Classifications

• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

• the invention relates to a pharmaceutical formulation of vortioxetine.
• Vortioxetine (l-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine) is a medicine used to treat depression in adults.
• Pharmaceutical preparations are formulated as tablets for oral use, and the drug can also be formulated in the form of a pharmaceutically acceptable salt, e.g. hydrobromide (in the preparations Trintellix, Brintellix).
• the vortioxetine molecule contains a secondary amine group and tends to form N-nitroso derivatives with nitrite impurities present in the formulation.
• the presence of nitrosamines in medicines is undesirable because, according to reports from the European Medicines Agency, they are genotoxic substances and potential carcinogens.
• Commercially available preparations may contain amounts of N-nitroso vortioxetine which are significantly higher than the original limit amount of 0.9 ppm which needed to be later increased to 20 ppm.
• the aim of the present invention is thus to provide a pharmaceutical formulation of vortioxetine or a salt thereof in which the formation of N-nitrosovortioxetine would be suppressed as much as possible.
• Object of the invention is a pharmaceutical composition containing vortioxetine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further contains ascorbic acid.
• the pharmaceutical composition may further comprise citric acid.
• the weight ratio of ascorbic acid and citric acid can be within the range of 2: 1 to 1 :4.
• the pharmaceutical preparation contains 3 to 10 wt. % of vortioxetine or a pharmaceutically acceptable salt thereof and 0.1 to 3 wt. % of ascorbic acid or a mixture of ascorbic acid and citric acid.
• a pharmaceutically acceptable salt of vortioxetine may be a salt with a pharmaceutically acceptable organic or inorganic acid. Most preferably, the pharmaceutically acceptable salt is vortioxetine hydrobromide.
• the pharmaceutical preparation may further contain at least one further pharmaceutically acceptable excipient, preferably selected from fillers, binders, disintegrants and glidants.
• the pharmaceutical composition of the invention further contains mannitol, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose and magnesium stearate.
• composition of the invention contains:
• magnesium stearate 0.5 to 3 wt. % of magnesium stearate, and the rest up to 100 wt. % is formed by mannitol.
• the pharmaceutical composition is in the form of tablets, which are preferably packed in a protective film.
• the most preferred protective film is a film based on nylon, aluminium and polyvinyl chloride (OPA/Alu/PVC//Al), but other films can be used, for example films based on polyvinyl chloride, polyvinylidene chloride and aluminium (PVC/PVDC//A1), or based on polyvinyl chloride and aluminium (PVC//A1), or based on polyvinyl chloride, polyethylene, polyvinylidene chloride and aluminium (PVC/PE/PVDC//A1).
• compositions were prepared with vortioxetine and agents for reducing the formation of N- nitroso derivatives.
• the compositions were prepared by wet granulation of the active ingredient, mannitol, microcrystalline cellulose, part of sodium starch glycolate and hydroxypropyl cellulose, the agent being added to the granulation liquid.
• the granulated phase was dried for 2 hours at 30°C and further mixed with a second portion of sodium starch glycolate at 30 rpm for 10 minutes and then with magnesium stearate at 30 rpm for 2 minutes.
• the mixture was then tableted into round tablets with a diameter of 7 mm, the weight of the tablets was 150 mg, the tableting force was 8 kN.
• the agents tested were: ascorbic acid mixture of ascorbic acid and citric acid in the weight ratio 1 : 1 sodium metabisulfite L-histidine chitosan
• Example 1 The compositions prepared in Example 1 were subjected to measurement of N-nitroso vortioxetine content. Each composition was divided into three parts. In the first part, the content of N-nitroso vortioxetine was measured immediately after preparation. The second part was left for 7 days at 60°C and 11% relative humidity (RH), and the third part was left for 7 days at 60°C and 75% relative humidity (RH). The second and third parts were measured after the period of 7 days.
• RH relative humidity
• RH relative humidity
• RH relative humidity
• RH relative humidity
• compositions were prepared with different amounts of ascorbic acid and with 1 wt. % citric acid.
• compositions corresponded to the following composition:
• each formulation was divided into three parts - the first part of tablets was wrapped in OPA25pm_Alu45pm_PVC60pm//Al 25 pm foil, the second part of tablets was wrapped in PVC250pm_PVDC90pm//Al 20pm foil, and the third part of tablets was wrapped in PVC250pm//Al 20pm foil.
• the testing conditions were: 25°C and 60% relative humidity (RH), and 40°C and 75% RH. -9-month storage was tested, and only in the case of the highest content of ascorbic acid, a storage period of 12 months was tested (NA - not measured). The amount of N-nitrosovortioxetine was measured by liquid chromatography with mass spectrometry detection and is reported in ppm.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• General Health & Medical Sciences (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

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Citations (3)

• 2023
  • 2023-01-17 CZ CZ2023-40677U patent/CZ36879U1/cs active IP Right Grant
• 2024
  • 2024-01-06 WO PCT/CZ2024/050002 patent/WO2024153274A1/en active Pending

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