vortioxetine pharmaceutical preparation

Abstract

The nitrosamine impurity SJ003-139 of vortioxetine is declared, this impurity exists in vortioxetine pharmaceutical raw material and pharmaceutical preparation, and the content of this impurity will increase during the preparation and storage of vortioxetine pharmaceutical raw material and pharmaceutical preparation. Therefore, the invention proposes a pharmaceutical preparation (I) with low nitrosamine impurity content. The pharmaceutical preparation of the invention has the advantage of low nitrosamine impurity content, ensuring the safety of drug use for patients.

Description

A vortioxetine pharmaceutical composition and its preparation method and application Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and specifically to a vortioxetine pharmaceutical composition, and in particular to a vortioxetine pharmaceutical composition with a low nitrosamine impurity content, and a preparation method and application thereof. Background Art

[0002] Vortioxetine (also known as vortioxetine) is chemically named 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine, and its English name is Vortioxetine. It is a multi-target antidepressant with both 5-HT3 receptor antagonism and 5-HT1A receptor agonism, and is used to treat major depressive disorder. Currently, the active ingredient in clinical practice is the hydrobromide salt of vortioxetine, which was jointly developed by Takeda Pharmaceuticals and Lundbeck. It was approved for marketing by the FDA on September 30, 2013 under the trade name Brintellix. There are four approved strengths: 5mg, 10mg, 15mg, and 20mg, and the dosage form is a film-coated tablet. The structural formula of vortioxetine is as follows:

[0003] Nitrosamines ((R1)(R2)NN=O) are genotoxic substances, some of which have been listed as possible or potential human carcinogens by the International Agency for Research on Cancer (IARC). The ICH guidelines recommend limiting intake of any known mutagens / carcinogens, including nitrosamines, to levels that pose a negligible risk to human cancer.

[0004] According to the literature Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug-Excipient Incompatibility. Wu, et al. AAPS PharmSciTech, 2011, 12(4), 1248-1263, some commonly used excipients contain -NO 2 , while -NO 2 Vortioxetine contains a piperazine ring, and secondary amines can react with secondary amines to form nitrosamine impurities during compound preparation, formulation preparation, and storage. However, there are currently no reports on controlling the content of nitrosamine impurities in vortioxetine pharmaceutical compositions.

[0005] In view of the toxicity of nitrosamine impurities, there is an urgent need for a vortioxetine pharmaceutical composition that can control the nitrosamine impurity content at a lower level.

[0006] Summary of the Invention

[0007] While researching vortioxetine pharmaceutical compositions, the applicant discovered that a nitrosamine impurity is generated during the preparation process of the vortioxetine API. Furthermore, the content of this nitrosamine impurity increases during the preparation and storage of vortioxetine pharmaceutical compositions, posing a safety risk to patients. Therefore, the present invention provides the structure of this nitrosamine impurity and a method for determining its content in vortioxetine or vortioxetine pharmaceutical compositions. Furthermore, the present invention provides a pharmaceutical composition with a low nitrosamine impurity content and a high safety profile, as well as a preparation method and use of this pharmaceutical composition.

[0008] The present invention is achieved through the following technical solutions:

[0009] In a first aspect of the present invention, a pharmaceutical composition is provided, comprising vortioxetine or a pharmaceutically acceptable salt thereof and a basic excipient, wherein the pharmaceutical composition contains a nitrosamine impurity content of no more than 20 ppm, and the structural formula of the nitrosamine impurity is shown in Formula SJ003-139:

[0010] In some embodiments of the present invention, the alkaline auxiliary material is at least one of trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, calcium phosphate, calcium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide or meglumine, preferably sodium carbonate.

[0011] In some embodiments of the present invention, the pharmaceutical composition further comprises an antioxidant having a phenol structure, butylated hydroxytoluene or butylated hydroxyanisole, preferably butylated hydroxytoluene.

[0012] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no greater than 19 ppm.

[0013] In some embodiments of the present invention, the nitrosamine impurity content of the pharmaceutical composition is no more than 18 ppm.

