AU777234B2 - Pharmaceutical effervescent formulation containing metamizol - Google Patents

Pharmaceutical effervescent formulation containing metamizol Download PDF

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Publication number
AU777234B2
AU777234B2 AU28040/00A AU2804000A AU777234B2 AU 777234 B2 AU777234 B2 AU 777234B2 AU 28040/00 A AU28040/00 A AU 28040/00A AU 2804000 A AU2804000 A AU 2804000A AU 777234 B2 AU777234 B2 AU 777234B2
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Prior art keywords
pharmaceutical composition
tabl
effervescent
effervescent formulation
sodium
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AU28040/00A
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AU2804000A (en
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Brigitte Freudensprung
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Hexal AG
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Hexal AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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

1- Effervescent pharmaceutical formulation containing metamizole The invention relates to a stable effervescent pharmaceutical formulation with metamizole and/or its pharmaceutically acceptable salts as active ingredients, the pH of the resulting solution being acidic.
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
Metamizole, N-methyl-N-(2,3-dimethyl-5-oxo-l-phenyl- 3-pyrazolin-4-yl)aminomethanesulfonic acid, is an analgesic with antipyretic effects. The analgesic effect arises through depression of central pain perception as a result of activation of neurons in the pain-inhibiting system. The reduction in elevated body temperature is mediated by the action on the hypothalamic heat-regulating center, resulting in increased dissipation of heat via the periphery.
After oral intake, the absorption of metamizole is preceded 20 by hydrolysis to 4-methylaminoantipyrine in the liver.
4-Methylaminoantipyrine and the 4-aminoantipyrine produced therefrom are the pharmacologically active metabolites of metamizole, while the other metabolites 4-acetylaminoantipyrine (main metabolite in the urine) and 4-formylaminoantipyrine are regarded as having very much less pharmacological activity or being inactive. After oral administration of tablets available on the market to date, the
*SSS
o• 2 pharmacologically active plasma concentration of 4methylaminoantipyrine is reached after 1.4 hours, and of 4-aminoantipyrine after 6.7 hours.
It is desirable for a pharmacologically active plasma concentration and thus a therapeutic effect to be reached as quickly as possible because metamizole is used to treat acute severe pain. The injection dosage form which is frequently used for this purpose requires care which can be provided only by specialist medical staff because, otherwise, an injection rate which is too fast and a dosage which is too high result in life-threatening side effects, such as, for example, sudden circulatory failure or agranulocytosis. In addition, patient compliance with an injection is very low.
The invention provides a stable effervescent formulation with metamizole and/or its pharmaceutically acceptable salts as active components, so that the pharmacologically effective plasma concentration and thus the therapeutic effect can be reached faster than with conventional dosage forms for oral administration, but direct *96 20 medical care during intake can be dispensed with because *I there is no risk of life-threatening side effects.
The stability of metamizole and its pharmaceutically acceptable salts is pH-dependent. Metamizole or its pharmaceutically acceptable salts is stable in neutral and basic medium. In acidic medium, however, hydrolysis takes place very rapidly and is indicated by a yellow coloration.
The excipients normally used to produce effervescent tablets
-S
3 generate an acidic medium in aqueous solution.
It has now been found, surprisingly, that despite an acidic pH of the effervescent formulation solution the active ingredient metamizole and/or its pharmaceutically acceptable salts is not subject to hydrolysis, that is to say is stable, without addition of special stabilizing substances, and a therapeutically effective plasma level is reached very quickly. An additional advantage compared with dosage forms for oral administration available on the market to date is that intake of the medicament is made more pleasant for the patient by flavoring the effervescent formulation.
