BG113694A - Pharmaceutical composition in tablet form containing metamizole, caffeine and drotaverine and method of its preparation - Google Patents

Abstract

The invention relates to a pharmaceutical composition in the form of a tablet for oral administration comprising metamizole, caffeine and drotaverine as well as to a method for its preparation, which find application in pharmacy and in medical practice for the treatment of high intensity pain of various origins. The tablet is molded from a tablet mixture comprising a granule including metamizole sodium monohydrate and caffeine and drotaverine, which is added to a powder mixture outside the granule. The composition of the tablet blend and the method of its preparation provide a tablet with high stability and low levels of degradation products of the active substances incorporated therein, which are released rapidly after tablet administration.

Description

A pharmaceutical composition in the form of a tablet containing metamizole, caffeine and drotaverine and a method for its preparation

FIELD OF ENGINEERING

The invention relates to a pharmaceutical composition in the form of a tablet for oral administration, containing metamizole, drotaverine and caffeine, as well as to a method for its preparation, which are used in pharmacy and in medical practice.

PRIOR ART

Metamizole, drotaverine and caffeine are the active substances well known and widely used in medical practice for the treatment of high-intensity pain of various origins, such as pain associated with contractile states of smooth muscles, pain associated with the genitourinary system, pain in intestinal colic, irritable bowel syndrome, cholecystitis and inflammation of the bile ducts.

Metamizole is known to have significant analgesic, antipyretic and moderate anti-inflammatory effects. It is used to treat pain of various origins. A problem in developing compositions based on metamizole sodium monohydrate is its stability with respect to decomposition products. The influence of physico-chemical factors on the kinetics of hydrolysis of metamizole sodium in aqueous solutions are well described in a study by H. Ergun et al (Characterization of the role of physicochemical factors on the hydrolysis of dipyrone, Journal of Pharmaceutical and Biomedical Analysis, Volume 35, Issue 3, 28 May 2004, Pages 479-487). By HPLC method of analysis, Η. Ergun studied the kinetics of hydrolysis as a function of concentration, temperature and pH. It was found that 4-methylaminoantipyrine, impurity C (European Pharmacopoeia) was mainly found in commercial tablet forms. It was also found that the stability of metamizole can be mainly affected by the temperature and pH of the medium, and the rate of hydrolysis of the molecule increases dramatically in acidic solutions, compared to more alkaline ones.

Caffeine is known to have a direct analgesic effect in some pain conditions, and its vasoconstrictor effect is effective in some types of headache. Caffeine is a phosphodiesterase inhibitor and a competitive antagonist of A1 and A2 adenosine receptors. It has the property of potentiating the effect of non-opioid analgesics.

Drotaverine exerts an antispasmodic and dose-dependent analgesic effect comparable in intensity and duration to that of metamizole. The chemical stability of drotaverine is a problem, in neutral and alkaline environment drotaverine chloride is oxidized to drotaveraldine by an oxidative degradation mechanism, while under the influence of light it decomposes to perparin and finally to perparaldine by dehydrogenation of the molecule. The chemical stability of solid preparations comprising drotaverine hydrochloride is affected by the tablet carrier, the moisture content of the granules and tablets and the pH (EP1200088, p.2, line 2-p.3, line 4). This necessitates pH control by incorporating acid stabilizers into the tableting excipients. (WO0107024; RU2232018)

Drotaverine and metamizole are active substances with different pH stability profiles. The method of production by their joint granulation is unsuccessful because a process of disintegration is initiated and an unacceptable increase in impurity values. This creates difficulties in formulating stable combination tablet forms.

Ways of stabilizing combined compositions containing drotaverine and metamizole by pre-separated granulation and encapsulation of the granules before preparation of the tablet mixture are known; by wrapping the resulting tablet, etc. methods. (WO2015089614)

Patent application EP3520781 describes a pharmaceutical composition containing in one dosage form metamizole, drotaverine and caffeine, wherein the metamizole in the composition is in the form of a granule, and the drotaverine and caffeine are present outside said granule. The pharmaceutical composition is in the form of coated single-layer or double-layer tablets.

The method of obtaining the tablet form involves the preparation of two intermediate products, one is a metamizole granule obtained by wet or dry granulation, and the second is a powder mixture or mixture of granules, of drotaverine and caffeine. The two intermediates are mixed, then the resulting mixture is tableted.

