WO2024221060A1 - Pharmaceutical composition in the form of a tablet, comprising metamizole, caffeine and drotaverine and a process for its preparation - Google Patents
Pharmaceutical composition in the form of a tablet, comprising metamizole, caffeine and drotaverine and a process for its preparation Download PDFInfo
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- WO2024221060A1 WO2024221060A1 PCT/BG2023/000013 BG2023000013W WO2024221060A1 WO 2024221060 A1 WO2024221060 A1 WO 2024221060A1 BG 2023000013 W BG2023000013 W BG 2023000013W WO 2024221060 A1 WO2024221060 A1 WO 2024221060A1
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- mixture
- tablet
- caffeine
- metamizole
- drotaverine
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Classifications
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- 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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
Definitions
- composition in the form of a tablet comprising metamizole, caffeine and drotaverine and a process for its preparation
- the invention relates to a pharmaceutucal composition in the form of a tablet for peroral application, comprising metamizole, drotaverine and caffeine, as well as to a method of its production, that find application in pharmacy and in medical practice.
- Metamizole, drotaverine and caffeine are the active substances, well known and widely used in medical practice for treatment of severe pain of different origin, such as pains, related to contractile states of the smooth muscles, pains, related to the genitourinary system, pains in intestinal colics, irritable bowel syndrome, cholecystitis and inflammation of the biliary duct.
- metamizole exhibits considerable analgesic, antipyretic and moderate anti-inflammatory effect. It is prescribed for treatment of pain of different origin.
- the problem with the development of compositions, based on metamizole sodium monohydrate, is its stability in terms of disintegration products.
- the influence of the physico-chemical factors on the hydrolysis kinetics of metamizole sodium in water solutions paaTBopn are well described in a study of 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).
- H. Ergun et al. Charge 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.
- Caffeine is a phosphodiesterase inhibitor and a competitive antagonist of A1 and A2 adenosine receptors. It has the property of potentiating the effect of nonopioid analgesics.
- Drotaverine exercises a spasmolytic and dose-dependent analgesic effect that, in terms of intensity and duration, is comparable to that of metamizole.
- drotaverine The chemical stability of drotaverine is problematic, since in neutral and alkaline environment drotaverine chloride is oxidized to drotaveraldine by a mechanism of oxidizing disintegration, while under the impact of light it is decomposed to perparine and, finally, to perparaldine by hydrogenation of the molecule.
- the chemical stability of solid preparations, including drotaverine hydrochloride is influenced by the tablet carrier, the moisture content of granules and tablets and pH (EP1200088, page 2, line 2 - page 3, line 4). This imposes pH control by including acidic stabilizers into the excipients during tableting. (WO0107024; RU2232018)
- Drotaverine and metamizole are active substances with different profiles of pH stability.
- the method of manufacturing by their combined granulation is unsuccessful, because is initiated process of disintegration and inacceptable increase in the value of impurities is initiated. This creates difficulties in formulating stable combined tablet forms.
- Patent application EP3520781 describes a pharmaceutucal composition, containing in one dosage form metamizole, drotaverine and caffeine, in which metamizole in the composition is in the form of granulate, and drotaverine and caffeine are present outside the afore-mentioned granulate.
- the pharmaceutical composition is in the form of wrapped single-filmed or dual-filmed tablets.
- the method of manufacturing the tablet form includes manufacturing two intermediate products, one of which is granulated metamizole, obtained by wet or dry granulation, and the second one - powder-like mixture of granules of drotaverine and caffeine.
- the two intermediate products are mixed, and then the mixture obtained is tableted.
- a combined tablet form is also known, including metamizole with caffeine and drotaverine, that is available on the market for more than 30 years under the trademark Quarelin or Algopyrin Complex.
- the Quarelin tablets include 400 mg of metamizole sodium monohydrate, 60 mg of caffeine, 40 mg of drotaverine hydrochloride, and excipients: potato starch, microcrystalline cellulose, povidone, talc and magnesium stearate.
- the aim of the current invention is to create a composition of a medicinal product, peroral tablet form, comprising a combination of metamizole sodium monohydrate, caffeine and drotaverine hydrochloride and method of its production that provide the production of a stable tablet form with low content of disintegration products and fast release after intake of the active substances, included in it.
- composition for a tablet form comprising the active substances metamizole sodium monohydrate, caffeine and drotaverine hydrochloride, in which tablet form metamizole and caffeine are included in the composition of a granule, and drotaverine is added to a powder mixture outside the granule.
