A stable solid dosage form

Abstract

This invention provides a stable solid pharmaceutical composition comprising at least one of vortioxetine or a pharmaceutically acceptable salt thereof, an antioxidant, and / or a basic agent, optionally further comprising one or more pharmaceutically acceptable excipients. The pharmaceutical composition provided by this invention effectively inhibits the increase of nitrosamine impurities in solid dosage forms during storage, while also exhibiting advantages such as minimal impact on related substances, good product storage stability, and similar dissolution characteristics to the reference formulation. This invention also provides a method for preparing the solid dosage form, which is simple to operate and suitable for industrial application.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical formulation technology, specifically relating to a stable solid dosage form, particularly a stable solid dosage form containing vortioxetine or its salt, and a method for preparing the same. Background Technology

[0002] Vortioxetine is a new-generation antidepressant jointly developed by H. Lundbeck A / S of Denmark and Takeda Pharmaceutical of Japan for the treatment of depression and anxiety. Vortioxetine hydrobromide tablets were first approved for marketing in the United States on September 30, 2013, for the treatment of major depressive disorder (MDD), under the brand name Brintellix. ® The dosage form is tablets, with strengths of 5mg, 10mg, and 20mg. The tablets contain vortioxetine hydrobromide as the active ingredient.

[0003] The chemical name of vortioxetine hydrobromide (i.e., vortioxetine hydrobromide) is 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine hydrobromide, and its structural formula is as follows: .

[0004] Example 1e of WO2003 / 029232 discloses vortioxetine in its free base form and discloses it as a compound with SERT activating activity.

[0005] During their research, the inventors discovered that nitrosamine impurities can be generated in the raw materials and formulations of vortioxetine or pharmaceutically acceptable salts. Even when the content of nitrosamine impurities is reduced or controlled within limits during the vortioxetine hydrobromide raw material stage, it is still impossible to avoid the trend of nitrosamine impurity growth in vortioxetine hydrobromide solid dosage forms during storage. This may be due to the formation of nitrosamine impurities in the drug product caused by nitrite, peroxide impurities, formaldehyde impurities, etc. in the excipients, or it may be due to the degradation of the raw material. Because nitrosamine impurities are highly carcinogenic even at extremely low exposure levels, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7(R1) guidance, "Assessing and controlling DNA-reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risks," clearly identifies nitrosamine impurities as substances of "concern."

[0006] Based on ICH M7(R1) and the maximum daily dose of vortioxetine hydrobromide, the limit for nitrosamine impurities in vortioxetine hydrobromide tablets should not exceed 20 ppm. However, no existing literature reports a method for controlling nitrosamine impurities in vortioxetine hydrobromide solid dosage forms during storage. Therefore, there is an urgent need in the art to develop a method for controlling nitrosamine impurities in vortioxetine hydrobromide solid dosage forms to improve their safety, meet regulatory requirements, and benefit patients. Summary of the Invention

[0007] To address the aforementioned problems in the prior art, the present invention aims to provide a stable solid pharmaceutical composition for vortioxetine hydrobromide, preferably a solid dosage form such as tablets or capsules. This pharmaceutical composition can effectively inhibit the growth of nitrosamine impurities in vortioxetine hydrobromide solid dosage forms and can control the nitrosamine impurities in solid dosage forms within the limit range, ensuring the safety of the drug and meeting the quality requirements of regulatory agencies.

[0008] Specifically, this invention provides a stable solid pharmaceutical composition comprising the following components: (a) Vortioxetine or a pharmaceutically acceptable salt thereof, (b) Selected from one or more antioxidants and basic reagents, Optionally, it also includes (c) one or more selected from diluents, adhesives, disintegrants and lubricants; The antioxidant is selected from one or more of the following: ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, ascorbyl palmitate, sodium ascorbate phosphate, magnesium ascorbate phosphate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), di-tert-butylhydroquinone, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium dithionite, potassium metabisulfite, and thymol. The alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.

[0009] In some preferred embodiments, the stable solid pharmaceutical composition wherein component (a) comprises vortioxetine or a pharmaceutically acceptable salt thereof in an amount of 3 to 20% by weight, for example, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 20% by weight, etc., and values ​​between any two numbers, preferably 4 to 5% by weight, or 8 to 9% by weight, or 12 to 13% by weight, etc.; more preferably 4 to 13% by weight; further preferably, component (a) is selected from vortioxetine hydrobromide, preferably in an amount of vortioxetine hydrobromide of 4.2% by weight, 8.3% by weight, 8.5% by weight, 10% by weight, or 12.7% by weight, etc.

[0010] In some preferred embodiments, the stable solid pharmaceutical composition includes component (b) comprising an antioxidant in an amount of 0.001 to 7% by weight, for example, 0.001% by weight, 0.005% by weight, 0.006% by weight, 0.007% by weight, 0.008% by weight, 0.009% by weight, 0.01% by weight, 0.015% by weight, 0.02% by weight, 0.025% by weight, 0.03% by weight, 0.035% by weight, 0.04% by weight, 0.045% by weight, 0.05% by weight, 0.055% by weight, 0.06% by weight, 0.07% by weight, 0.08% by weight, 0.09% by weight, 0%. The amounts are 1% by weight, 0.11% by weight, 0.12% by weight, 0.13% by weight, 0.14% by weight, 0.15% by weight, 0.16% by weight, 0.17% by weight, 0.18% by weight, 0.19% by weight, 0.2% by weight, 0.25% by weight, 0.3% by weight, 0.35% by weight, 0.4% by weight, 0.45% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 1% by weight, 1.5% by weight, 2% by weight, 2.5% by weight, 3% by weight, etc., and any range between two numbers; preferably, the amount of the antioxidant is 0.001 to 3% by weight, or 0.001 to 0.05% by weight, or 0.001 to 0.0% by weight. 2% by weight, or 0.001 to 0.01% by weight, or 0.001 to 0.15% by weight, or 0.001 to 0.25% by weight, or 0.001 to 0.1% by weight, or 0.001 to 0.2% by weight, or 0.005 to 0.02% by weight, or 0.005 to 0.01% by weight, or 0.01 to 0.1% by weight, or 0.01 to 0.2% by weight, or 0.01 to 0.3% by weight, or 0.01 to 0.5% by weight, or 0.01 to 1% by weight, or 0.05 to 0.5% by weight, or 0.05 to 1% by weight, or 0.1 to 0.3% by weight, or 0.1 to 0.5% by weight, or 0.02 to 0.1% by weight, more preferably 0.01 to 0.2% by weight; Preferably, the antioxidant is selected from one or more of the following: ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, ascorbyl palmitate, sodium ascorbate phosphate, magnesium ascorbate phosphate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, sodium bisulfite, and thymol. More preferably, the antioxidant is selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, and sodium sulfite.