[0014] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no greater than 17 ppm.

[0015] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no greater than 16 ppm.

[0016] In some embodiments of the present invention, the pharmaceutical composition contains nitrosamine impurities at a content of no greater than 15 ppm.

[0017] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no greater than 14 ppm.

[0018] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no greater than 13 ppm.

[0019] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no more than 12 ppm.

[0020] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no more than 11 ppm.

[0021] In some embodiments of the present invention, the pharmaceutical composition contains nitrosamine impurities at a content of no greater than 10 ppm.

[0022] In some embodiments of the present invention, the pharmaceutical composition contains nitrosamine impurities at a content of no greater than 9 ppm.

[0023] In some embodiments of the present invention, the nitrosamine impurity content of the pharmaceutical composition is no more than 8 ppm.

[0024] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no greater than 7 ppm.

[0025] In some embodiments of the present invention, the pharmaceutical composition has a nitrosamine impurity content of no greater than 6.7 ppm.

[0026] In some embodiments of the present invention, the pharmaceutical composition contains nitrosamine impurities at a content of no greater than 6 ppm.

[0027] In some embodiments of the present invention, the pharmaceutical composition contains nitrosamine impurities at a content of no greater than 5 ppm.

[0028] In some embodiments of the present invention, the pharmaceutical composition contains nitrosamine impurities at a content of no greater than 4 ppm.

[0029] In some embodiments of the present invention, the pharmaceutical composition contains nitrosamine impurities at a content of no greater than 3 ppm.

[0030] In some embodiments of the present invention, the pharmaceutical composition contains nitrosamine impurities at a content of no greater than 2 ppm.

[0031] In some embodiments of the present invention, the pharmaceutical composition further comprises two or more of the following pharmaceutically acceptable excipients: a diluent, a disintegrant, a glidant, and a lubricant, wherein the diluent is selected from one or two of mannitol, sorbitol, xylitol, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, and anhydrous lactose, preferably one or two of mannitol or microcrystalline cellulose, more preferably mannitol;

[0032] The disintegrant is selected from at least two of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, and sodium carboxymethyl starch, preferably cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose;

[0033] The glidant is selected from at least two of talc, gel silicon dioxide, and magnesium silicate, preferably talc and gel silicon dioxide;

[0034] The lubricant is selected from at least one of magnesium stearate, stearic acid, sodium lauryl sulfate, and talc, preferably magnesium stearate;

[0035] Optionally, the pharmaceutical composition further comprises at least one of a flavoring agent and a taste-masking agent, wherein the flavoring agent is selected from at least one of L-menthol, neotame, sodium glutamate, and saccharin, preferably L-menthol or neotame; and the taste-masking agent is selected from at least one of methacrylate aminoalkyl copolymer, polyacrylic resin II, polyacrylic resin III, and polyvinyl acetate phthalate, preferably methacrylate aminoalkyl copolymer.

[0036] In some embodiments of the present invention, the pharmaceutical composition comprises: 10-20% vortioxetine or a pharmaceutically acceptable salt thereof; 0.2-5% alkaline excipient; 0.02-0.1% antioxidant; 30-85% diluent; 1.5-15% disintegrant; 1.0-12% glidant; 0.25-5% lubricant; and 1-25% taste masking agent.

[0037] In some embodiments of the present invention, the pharmaceutical composition comprises 10-20% vortioxetine or a pharmaceutically acceptable salt thereof; 0.2-5% anhydrous sodium carbonate; 0.02-0.1% butylated hydroxytoluene; 30-85% mannitol; 1-5% cross-linked polyvinylpyrrolidone; 0.5-8% cross-linked sodium carboxymethyl cellulose; 1-10% talc; 0.1-1.0% gel silica; 0.25-5% magnesium stearate; and 1-25% aminoalkyl methacrylate copolymer, wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, or hemihydrobromide.

[0038] In some embodiments of the present invention, the pharmaceutical composition is an oral solid preparation, preferably a tablet or granule.