The effervescent formulation of the invention may contain metamizole and/or its pharmaceutically acceptable salts as active ingredients. Possible and suitable metamizole salts are, in particular, alkali metal salts such as, for example, the potassium, sodium and lithium salts, especially metamizole sodium monohydrate, and the ammonium salt.
In a first aspect, the invention provides a pharmaceutical composition in the form of an effervescent S: 20 formulation, comprising at least one alkali and/or ammonium salts of metamizole as the active constituent.
The effervescent formulation of the invention can comprise an effective amount of 200-1000 mg, in particular of 400-600 mg, of metamizole and/or its pharmaceutically acceptable salts per dosage unit.
The preferred effervescent formulation of the invention comprises 500 mg of metamizole sodium monohydrate per dosage oe 3a unit.
The effervescent formulation of the invention dissolved in water has a pH of from 3 to 6.5, in particular of from 4 to 6, preferably of from 4.5-5, and the resulting solution is stable and clear for at least one hour.
It is possible to use as source of carbon dioxide in the effervescent formulation of the invention the carbonate_ *o i" *ooo oo *o*oo *°o 4 and/or bicarbonate of the alkali metals 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 conjunction with at least one acid, for example citric acid, monosodium citrate, ascorbic acid, gluconic acid, lactic acid, maleic acid, and tartaric acid. In the preferred effervescent formulation of the invention, citric acid is used with a combination of sodium carbonate and sodium bicarbonate as effervescent mixture. In this case the ratio by weight of the acid(s) to the carbonate and/or the bicarbonate can be between 0.7 and 2.4, in particular between 1.1 and 2.2.
An acceptable taste of the resulting solution of the active ingredient can be achieved by adding suitable masking flavors such as flavorings, sugar, sucrose or sugar substitutes. Sugar or sugar substitutes may be present in an amount of up to about 50% by weight. Masking flavors suitable for producing the effervescent formulation of the invention are artificial or natural sweeteners (0.5 to 5% by weight), preferably saccharin sodium, sodium cyclamate, sorbitol, aspartame or mannitol, or artificial or natural flavorings, preferably lemon, banana, peppermint, caramel, wild fruit and raspberry flavor. The flavors are preferably used in an amount of from 0.5 to 3% by weight.
In addition, water-soluble pharmaceutical tablet excipients known from the prior art are used to produce the effervescent formulation of the invention, for example 5 fillers and binders (mannitol), and lubricants (polyethylene glycols, Compritol, L-leucine, magnesium stearate, stearic acid). As other possible tablet excipients it is possible to add where appropriate one or more polysaccharides. Preferred polysaccharides are cyclodextrins. Possible representatives are y-cyclodextrin and/or their pharmaceutically acceptable derivatives, in particular p-cyclodextrin.
The effervescent formulation of the invention may be in the form of a powder, tablets or granules, which can be packed in sachets. The preferred effervescent formulation is in the form of tablets.
Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".
The invention is illustrated in the table by the following examples without, however, thereby restricting the 20 scope of the invention.
Example 1: Metamizole sodium monohydrate 500 mg/tabl.
::Citric acid 1 230 mg/tabl.
25 Sodium carbonate 650 mg/tabl.
Sodium hydrogen carbonate (bicarbonate) 75 mg/tabl.
Ascorbic acid 75 mg/tabl.
oeeee Sa Lactose Saccharin sodium PEG 6000 Sodium cyclamate Flavor (lemon) 500 mg/tabl.
5 mg/tabl.
155 mg/tabl.
50 mg/tabl.
50 mg/tabl.
6 The total weight of a tablet is 3290 mg.
Metamizole sodium monohydrate and PEG 6000 are ground and screened, and the remaining ingredients are admixed. The mixture is compressed to 3 290 mg tablets with a diameter of mm. Dissolution results in a clear solution. The active ingredient is stable for one hour. The ratio by weight of citric acid to carbonate/bicarbonate corresponds to about 1.7.