[0011] More preferably, the antioxidant is selected from one or more of ascorbic acid, sodium ascorbate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite.

[0012] In some embodiments, the stable solid pharmaceutical composition, wherein component (b) comprises one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, ascorbyl palmitate, sodium ascorbate phosphate, and magnesium ascorbate phosphate, preferably component (b) is an antioxidant comprising one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, ascorbyl palmitate, sodium ascorbate phosphate, and magnesium ascorbate phosphate, wherein the content of the antioxidant is 0.001 to 0.5% by weight, preferably 0.01 to 0.1% by weight, or 0.05 to 0.1% by weight; further preferably component (b) is an antioxidant comprising ascorbic acid or sodium ascorbate, wherein the content of the ascorbic acid or sodium ascorbate is 0.001 to 0.5% by weight, preferably 0.01 to 0.1% by weight, or 0.05 to 0.1% by weight.

[0013] In other embodiments, the stable solid pharmaceutical composition includes component (b) comprising sodium carbonate in an amount of 0.5 to 1.5% by weight, preferably 0.5 to 1.2% by weight.

[0014] In other embodiments, the stable solid pharmaceutical composition wherein component (b) comprises one or more of gallic acid, propyl gallate, or octyl gallate; the total content of one or more of gallic acid, propyl gallate, or octyl gallate is 0.001 to 0.5% by weight, preferably 0.001 to 0.25% by weight, or 0.01 to 0.2% by weight, or 0.001 to 0.15% by weight, or 0.01 to 0.3% by weight, or 0.1 to 0.3% by weight, or 0.01 to 0.25% by weight, or 0.1 to 0.25% by weight.

[0015] In some embodiments, the stable solid pharmaceutical composition, wherein component (b) comprises one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; preferably, the total content of one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite, and sodium thiosulfate is 0.005 to 1.0% by weight, more preferably 0.01 to 0.5% by weight, and more preferably 0.1 to 0.2% by weight.

[0016] In some embodiments, the stable solid pharmaceutical composition includes component (b) comprising one or both of BHT or BHA, wherein the total content of one or both of BHT or BHA is 0.005 to 7% by weight, preferably 0.005 to 0.5% by weight, more preferably 0.02 to 0.1% by weight.

[0017] In some embodiments, the stable solid pharmaceutical composition, wherein component (b) comprises one or both of α-tocopherol or tocopherol acetate, wherein the total content of one or both of α-tocopherol or tocopherol acetate is 0.01 to 0.5% by weight, preferably 0.01 to 0.1% by weight.

[0018] In some embodiments, the stable solid pharmaceutical composition, wherein component (b) comprises one or both of cysteine ​​or cysteine ​​hydrochloride, wherein the total content of the one or both of cysteine ​​or cysteine ​​hydrochloride is 0.001 to 0.1% by weight, preferably 0.01 to 0.05% by weight.

[0019] In some preferred embodiments, the stable solid pharmaceutical composition, wherein component (b) comprises an alkaline reagent in an amount of 0.5 to 2 wt%, for example, 0.1 wt%, 0.5 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, or 2 wt%, or any value between any two numbers. Preferably, the alkaline reagent is in an amount of 0.5 to 2 wt%, or 0.5 to 1.5 wt%. More preferably, the alkaline reagent is sodium carbonate, used in an amount of 0.5 to 1.2 wt%.

[0020] In some preferred embodiments, the stable solid pharmaceutical composition, wherein component (c) comprises a diluent, the diluent being present in an amount of 50-95% by weight, for example, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, 95% by weight, 50-90% by weight, 60-95% by weight, 60-90% by weight, 70-90% by weight, 70-80% by weight, 70-75% by weight, 75-90% by weight, 75-95% by weight, 80-90% by weight, 80-95% by weight, etc., and values ​​between any two numbers, preferably the diluent being present in an amount of 60-90% by weight. More preferably, the diluent is selected from one or more of mannitol, microcrystalline cellulose, lactose, sorbitol, sucrose, starch, and dicalcium phosphate; in a more preferred embodiment, the diluent is selected from one or both of mannitol and microcrystalline cellulose, particularly preferably, the diluent is selected from mannitol and microcrystalline cellulose, wherein when the diluent contains mannitol and microcrystalline cellulose, the content of the mannitol is 10-80% by weight, for example 10%, 20%, 30%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 45-80%, 50% by weight. The mannitol content is preferably 45-75% by weight, and the microcrystalline cellulose content is preferably 10-30% by weight, for example, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30% by weight, for example, 15-30% by weight, more preferably 15-25% by weight, for example, 20-22% by weight.

[0021] In some preferred embodiments, the stable solid pharmaceutical composition, wherein component (c) comprises a binder, the binder being present in an amount of 0.5 to 15 wt%, for example 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, 10 wt%, 10.5 wt%, 11 wt%, 11.5 wt%, 12 wt%, 12.5 wt%, 13 wt%, 13.5 wt%, 14 wt%, 14.5 wt%, 15 wt%, or 1 to 7 wt%, or 1 to 5 wt%, or 1 to 3 wt%, etc., and values ​​between any two numbers, preferably the binder being present in an amount of 1 to 10 wt%, particularly preferably 1 to 7 wt%.

[0022] Further preferably, the adhesive is selected from one or more of hydroxypropyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, and polyvinylpyrrolidone, and particularly preferably, the adhesive is one or more of hydroxypropyl cellulose or polyvinylpyrrolidone.

[0023] In some preferred embodiments, the stable solid pharmaceutical composition, wherein component (c) comprises a disintegrant, the disintegrant being present in an amount of 0.1 to 10 wt%, for example, 0.1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, or 10 wt%, or any value between any two numbers, preferably the disintegrant being present in an amount of 1 to 5 wt%, more preferably 1 to 3 wt%.

[0024] Further preferably, the disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; particularly preferably, the disintegrant is one or more of sodium carboxymethyl starch and crospovidone.

[0025] In some preferred embodiments, the stable solid pharmaceutical composition, wherein component (c) comprises a lubricant, the lubricant being present in a content of 1 to 5% by weight, for example, 1% by weight, 1.5% by weight, 2% by weight, 2.5% by weight, 3% by weight, 3.5% by weight, 4% by weight, 4.5% by weight, or 5% by weight, and any value between any two numbers, preferably the lubricant being present in a content of 1 to 3% by weight.

[0026] Further preferably, the lubricant is selected from one or more of micronized silica gel, magnesium stearate, talc, stearic acid, and sodium stearate fumarate; particularly preferably, the lubricant is one or a mixture of magnesium stearate or micronized silica gel.

[0027] In some preferred embodiments, the stable solid pharmaceutical composition includes component (c) which simultaneously comprises a diluent, a binder, a disintegrant, and a lubricant.

[0028] More preferably, the solid pharmaceutical composition is a tablet, and particularly preferably, the solid pharmaceutical composition is a film-coated tablet.