[0039] In some embodiments of the present invention, the pharmaceutical composition is an orally disintegrating tablet.

[0040] In a second aspect of the present invention, there is provided use of the pharmaceutical composition described in the first aspect in the preparation of antidepressant drugs and drugs for treating cognitive impairment.

[0041] The advantages of the present invention are:

[0042] The applicant discovered that since water is inevitably used in the preparation of vortioxetine, and water contains nitrite, vortioxetine can react with nitrite in water to produce nitrosamine impurity SJ003-139. In addition, in the preparation of vortioxetine pharmaceutical compositions, some pharmaceutical excipients (such as anhydrous lactose, microcrystalline cellulose and hydroxypropyl cellulose) also contain -NO 2 The pharmaceutical composition of vortioxetine containing these excipients is prepared and stored in the process of vortioxetine and -NO 2 The present applicant has discovered that adding an alkaline excipient (such as anhydrous sodium carbonate) or an antioxidant to a vortioxetine pharmaceutical composition can inhibit the conversion of the active ingredient vortioxetine into the nitrosamine impurity SJ003-139. The simultaneous addition of an alkaline excipient and an antioxidant is more effective in inhibiting the conversion of the active ingredient vortioxetine into the nitrosamine impurity SJ003-139. This reduces the amount of genotoxic impurities in the drug, thus ensuring medication safety for patients.

[0043] In order to improve the taste or increase the compliance of the tablets of the present invention, one or more flavoring agents selected from L-menthol, neotame, sodium glutamate or saccharin may be optionally added. DETAILED DESCRIPTION

[0044] The above contents of the present invention are further described in detail below through specific embodiments, but this should not be construed as limiting the present invention.

[0045] Examples of diluents in the present invention include mannitol 100SD available from Roquette Freres; microcrystalline cellulose available from Microcellulose Weissenborn GmbH + Co. KG, model PH102, or 112;

[0046] Examples of disintegrants of the present invention include cross-linked polyvinylpyrrolidone XL-10 from Chongqing Steckreidenmeier Material Technology Co., Ltd.;

[0047] Examples of the glidant of the present invention include gel silicon dioxide 244FP from Grace GmbH;

[0048] Examples of the lubricant of the present invention include magnesium stearate available from Beijing Fengli Company.

[0049] The antioxidant "BHT" in the present invention is the abbreviation of butylated hydroxytoluene.

[0050] When detecting impurities in SJ003-139 in the present invention, in addition to measuring the initial impurity content of the tablets, the impurity content of SJ003-139 is measured after the tablets are placed in the commercial packaging or the intended commercial packaging for the number of days for the experiment.

[0051] ppm: parts per million, one part per million, 1ppm is one part per million.

[0052] Reagents or instruments used without manufacturer indication may be commercially available products purchased through regular channels.

[0053] Example 1 Preparation of Nitrosamine Impurity SJ003-139

[0054] Add 2g of vortioxetine and 10ml of ethanol to the reaction flask, add 1.7g of concentrated hydrochloric acid while stirring, and cool to below 30℃; add 10ml of NaNO 2 solution (concentration of 0.5 g / ml); TLC monitored the completion of the reaction, cooled the solid to precipitate, filtered, and vacuum dried to obtain 1.5 g of the target compound.

[0055] 1 H NMR(600MHz,Chloroform-d)δ7.38(d,J=7.8Hz,1H),7.17(s,1H),7.12-7.07(m,1H),7.05(d,J=7.7Hz,1H),7.03-6.99(m,1H),6.96-6.89 (m,1H),6.57(dd,J=7.9,1.3Hz,1H),4.48-4.39(m,2H),4.03(s,2H),3.32-3.23(m,2H),3.04(t,J=5.2Hz,2H),2.37(s,3H),2.34(s,3H).

[0056] Example 2 Preparation of Vortioxetine Hemihydrobromide

[0057] 10 g of vortioxetine and 100 ml of ethyl acetate were added to a reaction flask, and 2.82 g of hydrobromic acid (48% wt) was added under stirring. The mixture was filtered and dried in vacuo to obtain 10.80 g of vortioxetine hemihydrobromide.

