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WO2025051372A1 - Fixed dosage combination of metamizole, caffeine, and chlorpheniramine maleate - Google Patents

Fixed dosage combination of metamizole, caffeine, and chlorpheniramine maleate Download PDF

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Publication number
WO2025051372A1
WO2025051372A1 PCT/EP2023/074678 EP2023074678W WO2025051372A1 WO 2025051372 A1 WO2025051372 A1 WO 2025051372A1 EP 2023074678 W EP2023074678 W EP 2023074678W WO 2025051372 A1 WO2025051372 A1 WO 2025051372A1
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WO
WIPO (PCT)
Prior art keywords
formulation
fixed dosage
metamizole
dosage formulation
caffeine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2023/074678
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French (fr)
Inventor
Luiz Paulo DOS REIS SANTOS
Thais Leme DRUMOND
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Opella Healthcare Group SAS
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Opella Healthcare Group SAS
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Publication date
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Priority to PCT/EP2023/074678 priority Critical patent/WO2025051372A1/en
Publication of WO2025051372A1 publication Critical patent/WO2025051372A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • 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]

Definitions

  • This disclosure relates to a fixed dosage combination containing the active pharmaceutical ingredients metamizole, caffeine, and chlorpheniramine maleate in a single dosage form, such as e.g., a pill.
  • metamizole, caffeine, and chlorpheniramine maleate are currently used to treat symptoms of cold and flu.
  • metamizole, caffeine, and chlorpheniramine maleate are currently provided as multiple pills requiring patients to take at least two pills at a time.
  • a two-pill dosage form is being sold. The first pill contains caffeine and metamizole and the second pill contains chlorpheniramine and metamizole.
  • This disclosure is directed to single dosage formulations of metamizole, caffeine, and chlorpheniramine maleate.
  • metamizole, caffeine, and chlorpheniramine maleate are the only active ingredients.
  • the formulations may contain various amounts of metamizole, caffeine, and chlorpheniramine maleate.
  • the formulation contains at least 65% (w/w) of metamizole, at least 4% (w/w) of caffeine, and at least 0.2% (w/w) of chlorpheniramine maleate.
  • the formulation comprises from about 65% (w/w) to about 75% (w/w) of metamizole, from about 3% (w/w) to about 5% (w/w) of caffeine, and from about 0.05% (w/w) to about 1% (w/w) of chlorpheniramine maleate.
  • the formulation can also contain a variety of other components.
  • the formulation also contains one or more of a disintegrant excipient, an anti- caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent.
  • the formulation includes a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent.
  • the formulation contains one or more of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent, and magnesium stearate.
  • the formulation contains each of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent (e.g., sodium edetate), and magnesium stearate.
  • the formulation includes: from about 1% (w/w) to about 8% (w/w) of HPC; from about 0.5% (w/w) to about 5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w) of a chelating agent; and from about 0.3% (w/w) to about 3% (w/w) of magnesium stearate.
  • the formulation includes: from about 1% (w/w) to about 8% (w/w) of HPC; from about 0.5% (w/w) to about 5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w) of sodium edetate; and from about 0.3% (w/w) to about 3% (w/w) of magnesium stearate.
  • the disclosure is also directed to packages containing the fixed dosage formulation.
  • One embodiment of the disclosure is a blister package containing the fixed dosage formulation (such as e.g., tablets).
  • the fixed dosage formulation is package in a bottle.
  • Another embodiment of the disclosure is directed to use of a fixed dosage formulation of the disclosure for treating cold and/or flu.
  • Another embodiment of the disclosure is use of a fixed dosage formulation of the disclosure in the manufacture of a medicament for treating cold and/or flu.
  • Yet another embodiment is a method of treating a cold and/or flu symptoms comprising administering a fixed dosage formulation of the disclosure to a patient in need thereof.
  • FIG. 1 shows the mean curve plasma concentration of metamizole of a single dosage form of the disclosure containing metamizole, caffeine, and chlorpheniramine compared to the reference drug (two tablets (caffeine and metamizole; caffeine and chlorpheniramine maleate)).
  • FIG. 2 shows the mean curve plasma concentration of chlorpheniramine of a single dosage form of the disclosure containing metamizole, caffeine, and chlorpheniramine compared to the reference drug (two tablets (caffeine and metamizole; caffeine and chlorpheniramine)) .
  • FIG. 3 shows the mean curve plasma concentration of caffeine of a single dosage form of the disclosure containing metamizole, caffeine, and chlorpheniramine compared to the reference drug (two tablets (caffeine and metamizole; caffeine and chlorpheniramine maleate)).
  • This disclosure provides for a single dosage form of metamizole, caffeine, and chlorpheniramine maleate.
  • the combination of these three APIs is beneficial once caffeine potentialize the metamizole action and minimize the drowsiness effect of chlorpheniramine maleate.
  • the single dosage forms of the disclosure provide improved dosage convenience to consumers, lead to a better patient compliance, and potentially reduce misusage and dosage errors (e.g., take only one pill instead of two). Additionally, the production of a single tablet instead of two can bring reduced production cost and energy savings which can bring sustainability appeal.
  • the claimed formulations overcome the challenge of combining three different API into a single formulation.
  • the terms “comprising,” “including,” “containing” and “characterized by” are exchangeable, inclusive, open-ended and do not exclude additional, unrecited elements or method steps. Any recitation herein of the term “comprising,” particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements.
  • the terms “comprising,” “including,” “containing” and “characterized by” are exchangeable, inclusive, open-ended and do not exclude additional, unrecited elements or method steps. Any recitation herein of the term “comprising,” particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements.
  • pill and “tablet” are synonymous and refer to any solid dosage form containing metamizole, caffeine, and chlorpheniramine maleate including capsules.
  • salt(s) thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
  • the salt is a pharmaceutically acceptable salt.
  • salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
  • Salts of interest include, but are not limited to, aluminum, ammonium, arginine, barium, benzathine, calcium, cesium, cholinate, ethylenediamine, lithium, magnesium, meglumine, procaine, N-methylglucamine, piperazine, potassium, sodium, tromethamine, zinc, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, ethanolamine, piperazine, diisopropylamine, diisopropylethylamine, triethylamine and triethanolamine salts.
  • chlorpheniramine maleate refers to the API chlorpheniramine maleate ((Z)-but-2-enedioic acid;3-(4-chlorophenyl)-A,A-dimethyl-3- pyridin-2-ylpropan-l -amine) having the following structure:
  • chlorpheniramine maleate also includes pharmaceutically acceptable salts of chlorpheniramine .
