BG1843U1 - Powdered fharmaceutical composition containing metamizole - Google Patents

Abstract

The utility model relates to a powdered pharmaceutical composition for per oral solution, which contains metamizole sodium monohydrate, stabilizer, anhydrous colloidal silica, sodium cyclamate and powder with strawberry flavor, wherein the amount of the components in the mixture is as follows: 0.500 to 1 g metamizole sodium monohydrate, 2.2 to 3.7 g stabilizer, 0.005 g anhydrous colloidal silica, 0.12 to 0.15 g sodium cyclamate and 0.005 g powder with strawberry flavor. In one embodiment, the powdered pharmaceutical composition comprises and other active substances such as 0.05 g caffeine, 0.04 g vitamin B1 or mixtures thereof. The composition according to the utility model has good rheological properties, is stable in storage, rapidly soluble in water and the resulting solution has an acceptable content of hydrolysis product of metamizole sodium, with good organoleptic properties and is low glycemic and therefore is suitable for diabetics.

Description

Field of technology

The utility model relates to a powdered pharmaceutical composition containing metamizole which is used in medicine.

BACKGROUND OF THE INVENTION

Metamizole is a drug from the group of pyrazolones with a strong analgesic, antipyretic and moderate anti-inflammatory effect. Metamizole is used in pharmaceutical compositions in the form of pharmaceutically acceptable sodium and magnesium salts. These salts are part of solid and liquid dosage forms for oral, injectable and rectal administration and are used in medical practice in several European countries.

European patent EP 1150660 describes a stable pharmaceutical composition of metamizole in the form of effervescent powder or granules which can be dosed in a sachet. The composition contains from 200 to 1000 mg of metamizole or its pharmaceutically acceptable salts in an effervescent mixture, a combination of citric acid or sodium citrate and sodium carbonate or bicarbonate, at least 50 wt. % sweetener and flavors, and the pH of the aqueous solution of this composition prepared for use is from 3 to 6.5. It is claimed that under these conditions metamizole is stable and does not hydrolyze for 1 hour of dissolution. As an indication of this, it is indicated that the solution remains colorless and does not turn yellow, but no quantitative analysis by liquid chromatography of the hydrolysis product 4-methylaminoantipyrine is presented.

The disadvantages of the effervescent composition is the high content of sodium, carbonates, the need for special technological conditions for preparation of the mixture, and the stability of the solid dosage form is low.

A product of metamizole powder in the form of an oral solution in a sachet is not known on the market and has not been described in the literature. However, metamizole sodium is highly soluble in water (I g / 1.5 ml) and is suitable for use in such form. The lack of such a commercial product may be due to the fact that the concentration of metamizole sodium in the resulting aqueous solution for oral administration is too low 0.5 - 1% (w / v), and according to the theory of the hydrolysis process to obtain impurity 4- methylaminoantipyrine, impurity C (European Pharmacopoeia), proceeds more rapidly in dilute solutions.

The purpose of the utility model is to provide a powdered pharmaceutical composition for oral solution, having good rheological characteristics, stable in storage, with good solubility in water, acceptable quality of the solution before use, in terms of metamizole sodium hydrolysis product content and good organoleptic properties of the solution, using a simplified technological scheme of production.

Technical essence of the utility model

To achieve this goal, a powdered pharmaceutical composition for an oral solution containing metamizole sodium monohydrate, a stabilizer, anhydrous colloidal silica, sodium cyclamate and strawberry-flavored powder has been developed, the amount of components in the mixture being as follows: from 0.500 to 1 g metamizole sodium monohydrate, 2.2 to 3.7 g stabilizer, 0.005 g anhydrous colloidal silicon dioxide, 0.12 to 0.15 g sodium cyclamate and 0.005 g strawberry flavor powder.

The stabilizer according to the utility model may be a polyol or a mixture of a polyol and sodium citrate. Preferably the polyol is D-mannitol or sorbitol.

In one embodiment of the utility model, the D-mannitol is obtained by spray drying.

The powdered pharmaceutical composition for oral solution may additionally include other active substances, such as 0.05 g of caffeine, 0.04 g of vitamin B1 or mixtures thereof.