[0029] In some specific embodiments, a stable solid pharmaceutical composition is provided, comprising the following components: (a) Vortioxetine hydrobromide, wherein the content of vortioxetine hydrobromide is 3-20%, preferably 4-13%; (b) At least one of an antioxidant and an alkaline reagent, wherein the antioxidant is present in an amount of 0.001 to 3% by weight, preferably 0.001 to 0.5% by weight, more preferably 0.01 to 0.2% by weight, even more preferably 0.01 to 0.1% by weight, and / or the alkaline reagent is present in an amount of 0.5 to 2% by weight, preferably 0.5 to 1.5% by weight, more preferably 0.5 to 1.2% by weight; (c) a diluent, a binder, a disintegrant, and a lubricant, wherein the diluent is present in a concentration of 50-95% by weight, preferably 60-90% by weight; the binder is present in a concentration of 0.5-15% by weight, preferably 1-10% by weight; the disintegrant is present in a concentration of 0.1-10% by weight, preferably 1-5% by weight; and the lubricant is present in a concentration of 1-5% by weight, preferably 1-3% by weight. Further preferably, the antioxidant is selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, propyl gallate, gallic acid, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite; the alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. More preferably, the diluent is selected from one or more of mannitol, microcrystalline cellulose, and dicalcium phosphate; The adhesive is selected from one or more of hydroxypropyl cellulose and polyvinylpyrrolidone; The disintegrant is selected from one or more of sodium carboxymethyl starch and crospovidone; The lubricant is selected from one or more of the following: micronized silica gel, magnesium stearate, talc, stearic acid, and sodium stearate fumarate.

[0030] In one specific embodiment, a stable solid pharmaceutical composition is provided, comprising the following components: (a) Vortioxetine or a pharmaceutically acceptable salt thereof, (b) Alkaline reagents, (c) One or more of the following: diluents, adhesives, disintegrants, and lubricants; The alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate; preferably, the alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. The diluent is selected from one or more of mannitol, microcrystalline cellulose, lactose, sorbitol, sucrose, starch, and dicalcium phosphate; and / or, The adhesive is selected from one or more of hydroxypropyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, and polyvinylpyrrolidone; and / or, The disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; and / or, The lubricant is selected from one or more of the following: micronized silica gel, magnesium stearate, talc, stearic acid, and sodium stearate fumarate.

[0031] More preferably, the diluent is selected from one or more of mannitol, microcrystalline cellulose, and dicalcium phosphate; and / or, The adhesive is selected from one or more of hydroxypropyl cellulose and polyvinylpyrrolidone; and / or, The disintegrant is selected from one or more of sodium carboxymethyl starch and crospovidone; and / or The lubricant is selected from one or more of the following: micronized silica gel, magnesium stearate, talc, stearic acid, and sodium stearate fumarate. The amount of the alkaline reagent used is 0.5-2% by weight, preferably 0.5-1.5% by weight, and more preferably 0.5-1.2% by weight; Further, the content of vortioxetine or its pharmaceutically acceptable salts is 3-20%, preferably 4-13%; and / or The diluent content is 50-95% by weight, preferably 60-90% by weight; and / or, The adhesive content is 0.5-15% by weight, preferably 1-10% by weight; and / or, The content of the disintegrant is 0.1-10% by weight, preferably 1-5% by weight; and / or, The lubricant content is 1-5% by weight, preferably 1-3% by weight.

[0032] In a preferred embodiment, a stable solid pharmaceutical composition is provided, comprising the following components: (a) Vortioxetine or a pharmaceutically acceptable salt thereof, wherein the content of said vortioxetine or a pharmaceutically acceptable salt thereof is 4 to 13% by weight, preferably 8 to 9% by weight; (b) at least one of an antioxidant or an alkaline reagent, wherein the antioxidant is present in an amount of 0.001 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.01 to 0.025% by weight, and the alkaline reagent is present in an amount of 0.5 to 1.5% by weight, preferably 0.5 to 1.2% by weight. (c) Diluent, binder, disintegrant, and lubricant; wherein the diluent content is 75-95% by weight, the binder content is 0.5-2% by weight, the disintegrant content is 2-5% by weight, and the lubricant content is 1-1.5% by weight. Further preferred, component (a) is selected from vortioxetine hydrobromide; Further preferably, component (b) is selected from antioxidants, or alkaline reagents, or a mixture of antioxidants and alkaline reagents; wherein the antioxidant is selected from ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, ascorbyl palmitate, sodium ascorbate phosphate, magnesium ascorbate phosphate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, and sulfite. The antioxidant is selected from one or more of sodium carbonate, sodium bisulfite, and thymol; more preferably, the antioxidant is selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, and sodium sulfite; the alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate. Preferably, component (b) is an antioxidant selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, propyl gallate, gallic acid, cysteine, and cysteine ​​hydrochloride, or component (b) is an alkaline reagent selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate. More preferably, the diluent is selected from one or more of mannitol, microcrystalline cellulose, lactose, and sorbitol; The adhesive is selected from one or more of hydroxypropyl cellulose, sodium carboxymethyl cellulose, or methyl cellulose; The disintegrant is selected from one or more of sodium carboxymethyl starch or croscarmellose sodium; The lubricant is selected from one or more of micronized silica gel, magnesium stearate, talc, or stearic acid.

[0033] In some preferred embodiments, a stable solid pharmaceutical composition is provided, comprising the following components: (a) Vortioxetine or a pharmaceutically acceptable salt thereof, wherein the content of said vortioxetine or a pharmaceutically acceptable salt thereof is 4 to 13% by weight, preferably 8 to 9% by weight; (b) An antioxidant selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite, or an alkaline reagent selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate; wherein the antioxidant content is 0.001 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.01 to 0.2% by weight, and the alkaline reagent content is 0.5 to 1.5% by weight, preferably 0.5 to 1.2% by weight. Preferably, component (b) is one or more antioxidants selected from ascorbic acid, sodium ascorbate, isoascorbic acid, and sodium isoascorbate, and the content of the antioxidant is 0.01~0.1% by weight; or, component (b) is selected from cysteine ​​or cysteine ​​hydrochloride, and the content of the antioxidant is 0.01~0.05% by weight; or, component (b) is selected from propyl gallate or gallic acid, and the content of the antioxidant is 0.1~0.25% by weight. (c) Mannitol and microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, and magnesium stearate, wherein the mannitol content is 45-75% by weight, the microcrystalline cellulose content is 15-30% by weight, the hydroxypropyl cellulose content is 1-10% by weight, preferably 1-7% by weight, the sodium carboxymethyl starch content is 1-5% by weight, preferably 2-4% by weight, and the magnesium stearate content is 1-3% by weight, preferably 1-1.5% by weight.