  • a “subject” or “patient,” as used therein, may be a human or non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the subject is a human.
  • Ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (z.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • This disclosure provides for a single fixed dosage formulation containing the active pharmaceutical ingredients metamizole, caffeine, and chlorpheniramine maleate.
  • the metamizole, caffeine, and chlorpheniramine maleate are the only API.
  • metamizole, caffeine, and chlorpheniramine maleate are the only active pharmaceutical ingredient in the fixed dosage formulation (combination).
  • the metamizole is metamizole sodium monohydrate.
  • the fixed dosage formulation contains at least 65% (w/w) of metamizole (metamizole sodium monohydrate), at least 4% (w/w) of caffeine, and at least 0.2% (w/w) of chlorpheniramine maleate.
  • the fixed dosage formulation contains: (a) from about 65% (w/w) to about 75% (w/w), alternatively from about 65% (w/w) to about 70% (w/w), alternatively from about 67% (w/w) to about 70% (w/w) of metamizole (e.g.
  • metamizole sodium monohydrate (b) from about 3% (w/w) to about 5% (w/w), alternatively from about 3.5% (w/w) to about 4.5% (w/w), alternatively from about 3.8% (w/w) to about 4.3% (w/w) of caffeine; and (c) from about 0.05% (w/w) to about 1% (w/w), alternatively from about 0.1% (w/w) to about 0.5% (w/w), alternatively from about 0.15% (w/w) to about 0.35% (w/w) of chlorpheniramine maleate.
  • the fixed dosage formulation also contains additional pharmaceutically acceptable ingredient.
  • the formulation includes one or more of a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent.
  • the formulation includes a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent.
  • the one pharmaceutically acceptable ingredient may have more than one function.
  • the fixed dosage formulation also contains a chelator (e.g., EDTA).
  • the fixed dosage formulation also contains a chelator e.g., EDTA) and one or more of a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, or a flow agent.
  • the formulation also contains one or more of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent (e.g., sodium edetate), and magnesium stearate.
  • HPC hydroxypropyl cellulose
  • crospovidone crospovidone
  • microcrystalline cellulose colloidal silicon dioxide
  • a chelating agent e.g., sodium edetate
  • magnesium stearate e.g., magnesium stearate.
  • the formulation contains from about 1% (w/w) to about 8% (w/w), alternatively from about 2% (w/w) to about 6% (w/w), alternatively from about 3% (w/w) to about 4.5% (w/w) of hydroxypropyl cellulose (HPC). In other embodiments, the formulation contains from about 0.5% (w/w) to about 5% (w/w), alternatively from about 1% (w/w) to about 4% (w/w), alternatively from about 1.5% (w/w) to about 3.5% (w/w) of crospovidone.
  • the formulation contains from about 10% (w/w) to about 20% (w/w), alternatively from about 11% (w/w) to about 19% (w/w), alternatively from about 12% (w/w) to about 16% (w/w) of microcrystalline cellulose. In additional embodiments, the formulation contains from about 0.2% (w/w) to about 3% (w/w), alternatively from about 0.3% (w/w) to about 2% (w/w), alternatively from about 0.5% (w/w) to about 1.5% (w/w) of colloidal silicon dioxide.
  • the formulation contains from about 0.05% (w/w) to about 0.25% (w/w), alternatively from about 0.06% (w/w) to about 0.2% (w/w), alternatively from about 0.07% (w/w) to about 0.15 % (w/w) of a chelating agent (e.g., sodium edetate).
  • a chelating agent e.g., sodium edetate
  • the formulation contains from about 0.05% (w/w) to about 0.25% (w/w), alternatively from about 0.06% (w/w) to about 0.2% (w/w), alternatively from about 0.07% (w/w) to about 0.15 % (w/w) of sodium edetate.
  • the formulation contains from about 0.3% (w/w) to about 3% (w/w), alternatively from about 0.4% (w/w) to about 2% (w/w), alternatively from about 0.8% (w/w) to about 1.7% (w/w) of magnesium stearate.
  • the formulation contains: from about 1% (w/w) to about 8% (w/w), alternatively from about 2% (w/w) to about 6% (w/w), alternatively from about 3% (w/w) to about 4.5% (w/w) of hydroxypropyl cellulose (HPC) from about 0.5% (w/w) to about 5% (w/w), alternatively from about 1% (w/w) to about 4% (w/w), alternatively from about 1.5% (w/w) to about 3.5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w), alternatively from about 11% (w/w) to about 19% (w/w), alternatively from about 12% (w/w) to about 16% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w), alternatively from about 0.3% (w/w) to about 2% (w/w), alternatively from about 0.5% (w/w) to about 2%
  • the formulation contains: from about 1% (w/w) to about 8% (w/w), alternatively from about 2% (w/w) to about 6% (w/w), alternatively from about 3% (w/w) to about 4.5% (w/w) of hydroxypropyl cellulose (HPC) from about 0.5% (w/w) to about 5% (w/w), alternatively from about 1% (w/w) to about 4% (w/w), alternatively from about 1.5% (w/w) to about 3.5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w), alternatively from about 11% (w/w) to about 19% (w/w), alternatively from about 12% (w/w) to about 16% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w), alternatively from about 0.3% (w/w) to about 2% (w/w), alternatively from about 0.5% (w/w) to about 2%
  • the formulation contains: at least 65% (w/w), alternatively from about 65% (w/w) to about 75% (w/w), alternatively from about 65% (w/w) to about 70% (w/w), alternatively from about 67% (w/w) to about 70% (w/w) of metamizole (e.g., metamizole sodium monohydrate); at least 4% (w/w), alternatively from about 3% (w/w) to about 5% (w/w), alternatively from about 3.5% (w/w) to about 4.5% (w/w), alternatively from about 3.8% (w/w) to about 4.3% (w/w) of caffeine; at least 0.2% (w/w), alternatively from about 0.05% (w/w) to about 1% (w/w), alternatively from about 0.1% (w/w) to about 0.5% (w/w), alternatively from about 0.15% (w/w) to about 0.35% (w/w) of chlorpheniramine maleate; from about
  • the formulation contains at least: at least 65% (w/w), alternatively from about 65% (w/w) to about 75% (w/w), alternatively from about 65% (w/w) to about 70% (w/w), alternatively from about 67% (w/w) to about 70% (w/w) of metamizole (e.g., metamizole sodium monohydrate); at least 4% (w/w), alternatively from about 3% (w/w) to about 5% (w/w), alternatively from about 3.5% (w/w) to about 4.5% (w/w), alternatively from about 3.8% (w/w) to about 4.3% (w/w) of caffeine; at least 0.2% (w/w), alternatively from about 0.05% (w/w) to about 1% (w/w), alternatively from about 0.1% (w/w) to about 0.5% (w/w), alternatively from about 0.15% (w/w) to about 0.35% (w/w) of chlorpheniramine maleate;
  • metamizole e.
