EP4651899A1 - Pharmaceutical composition containing vortioxetine - Google Patents

Pharmaceutical composition containing vortioxetine

Info

Publication number
EP4651899A1
EP4651899A1 EP24702669.3A EP24702669A EP4651899A1 EP 4651899 A1 EP4651899 A1 EP 4651899A1 EP 24702669 A EP24702669 A EP 24702669A EP 4651899 A1 EP4651899 A1 EP 4651899A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
ascorbic acid
vortioxetine
composition according
pharmaceutically acceptable
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
EP24702669.3A
Other languages
German (de)
French (fr)
Inventor
Jaroslava SVOBODOVA
Michal Dousa
Petr Mikes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP4651899A1 publication Critical patent/EP4651899A1/en
Pending legal-status Critical Current

Links

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 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.

Landscapes

  • 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)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a pharmaceutical composition containing vortioxetine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further contains ascorbic acid, optionally in a mixture with citric acid. The ascorbic acid, optionally in a mixture with citric acid, reduced the formation of the undesirable N-nitrosovortioxetine derivative during storage.

Description

Pharmaceutical composition containing vortioxetine
Field of Art
The invention relates to a pharmaceutical formulation of vortioxetine.
Background Art
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.
Disclosure of the Invention
Object of the invention is a pharmaceutical composition containing vortioxetine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further contains ascorbic acid.
It was found that ascorbic acid acts as a kinetic competitor of vortioxetine in the reaction with nitrosating agents. Ascorbic acid reacts preferentially with the nitrosating agents and thus prevents or at least reduces the formation of N-nitrosovortioxetine. In some embodiments, 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.
In a preferred embodiment, 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.
Preferably, the pharmaceutical composition of the invention further contains mannitol, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose and magnesium stearate.
More preferably, the pharmaceutical composition of the invention contains:
3 to 10 wt. % of vortioxetine or a pharmaceutically acceptable salt thereof, 0.1 to 3 wt. % of ascorbic acid or a mixture of ascorbic acid and citric acid, 10 to 20 wt. % of microcrystalline cellulose,
1 to 5 wt. % of hydroxypropyl cellulose,
1 to 5 wt. % of sodium starch glycolate,
0.5 to 3 wt. % of magnesium stearate, and the rest up to 100 wt. % is formed by mannitol.
Preferably, 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).
Examples
Example 1
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 amounts below correspond to the percentages by weight of the ingredients:
The agents tested were: ascorbic acid mixture of ascorbic acid and citric acid in the weight ratio 1 : 1 sodium metabisulfite L-histidine chitosan
Furthermore, a formulation without any agent was prepared. The amount corresponding to the agent was replaced by mannitol.
Example 2
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.
The results are shown in the table below, the amount of N-nitrosovortioxetine was measured by liquid chromatography with mass spectrometry detection and is given in ppm.
The results show that ascorbic acid and mixture of ascorbic and citric acids were effective agents. Example 3
In this example, compositions were prepared with different amounts of ascorbic acid and with 1 wt. % citric acid.
The formulations 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. For each part, 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.

Claims

1. A pharmaceutical composition containing vortioxetine or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutical composition further contains ascorbic acid.
2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition further contains citric acid, preferably the weight ratio of ascorbic acid and citric acid is within the range of 2: 1 to 1 :4.
3. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition contains 3 to 10 wt. % of vortioxetine or a pharmaceutically acceptable salt thereof and 0.1 to 3 wt. % of ascorbic acid or of a mixture of ascorbic acid and citric acid.
4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the pharmaceutical composition further contains at least one pharmaceutically acceptable excipient selected from the group of filler, binder, disintegrant and glidant.
5. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the pharmaceutical composition further contains mannitol, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose and magnesium stearate.
6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the pharmaceutical composition contains
3 to 10 wt. % vortioxetine or a pharmaceutically acceptable salt thereof, 0.1 to 3 wt. % ascorbic acid or of a mixture of ascorbic acid and citric acid, 10 to 20 wt. % microcrystalline cellulose,
1 to 5 wt. % hydroxypropyl cellulose,
1 to 5 wt. % sodium starch glycolate,
0.5 to 3 wt. % magnesium stearate, and the balance to 100 wt. % is formed by mannitol.
7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that the pharmaceutical composition is in the form of tablets wrapped in a protective film.
8. The pharmaceutical composition according to claim 7, characterized in that the protective film is a film based on nylon, aluminum and polyvinyl chloride, or a film based on polyvinyl chloride, polyvinylidene chloride and aluminum.
EP24702669.3A 2023-01-17 2024-01-06 Pharmaceutical composition containing vortioxetine Pending EP4651899A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2023-40677U CZ36879U1 (en) 2023-01-17 2023-01-17 A pharmaceutical preparation containing vortioxetine
PCT/CZ2024/050002 WO2024153274A1 (en) 2023-01-17 2024-01-06 Pharmaceutical composition containing vortioxetine

Publications (1)

Publication Number Publication Date
EP4651899A1 true EP4651899A1 (en) 2025-11-26

Family

ID=85384255

Family Applications (1)

Application Number Title Priority Date Filing Date
EP24702669.3A Pending EP4651899A1 (en) 2023-01-17 2024-01-06 Pharmaceutical composition containing vortioxetine

Country Status (3)

Country Link
EP (1) EP4651899A1 (en)
CZ (1) CZ36879U1 (en)
WO (1) WO2024153274A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025132869A1 (en) * 2023-12-21 2025-06-26 H. Lundbeck A/S Method for the preparation of vortioxetine pharmaceutical compositions with low amounts of nitrosamine impurities

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170333424A1 (en) * 2014-10-24 2017-11-23 Hexal Ag Amorphous Vortioxetine Hydrobromide
CN104873458A (en) * 2015-06-24 2015-09-02 万特制药(海南)有限公司 Vortioxetine freeze-dried orally disintegrating tablet and preparation method thereof
CN115212190B (en) * 2021-04-20 2024-08-30 长沙晶易医药科技股份有限公司 Taste-masking vortioxetine oral instant membrane and preparation method thereof

Also Published As

Publication number Publication date
CZ36879U1 (en) 2023-02-24
WO2024153274A1 (en) 2024-07-25

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