[0034] In a preferred embodiment, a stable solid pharmaceutical composition is provided, comprising the following components: (a) Vortioxetine or a pharmaceutically acceptable salt thereof, wherein the content of said vortioxetine or a pharmaceutically acceptable salt thereof is 4 to 13% by weight, preferably 8 to 9% by weight; (b) An antioxidant selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite, or an alkaline reagent selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate; wherein the antioxidant content is 0.001 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.01 to 0.2% by weight, and the alkaline reagent content is 0.5 to 1.2% by weight. Further preferably, component (b) is one or more antioxidants selected from ascorbic acid, sodium ascorbate, isoascorbic acid, and sodium isoascorbate, wherein the content of the antioxidant is 0.01~0.1% by weight; or, component (b) is selected from cysteine ​​or cysteine ​​hydrochloride, wherein the content of the antioxidant is 0.01~0.05% by weight; or, component (b) is selected from propyl gallate or gallic acid, wherein the content of the antioxidant is 0.1~0.25% by weight. (c) Mannitol and microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate and micronized silica, wherein the mannitol content is 45-75% by weight, the microcrystalline cellulose content is 15-30% by weight, the hydroxypropyl cellulose content is 1-5% by weight, the sodium carboxymethyl starch content is 1-5% by weight, the magnesium stearate content is 0.5-3% by weight, and the micronized silica content is 1-3% by weight.

[0035] In a preferred embodiment, a stable solid pharmaceutical composition is provided, comprising the following components: (a) Vortioxetine or a pharmaceutically acceptable salt thereof, wherein the content of said vortioxetine or a pharmaceutically acceptable salt thereof is 4 to 13% by weight, preferably 8 to 9% by weight; (b) An antioxidant selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite, or an alkaline reagent selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate; wherein the antioxidant content is 0.05-1% by weight, preferably 0.01-0.5% by weight, more preferably 0.01-0.2% by weight, and the alkaline reagent content is 0.5-1.2%; Further preferably, component (b) is one or more antioxidants selected from ascorbic acid, sodium ascorbate, isoascorbic acid, and sodium isoascorbate, wherein the content of the antioxidant is 0.01~0.1% by weight; or, component (b) is selected from cysteine ​​or cysteine ​​hydrochloride, wherein the content of the antioxidant is 0.01~0.05% by weight; or, component (b) is selected from propyl gallate or gallic acid, wherein the content of the antioxidant is 0.1~0.25% by weight. (c) Mannitol and microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, and magnesium stearate, wherein the mannitol content is 60-70% by weight, the microcrystalline cellulose content is 15-25% by weight, the hydroxypropyl cellulose content is 1-2% by weight, the sodium carboxymethyl starch content is 2-4% by weight, and the magnesium stearate content is 1-1.5% by weight.

[0036] In some embodiments, a stable solid pharmaceutical composition comprising vortioxetine hydrobromide is provided, comprising the following components: (a) Vortioxetine hydrobromide, wherein the content of vortioxetine hydrobromide is 8-13% by weight; (b) An antioxidant selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, propyl gallate, gallic acid, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite; or an alkaline reagent selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; wherein the antioxidant content is 0.001~1% by weight, preferably 0.01~0.2% by weight, more preferably 0.01~0.1% by weight, and the alkaline reagent content is 0.5~1.2% by weight. Further preferably, component (b) is one or more antioxidants selected from ascorbic acid, sodium ascorbate, isoascorbic acid, and sodium isoascorbate, and the content of the antioxidant is 0.01~0.1% by weight; or, component (b) is selected from cysteine ​​or cysteine ​​hydrochloride, and the content of the antioxidant is 0.01~0.05% by weight; or, component (b) is selected from propyl gallate or gallic acid, and the content of the antioxidant is 0.1~0.25% by weight; (c) diluent, binder, disintegrant, and lubricant, wherein the diluent content is 75~95% by weight, preferably 80~90% by weight; the binder content is 0.5~2% by weight, preferably 1~2% by weight; the disintegrant content is 2~5% by weight, preferably 2~4% by weight; and the lubricant content is 1~1.5% by weight. The weight percentages mentioned are relative to the total weight of (a), (b) and (c); The diluent is selected from one or more of mannitol, microcrystalline cellulose, lactose, and sorbitol; preferably, the diluent is one or two of mannitol and microcrystalline cellulose; more preferably, the diluent is mannitol and microcrystalline cellulose; even more preferably, the mannitol content is 60-70% by weight, for example 65-70% by weight; and the microcrystalline cellulose content is 15-25% by weight, preferably 19-21% by weight.

[0037] The binder is selected from one or more of hydroxypropyl cellulose, sodium carboxymethyl cellulose, and methylcellulose; preferably, the binder is selected from hydroxypropyl cellulose. The binder affects one or more properties of the particles during wet granulation, such as flowability, handling, strength, resistance to separation, dust content, appearance, solubility, compressibility, or drug release. In the technical solution provided by this invention, the inventors have found that when the binder content is 0.5-2% by weight, the performance of the drug composition (such as particle shape, flowability, tablet dissolution behavior, and ease of preparation) is optimal, and the dissolution behavior is closest to that of the reference formulation. Conversely, when the binder content is too high, in addition to sticking and tumbling, the dissolution rate is also too fast. Further, when the solid drug composition is wet-granulated, the binder hydroxypropyl cellulose is used in an aqueous solution with a concentration of 7-9% by weight, preferably 8% by weight, during the wet granulation process.

[0038] The disintegrant is selected from one or more of sodium carboxymethyl starch and croscarmellose sodium; preferably, the disintegrant is selected from sodium carboxymethyl starch; more preferably, the content of the disintegrant is 2.5-3% by weight. The lubricant is selected from one or more of micronized silica gel, magnesium stearate, talc, and stearic acid; preferably, the lubricant is selected from one or two of micronized silica gel or magnesium stearate, more preferably, the lubricant is magnesium stearate; even more preferably, the lubricant content is 0.5~1.0 by weight.

[0039] In a preferred embodiment, a stable solid pharmaceutical composition comprising vortioxetine hydrobromide is provided, comprising the following components: (a) Vortioxetine hydrobromide, wherein the content of vortioxetine hydrobromide is 8.47% by weight; (b) An antioxidant selected from one or more of ascorbic acid, α-tocopherol, propyl gallate, gallic acid, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite; wherein the antioxidant content is 0.001 to 0.5% by weight, preferably 0.01 to 0.2% by weight; Further preferably, component (b) is an antioxidant selected from ascorbic acid, and the content of the antioxidant is 0.01~0.1% by weight; or, component (b) is selected from cysteine ​​or cysteine ​​hydrochloride, and the content of the antioxidant is 0.01~0.05% by weight; or, component (b) is selected from propyl gallate or gallic acid, and the content of the antioxidant is 0.1~0.25% by weight. (c) Mannitol, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate; wherein the content of mannitol is 60-65% by weight, the content of microcrystalline cellulose is 20-21% by weight, the content of hydroxypropyl cellulose is 1.5-2.0% by weight, the content of sodium carboxymethyl starch is 2.5-3% by weight, and the content of magnesium stearate is 0.5-1.0% by weight. The weight percentages mentioned are relative to the total weight of (a), (b) and (c).