The powdered pharmaceutical composition for oral solution is suitable for single-dose sachet administration.

The powdered pharmaceutical composition for oral solution according to the utility model is prepared by sequentially mixing the pre-weighed amounts of active substance metamizole sodium monohydrate, polyol and glidant. The mixture is homogenized in

1843 UI for 15 min. The sweetener, flavoring and other excipients and active substances included in the composition are added to the homogenized mixture. The mixture is homogenized again, then sieved through a sieve and dosed in a sachet of three-layer foil.

The powdered pharmaceutical composition for oral solution, according to the utility model, has good rheological characteristics and storage stability, dissolves rapidly in water, the aqueous solution has a stability of 15 minutes before administration, and the resulting solution has an acceptable content of metamysal sodium hydrolysis product. not more than 2.8%, good organoleptic properties and is low glycemic, which is why it is also suitable for diabetics.

Examples of implementation of the utility model

The utility model is illustrated by the following embodiments.

Example 1.

The powdered pharmaceutical composition for oral solution in a sachet containing 500 mg metamizole sodium monohydrate includes the following components:

Ingredients d / sachet ^% ПартидаЮООбр. kg Metamizole sodium monohydrate 0.500 11.11 0.500 Pearlitol® SD 200 * 3,775 th most common 83.89 3,775 th most common Sodium cyclamate 0.150 3.33 0.150 Powder with strawberry aroma 0.070 1.56 0.070 Aerosil® 200 ** 0.005 0.11 0.005 Total 4,500 th most common I 100.0 4,500 th most common

Peartitol * SD 200 is a trademark of D-mannitol, obtained by spray drying, manufactured by ROQUETTE FRERES.

AerosiF '200 is a trademark of anhydrous colloidal silicon dioxide manufactured by Degussa GmbH.

0.500 kg of metamizole sodium monohydrate, 3.775 kg of Pearlitol® SD 200 and 0.005 kg of Aerosil® 200 are loaded successively into a suitable diffusion mixer. The mixture is homogenized for 15 minutes. Add the other ingredients according to the recipe and homogenize the mixture for 30 minutes, then sieve through a sieve with a clear aperture of 1.25 mm. The finished mixture is dosed in a sachet of three-layer foil by means of a packaging machine at an average weight of 4.5 g.

A powdered pharmaceutical composition for oral solution with a composition prepared by the method described in Example 2 was tested for stability under observation conditions: 25 ± 2 ° C and relative humidity 60 ± 5% RH for 24 months. The results of the study are shown in Table 1.

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Table 1.

Tested indicators Initial analysis Test after 3 m, Test after 6 m. Test after 9 m. Test after 12 m. Test after 18 m. Test after 24 m. Appearance He answers He answers He answers He answers He answers He answers He answers Identity He answers He answers He answers He answers He answers He answers He answers Mass of contents in one sachet, g 4,525 th most common 4,528 th most common 4,532 th most common 4,533 th most common 4,535 th most common 4,536 th most common 4,537 th most common Related substances. % - impurity C <0.5 0.017 0.050 0.050 0.100 0.150 0.200 - single impurity <0.2 0.006 0.007 0.007 0.007 0.008 0.008 - total impurities <0.5 0.033 0.057 0.057 0.107 0.158 0.208 Content of Metamizole sodium, g 0.508 0.512 0.507 0.507 0.507 0.505 0.505 Microbiological quality - total number of aerobic bacteria. CFU ‘g Under 10 ' Under 10 Under 10 Under 10 Under 10 Under 10 Under 10 --total number of molds and yeast. CF-TJ / g Under 10 ² Under 10 Under 10 Under 10 PodYu ² Under 10 ² Under 10 ² Escherichia coli Absence Absence Absence Absence Absence Absence Absence

Example 2.