- the excipients included in the composition of the granule are: corn starch, Kollidon K25 and purified water, the quantitative proportions of the components in weight % relative to the total weight of the tableting mixture being, 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 Kollidon K25.
- the excipients included are microcrystalline cellulose PH102, croscarmellose sodium, anhydrous colloidal silicon dioxide, glycerol dibehenate and magnesium stearate, the quantitative proportions of the components in weight % relative to the total weight of the tableting mixture being, 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 silicon dioxide; from 2,87 to 3,62 glycerol dibehenate and from 1 ,06 to 1 ,16 magnesium stearate.
- the combination of bonding substances used - microcrystalline cellulose plus Kollidon ensures the production of tablets with sufficiently high mechanical strength, and the lubricating system used - a combination of glycerol dibehenate and magnesium stearate, contributes to the problem-free tableting of the mixture.
- the tablet form, subject of the invention is produced by mixing a granule, obtained by granulation of a mixture of metamizole sodium monohydrate, caffeine and corn starch with water solution of Kollidon K25, prepared in advance.
- the moist mixture obtained is sieved through a granulator with mesh size 2.0 mm, the granules are dried in a chamber drier at a temperature of 50 °C to residual moisture of 2 %, and then are sieved through a granulator and are added to the poiserlike mixture, which is obtained by mixing the necessary quantities of drotaverine hydrochloride, microcrystalline cellulose PH 102, croscarmellose sodium and anhydrous silicon dioxide. To the mixture obtained, glycerol dibehenate and magnesium stearate are added in succession.
- the tableting mixture, well homogenized, is tableted on a rotary tableting press.
- composition and method of its production ensure a stable tablet form, with low content of disintegration products from the active substances included therein, which are released quickly after the intake of the tablet.
- Example 1 To produce a tablet for, containing 400 mg of metamizole sodium monohydrate, 60 mg of caffeine and 40 mg of drotaverine hydrochloride, the following components are used:
- Vivasol is trade name of croscarmellose sodium
- Aerosil 200 is trade name of anhydrous silicon dioxide
- Compritol 888 ATO is trade name of glycerol dibehenate, manufactured by Gattefosse
- the method for manufacturing the tablet combined for comprises several phases:
- Kollidon K25 is dissolved in purified water by stirring in for 20 min. Metamizole sodium monohydrate, caffeine and corn starch are loaded in a mixer. The mass is mixed dryly for 5 minutes. The dry mixture obtained is moistened with the bonding solution of Kollidon K25, that is added to the mixture for 5 minutes. The moist granules are sieved through a granulator, equipped with a sieve with mesh size of 2.0 mm. The moist granules are dried in a chamber drier at a temperature of 50 °C and residual moisture of 2 %, and then the dry granules are sieved through a granulator, equipped with a sieve with mesh size of 1 .60 mm.
- drotaverine hydrochloride drotaverine hydrochloride, microcrystalline cellulose PH 102, croscarmellose sodium and Aerosil 200 are mixed in a diffusion mixer for 20 minutes.
- the granules from Phase 1 are added to the obtained dry uniform mixture.
- the mixture is homogenized.
- the lubricating substance glycerol dibehenatea (Compritol 888 ATO) is added and the mixture is homogenized again for 5 min. Finally, magnesium stearate is added and mixing continues for 5 min more.
- the mixture obtained is tableted on a rotary tableting press.
- Example 2 To produce a tablet form in accordance with the invention, containing 400 mg of metamizole sodium monohydrate, 60 mg of caffeine and 40 mg of drotaverine hydrochloride, the following components are used:
- Vivasol is trade name of croscarmellose sodium
- Aerosil 200 is trade name of anhydrous silicon dioxide
- Compritol 888 ATO is trade name of glycerol dibehenate, manufactured by Gattefosse The tablet form was produced by the method, described in Example 1.
- Example 3 Investigation of the stability of the tablet form with composition, according to Example 2.
- the batch of tablets was packed in blisters of transparent colourless PVC/PVdC and aluminium foil (20 ⁇ m) and stability tests were conducted in accelerated conditions - 40 °C/75 % RH for three months.
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- Animal Behavior & Ethology (AREA)
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Abstract
The invention relates to a pharmaceutucal composition in the form of a tablet for peroral application, containing metamizole, drotaverine and caffeine, as well as to a method for its production, which find application in pharmacy and in medical practice for treatment of severe pain of various origin. The tablet is formed from a tableting mixture, containing a granule, including metamizole sodium monohydrate and caffeine and drotaverine, that is added to a powderlike mixture outside of the granule. The composition of the tableting mixture and the method of its production ensure production of a tablet with high stability and with low content of disintegration products of the active substances, included in the tablet, that are released quickly after intake of the tablet.