A combined tablet form including metamizole with caffeine and drotaverine is also known, which has been on the market for over 30 years under the trade name Quarelin or Algopyrin Complex. Quarelin tablets include 400 mg of metamizole sodium monohydrate, caffeine 60 mg, drotavarin hydrochloride 40 mg, and excipients: potato starch, microcrystalline cellulose, povidone, talc and magnesium stearate.

A disadvantage of this medicinal composition is the high content of impurities, decay products of the active components, which increases during the storage process. (EP3520781, page 13, Table 6, column 2)

The task of the present invention is to create a composition of a medicinal product, an oral tablet form, including a combination of metamizole sodium monohydrate, caffeine and drotaverine hydrochloride and a method for its preparation, which ensure the preparation of a stable tablet form, with a low content of disintegration products and a rapid release after taking the active substances included in it.

TECHNICAL ESSENCE OF THE INVENTION

The task is solved by creating a composition for tablet form, including the active substances metamizole sodium monohydrate, caffeine and drotaverine hydrochloride, where metamizole and caffeine are included in the composition of a granule, and drotaverine is added to a powder mixture outside the granule. The composition of the granule as excipients includes: corn starch, collidon K25 and purified water, and the quantitative ratios of its components by weight. % relative to the total weight of the tableting mixture is as follows: from 57.97 to 60.42 metamizole sodium monohydrate; from 8.70 to 9.06 caffeine; from 2.27 to 2.90 corn starch, from 1.51 to 2.17 collidon K25. In the powder mixture, in which drotaverine hydrochloride was added, microcrystalline cellulose PH102, croscarmellose sodium, anhydrous colloidal silicon dioxide, glycerol dibehenate and magnesium stearate were included as excipients, in quantitative ratios by weight. % by weight of the tablet mixture as follows: from 5.80 to 6.04 drotaverine hydrochloride; from 13.82 to 14.13 microcrystalline cellulose PH102; from 2.57 to 3.04 croscarmellose sodium; from 0.38 to 0.51 anhydrous colloidal silica; 2.87 to 3.62 glycerol dibehenate and 1.06 to 1.16 magnesium stearate.

The used combination of binders - microcrystalline cellulose plus collidon ensures the production of tablets with sufficiently high mechanical strength, and the selected lubricant system - a combination of glycerol dibehenate and magnesium stearate contributes to the problem-free tableting of the mixture.

The tablet form object of the invention is obtained by mixing a granule obtained by granulating a mixture of metamizole sodium monohydrate, caffeine and corn starch with a previously prepared aqueous solution of collidon K25. The resulting wet mixture is sieved through a granulator with a 2.0 mm sieve, the granules are dried in a chamber drier at a temperature of 50°C to a residual moisture of 2%, then sieved through a granulator and added to the powdery mixture obtained by mixing of the required amounts of drotaverine hydrochloride, microcrystalline cellulose PH102, croscarmellose sodium and anhydrous silica. Glycerol dibehenate and magnesium stearate are successively added to the resulting mixture.

The well-homogenized tablet mixture is tableted on a rotary tablet press.

An advantage of the invention is that the composition and the method of its preparation provide a stable tablet form, with a low content of breakdown products of the active substances included in it, which are released quickly after taking the tablet.

EXAMPLES OF IMPLEMENTATION OF THE INVENTION

The invention is illustrated by the following exemplary embodiments:

Example 1. To prepare a tablet form containing 400 mg of metamizole sodium monohydrate, 60 mg of caffeine and 40 mg of drotaverine hydrochloride, the following components are used:

Names of ingredients Quantity mg/tablet %w/w Granules Metamizole sodium monohydrate 400.0 60.42 Caffeine 60.0 9.06 Corn starch 15.0 2.27 Collidon K25 10.0 1.51 Purified water* 58.0 Mixture for tableting Granules 485.0 Drotaverine hydrochloride 40.0 6.04 Microcrystalline cellulose pH 102 91.5 13.82 Vivasol* 17.0 2.57 Aerosil 200** 2.5 0.38 Compritol 888 ΑΤΟ*** 19.0 2.87 Magnesium stearate 7.0 1.06 Total 662.0 100.0

* Water evaporates during the production process.