[0058] LC-MS analysis conditions:

[0059] Instrument: Shimadzu LC-20ADXR LC with Sciex API 4000 QTrap or equivalent, Agilent Poroshell 120 EC C18, 3.0 mm × 100 mm, 2.7 μm;

[0060] Chromatographic parameters: flow rate: 0.5 mL / min; column temperature: 35°C; sample chamber temperature: 25°C; injection volume: 5 μL; diluent: acetonitrile: water = 60:40 (V / V); mobile phase A: ammonium acetate buffer; mobile phase B: acetonitrile

[0061] Gradient elution program:

[0062] Mass spectrometry operating parameters:

[0063] MRM channels: Multiple reaction monitoring mode parameters

[0064] A sample of vortioxetine hemihydrobromide prepared in this example was prepared with a concentration of 2 mg / ml. After detection using the above-mentioned LC-MS analysis conditions, the SJ003-139 content in the vortioxetine hemihydrobromide prepared in this example was 0.23 ppm.

[0065] Example 3 Preparation of Vortioxetine Hydrobromide

[0066] To the reaction flask, 10.0 g of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine and 100 ml of ethyl acetate were added. The temperature was raised to 60° C., and 5.65 g of aqueous hydrobromic acid solution (48% wt) was added. A large amount of solid gradually precipitated. The temperature was lowered to 0-10° C., filtered, and dried in vacuo to obtain 12.30 g of vortioxetine hydrobromide as a white solid.

[0067] The SJ003-139 content in vortioxetine hydrobromide was determined to be 0.25 ppm by LC-MS / MS. The LC-MS / MS detection conditions were the same as those in Example 2.

[0068] Example 4 Preparation of Vortioxetine Hydrochloride

[0069] To the reaction flask, 10.0 g of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine and 80 ml of ethyl acetate were added. The temperature was raised to 60°C and 3.40 g of concentrated hydrochloric acid was added dropwise. After the addition was completed, a large amount of solid gradually precipitated. The temperature was lowered to 0-10°C, filtered, and dried in vacuo to obtain 10.30 g of vortioxetine hydrochloride as a white solid.

[0070] The content of SJ003-139 in vortioxetine hydrochloride was determined to be 0.28 ppm by LC-MS / MS. The LC-MS / MS detection conditions were the same as those in Example 2.

[0071] Example 5

[0072] Tablet preparation method:

[0073] 1. Preparation of inner granules: Dissolve the taste masking agent and antioxidant in anhydrous ethanol, add the main drug and flow aid under stirring, granulate in a fluidized bed, dry, sieve, and mix to obtain inner granules;

[0074] 2. Preparation of tablets: Mix a diluent, a disintegrant, and an alkaline excipient to obtain a mixture I. Mix the mixture I, a lubricant, and the inner granules obtained in step 1 to obtain a mixture II. Sieve the mixture II to obtain granules, and compress the mixture into tablets to obtain tablets.

[0075] Table 1 Investigation of basic excipients and antioxidants in the formulation of vortioxetine hemihydrobromide tablets

[0076] Table 1 provides the formulations of vortioxetine hemihydrobromide tablets containing anhydrous sodium carbonate, BHT, vitamin C, anhydrous sodium carbonate and BHT, and not containing anhydrous sodium carbonate and BHT. The weight of vortioxetine hemihydrobromide in Table 1 is 20 mg per tablet, calculated based on vortioxetine. The initial tablets of each formulation in Table 1 and the tablets after being stored at 60°C for 10 days were tested. The content of impurity SJ003-139 is shown in Table 2.

[0077] Table 2 Impurity content of tablets No. 1 to No. 5

[0078] “-” in the table means that it does not contain antioxidants and alkaline excipients.