Description
Pharmaceutical composition in the form of a tablet, comprising metamizole, caffeine and drotaverine and a process for its preparation
FIELD OF THE TECHNOLOGY
The invention relates to a pharmaceutucal composition in the form of a tablet for peroral application, comprising metamizole, drotaverine and caffeine, as well as to a method of its production, that find application in pharmacy and in medical practice.
BACKGROUND
Metamizole, drotaverine and caffeine are the active substances, well known and widely used in medical practice for treatment of severe pain of different origin, such as pains, related to contractile states of the smooth muscles, pains, related to the genitourinary system, pains in intestinal colics, irritable bowel syndrome, cholecystitis and inflammation of the biliary duct.
It is known that metamizole exhibits considerable analgesic, antipyretic and moderate anti-inflammatory effect. It is prescribed for treatment of pain of different origin. The problem with the development of compositions, based on metamizole sodium monohydrate, is its stability in terms of disintegration products. The influence of the physico-chemical factors on the hydrolysis kinetics of metamizole sodium in water solutions paaTBopn are well described in a study of 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). Using a HPLC method for analysis, H. Ergun investigated the kinetics of hydrolysis as a function of concentration, temperature and pH. It is established that in commercial tablet forms, basically, 4-methylaminoantipyrine, impurity C (European Pharmacopoeia) is detected. It is also established that the stability of metamizole can be affected primarily by the temperature and pH of the ambience, the velocity of molecular hydrolysis increasing drastically in acidic solutions, in comparison with more alkaline solutions.
It is known that caffeine has direct analgesic effect on some pain conditions, and it has vasoconstrictive effect on some kinds 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 nonopioid analgesics.
Drotaverine exercises a spasmolytic and dose-dependent analgesic effect that, in terms of intensity and duration, is comparable to that of metamizole. The chemical stability of drotaverine is problematic, since in neutral and alkaline environment drotaverine chloride is oxidized to drotaveraldine by a mechanism of oxidizing disintegration, while under the impact of light it is decomposed to perparine and, finally, to perparaldine by hydrogenation of the molecule. The chemical stability of solid preparations, including drotaverine hydrochloride is influenced by the tablet carrier, the moisture content of granules and tablets and pH (EP1200088, page 2, line 2 - page 3, line 4). This imposes pH control by including acidic stabilizers into the excipients during tableting. (WO0107024; RU2232018)
Drotaverine and metamizole are active substances with different profiles of pH stability. The method of manufacturing by their combined granulation is unsuccessful, because is initiated process of disintegration and inacceptable increase in the value of impurities is initiated. This creates difficulties in formulating stable combined tablet forms.
Methods of stabilization of combined compositions, containing drotaverine and metamizole, are known by preliminary divided granulation and wrapping of granules before preparation of the tableting mixture; by wrapping of the tablet obtained tablet and other techniques. (WO2015089614)
Patent application EP3520781 describes a pharmaceutucal composition, containing in one dosage form metamizole, drotaverine and caffeine, in which metamizole in the composition is in the form of granulate, and drotaverine and caffeine are present outside the afore-mentioned granulate. The pharmaceutical composition is in the form of wrapped single-filmed or dual-filmed tablets.
The method of manufacturing the tablet form includes manufacturing two intermediate products, one of which is granulated metamizole, obtained by wet or dry granulation, and the second one - powder-like mixture of granules of drotaverine and caffeine. The two intermediate products are mixed, and then the mixture obtained is tableted.
A combined tablet form is also known, including metamizole with caffeine and drotaverine, that is available on the market for more than 30 years under the trademark Quarelin or Algopyrin Complex. The Quarelin tablets include 400 mg of metamizole sodium monohydrate, 60 mg of caffeine, 40 mg of drotaverine hydrochloride, and
excipients: potato starch, microcrystalline cellulose, povidone, talc and magnesium stearate.
Disadvantage of this medicinal composition is the high content of impurities - disintegration products of the active components, that increases in the storage process. (EP3520781 , page 13, Table 6, column 2)
The aim of the current invention is to create a composition of a medicinal product, peroral tablet form, comprising a combination of metamizole sodium monohydrate, caffeine and drotaverine hydrochloride and method of its production that provide the production of a stable tablet form with low content of disintegration products and fast release after intake of the active substances, included in it.
