful conditions (60 ° C, 38 days of storage, which is equivalent to 2.5 years at 25 ° C; Fig. 2) [State Pharmacopoeia of the Russian Federation. XIII edition, 2015, OFS.1.1.0009.15, p. 192-206].

Experiments have shown that a liquid pharmaceutical composition of nitrofural for the preparation of a solution for local and external use (4 mg / ml), obtained according to Example 1:

when stored at a temperature of 40 ° C for 6 months (which is equivalent to 2 years of storage at a temperature of 25 ° C), the content of a single impurity does not exceed 0.5%, and the total content of impurities does not exceed 3.0% (Fig. 1);

when stored at a temperature of 60 ° C for 38 days (which is equivalent to 2.5 years of storage at a temperature of 25 ° C), the content of a single impurity does not exceed 1.0%, and the total content of impurities does not exceed 6.0% (Fig. 1) ...

For comparison, an experiment was carried out to study the stability of a ready-to-use nitrofural solution with a concentration of 0.02% in 0.9% sodium chloride solution (model of a commercial drug Furacilin, solution for local and external use, 0.2 mg / ml), stored at temperature 25 ° С in a glass bottle (400 ml) for blood, transfusion and infusion preparations, sealed with a rubber stopper and crimped with an aluminum cap, in a cardboard box. For this solution, after seven months of storage at a temperature of 25 ° C in the original packaging, the content of a single impurity was 1.61%, and the total impurity was 5.26% (Fig. 3). The results obtained make it possible to predict an increase in the content of a single impurity to the level of 5.5%, the amount of impurities to the level of 18.0% for 2 years of storage under the same conditions.

Thus, a comparison of the equivalent growth rate of impurities in a nitrofural solution for

- 10 038471 for external and external use, prepared in accordance with paragraph 2 of Example 9 from a liquid pharmaceutical composition of nitrofural obtained in accordance with Example 1, and the growth rate of impurities in a solution of nitrofural with a concentration of 0.02% in 9% sodium chloride solution (model commercial drug Furacilin, solution for local and external use, 0.2 mg / ml), showed a higher stability of the furacilin concentrate obtained in accordance with Example 1.

Obtained according to Example 9 solutions for local and external use are used as an antimicrobial drug for purulent wounds, bedsores, minor skin lesions, including abrasions, scratches, cracks, cuts; infectious and inflammatory diseases of the mouth and throat, including tonsillitis, stomatitis, gingivitis, tonsillitis. It was found that the solutions obtained according to example 9 for local and external use are not inferior in their antimicrobial properties to nitrofural (furacilin) solutions available on the Russian market.

Claims (16)

CLAIM 1. A method of obtaining a liquid pharmaceutical composition for the preparation of a solution for local and external use with antimicrobial action, which includes: stage (a) dissolving nitrofural in a solvent or cosolvent or in a mixture of solvent and cosolvent and stage (b) filtering the resulting concentrated solution, and stage (a) dissolving is carried out with vigorous stirring for 1 to 30 minutes at a temperature of 20 to 70 ° WITH; moreover, polyethylene glycol 400 (PEG-400) is used as a solvent, a substance selected from the group consisting of water, dimethyl sulfoxide (DMSO), ethanol, propylene glycol is used as a co-solvent. 2. A method for producing a liquid pharmaceutical composition according to claim 1, characterized in that the method further comprises the step of adding a nonionic surfactant (surfactant) and / or an anticrystallizer to the solution obtained in step (a), wherein the nonionic surfactant is used a substance selected from the group consisting of polysorbate-80, polyoxyethylene castor oil ether and polyethylene glycol- (15) -hydroxystearate, polyvinylpyrrolidone (povidone) or a block copolymer of polyethylene oxide and polypropylene oxide is used as an anticrystallizer. 3. A method for producing a liquid pharmaceutical composition according to claim 1, characterized in that the steps of the method are carried out while bubbling with an inert gas or in an inert gas atmosphere. 4. A method for producing a liquid pharmaceutical composition according to claim 1, characterized in that membrane filters are used in the filtration step (b). 5. A method for producing a liquid pharmaceutical composition according to claim 1, characterized in that at all stages the components of the liquid pharmaceutical composition are protected from UV and visible light. 6. A method for producing a liquid pharmaceutical composition according to claim 1, characterized in that the concentration of nitrofural in the composition obtained by said method is from 1 to 250 mg / ml. 7. Liquid pharmaceutical composition for the preparation of a solution for local and external use with antimicrobial action, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural - 0.094-0.357; PEG-400 42.561-78.746; povidone - up to 3.565; water - up to 100. 8. Liquid pharmaceutical composition for the preparation of a solution for local and external use with an antimicrobial effect, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural 0.094-0.357; PEG-400 42.561-78.746; water - up to 100. 9. Liquid pharmaceutical composition for the preparation of a solution for local and external use with an antimicrobial effect, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural - 0.096-0.358; PEG-400 - 32,500-70,815; povidone - up to 3.522; DMSO - 1.432-4.263; water - up to 100. 10. Liquid pharmaceutical composition for the preparation of a solution for local and external - 11,038471 applications with antimicrobial action, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural - 0.096-0.358; PEG-400 - 32,500-70,815; DMSO - 1.432-4.263; water - up to 100. 11. Liquid pharmaceutical composition for the preparation of a solution for local and external use with an antimicrobial effect, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural - 0.179-0.623; ethanol - up to 7.622; propylene glycol - up to 14.854; PEG-400 - up to 100. 12. Liquid pharmaceutical composition for the preparation of a solution for local and external use with an antimicrobial effect, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural - 0.179-0.623; propylene glycol - up to 14.854; PEG-400 - up to 100. 13. Liquid pharmaceutical composition for the preparation of a solution for local and external use with an antimicrobial effect, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural - 0.179-0.623; ethanol - up to 7.622; PEG-400 - up to 100. 14. Liquid pharmaceutical composition for the preparation of a solution for local and external use with an antimicrobial effect, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural - 0.265-2.182; DMSO - 7.073-27.923; PEG-400 - up to 100. 15. Liquid pharmaceutical composition for the preparation of a solution for local and external use with an antimicrobial effect, which is obtained by the method according to any one of claims 1 to 6, and the said composition contains, wt%: nitrofural - 4.464-17.841; nonionic surfactant - 26.786-32.471; DMSO - 49.688-68.750. 16. A solution for local and external use with antimicrobial action, which is prepared by adding purified water or isotonic solution to a liquid pharmaceutical composition according to any one of claims 7-15.