**Vivasol is the trade name of croscarmellose sodium ***Aerosil 200 is the trade name of anhydrous silica **** Compritol 888 ΑΤΟ is the trade name of glycerol dibehenate, manufactured by Gattefosse

The method of obtaining the tablet combined form includes several stages:

Preparation of granules containing metamizole sodium monohydrate and caffeine

In a suitable vessel, collidon K25 is dissolved in purified water by stirring for 20 min. Metamizole sodium monohydrate, caffeine and corn starch are charged into a blender. The mass is mixed dry for 5 minutes. The resulting dry mixture was moistened with the binding solution of collidon K25, which was added to the mixture for 5 minutes. The wet granules are sieved through a granulator equipped with a 2.0 mm sieve. The wet granules are dried in a chamber dryer at a temperature of 50°C and a residual moisture of 2%, after which the dry granules are sieved through a granulator equipped with a 1.60 mm sieve.

Preparation of the dry mixture containing drotaverine hydrochloride

To prepare the mixture, drotaverine hydrochloride, microcrystalline cellulose PH 102, croscarmellose sodium and Aerosil 200 are mixed in a diffusion mixer for 20 minutes.

Preparation of the mixture for tableting

The granules from stage 1 are added to the resulting dry homogeneous mixture. The mixture is homogenized. Add the lubricant glycerol dibehenate (Compritol 888 ΑΤΟ) and homogenize again for 5 min. Finally, magnesium stearate is added and mixed for another 5 min.

The resulting mixture is tableted on a rotary tablet press.

The resulting tablets were analyzed, and the results of the analysis are reflected in the following table:

Table 1. Results of tested physico-chemical parameters

Tested parameters Assessment Bulk density of granules p ₀ , g/ml 0.476 Granular crushing density p _s , g/ml 0.500 Hausner ratio of granules, HF = p _s / ro 1,050 Loss on drying, % 1.8 Bulk density of tablet mixture p ₀ , g/ml 0.625 Density when shaking tablet mixture p _s , d/ml 0.625 Hausner ratio of tablet mixture, HF = p _s / p ₀ 1,000 Average mass per tablet (mg) 662.4 Mechanical strength (N) n=10; ± S.D 120 ± 9.6 Disintegration time (min) 9.0 Erasability (%) 0.08 Defects in the appearance of tablets, % there isn't Content of related substances in metamizole sodium monohydrate, HPLC, %: - Impurity "C" - Every single impurity - Total impurities 0.09 < LOQ 0.09 Content of related substances of drotaverine hydrochloride, HPLC, %: - Impurity Drotaveraldine - Any unspecified impurity - Total impurities 0.02 0.05 0.07

The results of the analysis show that the content of related substances is low.

Example 2. To prepare a tablet form, according to the invention, containing 400 mg of metamizole sodium monohydrate, 60 mg of caffeine and 40 mg of drotaverine hydrochloride, the following components are used:

Names of ingredients Quantity mg/tablet %w/w Granules Metamizole sodium monohydrate 400.0 57.97 Coffee 60.0 8.70 Corn starch 20.0 2.90 Collidon K25 15.0 2.17 Purified water* 58.0 Mixture for tableting Granules 495.0 Drotaverine hydrochloride 40.0 5.80 Microcrystalline cellulose pH 102 97.50 14.13 Vivasol** 21.00 3.04 Aerosil 200*** 3.50 0.51 Compritol 888 ΑΤΟ**** 25.00 3.62 Magnesium stearate 8.00 1.16 Total 690.0 100.0

* Water evaporates during the production process.

**Vivasol is the trade name of croscarmellose sodium *** Aerosil 200 is the trade name of anhydrous silica **** Compritol 888 ΑΤΟ is the trade name of glycerol dibehenate. province of Gattefosse

The tablet form was prepared according to the method described in Example 1.

Example 3. Stability study of a tablet form with a composition according to example 2.

The batch of tablets was packed in clear, colorless PVC/PVdC blisters and aluminum foil (20 pm) and stability tests were carried out under accelerated conditions - 40 °C/75 % RH for three months.