[0040] Preferably, the pharmaceutical composition uses ascorbic acid as an antioxidant at a content of 0.01 to 0.1% by weight; or uses propyl gallate as an antioxidant at a content of 0.1 to 0.25% by weight, particularly 0.1 to 0.2% by weight; or uses α-tocopherol as an antioxidant at a content of 0.1 to 0.5% by weight; or uses cysteine ​​hydrochloride as an antioxidant at a content of 0.01 to 0.05% by weight.

[0041] In one embodiment, the solid pharmaceutical composition of the present invention is placed at 40°C±2°C and 75%±5%RH for at least one month, preferably at least three months, and the nitrosamine impurities in the pharmaceutical composition are controlled at a level of ≤20ppm. Further preferably, the content of oxidative impurities and the maximum unknown single impurity in the pharmaceutical composition is within the limit range of ≤0.2%, and the total impurities are within the limit range of ≤1.0%. Further preferably, the nitrosamine impurity is N-nitrosovothioxine.

[0042] Further preferably, the solid pharmaceutical composition of the present invention is suitable for use under the following conditions: high temperature (60℃±2℃), high humidity (25±2℃ / 75%±5%RH), and light irradiation (total illuminance of the light source not less than 1.2). 10 6 Lux.hr, near-ultraviolet lamp energy not less than 200w.hr / m 2The pharmaceutical composition is placed under the following conditions for 1 month, and / or under accelerated testing conditions of 40℃±2℃ and 75%±5%RH for at least 1 month, preferably at least 3 months, or 6 months, wherein the nitrosamine impurities in the pharmaceutical composition are controlled at ≤20ppm; and the content of oxidative impurities and the maximum unknown single impurity in the pharmaceutical composition are both within the limit range of ≤0.2%, and the total impurities are within the limit range of ≤1.0%.

[0043] In one embodiment, the solid pharmaceutical composition of the present invention is a tablet, film-coated granules, or capsule, etc.; preferably, the solid pharmaceutical composition is a tablet, which can be coated to obtain a film-coated tablet. Sustained-release coating includes polymer coating, such as ethyl cellulose, cellulose acetate, and cellulose acetate butyrate. The polymer can be used in the form of a solution in an organic solvent, an aqueous dispersion, or a latex. The coating operation can be performed in standard equipment, such as a fluidized bed coater or a rotating bed coater. The capsule has a shell including a membrane that causes a delay in the release of the active ingredient. In one embodiment, preferably, the delayed-release film-coated tablet utilizes pH-sensitive coating to achieve the delay. In particular, at a pH simulating a gastric fluid environment, the coating remains substantially intact, for example, it does not dissolve or disintegrate, thereby substantially preventing the release of the active ingredient. Furthermore, at a pH simulating an intestinal fluid environment (e.g., the small intestine), the coating disintegrates or dissolves (or a similar phenomenon), releasing the active pharmaceutical ingredient.

[0044] The solid pharmaceutical composition of the present invention is coated with a pH-sensitive coating, so that vortioxetine hydrobromide is released essentially only in the small intestine. This coating is called an enteric coating. Such coating materials include, for example, acrylic acid and acrylate copolymers, polymethacrylic acid and its esters, and polymethacrylic acid copolymers. This type of enteric coating is commercially available (e.g., under the trade name Eudragit). Suitable products of the present invention include Eudragit L (which comprises a methacrylic acid-ethyl acrylate copolymer (1:1)) and Eudragit S (which comprises a methacrylic acid-ethyl acrylate copolymer (1:2)). Eudragit L dissolves at approximately pH 5.5, and Eudragit S dissolves at approximately pH 7. Thus, by applying the pure form of the Eudragit polymer or a mixture thereof, the release segment in the intestine can be controlled.

[0045] In some preferred embodiments, the coating material is a gastrointestinal film coating material, which typically consists mainly of hydroxypropyl methylcellulose, plasticizers, and colorants. In a preferred embodiment, the coating material of this invention is a coating premix comprising hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and iron oxide yellow. Such coating materials are available, for example, from Calex, such as the 03B22082-CN film coating premix provided by Calex.

[0046] In one embodiment, the present invention provides coated tablets comprising the stable solid pharmaceutical composition described herein, for example, by compressing the stable solid pharmaceutical composition into uncoated tablets (also called "tablet cores"), and then coating the resulting uncoated tablets with a suitable coating material, for example, by spraying a solution containing the coating material onto the uncoated tablets. The coating operation can be performed in standard equipment, such as a fluidized bed coater or a rotary bed coater. The coating material is a gastrointestinal film-coating premix comprising a mixture of hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and iron oxide yellow, such as the 03B22082-CN film-coating premix provided by Calcon.

[0047] In a second aspect, the present invention also provides a method for preparing the pharmaceutical composition, the method comprising any one of direct powder compression, dry granulation, or wet granulation.

[0048] The powder direct compression method includes the following steps: mixing a prescribed amount of vortioxetine or its pharmaceutically acceptable salt, diluent, disintegrant, antioxidant and / or alkaline reagent evenly, then adding a lubricant and mixing evenly before directly compressing into tablets. Preferably, it also includes a step of coating after tableting.

[0049] The dry granulation process includes: uniformly mixing a prescribed amount of vortioxetine or its pharmaceutically acceptable salt, diluent, binder, disintegrant, antioxidant and / or alkaline reagent, then adding it to a dry granulator for granulation, mixing the granules obtained by dry granulation with a lubricant such as magnesium stearate, and then compressing the mixture into tablets. Preferably, the process further includes a coating step after tableting.

[0050] The coating step, for example, involves uniformly dispersing the Opadry film-coating premix in water as a dispersion system and coating it using a high-efficiency coating machine to obtain vortioxetine or its pharmaceutically acceptable salt film-coated tablets.

[0051] The preferred method is wet granulation, particularly compressing a stable solid pharmaceutical composition into tablets by wet granulation, and preferably further coating the resulting tablets to obtain vortioxetine hydrobromide coated tablets.

[0052] In one specific embodiment, the present invention provides a method for preparing the stable solid pharmaceutical composition, which employs wet granulation, preferably high-shear wet granulation. This method involves first adding the prescribed amount of diluent, antioxidant and / or alkaline reagent, vortioxetine or a pharmaceutically acceptable salt thereof to a wet granulator, mixing thoroughly, then adding a pre-prepared binder for granulation; subsequently drying and granulating to obtain dry granules; then mixing the dry granules thoroughly with a disintegrant and a lubricant, followed by tableting.