Example 2: Metamizole sodium monohydrate Citric acid Sodium carbonate Sodium hydrogen carbonate (bicarbonate) Ascorbic acid Lactose monohydrate Saccharin sodium PEG 6000 Sodium cyclamate Flavor (raspberry) 500 mg/tabl.
1 230 mg/tabl.
650 mg/tabl.
75 mg/tabl.
75 mg/tabl.
500 mg/tabl.
5 mg/tabl.
155 mg/tabl.
50 mg/tabl.
30 mg/tabl.
The total weight of a tablet is 3270 mg.
Metamizole sodium monohydrate and PEG 6000 are ground and screened, and the remaining ingredients are admixed. The mixture is compressed to 3270 mg tablets with a diameter of mm using a rotary tableting machine. Dissolution results in a clear solution. The active ingredient is stable for one 7 hour. The ratio by weight of citric acid to carbonate/ bicarbonate corresponds to about 1.7.
Example 3: Metamizole sodium monohydrate Citric acid Sodium carbonate anhydrous Sodium hydrogen carbonate (bicarbonate) PEG 6000 Saccharin sodium Sodium cyclamate Ascorbic acid Lactose Flavor (raspberry) 500 mg/tabl.
1 500 mg/tabl.
630 mg/tabl.
70 mg/tabl.
150 mg/tabl.
5 mg/tabl.
30 mg/tabl.
75 mg/tabl.
820 mg/tabl.
30 mg/tabl.
The total weight of a tablet is 3830 mg.
Metamizole sodium monohydrate, mannitol and PEG 6000 are ground and screened, and the remaining ingredients are admixed. The mixture is compressed to 3 830 mg tablets with a diameter of 22 mm. The ratio by weight of citric acid to carbonate/bicarbonate corresponds to about 2.14. The pH of the solution is 4.50-4.61.
Example 4: Metamizole sodium monohydrate 500 mg/tabl.
Citric acid 750 mg/tabl.
Sodium carbonate anhydrous 900 mg/tabl.
Sodium hydrogen carbonate (bicarbonate) 50 mg/tabl.
8 Mannitol P-Cyclodextrin PEG 6000 Saccharin sodium Sodium cyclamate Ascorbic acid Lactose and PVP Flavor (lemon) 30 mg/tabl.
100 mg/tabl.
96 mg/tabl.
4 mg/tabl.
15 mg/tabl.
75 mg/tabl.
80 mg/tabl.
50 mg/tabl.
The total weight of a tablet is 2650 mg.
Metamizole sodium monohydrate, mannitol and PEG 6000 are ground and screened, and the remaining ingredients are admixed. The mixture is compressed to 2650 mg tablets with a diameter of 22 mm. The pH of the solution is about 5. The ratio by weight of citric acid to carbonate/bicarbonate corresponds to about 0.79.
Example Metamizole sodium monohydrate Citric acid Sodium carbonate anhydrous Sodium hydrogen carbonate (bicarbonate) PEG 6000 Saccharin sodium Sodium cyclamate Maleic acid Lactose 500 1 200 600 118 350 4 40 300 120 mg/tabl.
mg/tabl.
mg/tabl.
mg/tabl.
mg/tabl.
mg/tabl.
mg/tabl.
mg/tabl.
mg/tabl.
9 Flavor (raspberry) 30 mg/tabl.
The total weight of a tablet is 3262 mg.
Metamizole sodium monohydrate and PEG 6000 are ground and screened, and the remaining ingredients are admixed. The mixture is compressed to tablets. Dissolution results in a clear solution. The active ingredient is stable for one hour.
The ratio by weight of citric acid to carbonate/bicarbonate corresponds to about 1.67. The pH of the solution is 4.56- 4.72.
Example 6: Metamizole sodium monohydrate Citric acid Sodium carbonate anhydrous Sodium hydrogen carbonate (bicarbonate) PEG 8000 Saccharin sodium Sodium cyclamate Ascorbic acid Lactose Flavor (wild berry/blackberry) 500 mg/tabl.
660 mg/tabl.
100 mg/tabl.
420 mg/tabl.
25 mg/tabl.
5 mg/tabl.
30 mg/tabl.
75 mg/tabl.
120 mg/tabl.
50 mg/tabl.
The total weight of a tablet is 1985 mg.
Metamizole sodium monohydrate and PEG 8000 are ground and screened, and the remaining ingredients are admixed. The mixture is compressed to tablets with a diameter of 20 mm.
10 The ratio by weight of citric acid to carbonate/bicarbonate corresponds to about 1.27.
Example 7: Metamizole sodium monohydrate Citric acid Sodium carbonate anhydrous Sodium hydrogen carbonate (bicarbonate) PEG 6000 Saccharin sodium Sodium cyclamate Maleic acid Lactose Flavor (raspberry) 500 mg/tabl.
666 mg/tabl.
633 mg/tabl.
100 mg/tabl.
350 mg/tabl.
4 mg/tabl.
40 mg/tabl.
200 mg/tabl.
276 mg/tabl.
30 mg/tabl.
The total weight of a tablet is 2799 mg.
Metamizole sodium monohydrate and PEG 6000 are ground and screened, and the remaining ingredients are admixed. The mixture is compressed to tablets. The ratio by weight of citric acid to carbonate/bicarbonate corresponds to about 0.91. The pH of the solution is 5.73-5.92.