Powdered pharmaceutical composition for oral solution in a sachet containing 500 mg

Metamizole sodium monohydrate contains the following components:

Ingredients d / sachet % Lot of 1000 pcs. kg Metamizole sodium monohydrate 0.500 16.67 0.500 Sorbitab® SD 250 * 2,295 th most common 76.50 2,295 th most common Sodium cyclamate 0.130 4.33 0.130 Powder with strawberry aroma 0.070 2.33 0.070 Aerosil® ⁵ 200 ** 0.005 0.17 0.005 Total _______ 3,000 100.0 3,000

Sorbitab '' SD 250 is a trademark of sorbitol, manufactured by SPI Pharma.

AerosiP 200 is a trademark of anhydrous colloidal silicon dioxide manufactured by Degussa GmbH.

The powdered pharmaceutical composition for oral solution was prepared according to the method described in Example 1.

The results of the stability studies of the dosage form obtained according to Example 3 are presented in Table 2. Observation conditions: 25 ± 2 ° C, 60 ± 5% RH over 24 months.

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Table 2.

Tested indicators Initial Testing Testing Testing Testing Testing Testing analysis after 3 m. after about m. after 9 νΓ. ’ 12 mi · cw’18 m. after 24 m. Appearance He answers He answers He answers He answers He answers He answers He answers Identity He answers He answers He answers He answers He answers He answers He answers The mass of the contents is one sachet, g 3,024 th most common 3,026 th most common 3,034 th most common 3,034 th most common 3,035 th most common 3,036 th most common 3,036 th most common Related substances,%: - impurity C <0.5 0.014 0.030 0.040 0.070 0.090 0.200 - single impurity <0.2 0.007 0.007 0.007 0.007 0.008 0.008 - total impurities <0.5 0.02) 0.037 0.047 0.077 0.098 0.208 Content of Metamizole sodium, g 0.502 0.504 0.506 0.505 0.506 0.507 0.506 I Microbiological 1 quality: | -ooui number of aerobic 1 bacteria, CFU g Under 10 ³ Under Yu Under 10 Under 10 Under 10 Under 10 Under 10 i -ooui number of molds and! yeast. CFC 'g Under 10 ¹ Under 10 Under 10 Under 10 Under 10 ² Under 10 ² Under 10 ² I Escherichia coli Absence Absence Absence Absence Absence Absence Absence

Example 3.

Powdered pharmaceutical composition for oral solution in a sachet containing 500 mg

Metamizole sodium monohydrate contains the following components:

Ingredients d / sachet ^% Batch ЮООбр. kg Metamizole sodium monohydrate 0.500 14.29 0.500 Pearlitol® SD 200 * 2,555 th most common 73.00 2,555 th most common Sodium cyclamate 0.120 3.43 0.120 Powder with strawberry aroma 0.070 2.00 0.070 Aerosil® 200 ** 0.005 0.14 0.005 Sodium citrate 0.250 7.14 0.250 Total 3,500 100.0 3,500

Pearlitol * 'SD 200 is a trademark of D-mannitol, obtained by spray drying, production of ROQUETTE

FRERES.

Aerosil 200 is a trademark of anhydrous colloidal silicon dioxide manufactured by Degussa GmbH.

The powdered pharmaceutical composition for oral solution was prepared according to the method described in Example 1.

The results of the stability studies of the dosage form obtained according to Example 4 are presented in Table 3. Observation conditions: 25 ± 2 ° C, 60 ± 5% RH over 24 months.

Table 3

Tested indicators Initial analysis Test after 3 m. Test after 6 and. Test after 9 m. Test after 12 m. Test after 18 m. Test after 24 m. Appearance He answers He answers He answers He answers He answers He answers He answers Identity He answers He answers He answers He answers He answers He answers He answers Mass of contents in one sachet, g 4,521 th most common 4,526 th most common 4,528 th most common 4,527 th most common 4,530 th most common 4,533 th most common 4,534 th most common Related substances,% - impurity C <0.5 0.015 0.020 0.025 0.030 0.040 0.100 • SDINIC impurity <0.2 0.005 0.006 0.006 0.007 0.007 0.007 - total impurities <0.5 0.020 0.026 0.031 0.037 0.047 0.107 Content of

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Metamizole sodium, g 0.498 0.502 0.503 ”” * 5,497 ‘- ^ 6 * , 0.4? ” 0.494 Microbiological quality: -total number of aerobic bacteria. CFUg - total number of molds and yeasts, CFL ¹ / g Escherichia coli Under 10 'Under 10 ^! Absence Under 10 Under 10 Absence Under 10 Under 10 Absence Under 10 Under 10 Absence Under 10 Under 10 ² Absence Under 10 Under 10 ² Absence Under 10 Under I0 ² Absence

Example 4.

