RU2578456C1 - Method for producing instant formulation of furacilin (optional) - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions is a method for producing instant medicinal forms Furacilin: in the first embodiment, the mixture Furacilin and polyvinylpyrrolidone with a molecular weight of 10,000±2,000 at a ratio of 1:1-3 was dissolved in ethanol 1: 100-300 95±5°C, half of the resulting solution of sodium bicarbonate powder is granulated in a ratio of 1.0:34.0-34.5 Furacilin the total weight, the other half is granulated citric acid powder in a ratio of 1.0 to the total weight of 39.0-39.5 Furacilin , granules mixed 1.00:1.12-1.14 and tableted or packed in sealed packages; second embodiment Furacilin mixture and polyvinylpyrrolidone 1:1-3 were placed in 30-40% ethanol at a ratio of 1:9-12 at 95±5°C, half of the resulting slurry granulated powder of sodium hydrogen carbonate in a ratio of 1.00:2.58-2.60 Furacilin the total weight, the other half is granulated citric acid powder in a ratio of 1.00: 2,96-3,00 by weight Furacilin, granules mixed 1.00:1.05-1.10, tableted or packed in airtight packaging.

EFFECT: implementation of the group of inventions and provides a simplification of the application dosage forms Furacilin increases its bioavailability.

2 cl, 2 ex, 4 tbl

Description

The invention relates to medicine, namely to pharmaceutical production and for the production of instant dosage forms of furacilin.

One of the conditions for the effectiveness of the treatment of bacterial infections in patients is the consideration of the pharmacokinetics of the drugs, in particular, such a parameter as bioavailability (DB).

The solubility of drugs (drugs) is their most important characteristic. All things being equal, it largely characterizes the pharmacological activity of drugs and is used for non-experimental prediction of its database.

Furacilin is a poorly soluble substance in water (1: 5000) and is widely used as a topical agent, including as a part of combined preparations.

Known factory tablets of furatsilin 0.02 g for the preparation of a solution for local and external use (Mashkovsky M.D. Medicines. - 16th ed., Revised., Rev. And add. - M .: RIA "New Wave": 2012 .-- 1216 p.). However, a significant disadvantage of these tablets is an inconvenient method of manufacturing a solution based on them - a long dissolution in boiling water.

A known method of obtaining a powdery soluble effervescent composition (RF Patent 2288594). The method involves mixing the initial powdery acidic and carbonate components, as well as auxiliary substances, medicinal and biologically active substances. Solid acid soluble acid or solid acid salts or mixtures thereof are used as acidic components. As the carbonate components, bicarbonates, a carbonate or basic carbonate of an alkali or alkaline earth metal or mixtures thereof are used. In this case, the mixture of the initial powdery components is subjected to mechanical treatment by impact-abrasion before the formation of agglomerates of ground particles of the processed components with a size of 30-300 microns. The mixture of all the previously mentioned components occurs simultaneously with their mechanical processing by impact-abrasion.

The disadvantages of this method are:

1. The possibility of using as water and biologically active substances substances only water-soluble or capable of forming water-soluble salts by interaction with an acid or carbonate component.

2. The possibility of using as drugs and biologically active substances substances that can form water-soluble complexes with auxiliary substances, being in the solid phase with mechanical mixing, excluding the use of drugs that do not form water-soluble complexes with polymers in the solid phase when mixing and grinding.

3. Use as starting components to obtain instant "effervescent" compositions, only solid powdered excipients and drugs, followed by joint grinding. This technological technique completely excludes the possibility of introducing liquid medicinal and auxiliary substances, as well as their solutions, into effervescent compositions.

The proposed method is acceptable exclusively for powdered, water-soluble medicinal substances and is absolutely not suitable for introducing into a effervescent tablet a powder of water-soluble furatsilin and its powder mixtures with polymers (not increasing the solubility of furatsilin in water when mixed), as well as for introduction into composition of effervescent compositions of liquid solutions of components of solid dispersions of furatsilin with polymers obtained by solvent removal to increase the solubility of the drug substance.