[0053] When the antioxidant and / or diluent has good water solubility, it can also be prepared by the following method: the prescribed amount of diluent and vortioxetine or its pharmaceutically acceptable salt are first added to a wet granulator and mixed evenly, and then a pre-prepared binder aqueous solution containing antioxidant and / or alkaline reagent is added for granulation; then dried and granulated to obtain dry granules, and then the dry granules are mixed evenly with disintegrant and lubricant, and tableted to obtain the final product.

[0054] In specific implementation schemes, the granulation method can be achieved, for example, by using a conical granulator or a swing granulator. More specifically, a granulator with a suitable screen aperture can be selected according to the requirements for controlling particle size. For example, the particle size can be controlled by selecting a conical granulator with different screen apertures or a swing granulator with different screen apertures. More preferably, a conical granulator with a 0.8 mm or 1.0 mm diameter round hole screen is used for granulation, or a swing granulator with a 24 mesh screen is used for granulation.

[0055] In specific implementations, the tableting is preferably performed using a shallow concave round punch. Alternatively, by adjusting the die size of the tableting machine, tablets of different specifications of vortioxetine hydrobromide can be obtained, such as tablets containing 5mg, 10mg, 15mg, or 20mg of vortioxetine per tablet. For example, a shallow concave round punch with a diameter of 5.0mm or 7.0mm can be used for tableting. Optionally, the tableting further includes coating the uncoated tablets (also called "tablet cores") obtained from the tableting process with a coating material to obtain coated tablets. The coating material is preferably a gastrointestinal film-coating premix, such as a coating premix containing hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and iron oxide yellow. This type of coating material can be obtained commercially available, such as the 03B22082-CN model coating premix powder provided by Calcon.

[0056] In the drying and granulation steps, the drying temperature is preferably no more than 60°C, for example, 40~50°C.

[0057] Optionally, the method may also include pretreatment of the auxiliary materials as needed, such as sieving before use.

[0058] The pharmaceutical composition containing vortioxetine hydrobromide provided by this invention is preferably in tablet form and administered in unit doses, wherein the unit dose contains about 1 to 50 mg of vortioxetine free base. The upper limit of use is set according to the concentration dependence of 5-HT3 activity. The total daily dose is typically about 1 to 20 mg, for example, about 1 to 10 mg, about 5 to 10 mg, about 10 to 20 mg, or about 10 to 15 mg of vortioxetine. Specifically, the daily dose is 5, 10, 15, or 20 mg of vortioxetine free base. The vortioxetine hydrobromide tablets provided by this invention preferably contain 5 mg / tablet to 20 mg / tablet, for example, 5 mg / tablet, 10 mg / tablet, 15 mg / tablet, or 20 mg / tablet.

[0059] A third aspect of the invention also provides the use of the pharmaceutical composition in the preparation of a medicament for treating and / or preventing central nervous system-related diseases; in one embodiment, the central nervous system-related diseases are selected from: mood disorders, depression, Alzheimer's disease, psychosis, cancer, aging or Parkinson's disease, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, panic attacks, phobias, social phobia, agoraphobia, stress urinary incontinence, vomiting, IBS, eating disorders, chronic pain, partial response, Alzheimer's disease, cognitive impairment, ADHD, depression, PTSD, hot flashes, sleep apnea, alcoholism, nicotine or carbohydrate addiction, drug abuse and alcohol or narcotics abuse, and pain.

[0060] Preferably, the central nervous system-related disease is depression; the depression includes mild depression, moderate depression, severe depression, treatment-resistant depression, and treatment-resistant bipolar depression. Optionally, the depression is tested using the Montgomery-Sberg Depression Rating Scale (MADRS), with the following criteria: extreme depression: MADRS ≥ 35; severe depression: 35 > MADRS ≥ 30; moderate depression: 30 > MADRS ≥ 22; mild depression: 22 > MADRS ≥ 12; remission period: MADRS < 12. That is, a MADRS ≥ 22 indicates moderate to severe depression.

[0061] Technical effect The inventors have discovered for the first time that existing vortioxetine formulations lead to an increase in N-nitrosovortioxetine during storage. The stable solid pharmaceutical composition provided by this invention effectively inhibits the growth of nitrosamine impurities (especially N-nitrosovortioxetine) in solid pharmaceutical formulations of vortioxetine or its pharmaceutically acceptable salts during preparation and storage, overcoming the problem of substandard product quality caused by the increase of nitrosamine impurities in existing vortioxetine hydrobromide solid formulations during storage. Compared to formulations without added antioxidants or alkaline reagents, the pharmaceutical composition provided by this invention can significantly reduce nitrosamine impurities from 2.8 ppm to 0.7-2.5 ppm, even under conditions of high temperature (60°C), high humidity (RH 75%), and light exposure (not less than 1.2 ppm). 10 6 The antioxidant can effectively inhibit the growth of nitrosamine impurities after being placed under Lux.hr conditions for 1 month and under accelerated test conditions (40℃±2℃, RH75%±5%) for 1 month, preferably 3 months or 6 months. In particular, when the antioxidant contains ascorbic acid, propyl gallate, cysteine ​​hydrochloride or tocopherol, the growth inhibition effect of nitrosamine impurities in the solid dosage form is obvious, and the content of nitrosamine impurities in the solid dosage form can be controlled below 20 ppm, which meets the safety requirements of the formulation.

[0062] In a further benefit, the pharmaceutical composition provided by this invention uses a very small amount of antioxidant, preferably no more than 0.5% by weight, and particularly preferably 0.01 to 0.2% by weight. This means that even at a low dosage, it still exhibits a very good effect in inhibiting the increase of nitrosamine impurities. The low dosage of antioxidant has significant industrialization value because each excipient has its safe usage range. Furthermore, the inventors discovered during their research that the low amount of antioxidant provided by this invention is of great significance for the chemical storage stability of the formulation. The inventors discovered that when too much antioxidant and / or alkaline reagent is added, although it has a good inhibitory effect on nitrosamine impurities in the formulation, it can lead to an increase in the content of known impurities such as oxidized impurities, formylated impurities, acetylated impurities, and disubstituted acetylated impurities, as well as the maximum unknown single impurity and total impurities, during storage, even exceeding the limit requirements, causing new quality non-compliance issues. As can be seen from Table 1.3 of Test Example 1 of this invention, different types of antioxidants and alkaline reagents have different effects on the content of related substances. Compared with ascorbic acid, cysteine ​​hydrochloride, and propyl gallate, the addition of sodium carbonate, for example, will introduce more new unknown single impurities, leading to the problem of exceeding the limit of related substances.