Powdered pharmaceutical composition for oral solution in a sachet containing 500 mg

Metamizole sodium monohydrate and 50 mg Caffeine includes the following components:

G-. g / sachet. ^% Lot YUOO no. Kfl Metamizole sodium monohydrate 0.500 14.29 0.500 Caffeine 0.050 1.43 0.050 Pearlite / SD 200 * 2,505 th most common 71.57 2,505 th most common Sodium cyclamate 0.120 3.43 0.120 Powder with strawberry aroma 0.070 2.00 0.070 Aerosil® 200 ** 0.005 0.14 0.005 Sodium citrate 0.250 7.14 0.250 1 Total 3,500 100.0 3,500

Pearlitol '' SD 200 is a trademark of D-mannitol obtained by spray drying. production of ROQUETTE FRERES.

Eros! ” 200 is a trademark of colloidal anhydrous silica manufactured by Degussa GmbH.

The pharmaceutical composition for oral solution was prepared according to the method described in Example 1.

The results of the stability studies of the dosage form obtained according to Example 5 are presented in Table 4. Observation conditions: 25 ± 2 ° C, 60 ± 5% RH over 24 months.

Table 4

Tested indicators Initial analysis Test after 3 m. Test after 6 m. Test after 9 m. Test after 12 m. Test after 18 m. Test after 24 m. Appearance He answers He answers He answers He answers He answers He answers He answers Identity He answers He answers He answers He answers He answers He answers He answers Table the contents in a sachet. g 4,518 th most common 4,519 th most common 4,519 th most common 4,521 th most common 4,522 th most common 4,523 th most common 4,524 th most common Related substances,% - impurity C <0.5 0.012 0.016 0.022 0.026 0.048 0.110 - single impurity <0.2 0.006 0.007 0.006 0.007 0.007 0.007 - total impurities <0.5 0.028 0.023 0.028 0.033 0.055 0.117 Content of Metamizole sodium, g 0.504 0.503 0.503 0.50) 0.501 0.498 0.496 Content of Caffeine, e 0.051 0.051 0.051 0.1) 50 0.050 0.049 0.049 Microbiological quality: -total number of aerobic bacteria. CFL 'g Under 10 ' Under 10 11of 10 Under 10 Under 10 Under 10 i Under 10 1 total number of imported and And yeast. CFC g Under 10 ' UNDER JU UNDER 10 Under 10 G »d 10 ' · PlyPO ² Under 10 ^: । Escherichia coli__________ Absence Absence Absence Absence Absence | Absence Absence

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Example 5.

Powdered pharmaceutical composition for oral solution in a sachet containing 1000 mg

Metamizole sodium monohydrate contains the following components:

Ingredients d / sachet % Lot of 1000 pcs. kg Metamizole sodium monohydrate 1,000 22.22 1,000 Pearlitol® SD 200 * 3,020 th most common 67.11 3,020 th most common Sodium cyclamate 0.150 3.33 0.150 Powder with strawberry aroma 0.070 1.56 0.070 Aerosil® 200 ** 0.010 0.22 0.010 Sodium citrate 0.250 5.56 0.250 Total 4,500 th most common 100.0 4,500 th most common

Pearlitol ’SD 200 is a trademark of D-mannitol. obtained by spray drying, production of ROQUETTE FRERES.

Aerosil® 200 is a trademark of colloidal anhydrous silica manufactured by Degussa GmbH.

The powdered pharmaceutical composition for oral solution was prepared according to the method described in Example 1.

The results of the stability studies of the dosage form obtained according to Example b are presented in Table 5. Observation conditions: 25 ± 2 ° C, 60 ± 5% R.H for 24 months.

Table 5.

