MXPA01008150A

MXPA01008150A - Pharmaceutical effervescent formulation containing metamizol

Info

Publication number: MXPA01008150A
Application number: MXPA/A/2001/008150A
Authority: MX
Inventors: Brigitte Freudensprung
Original assignee: Brigitte Freudensprung; Hexal Ag
Priority date: 1999-02-11
Filing date: 2001-08-10
Publication date: 2002-03-26

Abstract

The invention relates to a stable pharmaceutical effervescent formulation with metamizol and/or its pharmaceutically acceptable salts as active ingredients, wherein the pH of the corresponding solution is acidic.

Description

EFFERVESCENT PHARMACEUTICAL FORMULATION THAT CONTAINS ME AMIZOL The invention relates to an effervescent pharmaceutical formulation with metamizole and / or its pharmaceutically acceptable salts as active ingredients, wherein the pH value of the solution formed is acidic. Metazimol, N-me t i 1-N- (2, 3-dime t i -5-oxo-1-phenyl-1 -3-pyrrazole-4-yl) amino and anosulonic acid, represents an analgesic with an antipyretic effect. The analgesic effect is realized by a reduction of the central perception of the pain as a result of an activation of the neurons in the pain inhibitor system. The reduction of the elevated body temperature is carried out by means of an effect on the center of the thermal regulation of the hypothalamus, as a consequence there is a greater thermal distribution in the periphery. After oral administration, resorption of metamizole occurs by hydrolysis to α-methylaminoant ipyrin in the liver. The 4-methylaminant ipyr ina and the 4-aminoantipyr ina derived from the first are pharmacologically active metopi s of metamizole, while the other metabolites 4-acetyl il amininoant ipyrin (main metabolite in urine) and 4-fro ilaminoant ipir ina are considered as pharmacologically very weakly effective or inactive. After the oral application of the tablets hitherto on the market, a pharmacologically active plasma concentration of 4-methylaminoantipyrine is reached after 1.4 hours and of 4-aminoantipyrine after 6.7 hours. The fastest possible obtaining of a pharmacologically effective plasma concentration and with this a therapeutic effect is desired, since metamizol serves for the treatment of acute severe pain. The most commonly used form of administration is injection and requires the guaranteed experience of medical personnel, since with a high injection speed in a high dosage can be life-threatening side effects, such as sudden circulatory problems or agranuloci tosis. In addition, the compliance of patients with an injection is very small. The task of the invention is now to prepare a stable effervescent formulation with metamizole and / or its pharmaceutically acceptable salts as active components. In such a way that the pharmacologically effective plasma concentration and thus the therapeutic effect are reached more quickly than with the common oral administration forms, but that medical control during ingestion can be avoided, since there is no danger of side effects that they put in life danger The stability of metamizole and its pharmaceutically acceptable salts depends on the pH. In neutral to basic media, metamizole or its pharmaceutically acceptable salts. In acidic media, a hydrolysis is carried out very quickly, which is shown by means of a yellow coloration. The usual excipients for effervescent tablets produce an acidic medium in aqueous solutions. It was surprisingly found that despite an acidic pH value of the effervescent formulation solution, the active ingredient metamizole and / or its pharmaceutically acceptable salts without the addition of special stabilizing substances does not undergo hydrolysis, this means that it is stable, and very rapidly a therapeutically effective blood level is reached. Furthermore, the oral administration forms found on the market so far have the advantage that, thanks to the addition of a flavoring to the effervescent formulation, it makes it more pleasant to ingest the medicine for patients. The effervescent formulation according to the invention may contain metamizole and / or its pharmaceutically acceptable salts as active constituent parts. Possible salts of metamizole are, in particular, alkali metal salts, such as, for example, potassium, sodium and lithium salts, especially sodium metamizole monohydrate., as well as the ammonium salt. The effervescent formulation according to the invention may contain, per dosage unit, an effective amount of metamizole and / or its pharmaceutically acceptable salts in an amount of 200-1000 mg, especially 400-600 mg. The effervescent formulation according to the invention preferably contains 500 mg of the sodium monohydrate of metamizole. The effervescent formulation according to the invention, dissolved in water, has a pH value of from 3 to 6.5, in particular from 4 to 6, preferably from 4.5 to 5 and the resulting solution is stable and transparent for at least one hour. The effervescent formulation according to the invention can be used as a source of carbon dioxide, the carbonate and / or carbonate of alkali and / or alkaline earth metals, for example sodium carbonate or sodium bicarbonate, calcium carbonate or calcium bicarbonate and / or magnesium carbonate or magnesium bicarbonate, in combination with at least one acid, citric acid, monosodium citrate, ascorbic acid, gluconic acid, lactic acid, malic acid and tartaric acid. A combination of citric acid with sodium carbonate and sodium bicarbonate is used in the preferred effervescent formulation according to the invention. Here may be the proportion by weight of or acids to carbonate and / or bicarbonate, between 0.7 and 2.4 especially between 1.1 and 2.2. An acceptable taste of the solution resulting from the active ingredient can be obtained by the addition of suitable flavor correctors, such as flavoring, sugar, sucrose or sugar substitutes. The sugar or sugar substitutes can be used in a proportion of up to about 50% by weight. Suitable flavor correctors for the effervescent formulation according to the invention are natural or synthetic sweeteners (0.5 to 5% by weight), preferably sodium saccharin, sodium cyclamate, sorbitan, aspartame or mannitol, or natural or synthetic flavors, preferably aromas of lemon, banana, mint, caramel, berries and raspberries. The aromas are preferably used in an amount of 0.5 to 3% by weight. Furthermore, according to the prior art, pharmaceutical excipients for water-soluble tablets are used for the effervescent formulation according to the invention, for example fillers and binders (Manite) as well as lubricants (polyethylene glycols, compritol, L-leucine, stearate magnesia, stearic acid). As other tablet additives, one or more polysaccharides can optionally be used. The preferred polysaccharides are cyclodextrins. Possible representatives are α-, β-, β- (cyclodextrin and / or their pharmaceutically acceptable derivatives, especially β-cyclodextrin The effervescent formulations according to the invention can be in the form of powder, tablets or granules, which they are used to fill sachets The preferred effervescent formulation is in the form of tablets The invention will be clarified by means of the following examples but without limiting the scope of the invention.

