Pharmaceutical composition containing vortioxetine

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

[0001] Pharmaceutical composition containing vortioxetine

[0002] Field of Art

[0003] The invention relates to a pharmaceutical formulation of vortioxetine.

[0004] Background Art

[0005] 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).

[0006] 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.

[0007] 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.

[0008] Disclosure of the Invention

[0009] Object of the invention is a pharmaceutical composition containing vortioxetine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further contains ascorbic acid.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] The pharmaceutical preparation may further contain at least one further pharmaceutically acceptable excipient, preferably selected from fillers, binders, disintegrants and glidants.

[0014] Preferably, the pharmaceutical composition of the invention further contains mannitol, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose and magnesium stearate.

[0015] More preferably, the pharmaceutical composition of the invention contains:

[0016] 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,

[0017] 1 to 5 wt. % of hydroxypropyl cellulose,

[0018] 1 to 5 wt. % of sodium starch glycolate,

[0019] 0.5 to 3 wt. % of magnesium stearate, and the rest up to 100 wt. % is formed by mannitol.

[0020] 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).

[0021] Examples

[0022] Example 1

[0023] 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.

[0024] The amounts below correspond to the percentages by weight of the ingredients:

[0025] The agents tested were: ascorbic acid mixture of ascorbic acid and citric acid in the weight ratio 1 : 1 sodium metabisulfite L-histidine chitosan

[0026] Furthermore, a formulation without any agent was prepared. The amount corresponding to the agent was replaced by mannitol.

[0027] Example 2

[0028] 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.

[0029] 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.

[0030] The results show that ascorbic acid and mixture of ascorbic and citric acids were effective agents. Example 3

[0031] In this example, compositions were prepared with different amounts of ascorbic acid and with 1 wt. % citric acid.

[0032] The formulations corresponded to the following composition:

[0033] 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

CLAIMS1. 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 contains3 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.

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