The objective of the invention is a method for producing instant dosage forms of furatsilina with increased pharmaceutical bioavailability.

The problem is solved by the method (option 1):

A method of obtaining instant dosage forms of furatsilin, namely, that a mixture of furatsilin and polyvinylpyrrolidone with a molecular weight of 10,000 ± 2,000 in a ratio of 1: 1-3 is dissolved in ethyl alcohol at a ratio of the mixture and ethanol 1: 100-300 at a temperature of 95 ± 5 ° C , half of the resulting solution granulates the powder of sodium bicarbonate, taken in a ratio of 1.0: 34.0-34.5 of the total mass of furatsilin, the other half granulates a powder of citric acid, taken in a ratio of 1.0: 39.0-39.5 from total mass of furatsilin, the obtained granules are mixed in a ratio of 1.00: 1.12-1.14 and tabletted or packaged in sealed packages.

The method according to option 1 is as follows.

Mix furatsilin and polyvinylpyrrolidone (PVP) with a molecular weight of 10,000 ± 2,000 in a ratio of 1: 1-3. This ratio allows to achieve smaller volumes of granulating liquid with a satisfactory viscosity, accelerate the granulation process and obtain granules with satisfactory technological performance. A mixture of furatsilin and PVP is dissolved in ethyl alcohol at a ratio of the mixture and ethanol 1: 100-300 at a temperature that does not cause their destruction - 95 ± 5 ° C. The resulting solution is divided into two equal parts, which are further separately granulated powders of sodium bicarbonate and citric acid, taken in a ratio of 1.00: 1.14-1.16. When a mixture of citric acid and sodium bicarbonate is dissolved in the indicated mass ratio, a solution is formed with a pH value of 5.3-5.7. This acidity indicator is most preferred for external use, as corresponds to the pH of the skin and mucous membranes in contact with the external environment.

The first part of the solution granulates the powder of the acid component, taken in a ratio of 1.0: 39.0-39.5 of the total mass of furacilin. The second part of the solution granulates the powder of the main component, taken in a ratio of 1.0: 34.0-34.5 of the total mass of furacilin. The obtained basic and acid granules are mixed in a ratio of 1.00: 1.12-1.14, dusted with a sliding auxiliary substance and tableted or packaged in sealed packages.

This option is most suitable for plants equipped with granulation plants, adapted for working with ethanol solutions and involving the regeneration of exhaust solvent vapor.

The invention is illustrated by the following example.

EXAMPLE 1. 12.9 g of furatsilin, 22.2 g of PVP-10000 are dissolved in 6 l of ethyl alcohol at a temperature of 95 ± 5 ° C. The solution is divided in half.

445.1 g of sodium bicarbonate powder, pre-ground and subsequently sieved through sieves with openings of 250 μ and 45 μ in diameter using an AS 200 control sieving machine (Germany), is loaded into the food container of the BOSCH Mycrolab granulation unit (Germany). Particle fractions greater than 250 µ and less than 45 µ are not granulated.

Next, by spraying, granulation of sodium hydrogen carbonate powder is carried out with the obtained alcohol solution heated to 95 ± 5 ° C, based on the calculation: 6.8 ± 0.1 ml of granulating solution per 1 g of granulated powder.

509.8 g of citric acid powder, pre-ground and subsequently sieved through sieves with openings of 250 μ and 45 μ in diameter using an AS 200 control sieving machine (Germany), are loaded into a food container. Particle fractions greater than 250 µ and less than 45 µ are not granulated.

Next, by spraying, granulation of citric acid powder is carried out with the obtained alcohol solution heated to 95 ± 5 ° C, based on the calculation: 6.0 ± 0.1 ml of granulating solution per 1 g of granulated powder.