Example 1 Metamizole sodium monohydrate 500 mg / tablet Citric acid 1230mg / tablet Sodium carbonate 650 mg / tablet Carbohydrate (bicarbonate) 75 mg / sodium tablet Ascorbic acid 75 mg / tablet Lactose 500 mg / tablet Saccharin sodium 5 mg / tablet PEG 6000 155 mg / tablet Sodium cyclamate 50 mg / tablet Aroma (lemon) 50 mg / tablet The total weight of a tablet is 3290 mg. The sodium monohydrate of metamizol and PEG 6000 are milled and sieved, the other ingredients are added to the mixture. The mixture is pressed into tablets with a diameter of 20 mm and 3290 mg. After the disintegration a clear solution is obtained. The active ingredient is stable for more than one hour. The weight ratio of citric acid to carbonate / bicarbonate corresponds to approximately 1.7.

Example 2; Metamizole sodium monohydrate 500 mg / tablet Citric acid 1230mg / tablet Sodium carbonate 650 mg / tablet Carbohydrate (bicarbonate) 75 g / sodium tablet Ascorbic acid 75 mg / tablet Lactose monohydrate 500 mg / tablet Saccharin sodium 5 mg / tablet PEG 6000 155 mg / tablet Sodium cyclamate 50 mg / tablet Aroma (raspberry) 30 mg / tablet The total weight of a tablet is 3270 mg. The sodium monohydrate of metamizol and PEG 6000 are milled and sieved, the other ingredients are added to the mixture. The mixture is pressed into tablets with a diameter of 25 mm and 3270 mg with the aid of a circulating tableting machine. After the disintegration a clear solution is obtained. The active ingredient is stable for more than one hour. The weight ratio of citric acid to carbonate / bicarbonate corresponds to approximately 1.7.

Example 3: Metamizole sodium monohydrate 500 mg / tablet Citric acid 1500mg / tablet Anhydrous sodium carbonate 630 mg / tablet Carbohydrate (bicarbonate) 70 mg / sodium tablet PEG 6000 150 mg / tablet Saccharin sodium 5 mg / t able Sodium cyclamate 50 mg / tablet Ascorbic acid 75 mg / tablet Lactose 820 mg / tablet Aroma (raspberry) 30 mg / tablet The total weight of a tablet is 3830 mg. The sodium monohydrate of metamizol and PEG 6000 are milled and sieved, the other ingredients are added to the mixture. The mixture is pressed into tablets with a diameter of 22 mm and 3830 mg. The weight ratio of citric acid to carbonate / bicarbonate corresponds to approximately 2.14. The pH value of the solution is 4.50-4.61.

Example 4 Metamizole sodium monohydrate 500 mg / tablet Citric acid 750 mg / tablet Anhydrous sodium carbonate 900 mg / tablet Carbohydrate (bicarbonate) 50 mg / tablet sodium Manita 30 mg / tablet ß-cyclodextrin 100 mg / tablet PEG 6000 96 mg / tablet Saccharin sodium 4 mg / tablet Sodium cyclamate 15 mg / tablet Ascorbic acid 75 mg / tablet Lactose and PVP 80 mg / tablet Aroma (lemon) 50 mg / tablet The total weight of a tablet is 2650 mg. Sodium monohydrate of metamizole, Manita and PEG 6000 are milled and sieved, the other ingredients are added to the mixture. The mixture is pressed into tablets with a diameter of 22 mm and 2650 mg. The pH value of the solution is about 5. The weight ratio of citric acid to carbonate / bicarbonate corresponds to about 0.79.