  • the formulation may contain from about 65% (w/w) to about 75% (w/w) of metamizole, from about 3.5% (w/w) to about 4.5% (w/w) of caffeine, and from about 0.15% to about 0.35% of chlorpheniramine maleate.
  • the single formulation is coated.
  • the single dosage form (formulation) can be coated with from about 2% to about 8% (w/w), alternatively from about 1% to about 5% (w/w), alternative from 3% to about 6% (w/w) of a coating.
  • the formulations do not contain sodium metabisulfite and/or talc.
  • the single dosage formulation is a tablet.
  • the tablet may have a variety of different shapes. In certain embodiments, the tablet is a round.
  • the single dosage formulation is a tablet and the tablet contains about 500 mg of metamizole, 30 mg of caffeine and 2 mg of chlorpheniramine maleate.
  • the tablet is coated.
  • the coating is formulated to reduce moisture uptake and mask against potentially offensive taste and odor.
  • the coating is multi-functional barrier coating system.
  • the coating is a spray coating.
  • kits containing the single dosage forms and instructions for use.
  • the single dosage formulation are packaged in a blister package.
  • formulation is packaged in a container, such as a vial or a bottle.
  • the bottle may include a label with instructions for use.
  • the formulation is a tablet and the tablet is formed through the wet granulation of the three APIs (metamizole, caffeine, and chlorpheniramine maleate).
  • the method include solubilizing one or more of the APIs (e.g.one or more of metamizole, caffeine, and chlorpheniramine maleate) into the binder solution and sprayed onto the other API to compose a single granule. The method assures the desired content uniformity. The method also includes mixing the other ingredients.
  • the disclosure also provides for methods of using the fixed dosage formulations to treat cold and/or flu or a symptom thereof.
  • One of embodiment of the disclosure is use of a fixed dosage formulation disclosed herein for treating cold and/or flu.
  • Another embodiment of the disclosure is use of a fixed dosage formulation disclosed herein in the manufacture of a medicament for treating cold and/or flu.
  • sample preparation and assay setup was also very challenging due to the low dosage of Chlorpheniramine Maleate (2mg) and its impurities in the concentration range (0.25% or 0.005mg). It was necessary to use an extremely concentrated solution of the sample and to select a suitable diluent that did not completely solubilize metamizole to eliminate the largest amount of this active, thus enabling the cleanup of the sample to obtain an adequate chromatogram. The use of agitators, centrifuge and 0.2 pm filtering elements was necessary to obtain an adequate solution for analysis.
  • a tablet containing the APIs metamizole sodium, caffeine, and chlorpheniramine maleate was generated using the protocol shown in Example 1.
  • the tablet also contained hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent (z.e., sodium edetate), and magnesium stearate.
  • HPC hydroxypropyl cellulose
  • crospovidone crospovidone
  • microcrystalline cellulose microcrystalline cellulose
  • colloidal silicon dioxide a chelating agent
  • magnesium stearate magnesium stearate
  • FIG. 1 1, 2 and 3 presents the mean curves of dipyrone, chlorpheniramine and caffeine plasma concentrations (test and reference drugs) versus time, from 51 subjects analyzed, respectively.
  • the testing shown in FIG. 1-3 shows that a fixed dosage formulation of the disclose is bioequivalent to a two-dosage formulation containing the same APIs (each dose containing caffeine and one of the other API).
  • Embodiment 1 A fixed dosage formulation comprising: metamizole; caffeine; and chlorpheniramine maleate.
  • Embodiment 2 The fixed dosage formulation of embodiments 1 or 2, wherein the formulation comprises at least 65% (w/w) of metamizole, at least 4% (w/w) of caffeine, and at least 0.2% (w/w) of chlorpheniramine maleate.
  • Embodiment 3 The fixed dosage formulation of embodiments 1 or 2, wherein the formulation comprises from about 65% (w/w) to about 75% (w/w) of metamizole, from about 3% (w/w) to about 5% (w/w) of caffeine, and from about 0.05% (w/w) to about 1% (w/w) of chlorpheniramine maleate.
  • Embodiment 4 The fixed dosage formulation of any one of embodiments 1 to 3, wherein the formulation comprises one or more of a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent.
  • Embodiment 5 The fixed dosage formulation of any one of embodiments 1 to 3, wherein the formulation comprises one or more of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent, and magnesium stearate.
  • HPC hydroxypropyl cellulose
  • crospovidone crospovidone
  • microcrystalline cellulose microcrystalline cellulose
  • colloidal silicon dioxide a chelating agent
  • magnesium stearate magnesium stearate
  • Embodiment 6 The fixed dosage formulation of embodiments 4 or 5, wherein the formulation comprises a chelating agent.
  • Embodiment 7 The fixed dosage formulation of any one of embodiments 1 to 3, wherein the formulation further comprises hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent, and magnesium stearate.
  • HPC hydroxypropyl cellulose
  • crospovidone crospovidone
  • microcrystalline cellulose microcrystalline cellulose
  • colloidal silicon dioxide a chelating agent
  • magnesium stearate magnesium stearate
  • Embodiment 9 The fixed dosage formulation of embodiment 8, wherein the formulation comprises: from about 1% (w/w) to about 8% (w/w) of HPC; from about 0.5% (w/w) to about 5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w) of a chelating agent; and from about 0.3% (w/w) to about 3% (w/w) of magnesium stearate.
  • Embodiment 10 The fixed dosage formulation of any one of embodiments 4 to
  • Embodiment 11 The fixed dosage formulation of any one of embodiments 1 to 4.
  • metamizole is metamizole sodium monohydrate.
  • Embodiment 12 The fixed dosage formulation of embodiment 11, wherein the formulation does not contain sodium metabisulfite and/or talc.
  • Embodiment 13 The fixed dosage formulation of any one of embodiments 1 to 12, wherein the formulation is a tablet.
  • Embodiment 14 The fixed dosage formulation of embodiment 13, wherein the tablet is coated.
  • Embodiment 15 The fixed dosage formulation of embodiment 14, wherein the coating is a spray coating.
  • Embodiment 16 A blister package comprising the fixed dosage formulation for any one of embodiments 1 to 15.
  • Embodiment 17 The fixed dosage formulation of any one of embodiments 1 to 15, wherein the formulation is packaged in a bottle.