Tested indicators Initial analysis Test after 3 m. Test after 6 m. Ice test 9 m. Test after 12 m. Test after 18 m. Test after 24 m. Appearance He answers He answers He answers He answers He answers He answers He answers Ideps He answers He answers He answers He answers He answers He answers He answers Mass of contents in a cauie, g 4,516 th most common 4,516 th most common 4,518 th most common 4,519 th most common 4,522 th most common 4,524 th most common 4,524 th most common Related substances,% - impurity C <0.5 0.011 0.014 0.022 0.032 0.044 0.116 - single impurity <0.2 0.006 0.006 0.006 0.007 0.006 0.007 - total impurities <0.5 0.027 0.020 0.028 0.039 0.050 0.123 Metamizole sodium content, g 1,009 th most common 1,008 th most common 1,009 th most common 1,007 th most common 1,006 th most common 1,004 th most common 1,002 th most common Microbiological quality - total number of aerobic bacteria, CFU g Under 10 ' Under 10 Under 10 Under 10 Under 10 Gender 10 Gender 10 total number of molds and yeasts. CFU. g Under 10 ² Under 10 Under 10 Under 10 Under 10 ^years Under 10 ² Under! 0 ² Escherichia coli Absence Absence Absence Absence Absence Absence Absence

Example 6.

Analysis and evaluation of the oral solution obtained by dissolving 1 dose of 0.500 g Metamizole sodium monohydrate and excipients in 100 ml of drinking water, at a temperature of 20 ° C, at initial intervals of 10, 15 minutes after reconstitution.

Although the reconstituted oral solution is intended to be taken immediately, an analysis of the solution was performed at initial time intervals - 10, 15 min in order to assess its quality - impurity C content. In the first minutes it is impossible to evaluate due to lag time in the technique of analysis. Each sample was tested three times.

The average data are presented in the following table;

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। Time (min) i Control Metamizoie sodium monohydrate 0.5 g Test Metamizoie 0.5 g plus Mannitol 3g Metamizoie test 0.5 g plus Sorbitol 3 g Sample Metamizoie 0.5 g plus Sodium citrate 0.250 g pH % Impurity C, HPLC pH % Impurity C, HPLC pH % Impurity C, HPLC pH % Impurity C, HPLC 1 ° - 0.09 - 0.04 - 0.04 0.04 '10 6.62 2.26 6.64 1.78 6.63 1.82 7.56 1.56 I and 15 6.63 4.20 6.65 2.67 6.64 2.53 7.56 2.24

The data show that the quality of the reconstituted excipient solution is maintained for up to 15 minutes in terms of the declared metamizole sodium monohydrate content of the product. The content of 4-methylaminoantipyrine in the solution up to 10 minutes is about 2%, which corresponds to the value found in liquid dosage forms of metamizole sodium 20 monohydrate. Compared with the solution of pure metamizole sodium monohydrate, the compositions with mannitol and sorbitol show a certain stabilizing effect on the hydrolysis process. The most pronounced stabilizing effect is observed in the composition with sodium citrate.

Claims (5)

Claims A powdered pharmaceutical composition comprising metamizole and excipients, characterized in that metamizole is the sodium salt monohydrate, the excipients being a stabilizer, anhydrous colloidal silicon dioxide, sodium cyclamate and strawberry-flavored powder. of the components in the mixture is as follows: from 0.500 to 1 g metamizole sodium monohydrate, from 2.2 to 3.7 g stabilizer, 0.005 g anhydrous colloidal silicon dioxide, from 0.12 to 0.15 g sodium cyclamate and 0.005 g powder with strawberry flavor. Powdered pharmaceutical composition according to claim 1, characterized in that the stabilizer is a polyol or a mixture of polyol and sodium citrate. Powdered pharmaceutical composition according to claims 1 and 2, characterized in that the polyol is D-mannitol or sorbitol. Powdered pharmaceutical composition according to claims 1 and 2, characterized in that the polyol is D-mannitol obtained by spray drying. Powdered pharmaceutical composition according to claims 1 to 4, characterized in that it also includes other active substances such as 0.05 g of caffeine, 0.04 g of vitamin B1 or mixtures thereof.