[0063] Thirdly, the solid pharmaceutical composition of the present invention, while effectively inhibiting the increase of nitrosamine impurity content, further ensures that the related substances remain within limits under accelerated testing and influencing factor testing conditions, effectively guaranteeing product safety. Furthermore, the solid pharmaceutical composition provided by the present invention, while inhibiting the increase of nitrosamine impurity content, has little impact on the in vitro dissolution rate of the solid formulation, and its dissolution behavior in simulated gastric and intestinal environments is similar to that of the reference formulation, exhibiting better dissolution performance and bioavailability.

[0064] Fourth, the pharmaceutical composition provided by the present invention reduces the amount of binder and lubricant by optimizing the types and contents of each excipient, and also increases the drug loading of the tablet. In the same specification of drug content, it can reduce the amount of excipients used and reduce the tablet weight, which is beneficial to improving the convenience of medication for the elderly, children and patients with difficulty swallowing.

[0065] Fifth, the present invention also provides a method for preparing the pharmaceutical composition, which has the advantages of being easy to operate, having low production costs, and being suitable for industrial application.

[0066] Terminology Definition This invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials described herein can be used to practice this invention. This invention is by no means limited to the methods and materials described herein.

[0067] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0068] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0069] The terms “comprising,” “including,” “containing,” “selected from,” or other variations are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0070] In the context of this invention, all figures disclosed herein are approximate, regardless of whether the words “about,” “approximately,” or “roughly” are used. Each figure may vary by less than 10% or by a difference that is considered reasonable by those skilled in the art, such as 1%, 2%, 3%, 4%, or 5%.

[0071] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0072] In the context of this invention, the terms “content”, “amount used” or “weight %” for each component in the pharmaceutical composition refer to all terms relative to the total weight of (a), (b) and (c) in the pharmaceutical composition.

[0073] The present invention f 2 refers to the similarity factor. In this invention, the dissolution curve comparison uses a model-independent similarity factor ( ). f 2) Method, through f The similarity factor (σ) was calculated to compare the dissolution curves of vortioxetine hydrobromide tablets prepared with different formulations and the reference formulation in the same solvent. f 2) The range of variation is 0 to 100, and the similarity factor ( f 2) The larger the value, the higher the similarity between the two dissolution curves. f If the value of 2 is approximately equal to 50, then the two dissolution curves are considered similar. f A value below 50 indicates a difference between the two.

[0074] The terms "core" and "uncoated tablet" are interchangeable, both referring to the portion of a coated tablet with the coating film removed.

[0075] The term "diluent," also known as a filler, refers to a component in a pharmaceutical preparation used to increase its volume or weight. Diluents can affect the formability (e.g., powder flowability, tablet hardness, wet or dry granulation formability, uniformity) and properties (e.g., content uniformity, disintegration, dissolution, appearance, hardness, friability, physicochemical stability) of the preparation. Commonly used diluents include starch, sucrose, lactose, pregelatinized starch, microcrystalline cellulose, inorganic salts, and sugar alcohols. In the pharmaceutical composition described in this invention, the diluent is preferably one or more of mannitol, microcrystalline cellulose, lactose, sorbitol, sucrose, starch, and dicalcium phosphate, with mannitol and microcrystalline cellulose being particularly preferred.

[0076] The term "binder" refers to a class of viscous solid powders or solutions that agglomerate non-viscous or insufficiently viscous material powders into granules or compress them. Wet granulation facilitates further processing of granules by improving one or more properties of the granules, such as flowability, handling, strength, resistance to segregation, dust content, appearance, solubility, compressibility, or drug release. Binders can be classified as: (1) natural polymers; (2) synthetic polymers; and (3) sugars. In this invention, binders include starch paste, cellulose derivatives, povidone, gelatin, and other binders. When preparing tablets using direct powder compression or dry granulation, the use of binders may be omitted.

[0077] The term "disintegrant" refers to an ingredient added to a formulation that causes the preparation to rapidly disintegrate into smaller units and dissolve the drug more quickly. When disintegrants come into contact with water, gastric juice, or intestinal fluid, they absorb the liquid, swell, dissolve, or form a gel, causing disruption and disintegration of the formulation structure and promoting drug dissolution. Disintegrants include natural, synthetic, or chemically modified natural polymers. Examples include: dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, effervescent disintegrants, etc. In the pharmaceutical compositions described in this invention, the disintegrant is preferably selected from one or more of sodium carboxymethyl starch and croscarmellose sodium, with sodium carboxymethyl starch being particularly preferred.

[0078] The term "lubricant" is used to reduce friction between particles and between the metal-to-metal contact surfaces of particles and tableting equipment, such as tablet punches and dies. Lubricants can be classified into interfacial lubricants, fluid film lubricants, and liquid lubricants. Interfacial lubricants are amphiphilic long-chain fatty acid salts (such as magnesium stearate) or fatty acid esters (such as sodium stearoyl fumarate), which adhere to solid surfaces (particles and machine parts) to reduce friction between particles or between particles and metals. Fluid film lubricants are solid fats (such as hydrogenated vegetable oil, type I), glycerides (glyceryl docosanoate and distearate), or fatty acids (such as stearic acid), which melt under pressure and form a film around the particles and tableting machine punches, thus reducing friction. The fluid film lubricant re-solidifies after the pressure is removed. Liquid lubricants are liquid substances that can be absorbed by the particles before compression and released from the particles under pressure; they can also be used to reduce metal-to-metal friction in manufacturing equipment. In this invention, the preferred lubricant includes one or more of the following: micronized silica gel, magnesium stearate, talc, stearic acid, and sodium stearate fumarate.

[0079] The antioxidants described in this invention are "butylated hydroxytoluene" (BHT), also known as 2,6-di-tert-butyl-p-cresol; and "butylated hydroxyanisole" (BHA), also known as 2(3)-tert-butyl-4-methoxyphenol. The preferred nitrosamine impurity described in this invention is N-nitrosovortioxitine or its salt, wherein the N-nitrosovortioxitine has the following structure: . Specific Implementation To better understand the technical solution of the present invention, the present invention will be further described below with reference to specific embodiments. Unless otherwise specified, if specific techniques or conditions are not explicitly described in the following embodiments, those skilled in the art can perform them according to common techniques or conditions in the art or according to the product instructions. Drugs, reagents, or instruments used without a specified manufacturer are all commercially available conventional products.

[0081] The hydroxypropyl cellulose (EXF, EF, LXF) used in the following examples was purchased from Ashland Specialty Ingredients GP. The reference formulation was vortioxetine hydrobromide tablets, trade name: Xindayue, licensee: H. Lundbeck A / S. The mannitol used was purchased from Roquette, France, under the trade name PEARLITOL®.

[0082] Solubility of some antioxidants and alkaline reagents in water:

[0084] Examples 1-9: The prescriptions for Examples 1 to 9 are shown in Table 1.1 below.