Example 5: Metamizole sodium monohydrate 500 g / tablet Citric acid 1200 mg / tablet Anhydrous sodium carbonate 600 mg / tablet Carbohydrate (bicarbonate) of 118 mg / tablet sodium PEG 6000 350 mg / tablet Saccharin sodium 4 mg / tablet Sodium cyclamate 40 mg / tablet Malic acid 300 mg / tablet Lactos at 120 mg / tablet Aroma (raspberry) 30 mg / tablet The total weight of a tablet is 3262 mg. Sodium monohydrate of metamizol and PEG 6000 are milled and sieved, the other ingredients are added to the mixture. The mixture is pressed into tablets. After the disintegration a clear solution is obtained. The active ingredient is stable for more than one hour. The weight ratio of citric acid to carbonate / bicarbonate corresponds to about 1.67. The pH value of the solution is 4.56-4.72.

Example 6; Metamizole sodium monohydrate 500 mg / tablet Citric acid 660 mg / tablet Anhydrous sodium carbonate 100 mg / tablet Carbohydrate (bicarbonate) 420 mg / tablet sodium PEG 8000 25 g / tablet Saccharin sodium 5 mg / tablet Sodium cyclamate 30 mg / tablet Ascorbic acid 75 mg / tabl e ta Lactose 120 mg / tablet Aroma (currant / 50 mg fruits / forest tablet) The total weight of a tablet is 1985 mg. The sodium monohydrate of meta izol and PEG 8000 are milled and sieved, the other ingredients are added to the mixture. The mixture is pressed into tablets with a diameter of 20 mm. The weight ratio of citric acid to carbonate / bicarbonate corresponds to approximately 1.27.

Example 7: Metamizole sodium monohydrate 500 mg / tablet Citric acid 6 66 mg / tablet Anhydrous sodium carbonate 633 mg / tablet Carbohydrate (bicarbonate) 100 mg / tablet sodium PEG 6000 350 mg / tablet Saccharin sodium 4 mg / tablet Sodium cyclamate 40 mg / tablet Alic acid 200 mg / tablet Lactose 276 mg / tablet Aroma (raspberry) 30 mg / tablet The total weight of a tablet is 2799 mg. Sodium monohydrate of metamizol and PEG 6000 are milled and sieved, the other ingredients are added to the mixture. The mixture is pressed into tablets. The weight ratio of citric acid to carbonate / bicarbonate corresponds to approximately 0.91. The pH value of the solution is 5.73-5.92.

Claims

CLAIMS 1. Pharmaceutical composition in the form of an effervescent formulation, characterized in that it cons as active ingredients, metamizole and / or its pharmaceutically acceptable salts.
2. Pharmaceutical composition in the form of an effervescent formulation according to claim 1, characterized in that alkaline salts and / or ammonium salts of metamizole are used as the active ingredient.
3. Pharmaceutical composition in the form of an effervescent formulation according to claims 1 6 2, characterized in that the sodium monohydrate of metamizole is used as an active ingredient.
4. Pharmaceutical composition in the form of an effervescent formulation according to one of the preceding claims, characterized in that a content of metamizole and / or its pharmaceutically acceptable salts of 200-1000 mg, especially 400-600 mg per dosage unit.
5. Pharmaceutical composition in the form of an effervescent formulation according to claim 4, characterized by a content of 500 mg of sodium monohydrate of metamizole per dosage unit.
6. Pharmaceutical composition in the form of an effervescent formulation according to one of the preceding claims, characterized in that an effervescent mixture of at least one physiologically acceptable acid or one of its sodium salts and a physiologically acceptable carbonate and / or bicarbonate in those proportions by weight that the resulting solution has a pH value of from 3 to 6.5, in particular from 4 to 6, preferably from 4.5 to 5.
7. Pharmaceutical composition in the form of an effervescent formulation according to claim 6, characterized in that an effervescent mixture cons citric acid or its monosodium salts in combination with sodium carbonate and sodium bicarbonate.
8. Pharmaceutical composition in the form of an effervescent formulation according to one of the preceding claims, characterized in that the proportion by weight in the effervescent mixture of the acid (s) to carbonate and / or bicarbonate is between 0.7 and 2.4, especially between 1.1 and 2.2.
9. Pharmaceutical composition in the form of an effervescent formulation according to one of the preceding claims, characterized by an optional content of a sweetener.
10. Pharmaceutical composition in the form of an effervescent formulation according to one of the preceding claims, characterized by an optional content of a flavoring.
11. Pharmaceutical composition in the form of an effervescent formulation according to the preceding claims in the form of powder, tablets or granules, can fill sachets, especially in the form of tablets.
12. Pharmaceutical composition in the form of an effervescent formulation characterized in that it presents sodium monohydrate of metamizole, sodium carbonate / bicarbonate, excipients for tablets, optionally flavorings and / or sweeteners, the resulting solution having a pH value of 3-6.5, especially 4.5- 5.
13. Pharmaceutical composition according to one of the claims 1-12 characterized in that the effervescent formulation is stable.
14. Pharmaceutical composition according to claims 1-12, characterized in that the solution for the effervescent formulation is stable and clear for at least one hour.
15. Pharmaceutical composition according to claim 13 or 14, characterized in that the effervescent formulation cons no additional stabilizing substances.