[0079] As can be seen from Table 2, prescription No. 3 contains both BHT and anhydrous sodium carbonate, and the impurity SJ003-139 content is the lowest, at 0.273 ppm; from the impurity content of prescriptions No. 2 and No. 4, it can be seen that the addition of the antioxidant BHT can effectively inhibit or reduce the impurity content. In the case of no BHT addition, the impurity content after being placed at 60°C for 10 days is higher than that of the prescription with BHT; from the impurity content of prescriptions No. 2 and No. 5, it can be seen that the impurity content of BHT as an antioxidant is significantly lower than that of the prescription with vitamin C as an antioxidant, indicating that the use of BHT as an antioxidant in tablets is better than that of vitamin C as an antioxidant in inhibiting the generation of impurities; from prescriptions No. 1 and No. 4, it can be seen that the impurity content of only 1% anhydrous sodium carbonate is significantly lower than that of no antioxidant and no anhydrous sodium carbonate.

[0080] Five batches of No. 3 tablets were placed in their intended commercial packaging at 25°C / 40RH (40% relative humidity) for 32 months, and the SJ003-139 content was detected to be 1.5 to 1.9 ppm. Original unopened Brintellix tablets (manufactured on December 2020) were placed for 32 months, and the SJ003-139 content was detected to be 9.21 ppm. The original Brintellix tablets do not contain anhydrous sodium carbonate and BHT, which also proves that the addition of antioxidants and alkaline excipients can inhibit the formation of SJ003-139.

[0081] The conclusions in Table 2 show that anhydrous sodium carbonate as an alkaline excipient and BHT as an antioxidant can inhibit the formation of impurities in tablets. Compared with adding only one of them, the addition of anhydrous sodium carbonate and BHT to the tablets is more effective in inhibiting the formation of nitrosamine impurities.

[0082] Example 6

[0083] Table 3 Vortioxetine hydrobromide tablets

[0084] Table 3 provides the components of vortioxetine hydrobromide tablets containing anhydrous sodium carbonate, BHT, anhydrous sodium carbonate and BHT, and no anhydrous sodium carbonate and BHT, respectively. The weight of vortioxetine hydrobromide in Table 3 is 20 mg / tablet, calculated based on vortioxetine. The tablets were prepared according to the method for preparing vortioxetine hemihydrobromide tablets in Example 1.

[0085] Table 4 Initial impurity content of tablets No. 6 to No. 9

[0086] Tablets No. 6 to No. 9 were placed at 60°C for 10 days respectively. Among them, the content of impurity SJ003-139 in tablets No. 6 to No. 8 did not exceed 6.7 ppm, while the content of impurity SJ003-139 in tablet No. 9 was 32.577 ppm after being placed at 60°C for 10 days.

[0087] The contents of impurity SJ003-139 in the four tablets in Table 4 indicate that anhydrous sodium carbonate as an alkaline excipient and BHT as an antioxidant can effectively inhibit the formation of impurity SJ003-139 in vortioxetine hydrobromide tablets.

[0088] Example 7

[0089] Table 5 Vortioxetine hydrochloride tablets prescription

[0090] Table 5 provides formulations for vortioxetine hydrochloride tablets containing anhydrous sodium carbonate, BHT, anhydrous sodium carbonate and BHT, and no anhydrous sodium carbonate and BHT, respectively. The weight of vortioxetine hydrochloride in Table 5 is 20 mg / tablet, calculated based on vortioxetine. The tablets were prepared according to the method for preparing vortioxetine hemihydrobromide tablets in Example 1.

[0091] The initial SJ003-139 impurity contents in tablets No. 10 to No. 13 were 1.210 ppm, 1.531 ppm, 0.933 ppm, and 25.711 ppm, respectively. After 10 days at 60°C, the SJ003-139 impurity contents in tablets No. 10 to No. 12 all did not exceed 6.7 ppm, and the SJ003-139 impurity content in tablet No. 13 was 34.731 ppm. The main ingredient in Example 6, vortioxetine hydrobromide, had a relatively higher impurity content than the vortioxetine hydrobromide hemi-salt tablets in Example 5. The main ingredient in this Example, vortioxetine hydrochloride, exhibited a higher SJ003-139 impurity content than the vortioxetine hydrobromide and vortioxetine hemi-hydrobromide tablets.