  • Embodiment 18 Use of a fixed dosage formulation of any one of embodiments 1 to 15 for treating cold and/or flu.
  • Embodiment 19 Use of a fixed dosage formulation of any one of embodiments 1 to 15 in the manufacture of a medicament for treating cold and/or flu.
  • Embodiment 20 A method of treating a cold and/or flu symptoms comprising administering a fixed dosage formulation of any one of embodiments 1 to 15 to a patient in need thereof.
  • Embodiment 21 A method of making the fixed dosage formulation of any one of embodiments 12 to 15 comprising solubilizing one or more of metamizole, caffeine, and chlorpheniramine maleate into a binder solution and spraying the solubilized metamizole, caffeine, and/or chlorpheniramine maleate onto one or more granule comprising one or more of metamizole, caffeine, and/or chlorpheniramine maleate.

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Abstract

This disclosure is directed to fixed dosage formulations containing metamizole, caffeine, and chlorpheniramine maleate. The fixed dosage formulations, which may be a tablet, contain one or more of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent (e.g., sodium edetate), and magnesium stearate. The disclosure also includes methods of making such fixed dosage formulation as well as their use to treat cold and/or flu or a symptom thereof.

Description

FIXED DOSAGE COMBINATION OF METAMIZOLE, CAFFEINE, AND CHLORPHENIRAMINE MALEATE
FIELD OF THE INVENTION
[0001] This disclosure relates to a fixed dosage combination containing the active pharmaceutical ingredients metamizole, caffeine, and chlorpheniramine maleate in a single dosage form, such as e.g., a pill.
BACKGROUND OF THE INVENTION
[0002] The combination of metamizole, caffeine, and chlorpheniramine maleate are currently used to treat symptoms of cold and flu. However, there is currently no single dosage form available for this combination. Rather, metamizole, caffeine, and chlorpheniramine maleate are currently provided as multiple pills requiring patients to take at least two pills at a time. Specifically, currently a two-pill dosage form is being sold. The first pill contains caffeine and metamizole and the second pill contains chlorpheniramine and metamizole.
[0003] Not only are such multiple dosages inconvenient to the consumers, but they also increase the potential for misuse and dosage errors. In addition, multiple dosages require additional packaging increasing the transportation cost, and lowering the sustainability aspect.
[0004] What is needed is a single dosage form of metamizole, caffeine, and chlorpheniramine maleate that overcomes these downsides.
SUMMARY OF THE INVENTION
[0005] This disclosure is directed to single dosage formulations of metamizole, caffeine, and chlorpheniramine maleate. In certain embodiments of the formulation metamizole, caffeine, and chlorpheniramine maleate are the only active ingredients.
[0006] The formulations may contain various amounts of metamizole, caffeine, and chlorpheniramine maleate. In one embodiment, the formulation contains at least 65% (w/w) of metamizole, at least 4% (w/w) of caffeine, and at least 0.2% (w/w) of chlorpheniramine maleate. In another embodiment, the formulation comprises from about 65% (w/w) to about 75% (w/w) of metamizole, from about 3% (w/w) to about 5% (w/w) of caffeine, and from about 0.05% (w/w) to about 1% (w/w) of chlorpheniramine maleate.
[0007] The formulation can also contain a variety of other components. In certain embodiments, the formulation also contains one or more of a disintegrant excipient, an anti- caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent. In certain embodiments, the formulation includes a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent. For example, in one embodiment, the formulation contains one or more of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent, and magnesium stearate. In another embodiment, the formulation contains each of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent (e.g., sodium edetate), and magnesium stearate.
[0008] In one embodiment, the formulation includes: from about 1% (w/w) to about 8% (w/w) of HPC; from about 0.5% (w/w) to about 5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w) of a chelating agent; and from about 0.3% (w/w) to about 3% (w/w) of magnesium stearate. In another embodiment, the formulation includes: from about 1% (w/w) to about 8% (w/w) of HPC; from about 0.5% (w/w) to about 5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w) of sodium edetate; and from about 0.3% (w/w) to about 3% (w/w) of magnesium stearate.
[0009] In certain embodiments, the metamizole is metamizole sodium monohydrate. In other embodiments, the formulation does not contain sodium metabisulfite and/or talc. [0010] In one embodiment, the formulation is a tablet. The tablet may be coated and the coating may be a spray coating.
[0011] The disclosure is also directed to packages containing the fixed dosage formulation. One embodiment of the disclosure is a blister package containing the fixed dosage formulation (such as e.g., tablets). In other embodiments, the fixed dosage formulation is package in a bottle.
[0012] Another embodiment of the disclosure is directed to use of a fixed dosage formulation of the disclosure for treating cold and/or flu. Another embodiment of the disclosure is use of a fixed dosage formulation of the disclosure in the manufacture of a medicament for treating cold and/or flu. Yet another embodiment is a method of treating a cold and/or flu symptoms comprising administering a fixed dosage formulation of the disclosure to a patient in need thereof.
[0013] Yet another aspect of the disclosure is a method of making the fixed dosage formulation of the disclosure which includes solubilizing chlorpheniramine maleate into a binder solution and spraying the solubilized chlorpheniramine maleate onto one or more granule comprising metamizole and caffeine.
[0014] Other features and advantages of the invention will be apparent from the detailed description and examples that follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended figures. For the purpose of illustrating the invention, the figures demonstrate embodiments of the present invention. It should be understood, however, that the invention is not limited to the precise arrangements, examples, and instrumentalities shown.
[0016] FIG. 1 shows the mean curve plasma concentration of metamizole of a single dosage form of the disclosure containing metamizole, caffeine, and chlorpheniramine compared to the reference drug (two tablets (caffeine and metamizole; caffeine and chlorpheniramine maleate)).
[0017] FIG. 2 shows the mean curve plasma concentration of chlorpheniramine of a single dosage form of the disclosure containing metamizole, caffeine, and chlorpheniramine compared to the reference drug (two tablets (caffeine and metamizole; caffeine and chlorpheniramine)) .
[0018] FIG. 3 shows the mean curve plasma concentration of caffeine of a single dosage form of the disclosure containing metamizole, caffeine, and chlorpheniramine compared to the reference drug (two tablets (caffeine and metamizole; caffeine and chlorpheniramine maleate)).
DETAILED DESCRIPTION
[0019] This disclosure provides for a single dosage form of metamizole, caffeine, and chlorpheniramine maleate. The combination of these three APIs is beneficial once caffeine potentialize the metamizole action and minimize the drowsiness effect of chlorpheniramine maleate.