Claims (9)

1. A pharmaceutical composition in the form of an effervescent formulation, comprising at least one alkali and/or ammonium salts of metamizole as the active constituent.
2. A pharmaceutical composition according to claim 1, wherein the active constituent is metamizole sodium monohydrate.
3. A pharmaceutical composition in the form of an effervescent formulation according to claim 1 or claim 2, wherein the amount of alkali and/or ammonium salt of metamizol is 200-1000 mg.
4. A pharmaceutical composition according to claim 3, wherein the amount of alkali and/or ammonium salt of metamizol is 400-600 mg per dosage unit. A pharmaceutical composition in the form of an effervescent formulation as claimed in claim 3 or 4, comprising 500 mg of metamizole sodium monohydrate per dosage unit. 20 6. A pharmaceutical composition in the form of an effervescent formulation as claimed in any of the preceding "i claims, comprising at least one physiologically compatible acid or its sodium salt and a physiologically compatible carbonate and/or bicarbonate as an effervescent mixture in 25 quantitative ratios such that the resulting solution has a pH from 3 to
7. A pharmaceutical composition according to claim 6, S 12 wherein the resulting solution has a pH from 4 to 6.
8. A pharmaceutical composition according to claim 6 or 7, wherein the resulting solution has a pH from 4.5 to
9. A pharmaceutical composition in the form of an effervescent formulation according to any one of claims 6 to 8, comprising citric acid or its monosodium salt in combination with sodium carbonate and sodium bicarbonate as an effervescent mixture. A pharmaceutical composition in the form of an effervescent formulation according to claim 9, wherein the ratio by weight of the acid(s) to the carbonate and/or bicarbonate in the effervescent mixture is between 0.7 and 2.4.
11. A pharmaceutical composition according to claim wherein the ratio by weight of the acid(s) to the carbonate and/or bicarbonate in the effervescent mixture is between 1.1 and 2.2. t 12. A pharmaceutical composition in the form of an effervescent formulation according to any one of claims 1 to 20 11, comprising a sweetener. S• 13. A pharmaceutical composition in the form of an Se effervescent formulation according to any one of claims 1 to 12, comprising a flavouring agent. S 14. A pharmaceutical composition in the form of an 25 effervescent formulation according to any one of claims 1 to eve. 13, in the form of powder, tablets or granules, which can be :te: packed in sachets, in particular in the form of S 13 tablets. A pharmaceutical composition in the form of an effervescent formulation according to any one of claims 1 to 14, whereby the alkali and/or ammonium salts of metamizol as the active constituents are stable in the effervescent formulation solution for at least one hour.
16. A pharmaceutical composition according to claim 1, substantially as herein described with reference to any one of the Examples. DATED this 19 t h day of May 2004 BALDWIN SHELSTON WATERS Attorneys for: HEXAL AG S* *o o *ooo •go** *oo oooo.
AU28040/00A 1999-02-11 2000-02-10 Pharmaceutical effervescent formulation containing metamizol Ceased AU777234B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19905581 1999-02-11
DE19905581 1999-02-11
PCT/EP2000/001096 WO2000047189A1 (en) 1999-02-11 2000-02-10 Pharmaceutical effervescent formulation containing metamizol