SUMMARY OF THE INVENTION
The problem is solved by creating a composition for a tablet form, comprising the active substances metamizole sodium monohydrate, caffeine and drotaverine hydrochloride, in which tablet form metamizole and caffeine are included in the composition of a granule, and drotaverine is added to a powder mixture outside the granule. The excipients included in the composition of the granule are: corn starch, Kollidon K25 and purified water, the quantitative proportions of the components in weight % relative to the total weight of the tableting mixture being, 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 Kollidon K25. In the powderlike mixture, into which drotaverine hydrochloride is added, the excipients included are microcrystalline cellulose PH102, croscarmellose sodium, anhydrous colloidal silicon dioxide, glycerol dibehenate and magnesium stearate, the quantitative proportions of the components in weight % relative to the total weight of the tableting mixture being, 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 silicon dioxide; from 2,87 to 3,62 glycerol dibehenate and from 1 ,06 to 1 ,16 magnesium stearate.
The combination of bonding substances used - microcrystalline cellulose plus Kollidon ensures the production of tablets with sufficiently high mechanical strength, and the lubricating system used - a combination of glycerol dibehenate and magnesium stearate, contributes to the problem-free tableting of the mixture.
The tablet form, subject of the invention, is produced by mixing a granule, obtained by granulation of a mixture of metamizole sodium monohydrate, caffeine and corn starch with water solution of Kollidon K25, prepared in advance. The moist mixture obtained is sieved through a granulator with mesh size 2.0 mm, the granules are dried in a chamber drier at a temperature of 50 °C to residual moisture of 2 %, and then are sieved through a granulator and are added to the powederlike mixture, which is obtained by mixing the necessary quantities of drotaverine hydrochloride, microcrystalline cellulose PH 102, croscarmellose sodium and anhydrous silicon dioxide. To the mixture obtained, glycerol dibehenate and magnesium stearate are added in succession.
The tableting mixture, well homogenized, is tableted on a rotary tableting press.
Advantage of the invention is that the composition and method of its production ensure a stable tablet form, with low content of disintegration products from the active substances included therein, which are released quickly after the intake of the tablet. EXEMPLARY IMPLEMENTATIONS OF THE INVENTION
The invention is illustrated with the following exemplary implementations:
Example 1. To produce a tablet for, containing 400 mg of metamizole sodium monohydrate, 60 mg of caffeine and 40 mg of drotaverine hydrochloride, the following components are used:
Water evaporates in the course of the manufacturing process.
** Vivasol is trade name of croscarmellose sodium
*** Aerosil 200 is trade name of anhydrous silicon dioxide
**** Compritol 888 ATO is trade name of glycerol dibehenate, manufactured by Gattefosse
The method for manufacturing the tablet combined for comprises several phases:
Preparation of granules, containing metamizole sodium monohydrate and caffeine
In a suitable container, Kollidon K25 is dissolved in purified water by stirring in for 20 min. Metamizole sodium monohydrate, caffeine and corn starch are loaded in a mixer. The mass is mixed dryly for 5 minutes. The dry mixture obtained is moistened with the bonding solution of Kollidon K25, that is added to the mixture for 5 minutes. The moist granules are sieved through a granulator, equipped with a sieve with mesh size of 2.0 mm. The moist granules are dried in a chamber drier at a temperature of 50 °C and residual moisture of 2 %, and then the dry granules are sieved through a granulator, equipped with a sieve with mesh size of 1 .60 mm.
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 tableting mixture
The granules from Phase 1 are added to the obtained dry uniform mixture. The mixture is homogenized. The lubricating substance glycerol dibehenatea (Compritol 888 ATO)
is added and the mixture is homogenized again for 5 min. Finally, magnesium stearate is added and mixing continues for 5 min more.
The mixture obtained is tableted on a rotary tableting press.
The tablets produced were analysed and the results of the analysis are presented in the following table:
Table 1. Results for tested physico-chemical parameters
The results of the analysis show that the content of related substances is low.
Example 2. To produce a tablet form in accordance with the invention, containing 400 mg of metamizole sodium monohydrate, 60 mg of caffeine and 40 mg of drotaverine hydrochloride, the following components are used:
Water evaporates in the course of the manufacturing process.
Vivasol is trade name of croscarmellose sodium
Aerosil 200 is trade name of anhydrous silicon dioxide
Compritol 888 ATO is trade name of glycerol dibehenate, manufactured by Gattefosse
The tablet form was produced by the method, described in Example 1.
Example 3. Investigation of the stability of the tablet form with composition, according to Example 2.
The batch of tablets was packed in blisters of transparent colourless PVC/PVdC and aluminium foil (20 μm) and stability tests were conducted in accelerated conditions - 40 °C/75 % RH for three months.