[0092] Example 8

[0093] Table 6 Prescriptions with vortioxetine hemihydrobromide as the main drug and calcium phosphate as the basic excipient

[0094] After testing, the initial content of SJ003-139 impurity in the No. 14 and No. 15 prescription tablets in Table 6 above was 0.198 ppm and 0.11 ppm, respectively, while the content of impurity SJ003-139 after being placed at 60°C for 10 days was 3.1 ppm and 2.7 ppm, respectively.

[0095] Example 9

[0096] Table 7 Prescriptions with vortioxetine hemihydrobromide as the main drug and sodium acetate as the basic excipient

[0097] Testing revealed that the initial SJ003-139 impurity levels in tablets with prescriptions No. 16, No. 17, and No. 18 in Table 7 were 0.683 ppm, 0.664 ppm, and 0.439 ppm, respectively. After 10 days at 60°C, the SJ003-139 impurity levels were all less than 6.7 ppm. The difference between prescription No. 2 in Table 1 and prescription No. 17 in Table 7 lies in their BHT content. The BHT content in prescription No. 17 is 4-5 times that of prescription No. 2. However, the increased BHT content did not reduce the SJ003-139 impurity content; instead, it showed an upward trend, indicating that a higher antioxidant content is not necessarily better.

[0098] Comparative Example 1: Investigating the impurity content of Brintellix tablets after adding BHT and sodium carbonate

[0099] Table 8 Vortioxetine hydrobromide tablets

[0100] Comparative Examples 1-1, 1-2, and 1-3 in Table 8 represent tablets prepared from the marketed Brintellix tablet formulation, further prepared with anhydrous sodium carbonate and / or BHT. These tablets are compared with Comparative Example 1-4, the original formulation. The impurity content of the initial tablets was measured, revealing that the SJ003-139 impurity content in Comparative Example 1-1 was 1.22 ppm; the SJ003-139 impurity content in Comparative Example 1-2 was 1.18 ppm; the SJ003-139 impurity content in Comparative Example 1-3 was 1.15 ppm; and the SJ003-139 impurity content in Comparative Example 1-4 was 4.0 ppm. The original marketed formulation, prepared without the addition of alkaline excipients and / or antioxidants, exhibited higher SJ003-139 levels than formulations containing alkaline excipients and / or antioxidants, demonstrating that alkaline excipients and / or antioxidants can significantly reduce the nitrosamine impurity content in tablets.

[0101] Comparative Example 2

[0102] Table 9 Tablet formulations of vortioxetine hydrobromide and excipients containing nitrite ions

[0103] In the above table, the content of impurity SJ003-139 in Comparative Example 2-1 is 1.25 ppm; the content of impurity SJ003-139 in Comparative Example 2-2 is 1.20 ppm; the content of impurity SJ003-139 in Comparative Example 2-3 is 1.16 ppm; the content of impurity SJ003-139 in Comparative Example 2-4 is 4.5 ppm. The tablets prepared by replacing vortioxetine hydrobromide in Comparative Example 2-4 with vortioxetine hydrochloride were tested to have an impurity SJ003-139 content of 6.74 ppm.

[0104] The anhydrous lactose, microcrystalline cellulose, and hydroxypropyl cellulose listed in Table 9 are commonly used excipients containing nitrites, as reported in the literature Reactive Impurities in Excipients: Profiling, Identification, and Mitigation of Drug-Excipient Incompatibility. Wu, et al. AAPS PharmSciTech, 2011, 12(4), 1248-1263. The original Brintellix tablets contain microcrystalline cellulose and hydroxypropyl cellulose, both of which are prone to generating nitrosamine impurities. The test results of the content of the four tablets SJ003-139 in Table 9 show that anhydrous sodium carbonate and BHT can inhibit the reaction of nitrites in these three excipients with vortioxetine to generate nitrosamine impurities.