[0020] Without being bound by theory, the single dosage forms of the disclosure provide improved dosage convenience to consumers, lead to a better patient compliance, and potentially reduce misusage and dosage errors (e.g., take only one pill instead of two). Additionally, the production of a single tablet instead of two can bring reduced production cost and energy savings which can bring sustainability appeal.
[0021] Furthermore, the claimed formulations overcome the challenge of combining three different API into a single formulation.
[0022] The general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as defined in the appended claims. Other aspects of the present invention will be apparent to those skilled in the art in view of the detailed description of the invention as provided herein.
Definitions
[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods, and materials are now described.
[0024] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.
[0025] It is noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.
[0026] Each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. As used herein, the term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of +.20% or + 10%, more preferably + 5%, even more preferably + 1%, and still more preferably + 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
[0027] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[0028] As used herein, the terms “comprising,” “including,” “containing” and “characterized by” are exchangeable, inclusive, open-ended and do not exclude additional, unrecited elements or method steps. Any recitation herein of the term “comprising,” particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements.
[0029] As used herein, the term “consisting of’ excludes any element, step, or ingredient not specified in the claim element.
[0030] As used herein, the term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of +.20% or + 10%, more preferably + 5%, even more preferably + 1%, and still more preferably + 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
[0031] Before certain embodiments are described in greater detail, it is to be understood that this invention is not limited to certain embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0032] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. [0033] As used herein, the term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of +.20% or + 10%, more preferably + 5%, even more preferably + 1%, and still more preferably + 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
[0034] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[0035] As used herein, the terms “comprising,” “including,” “containing” and “characterized by” are exchangeable, inclusive, open-ended and do not exclude additional, unrecited elements or method steps. Any recitation herein of the term “comprising,” particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements.
[0036] As used herein the terms “pill” and “tablet” are synonymous and refer to any solid dosage form containing metamizole, caffeine, and chlorpheniramine maleate including capsules.
[0037] As used herein, the term “consisting of’ excludes any element, step, or ingredient not specified in the claim element.
[0038] The term “pharmaceutically acceptable salt” means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, and the like. Pharmaceutically acceptable salts of interest include, but are not limited to, aluminum, ammonium, arginine, barium, benzathine, calcium, cholinate, ethylenediamine, lysine, lithium, magnesium, meglumine, procaine, potassium, sodium, tromethamine, N-methylglucamine, N,N '-dibenzylethylenediamine, chloroprocaine, diethanolamine, ethanolamine, piperazine, zinc, diisopropylamine, diisopropylethylamine, triethylamine and triethanolamine salts.
[0039] The term “salt(s) thereof’ means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Preferably, the salt is a pharmaceutically acceptable salt. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt. Salts of interest include, but are not limited to, aluminum, ammonium, arginine, barium, benzathine, calcium, cesium, cholinate, ethylenediamine, lithium, magnesium, meglumine, procaine, N-methylglucamine, piperazine, potassium, sodium, tromethamine, zinc, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, ethanolamine, piperazine, diisopropylamine, diisopropylethylamine, triethylamine and triethanolamine salts.
[0040] As used herein, the term “API” refers to active pharmaceutical ingredient.
[0041] As used herein, the term “metamizole” refers to the API metamizole (dipyrone) having following structure:
Figure imgf000008_0001
The term “metamizole” also includes pharmaceutically acceptable salts of metamizole. [0042] As used herein, the term “chlorpheniramine maleate” refers to the API chlorpheniramine maleate ((Z)-but-2-enedioic acid;3-(4-chlorophenyl)-A,A-dimethyl-3- pyridin-2-ylpropan-l -amine) having the following structure:
Figure imgf000008_0002
The term “chlorpheniramine maleate” also includes pharmaceutically acceptable salts of chlorpheniramine .
[0043] Before certain embodiments are described in greater detail, it is to be understood that this invention is not limited to certain embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0044] A “subject” or “patient,” as used therein, may be a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the subject is a human.
[0045] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
[0046] As used herein, and as well-understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (z.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
[0047] For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into subsections that describe or illustrate certain features, embodiments, or applications of the present invention.
Dosase Forms
[0048] This disclosure provides for a single fixed dosage formulation containing the active pharmaceutical ingredients metamizole, caffeine, and chlorpheniramine maleate. In certain embodiments, the metamizole, caffeine, and chlorpheniramine maleate are the only API. [0049] In certain embodiments, metamizole, caffeine, and chlorpheniramine maleate are the only active pharmaceutical ingredient in the fixed dosage formulation (combination). In other embodiments, the metamizole is metamizole sodium monohydrate.
[0050] In certain embodiments, the fixed dosage formulation contains at least 65% (w/w) of metamizole (metamizole sodium monohydrate), at least 4% (w/w) of caffeine, and at least 0.2% (w/w) of chlorpheniramine maleate. In other embodiments, the fixed dosage formulation contains: (a) from about 65% (w/w) to about 75% (w/w), alternatively from about 65% (w/w) to about 70% (w/w), alternatively from about 67% (w/w) to about 70% (w/w) of metamizole (e.g. metamizole sodium monohydrate); (b) from about 3% (w/w) to about 5% (w/w), alternatively from about 3.5% (w/w) to about 4.5% (w/w), alternatively from about 3.8% (w/w) to about 4.3% (w/w) of caffeine; and (c) from about 0.05% (w/w) to about 1% (w/w), alternatively from about 0.1% (w/w) to about 0.5% (w/w), alternatively from about 0.15% (w/w) to about 0.35% (w/w) of chlorpheniramine maleate.
[0051] The fixed dosage formulation also contains additional pharmaceutically acceptable ingredient. In certain embodiments, the formulation includes one or more of a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent. In certain embodiments, the formulation includes a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent. In certain embodiments, the one pharmaceutically acceptable ingredient may have more than one function.
[0052] In one embodiment, the fixed dosage formulation also contains a chelator (e.g., EDTA). In another embodiment, the fixed dosage formulation also contains a chelator e.g., EDTA) and one or more of a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, or a flow agent.
[0053] In some embodiments, the formulation also contains one or more of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent (e.g., sodium edetate), and magnesium stearate. In other embodiments, the formulation contains each of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent (e.g., sodium edetate), and magnesium stearate.