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AU2804000A AU2804000A (en) 2000-08-29
AU777234B2 true AU777234B2 (en) 2004-10-07

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EP (1) EP1150660B1 (en)
JP (1) JP2002536401A (en)
AT (1) ATE258046T1 (en)
AU (1) AU777234B2 (en)
BR (1) BR0008442B1 (en)
CA (1) CA2362757C (en)
DE (1) DE50005076D1 (en)
ES (1) ES2215025T3 (en)
HU (1) HUP0200336A3 (en)
PL (1) PL201844B1 (en)
PT (1) PT1150660E (en)
TR (1) TR200102279T2 (en)
WO (1) WO2000047189A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103610656B (en) * 2013-12-05 2016-02-03 昆明振华制药厂有限公司 A kind of preparation method of analgin tablet
US20160317662A1 (en) * 2013-12-16 2016-11-03 Hypermarcas S.A. Stable oral pharmaceutical composition
CN104434862A (en) * 2014-11-06 2015-03-25 石家庄正大鸿福牧业有限公司 Veterinary metamizole sodium effervescent tablets and preparation method thereof
BG112443A (en) 2017-01-19 2018-07-31 Adifarm Ead Effervescent composition containing metamizole sodium monohydrate and preparation method
EP3928766A1 (en) 2020-06-26 2021-12-29 Usso Barnas Pharmaceutical composition and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0637448A1 (en) * 1993-07-19 1995-02-08 Iscofar Sas Di Paolo E. Ghirardi Combinations of glycinamide or N-acetylglycinamide with analgesic compounds
WO1998047534A1 (en) * 1997-04-18 1998-10-29 Klinge Pharma Gmbh Stabilized medicaments containing cysteinyl derivatives

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD41306A (en) *
JPS52156915A (en) * 1976-06-19 1977-12-27 Hokuriku Pharmaceutical Production of stable injection without blood solubulizing property
DE19822036A1 (en) * 1998-05-15 1999-11-18 Bayer Ag Effervescent pharmaceutical composition with improved stability

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0637448A1 (en) * 1993-07-19 1995-02-08 Iscofar Sas Di Paolo E. Ghirardi Combinations of glycinamide or N-acetylglycinamide with analgesic compounds
WO1998047534A1 (en) * 1997-04-18 1998-10-29 Klinge Pharma Gmbh Stabilized medicaments containing cysteinyl derivatives

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HUP0200336A3 (en) 2005-04-28
BR0008442A (en) 2001-10-09
TR200102279T2 (en) 2001-11-21
ATE258046T1 (en) 2004-02-15
ES2215025T3 (en) 2004-10-01
EP1150660B1 (en) 2004-01-21
EP1150660A1 (en) 2001-11-07
HUP0200336A2 (en) 2002-06-29
DE50005076D1 (en) 2004-02-26
CA2362757A1 (en) 2000-08-17
JP2002536401A (en) 2002-10-29
CA2362757C (en) 2010-08-24
BR0008442B1 (en) 2014-04-01
PT1150660E (en) 2004-06-30
PL350413A1 (en) 2002-12-02
PL201844B1 (en) 2009-05-29
WO2000047189A1 (en) 2000-08-17
AU2804000A (en) 2000-08-29

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