Results are presented in the following table:

Table 2. Results of a study of the stability of the tablets by the method of accelerated aging______________________________________

Indicators Norms Results 1. Appearance Pale yellow, round, flat tablets, diameter 13 mm, scored Responds 2. Identity: - metamizole sodium monohydrate: color reactions, HPLC - caffeine: color reaction, HPLC - drotaverine hydrochloride: color reaction, HPLC To meet the tests Responds 3. Average mass and mass uniformity, mg From 628.9 to 695.1 (662 ± 5 %) 663.2 4. Degradability, min No more than 15 9.5 5. Uniformity of dosage units, such as mass variation: - metamizole sodium monohydrate AV < 15.0 (L1) Responds

- caffeine as content - drotaverine hydrochloride AV < 15.0 (L1) AV< 15.0 (L1) Responds Responds 6. Degree of dissolution, % for 45 min of: - Metamizol sodium monohydrate, - Caffeine, - Drotaverine hydrochloride He less than Q = 80 He less than Q = 80 He less than Q = 80 92.8 100.4 89.3 7. Content of related substances of metamizole sodium monohydrate, HPLC, %: - Impurity C** - Every single impurity - Total impurities He is more than 0.5 He is more than 0.2 He is more than 1.0 0.15 < LOQ 0.15 8. Content of related substances of Caffeine, HPLC, %: - Any unspecified impurity - Total impurity Not more than 0.1 Not more than 0.5 0.10 0.10 9. Content of related substances of drotaverine hydrochloride, HPLC, %: - Impurity Drotaveraldine - Any unspecified impurity - Total impurity Not more than 1.0 Not more than 0.2 No more than 2.0 0.06 0.10, 0.12 0.28 10. Content in one tablet, in mg, of: - metamizole sodium monohydrate - caffeine - drotaverine hydrochloride From 380.0 to 420.0(95.0105.0 %) From 57.0 to 63.0 (95.0- 105.0 %) From 38.0 to 42.0 (95.0 - 105.0 %) 400.6 60.8 39.4 11. Microbiological quality Total number of aerobic microorganisms (TAMS), CFU/g Total number of molds and yeasts (TYMC), CFU/g Escherichia coli,/g Not more than 10 ³ Not more than 10 ² Not allowed < 10 < 10 Absent

Analysis of the stability data shows that the product remains stable during the shelf life, with unchanged physicochemical properties, low content of degradation products and disintegration time up to 9.5 min.

Claims (2)

PATENT CLAIMS 1. Pharmaceutical composition in the form of a tablet containing metamizole, drotaverine, caffeine and excipients, characterized in that the tablet is formed from a tablet mixture including a granule obtained by wet granulation and composed of metamizole sodium monohydrate, caffeine, corn starch and collidon K25 and a powder mixture composed of drotaverine hydrochloride, microcrystalline cellulose, croscarmellose sodium, anhydrous colloidal silica, glycerol dibehenate and magnesium stearate, as the ratio of the components in the tablet mixture by weight. %, relative to the weight of the tablet mixture is: from 57.97 to 60.42 metamizole sodium monohydrate; from 8.70 to 9.06 caffeine; from 2.27 to 2.90 corn starch and from 1.51 to 2.17 collidone K25, from 5.80 to 6.04 drotaverine hydrochloride; from 13.82 to 14.13 microcrystalline cellulose PH102; from 2.57 to 3.04 croscarmellose sodium; from 0.38 to 0.51 anhydrous colloidal silica; 2.87 to 3.62 glycerol dibehenate and 1.06 to 1.16 magnesium stearate. 2. Method for obtaining the pharmaceutical composition in the form of a tablet, according to claim 1, characterized in that the tablet mixture is obtained by mixing a granule, which is obtained by granulating a mixture of metamizole sodium monohydrate, caffeine and corn starch with pre- prepared aqueous solution of collidon K25, the wet mixture is sieved through a granulator with a 2.0 mm sieve, the granules are dried in a chamber dryer at temperature 50°C to a residual moisture of no more than 2%, sieved through a granulator and added to a powder mixture obtained by mixing the necessary amounts of drotaverine hydrochloride, microcrystalline cellulose PH102, croscarmellose sodium and anhydrous silica, and to the resulting mixture before tableting, glycerol dibehenate and magnesium stearate are added sequentially.