[0054] In some embodiments, the formulation contains from about 1% (w/w) to about 8% (w/w), alternatively from about 2% (w/w) to about 6% (w/w), alternatively from about 3% (w/w) to about 4.5% (w/w) of hydroxypropyl cellulose (HPC). In other embodiments, the formulation contains from about 0.5% (w/w) to about 5% (w/w), alternatively from about 1% (w/w) to about 4% (w/w), alternatively from about 1.5% (w/w) to about 3.5% (w/w) of crospovidone. In further embodiments, the formulation contains from about 10% (w/w) to about 20% (w/w), alternatively from about 11% (w/w) to about 19% (w/w), alternatively from about 12% (w/w) to about 16% (w/w) of microcrystalline cellulose. In additional embodiments, the formulation contains from about 0.2% (w/w) to about 3% (w/w), alternatively from about 0.3% (w/w) to about 2% (w/w), alternatively from about 0.5% (w/w) to about 1.5% (w/w) of colloidal silicon dioxide. In further embodiments, the formulation contains from about 0.05% (w/w) to about 0.25% (w/w), alternatively from about 0.06% (w/w) to about 0.2% (w/w), alternatively from about 0.07% (w/w) to about 0.15 % (w/w) of a chelating agent (e.g., sodium edetate). In some embodiments, the formulation contains from about 0.05% (w/w) to about 0.25% (w/w), alternatively from about 0.06% (w/w) to about 0.2% (w/w), alternatively from about 0.07% (w/w) to about 0.15 % (w/w) of sodium edetate. In further embodiments, the formulation contains from about 0.3% (w/w) to about 3% (w/w), alternatively from about 0.4% (w/w) to about 2% (w/w), alternatively from about 0.8% (w/w) to about 1.7% (w/w) of magnesium stearate. [0055] In some embodiments, the formulation contains: from about 1% (w/w) to about 8% (w/w), alternatively from about 2% (w/w) to about 6% (w/w), alternatively from about 3% (w/w) to about 4.5% (w/w) of hydroxypropyl cellulose (HPC) from about 0.5% (w/w) to about 5% (w/w), alternatively from about 1% (w/w) to about 4% (w/w), alternatively from about 1.5% (w/w) to about 3.5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w), alternatively from about 11% (w/w) to about 19% (w/w), alternatively from about 12% (w/w) to about 16% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w), alternatively from about 0.3% (w/w) to about 2% (w/w), alternatively from about 0.5% (w/w) to about 1.5% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w), alternatively from about 0.06% (w/w) to about 0.2% (w/w), alternatively from about 0.07% (w/w) to about 0.15 % (w/w) of a chelating agent; and from about 0.3% (w/w) to about 3% (w/w), alternatively from about 0.4% (w/w) to about 2% (w/w), alternatively from about 0.8% (w/w) to about 1.7% (w/w) of magnesium stearate. [0056] In other embodiments, the formulation contains: from about 1% (w/w) to about 8% (w/w), alternatively from about 2% (w/w) to about 6% (w/w), alternatively from about 3% (w/w) to about 4.5% (w/w) of hydroxypropyl cellulose (HPC) from about 0.5% (w/w) to about 5% (w/w), alternatively from about 1% (w/w) to about 4% (w/w), alternatively from about 1.5% (w/w) to about 3.5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w), alternatively from about 11% (w/w) to about 19% (w/w), alternatively from about 12% (w/w) to about 16% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w), alternatively from about 0.3% (w/w) to about 2% (w/w), alternatively from about 0.5% (w/w) to about 1.5% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w), alternatively from about 0.06% (w/w) to about 0.2% (w/w), alternatively from about 0.07% (w/w) to about 0.15 % (w/w) of sodium edetate; and from about 0.3% (w/w) to about 3% (w/w), alternatively from about 0.4% (w/w) to about 2% (w/w), alternatively from about 0.8% (w/w) to about 1.7% (w/w) of magnesium stearate.
[0057] In alternate embodiments, the formulation contains: at least 65% (w/w), alternatively from about 65% (w/w) to about 75% (w/w), alternatively from about 65% (w/w) to about 70% (w/w), alternatively from about 67% (w/w) to about 70% (w/w) of metamizole (e.g., metamizole sodium monohydrate); at least 4% (w/w), alternatively from about 3% (w/w) to about 5% (w/w), alternatively from about 3.5% (w/w) to about 4.5% (w/w), alternatively from about 3.8% (w/w) to about 4.3% (w/w) of caffeine; at least 0.2% (w/w), alternatively from about 0.05% (w/w) to about 1% (w/w), alternatively from about 0.1% (w/w) to about 0.5% (w/w), alternatively from about 0.15% (w/w) to about 0.35% (w/w) of chlorpheniramine maleate; from about 1% (w/w) to about 8% (w/w), alternatively from about 2% (w/w) to about 6% (w/w), alternatively from about 3% (w/w) to about 4.5% (w/w) of hydroxypropyl cellulose (HPC); from about 0.5% (w/w) to about 5% (w/w), alternatively from about 1% (w/w) to about 4% (w/w), alternatively from about 1.5% (w/w) to about 3.5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w), alternatively from about 11% (w/w) to about 19% (w/w), alternatively from about 12% (w/w) to about 16% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w), alternatively from about 0.3% (w/w) to about 2% (w/w), alternatively from about 0.5% (w/w) to about 1.5% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w), alternatively from about 0.06% (w/w) to about 0.2% (w/w), alternatively from about 0.07% (w/w) to about 0.15 % (w/w) of a chelating agent; and from about 0.3% (w/w) to about 3% (w/w), alternatively from about 0.4% (w/w) to about 2% (w/w), alternatively from about 0.8% (w/w) to about 1.7% (w/w) of magnesium stearate.
[0058] In yet alternate embodiments, the formulation contains at least: at least 65% (w/w), alternatively from about 65% (w/w) to about 75% (w/w), alternatively from about 65% (w/w) to about 70% (w/w), alternatively from about 67% (w/w) to about 70% (w/w) of metamizole (e.g., metamizole sodium monohydrate); at least 4% (w/w), alternatively from about 3% (w/w) to about 5% (w/w), alternatively from about 3.5% (w/w) to about 4.5% (w/w), alternatively from about 3.8% (w/w) to about 4.3% (w/w) of caffeine; at least 0.2% (w/w), alternatively from about 0.05% (w/w) to about 1% (w/w), alternatively from about 0.1% (w/w) to about 0.5% (w/w), alternatively from about 0.15% (w/w) to about 0.35% (w/w) of chlorpheniramine maleate; and from about 0.05% (w/w) to about 0.25% (w/w), alternatively from about 0.06% (w/w) to about 0.2% (w/w), alternatively from about 0.07% (w/w) to about 0.15 % (w/w) of a chelating agent e.g., EDTA).
[0059] Other embodiments of the formulations are shown in the table below. Each of the amounts for the ingredients may be combined and used together. For example, the formulation may contain from about 65% (w/w) to about 75% (w/w) of metamizole, from about 3.5% (w/w) to about 4.5% (w/w) of caffeine, and from about 0.15% to about 0.35% of chlorpheniramine maleate.