After manufacture, the acidic and basic granules are mixed in a ratio of 1.63: 1.44 (by weight), a sliding auxiliary substance, magnesium stearate, is introduced in an amount of 1% of the dusted mass. Then they are tabletted at 200 MPa in a tablet press with a diameter of punches of 2 cm and a finished tablet weighing 3.105 g is obtained.

The resulting tablets before use are dissolved in 200 ml of water with a temperature of 37 ± 5 ° C. Dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 1 min 30 sec. After complete dissolution of the tablet and the end of gas evolution, a 0.02% yellow yellow furatsilin solution is formed with a pH of 5.5 ± 0.2, suitable for antiseptic treatment of hands, cavities, surfaces.

In those cases when granulators are used in production that are not suitable for working with pure ethanol solutions, and water-alcohol mixtures are used as granulating liquid, another option is possible.

Option 2

A method of obtaining instant dosage forms of furatsilin, which consists in the fact that a mixture of furatsilin and polyvinylpyrrolidone with a molecular weight of 10,000 ± 2,000 in a ratio of 1: 1-3 is placed in ethyl alcohol 30-40% at a ratio of a mixture of powders and alcohol 1: 9-12 at a temperature 95 ± 5 ° C, half the suspension obtained granulate sodium bicarbonate powder, taken in the ratio of 1.00: 2.58-2.60 of the total mass of furatsilina, the other half granulates the citric acid powder, taken in the ratio of 1.00: 2.96 -3.00 of the total mass of furatsilina, obtained granules mix melt in a ratio of 1.00: 1.05-1.10, tabletted or packaged in sealed packages.

The method according to option 2 is as follows.

Furacilin and PVP are mixed with a molecular weight of 10,000 ± 2,000 in a ratio of 1.00: 1.00-3.00. A mixture of furatsilin and PVP is placed in a mixture of water and ethyl alcohol, taken in the ratio (1: 2-4 by volume) at a ratio of the mixture of powders and solvent mixture 1: 9-12 at a temperature that does not cause their destruction - 95 ± 5 ° C. The resulting suspension is divided into two equal parts, which are further separately granulated powders of sodium bicarbonate and citric acid, taken in a ratio of 1.00: 1.14-1.16.

Using the first part of the solution, the acid component powder is granulated, taken in a ratio of 1.00: 2.96-3.00 of the total mass of furatsilin. Using the second part of the solution, the powder of the main component is granulated, taken in a ratio of 1.00: 2.58-2.60 of the total mass of furatsilin. The obtained basic and acid granules are mixed in a ratio of 1.00: 1.05-1.10, dusted with a sliding auxiliary substance and tabletted or Packed in sealed packages.

The invention is illustrated by the following example.

EXAMPLE 2

1 liter of ethyl alcohol is mixed with 3 liters of water. In the resulting water-alcohol mixture of 30-40% at a temperature of 95 ± 5 ° C, 120.0 g of furatsilin, 204.6 g of PVP-10000 are placed with stirring. The mixture is divided in half.

309.9 g of sodium bicarbonate powder, pre-ground and subsequently sieved through sieves with openings of 250 μ and 45 μ using a sieving machine, is loaded into the food container of the Uni-Glatt granulator dryer Glatt GmbH Grunaer Weg26 D-01277 (Germany) AS 200 control (Germany). Particle fractions greater than 250 µ and less than 45 µ are not granulated.

Then, by spraying, sodium bicarbonate powder is granulated with the obtained water-alcohol mixture containing furatsilin in a partially suspended form and heated to 95 ± 5 ° C, based on the calculation: 6.6 ± 0.1 ml of granulating mixture per 1 g of granulated powder.

355.5 g of citric acid powder, pre-ground and subsequently sieved through sieves with a hole diameter of 250 μ and 45 μ using a screening machine AS 200 control (Germany), is loaded into a food container. Particle fractions greater than 250 µ and less than 45 µ are not granulated.

Next, by spraying, granulation of citric acid powder is carried out with the obtained water-alcohol mixture containing furatsilin in partially suspended form and heated to 95 ± 5 ° C, based on the calculation: 5.8 ± 0.1 ml of granulating mixture per 1 g of granulated powder.