[0105] Equivalent schemes and scope

[0106] The foregoing description has described some non-limiting preferred embodiments of the present invention. Those skilled in the art may make various changes and modifications to this description without departing from the true scope of the present invention as defined by the claims. Such changes and modifications should also be considered as the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises vortioxetine or a pharmaceutically acceptable salt thereof and an alkaline excipient, wherein the nitrosamine impurity content of the pharmaceutical composition is not greater than 20 ppm, and the structural formula of the nitrosamine impurity is shown in Formula SJ003-139:

2. The pharmaceutical composition according to claim 1, characterized in that The alkaline auxiliary material is at least one of trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, calcium phosphate, calcium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide or meglumine, preferably sodium carbonate.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The pharmaceutical composition further comprises butylated hydroxytoluene or butylated hydroxyanisole, an antioxidant having a phenol structure, preferably butylated hydroxytoluene.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The nitrosamine impurity content of the pharmaceutical composition is no more than 19 ppm, no more than 18 ppm, no more than 17 ppm, no more than 16 ppm, no more than 15 ppm, no more than 14 ppm, no more than 13 ppm, no more than 12 ppm, no more than 11 ppm, no more than 10 ppm, no more than 9 ppm, no more than 8 ppm, no more than 7 ppm, no more than 6.7 ppm, no more than 6 ppm, no more than 5 ppm, no more than 4 ppm, no more than 3 ppm, or no more than 2 ppm.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition has a nitrosamine impurity content of no greater than 6.7 ppm, no greater than 6 ppm, no greater than 5 ppm, no greater than 4 ppm, no greater than 3 ppm, or no greater than 2 ppm.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The pharmaceutical composition further comprises two or more of the following pharmaceutically acceptable excipients: a diluent, a disintegrant, a glidant, and a lubricant, wherein The diluent is selected from one or two of mannitol, sorbitol, xylitol, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, and anhydrous lactose, preferably one or two of mannitol or microcrystalline cellulose, more preferably mannitol; The disintegrant is selected from at least two of crospovidone, croscarmelose sodium, and sodium carboxymethyl starch, preferably crospovidone and croscarmelose sodium; The glidant is selected from at least two of talc, gel silicon dioxide, and magnesium silicate, preferably talc and gel silicon dioxide; The lubricant is selected from at least one of magnesium stearate, stearic acid, sodium lauryl sulfate, and talc, preferably magnesium stearate; Optionally, the pharmaceutical composition further comprises at least one of a flavoring agent and a taste masking agent, wherein the flavoring agent is selected from L- At least one of menthol, neotame, sodium glutamate, and saccharin, preferably L-menthol or neotame; the taste masking agent is selected from at least one of methacrylate aminoalkyl copolymer, polyacrylic acid resin II, polyacrylic acid resin III, and polyvinyl acetate phthalate, preferably methacrylate aminoalkyl copolymer.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The pharmaceutical composition comprises: Vortioxetine or its pharmaceutically acceptable salt 10-20%; Alkaline auxiliary material 0.2-5%; Antioxidant 0.02-0.1%; Diluent 30-85%; Disintegrant 1.5-15%; Glidant 1.0-12%; Lubricant 0.25-5%; Taste masking agent 1-25%.

8. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The pharmaceutical composition comprises Vortioxetine or its pharmaceutically acceptable salt 10-20%; Anhydrous sodium carbonate 0.2-5%; Butylated hydroxytoluene 0.02-0.1%; Mannitol 30-85%; Crospovidone 1-5%; Croscarmellose sodium 0.5-8%; Talc 1-10%; Gel silicon dioxide 0.1~1.0%; Magnesium stearate 0.25-5%; Methacrylate amine alkyl copolymer 1-25%; Wherein, the pharmaceutically acceptable salt is hydrochloride, hydrobromide or hemihydrobromide.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that The pharmaceutical composition is an oral solid preparation, preferably a tablet or granule, more preferably an orodisintegrating tablet.

10. Use of the pharmaceutical composition according to claims 1 to 9 in the preparation of antidepressant drugs and drugs for treating cognitive impairment.