Figure imgf000014_0001
In addition, in certain embodiments, the single formulation is coated. The single dosage form (formulation) can be coated with from about 2% to about 8% (w/w), alternatively from about 1% to about 5% (w/w), alternative from 3% to about 6% (w/w) of a coating.
[0060] In certain embodiments, the formulations do not contain sodium metabisulfite and/or talc.
[0061] In one embodiment, the single dosage formulation is a tablet. The tablet may have a variety of different shapes. In certain embodiments, the tablet is a round. [0062] In certain embodiments, the single dosage formulation is a tablet and the tablet contains about 500 mg of metamizole, 30 mg of caffeine and 2 mg of chlorpheniramine maleate.
[0063] In certain embodiments, the tablet is coated. In some embodiments, the coating is formulated to reduce moisture uptake and mask against potentially offensive taste and odor. In other embodiments, the coating is multi-functional barrier coating system. In certain embodiments, the coating is a spray coating.
Kits and Packaging
[0064] Other embodiments are directed to kits containing the single dosage forms and instructions for use.
[0065] In certain embodiments of the disclosure, the single dosage formulation are packaged in a blister package. In other embodiments, formulation is packaged in a container, such as a vial or a bottle. The bottle may include a label with instructions for use. Methods of Making
[0066] In certain embodiment the formulation is a tablet and the tablet is formed through the wet granulation of the three APIs (metamizole, caffeine, and chlorpheniramine maleate). The method include solubilizing one or more of the APIs (e.g.one or more of metamizole, caffeine, and chlorpheniramine maleate) into the binder solution and sprayed onto the other API to compose a single granule. The method assures the desired content uniformity. The method also includes mixing the other ingredients.
Methods and uses
[0067] The disclosure also provides for methods of using the fixed dosage formulations to treat cold and/or flu or a symptom thereof. One of embodiment of the disclosure is use of a fixed dosage formulation disclosed herein for treating cold and/or flu. Another embodiment of the disclosure is use of a fixed dosage formulation disclosed herein in the manufacture of a medicament for treating cold and/or flu.
[0068] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples, therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure. Examples
Example 1: Design of Tablets
[0069] A new formulation containing the three APIs metamizole sodium, caffeine, and chlorpheniramine maleate in a single tablet was designed.
Generating the new tablet required overcoming several difficulties. One of the main difficulties that was overcome during formulation development was ensuring content uniformity, in particular for the lowest dosage API (chlorpheniramine maleate). Due to large differences in API concentrations in a single tablet and the physical-chemical differences in API characteristics, achieving the proper content uniformity was challenging.
Analysis of formulations
[0070] A major analytical challenge that arouses when attempting to combine the three APIs into a single tablet was to develop a stability indicating method for the low-dose active (Chlorpheniramine Maleate) in the presence of two high-dose active (metamizole and Caffeine). The impurities of the higher dosage API greatly interfered which Chlorpheniramine Maleate chromatography. Accordingly, it was necessary to perform a design of experiments with more than 300 tests performed to achieve a selective method that met the criteria for analytical validation and forced degradation.
[0071] Furthermore, sample preparation and assay setup was also very challenging due to the low dosage of Chlorpheniramine Maleate (2mg) and its impurities in the concentration range (0.25% or 0.005mg). It was necessary to use an extremely concentrated solution of the sample and to select a suitable diluent that did not completely solubilize metamizole to eliminate the largest amount of this active, thus enabling the cleanup of the sample to obtain an adequate chromatogram. The use of agitators, centrifuge and 0.2 pm filtering elements was necessary to obtain an adequate solution for analysis.
Example 2: Stability studies
[0072] A tablet containing the APIs metamizole sodium, caffeine, and chlorpheniramine maleate was generated using the protocol shown in Example 1. The tablet also contained hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent (z.e., sodium edetate), and magnesium stearate.
[0073] Stability studies were performed for 12-months and showed that the formulation and APIs are stable on accelerated and long-term conditions.
[0074] The table below provides a summary of the stability studies performed on the formulation of Example 1 on accelerated and long-term conditions. The stability testing is shown in Tables 2-1 and Table 2-2 below.
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000018_0001
Example 3 - Bioequivalence
[0075] Bioequivalence studies were done comparing the tablet of the disclosure to a commercially available formulation of a two-tablet embodiment in which one pill contains metamizole sodium and caffeine and the other pill contains metamizole sodium and chlorpheniramine maleate.
[0076] The study confirmed that the current formulation is bioequivalent to the commercially available formulation, once is in accordance with the required specifications and the legislation in force. [0077] The ratio of geometric means, confidence intervals, intra-individual coefficients of variation and test power, referring to parameters Cmax and AUCo-t for metamizole (dipyrone( and caffeine and Cmax and AUC0-72 for chlorpheniramine of test and reference products, appear in the Tables 3-1 to 3-3 below.
Figure imgf000018_0002
Figure imgf000019_0001
Figure imgf000019_0002
[0078] FIG. 1 1, 2 and 3 presents the mean curves of dipyrone, chlorpheniramine and caffeine plasma concentrations (test and reference drugs) versus time, from 51 subjects analyzed, respectively. The testing shown in FIG. 1-3 shows that a fixed dosage formulation of the disclose is bioequivalent to a two-dosage formulation containing the same APIs (each dose containing caffeine and one of the other API).
[0079] While the invention has been described and illustrated herein by references to various specific materials, procedures, and examples, it is understood that the invention is not restricted to the particular combinations of material and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary, only, with the true scope and spirit of the invention being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety. EMBODIMENTS
[0080] The invention provides also the following non-limiting embodiments.
[0081] Embodiment 1. A fixed dosage formulation comprising: metamizole; caffeine; and chlorpheniramine maleate.
[0082] Embodiment 2. The fixed dosage formulation of embodiments 1 or 2, wherein the formulation comprises at least 65% (w/w) of metamizole, at least 4% (w/w) of caffeine, and at least 0.2% (w/w) of chlorpheniramine maleate.
[0083] Embodiment 3. The fixed dosage formulation of embodiments 1 or 2, wherein the formulation comprises from about 65% (w/w) to about 75% (w/w) of metamizole, from about 3% (w/w) to about 5% (w/w) of caffeine, and from about 0.05% (w/w) to about 1% (w/w) of chlorpheniramine maleate.
[0084] Embodiment 4. The fixed dosage formulation of any one of embodiments 1 to 3, wherein the formulation comprises one or more of a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent.