The results are presented in the following table:
Table 2. Results of investigation on the tablet stability by the method of accelerated ageing
Analysis of stability data shows that the product remains stable within the shelf-life, with unchanged physico-chemical properties, low content of disintegration products and disintegratability up to 9,5 MиH.
Claims
1. Pharmaceutucal composition in the form of a tablet, comprising metamizole, drotaverine, caffeine and excipients, wherein the tablet is formed from a tableting mixture, including granules, obtained by wet granulation and composed of metamizole sodium monohydrate, caffeine, corn starch and Kollidon K25, and powder-like mixture, composed of drotaverine hydrochloride, microcrystalline cellulose, croscarmellose sodium, anhydrous colloidal silicon dioxide, glycerol dibehenate and magnesium stearate, the ratio of the components in the tableting mixture in weight %, relative to the weight of the tableting mixture being: 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 Kollidon 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 silicon dioxide; from 2,87 to 3,62 glycerol dibehenate and from 1 ,06 to 1 ,16 magnesium stearate.
2. Method for obtainment of the pharmaceutical composition in the form of a tablet, according to Claim 1 , wherein the tableting mixture is obtained by mixing of a granule, which is obtained by granulation of a mixture of metamizole sodium monohydrate, caffeine and corn starch with water solution of Kollidon K25, prepared in advance, the wet mixture is sieved through a granulator with mesh size of 2.0 mm, the granules are dried in a chamber drier at a temperature of 50 °C to residual moisture not more than 2 %, are sieved through a granulator and are added to a powderlike mixture, which is obtained by mixing the necessary quantities of drotaverine hydrochloride, microcrystalline cellulose PH 102, croscarmellose sodium and anhydrous silicon dioxide, and before tableting, glycerol dibehenate and magnesium stearate are added in succession to the obtained mixture.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG113694 | 2023-04-26 | ||
| BG113694A BG113694A (en) | 2023-04-26 | 2023-04-26 | Pharmaceutical composition in tablet form containing metamizole, caffeine and drotaverine and method of its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024221060A1 true WO2024221060A1 (en) | 2024-10-31 |
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ID=86688476
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/BG2023/000013 Pending WO2024221060A1 (en) | 2023-04-26 | 2023-05-11 | Pharmaceutical composition in the form of a tablet, comprising metamizole, caffeine and drotaverine and a process for its preparation |
Country Status (2)
| Country | Link |
|---|---|
| BG (1) | BG113694A (en) |
| WO (1) | WO2024221060A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001007024A2 (en) | 1999-07-28 | 2001-02-01 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Paracetamol and drotaverine containing composition |
| RU2232018C2 (en) | 2002-10-09 | 2004-07-10 | Открытое акционерное общество "Ирбитский химико-фармацевтический завод" | Spasmolytic medicinal agent |
| WO2015089614A1 (en) | 2013-12-16 | 2015-06-25 | Hypermarcas S.A. | Stable oral pharmaceutical composition |
| EP3520781A1 (en) | 2018-02-05 | 2019-08-07 | Adamed sp. z o.o. | A pharmaceutical composition comprising metamizole, drotaverine, and caffeine |
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2023
- 2023-04-26 BG BG113694A patent/BG113694A/en unknown
- 2023-05-11 WO PCT/BG2023/000013 patent/WO2024221060A1/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001007024A2 (en) | 1999-07-28 | 2001-02-01 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Paracetamol and drotaverine containing composition |
| EP1200088A2 (en) | 1999-07-28 | 2002-05-02 | CHINOIN Gyògyszer és Vegyészeti Termékek Gyára RT. | Paracetamol and drotaverine containing composition |
| RU2232018C2 (en) | 2002-10-09 | 2004-07-10 | Открытое акционерное общество "Ирбитский химико-фармацевтический завод" | Spasmolytic medicinal agent |
| WO2015089614A1 (en) | 2013-12-16 | 2015-06-25 | Hypermarcas S.A. | Stable oral pharmaceutical composition |
| EP3520781A1 (en) | 2018-02-05 | 2019-08-07 | Adamed sp. z o.o. | A pharmaceutical composition comprising metamizole, drotaverine, and caffeine |
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| Title |
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| H. ERGUN ET AL.: "Characterization of the role of physicochemical factors on the hydrolysis of dipyrone", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 35, 28 May 2004 (2004-05-28), pages 479 - 487 |
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| Publication number | Publication date |
|---|---|
| BG113694A (en) | 2024-10-31 |
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