After manufacture, the acidic and basic granules are mixed in a ratio of 1.70: 1.60 (by weight), a sliding auxiliary substance, magnesium stearate, is introduced in an amount of 1% of the dusted mass. Then tabletted at 50 MPa on a tablet press with a diameter of punches of 2 cm and get a finished tablet weighing 3.333 g

The resulting tablets before use are dissolved in 200 ml of water with a temperature of 37 ± 5 ° C. Dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 1 min 30 sec. After complete dissolution of the tablet and the end of gas evolution, a 0.02% yellow opalescent solution of furatsilin with a pH of 5.5 ± 0.2 is formed suitable for antiseptic treatment of hands, cavities, surfaces.

The tablets obtained from the mixture of granules are well tableted and disintegrate within the limits specified in the State Pharmacopoeia XII.

The technological characteristics of the developed granules are presented in table 1.

The results of the dissolution of furatsilin from tablets obtained by the described options are presented in table 3.

As can be seen from the data presented in table 3, the release of furatsilin from factory tablets at 37 ± 5 ° C is extremely slow, at 45 minutes it is only 0.021 g / l and remains the same by 60 minutes. This indicates a rather low release of furatsilin from factory tablets at 37 ± 5 ° C.

Upon receipt of tablets according to the technology described in the proposed options, there is a significant increase in the rate of dissolution and release of furatsilin compared with factory tablets. Already at 5 minutes (in the first 1 minute 30 seconds), the concentration of furatsilin in the solution of the developed effervescent tablets is almost 10 times higher than that of the factory ones, is 0.2 g / l and is therapeutic.

Preservation of the antimicrobial activity of furatsilin in the developed instant tablets was proved by means of a microbiological test with standard strains. The determination was carried out by comparing the sizes of zones of inhibition of growth of test microorganisms formed during the testing of solutions of the studied samples. The research results are presented in table 4.

According to the results of the study, the antimicrobial activity of furatsilin in the composition of the developed tablets is preserved and corresponds to the activity of a saturated (0.02%) solution of furatsilin obtained previously known long-term method of dissolving tablets 0.02 g of furatsilin in 0.2 l of boiling water.

The proposed variants of the method for producing instant (effervescent) dosage forms of furatsilin can increase its bioavailability, significantly reduce the time and simplify the method of preparation and use, making them convenient.

Claims (2)

1. A method of obtaining instant dosage forms of furatsilin, which consists in the fact that a mixture of furatsilin and polyvinylpyrrolidone with a molecular weight of 10,000 ± 2,000 in a ratio of 1: 1-3 is dissolved in ethyl alcohol at a ratio of mixture and ethanol of 1: 100-300 at a temperature of 95 ± 5 ° C, half of the resulting solution granulates the powder of sodium bicarbonate, taken in the ratio of 1.0: 34.0-34.5 of the total mass of furatsilina, the other half granulates the powder of citric acid, taken in the ratio of 1.0: 39.0-39, 5 of the total mass of furatsilin, the resulting granules are mixed t in a ratio of 1.00: 1.12-1.14 and tabletted or packaged in sealed packages. 2. A method of obtaining instant dosage forms of furatsilin, which consists in the fact that a mixture of furatsilin and polyvinylpyrrolidone with a molecular weight of 10,000 ± 2,000 in a ratio of 1: 1-3 is placed in ethyl alcohol 30-40% at a ratio of a mixture of powders and alcohol 1: 9-12 at a temperature of 95 ± 5 ° C, half the suspension obtained is granulated with sodium bicarbonate powder, taken in the ratio of 1.00: 2.58-2.60 of the total mass of furatsilin, the other half is granulated with citric acid powder, taken in the ratio of 1.00: 2 , 96-3.00 of the total mass of furatsilina obtained granules ivayut in the ratio of 1.00: 1.05-1.10, tableted or packed in airtight packaging.