[0085] Embodiment 5. The fixed dosage formulation of any one of embodiments 1 to 3, wherein the formulation comprises one or more of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent, and magnesium stearate.
[0086] Embodiment 6. The fixed dosage formulation of embodiments 4 or 5, wherein the formulation comprises a chelating agent.
[0087] Embodiment 7. The fixed dosage formulation of any one of embodiments 1 to 3, wherein the formulation further comprises hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent, and magnesium stearate.
[0088] Embodiment 8. The fixed dosage formulation of embodiment 7, wherein the formulation comprises: hydroxypropyl cellulose (HPC); crospovidone; microcrystalline cellulose; colloidal silicon dioxide; a chelating agent; and magnesium stearate.
[0089] Embodiment 9. The fixed dosage formulation of embodiment 8, wherein the formulation comprises: from about 1% (w/w) to about 8% (w/w) of HPC; from about 0.5% (w/w) to about 5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w) of a chelating agent; and from about 0.3% (w/w) to about 3% (w/w) of magnesium stearate. [0090] Embodiment 10. The fixed dosage formulation of any one of embodiments 4 to
9, wherein the chelating agent is sodium edetate.
[0091] Embodiment 11. The fixed dosage formulation of any one of embodiments 1 to
10, wherein the metamizole is metamizole sodium monohydrate.
[0092] Embodiment 12. The fixed dosage formulation of embodiment 11, wherein the formulation does not contain sodium metabisulfite and/or talc.
[0093] Embodiment 13. The fixed dosage formulation of any one of embodiments 1 to 12, wherein the formulation is a tablet.
[0094] Embodiment 14. The fixed dosage formulation of embodiment 13, wherein the tablet is coated.
[0095] Embodiment 15. The fixed dosage formulation of embodiment 14, wherein the coating is a spray coating. [0096] Embodiment 16. A blister package comprising the fixed dosage formulation for any one of embodiments 1 to 15.
[0097] Embodiment 17. The fixed dosage formulation of any one of embodiments 1 to 15, wherein the formulation is packaged in a bottle.
[0098] Embodiment 18. Use of a fixed dosage formulation of any one of embodiments 1 to 15 for treating cold and/or flu.
[0099] Embodiment 19. Use of a fixed dosage formulation of any one of embodiments 1 to 15 in the manufacture of a medicament for treating cold and/or flu.
[0100] Embodiment 20. A method of treating a cold and/or flu symptoms comprising administering a fixed dosage formulation of any one of embodiments 1 to 15 to a patient in need thereof.
[0101] Embodiment 21. A method of making the fixed dosage formulation of any one of embodiments 12 to 15 comprising solubilizing one or more of metamizole, caffeine, and chlorpheniramine maleate into a binder solution and spraying the solubilized metamizole, caffeine, and/or chlorpheniramine maleate onto one or more granule comprising one or more of metamizole, caffeine, and/or chlorpheniramine maleate.

Claims

1. A fixed dosage formulation comprising: metamizole; caffeine; and chlorpheniramine maleate.
2. The fixed dosage formulation of claims 1, wherein the formulation comprises at least 65% (w/w) of metamizole, at least 4% (w/w) of caffeine, and at least 0.2% (w/w) of chlorpheniramine maleate.
3. The fixed dosage formulation of claims 1 or 2, wherein the formulation comprises from about 65% (w/w) to about 75% (w/w) of metamizole, from about 3% (w/w) to about 5% (w/w) of caffeine, and from about 0.05% (w/w) to about 1% (w/w) of chlorpheniramine maleate.
4. The fixed dosage formulation of any one of claims 1 to 3, wherein the formulation comprises one or more of a disintegrant excipient, an anti-caking agent, an adsorbent, a disintegrant, glidant, a chelating agent or a flow agent.
5. The fixed dosage formulation of any one of claims 1 to 3, wherein the formulation comprises one or more of hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent, and magnesium stearate.
6. The fixed dosage formulation of claims 4 or 5, wherein the formulation comprises a chelating agent.
7. The fixed dosage formulation of any one of claims 1 to 3, wherein the formulation further comprises hydroxypropyl cellulose (HPC), crospovidone, microcrystalline cellulose, colloidal silicon dioxide, a chelating agent, and magnesium stearate.
8. The fixed dosage formulation of claim 7, wherein the formulation comprises: hydroxypropyl cellulose (HPC); crospovidone; microcrystalline cellulose; colloidal silicon dioxide; a chelating agent; and magnesium stearate.
9. The fixed dosage formulation of claim 8, wherein the formulation comprises: from about 1% (w/w) to about 8% (w/w) of HPC; from about 0.5% (w/w) to about 5% (w/w) of crospovidone; from about 10% (w/w) to about 20% (w/w) of microcrystalline cellulose; from about 0.2% (w/w) to about 3% (w/w) of colloidal silicon dioxide; from about 0.05% (w/w) to about 0.25% (w/w) of a chelating agent; and from about 0.3% (w/w) to about 3% (w/w) of magnesium stearate.
10. The fixed dosage formulation of any one of claims 4 to 9, wherein the chelating agent is sodium edetate.
11. The fixed dosage formulation of any one of claims 1 to 10, wherein the metamizole is metamizole sodium monohydrate.
12. The fixed dosage formulation of claim 11, wherein the formulation does not contain sodium metabisulfite and/or talc.
13. The fixed dosage formulation of any one of claims 1 to 12, wherein the formulation is a tablet.
14. The fixed dosage formulation of claim 13, wherein the tablet is coated.
15. The fixed dosage formulation of claim 14, wherein the coating is a spray coating.
16. A blister package comprising the fixed dosage formulation for any one of claims 1 to 15.
17. The fixed dosage formulation of any one of claims 1 to 15, wherein the formulation is packaged in a bottle.
18. Use of a fixed dosage formulation of any one of claims 1 to 15 for treating cold and/or flu.
19. Use of a fixed dosage formulation of any one of claims 1 to 15 in the manufacture of a medicament for treating cold and/or flu.
20. A method of treating a cold and/or flu symptoms comprising administering a fixed dosage formulation of any one of claims 1 to 15 to a patient in need thereof.
21. A method of making the fixed dosage formulation of any one of claims 12 to 15 comprising solubilizing one or more of metamizole, caffeine, and chlorpheniramine maleate into a binder solution and spraying the solubilized c metamizole, caffeine, and/or chlorpheniramine maleate onto one or more granule comprising metamizole and caffeine.
PCT/EP2023/074678 2023-09-07 2023-09-07 Fixed dosage combination of metamizole, caffeine, and chlorpheniramine maleate Pending WO2025051372A1 (en)

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