[0085] Table 1.1: Formulation of Vortioxetine Hydrobromide Solid Pharmaceutical Composition

[0086] Note: The total weight of each prescription in the table is 150mg for the unprocessed tablets. The amount of each excipient (mg) = percentage of excipient amount multiplied by 150mg (the same applies below). The active pharmaceutical ingredient vortioxetine hydrobromide used in Examples 1-9 in the table is from the same production batch.

[0087] Preparation process of Example 1: Mannitol was sieved to disperse large clumps. The prescribed amounts of mannitol, vortioxetine hydrobromide, and microcrystalline cellulose (Table 1.1, Example 1) were added to a wet granulator. The prescribed amount of microcrystalline cellulose was used to "wash" the raw material pharmaceutical bag. The mixture was stirred and sheared for 5-10 minutes. Hydroxypropyl cellulose aqueous solution (8% w / w) was added for wet granulation. The wet granules were dried using a fluidized bed, controlling the moisture content to ≤3%. Granulation was performed using a conical granulator with a 1.0mm round-hole sieve. Finally, the excipients sodium carboxymethyl starch (Type A) and magnesium stearate were added and mixed thoroughly. Tableting was performed using a 7.0mm shallow round punch, with the tablet weight controlled at 150mg ± 7.5% and the hardness range controlled at 30-70N, yielding vortioxetine hydrobromide tablets.

[0088] Preparation processes of the formulations in Examples 2 and 3: Mannitol was sieved to disperse large clumps. The amounts of mannitol, vortioxetine hydrobromide, microcrystalline cellulose, and antioxidant (BHT or BHA) prescribed in Examples 2 and 3 of Table 1.1 were added to a wet granulator. The pharmaceutical raw material bag was "washed" with the prescribed amount of microcrystalline cellulose. The mixture was stirred and sheared for 5-10 minutes. Hydroxypropyl cellulose aqueous solution (8% w / w) was added for wet granulation. The wet granules were dried using a fluidized bed, controlling the moisture content to ≤3%. Granulation was performed using a conical granulator with a 1.0mm round-hole sieve. Finally, the excipients sodium carboxymethyl starch (Type A) and magnesium stearate were added and mixed thoroughly. Tableting was performed using a 7.0mm shallow round punch, with the tablet weight controlled at 150mg ± 7.5% and the hardness range controlled at 30-70N, yielding vortioxetine hydrobromide tablets.

[0089] Examples 4-9: Formulation Preparation Process Mannitol was sieved to disperse large clumps. The prescribed amounts of mannitol, vortioxetine hydrobromide, and microcrystalline cellulose (Table 1.1 Examples 4-9) were added to a wet granulator. The raw material bag was "washed" with the prescribed amount of microcrystalline cellulose. The mixture was stirred and sheared for 5-10 minutes. Hydroxypropyl cellulose aqueous solution (8% w / w) containing the prescribed amount of antioxidant or alkaline reagent was added for wet granulation. The wet granules were dried using a fluidized bed, controlling the moisture content to ≤3%. Granulation was performed using a conical granulator with a 1.0mm round-hole sieve. Finally, the excipients sodium carboxymethyl starch (Type A) and magnesium stearate were added and mixed thoroughly. Tableting was performed using a 7.0mm shallow round punch, with the tablet weight controlled at 150mg ± 7.5% and the hardness range controlled at 30-70N, yielding vortioxetine hydrobromide tablets.

[0090] Coating process: The vortioxetine hydrobromide tablets prepared by the above method were used as uncoated tablets and coated with a common gastric-soluble film. The coating material included a mixture of hydroxypropyl methylcellulose, polyethylene glycol 4, titanium dioxide, and iron oxide yellow powder. The premixed coating powder of model 03B22082-CN had the same composition as the above coating material, so this model of coating powder was selected for the coating process investigation. A high-efficiency coating machine was used for coating to obtain the vortioxetine hydrobromide coated tablets of the formulations in Examples 1-9, respectively.

[0091] Test Example 1: Stability Test: (1) Influencing factor test: Vortioxetine hydrobromide coated tablets prepared according to the formulations of Examples 1-9 were placed in high temperature (60℃±2℃), high humidity (25℃±2℃, 75%±5%RH), and light (total illuminance of the light source not less than 1.2 ppm). 10 6 Lux.hr, near-ultraviolet lamp energy not less than 200w.hr / m 2 The tablets were placed under the specified conditions, and samples were taken on day 0, day 10 (or day 11), and day 30 to test the content of nitrosamine impurities (N-nitrosovothioxine) and related substances in the coated tablets.

[0092] (2) Accelerated test: The vortioxetine hydrobromide coated tablets prepared according to the formulations of Examples 1 to 9 were cold-packaged in aluminum and placed under accelerated test conditions (temperature 40℃±2℃, humidity 75%±5%RH). Samples were taken on day 0, month 1, month 2 (2M), and month 4 (4M) to detect the content of nitrosamine impurities (i.e., N-nitrosovortioxetine) and related substances in the vortioxetine raw material.

[0093] (3) Long-term stability test: The stability of the solid pharmaceutical composition prepared in this invention was studied under long-term stability test conditions (30℃±2℃ / 60±5%RH). The coated tablets prepared in the examples were packaged in aluminum foil bags and placed at 30℃±2℃ / 60±5%RH. Samples were taken at 0 days, 1 month, 3 months, 6 months, 12 months, 18 months, and 24 months to detect the content of nitrosamine impurities (N-nitrosovortioxetine) and related substances in the coated tablets. The content of nitrosamine impurities was detected by high performance liquid chromatography-mass spectrometry (UPLC-MS) (Chinese Pharmacopoeia 2020 Edition, Part IV, 0431 Mass Spectrometry); the content of related substances was detected by high performance liquid chromatography (HPLC) (Chinese Pharmacopoeia 2020 Edition, Part IV, 0512 High Performance Liquid Chromatography).

[0094] The test results showed that on day 0, the nitrosamine impurity content of vortioxetine hydrobromide prepared by the formulation of Example 1 without the addition of antioxidants or alkaline reagents was 2.8 ppm, which was higher than that of Examples 2-7 and Example 9; the nitrosamine impurity content of Example 8 with the addition of sodium dihydrogen phosphate (monohydrate) was higher than that of Example 1 at 5.6 ppm. Since the nitrosamine content of the coated tablets prepared by the formulation of Example 8 already exceeded that of the formulation without antioxidants on day 0, stability was not further investigated.

[0095] The results of influencing factor tests and accelerated testing showed that, compared with the formulation of Example 1, the formulations of Examples 2-7 and Example 9 could inhibit the increase of nitrosamine impurities in the formulation process. Influencing factor tests (including high temperature, high humidity, and light exposure) and accelerated testing results lasting at least one month showed that, compared with Example 1, the solid pharmaceutical composition containing antioxidants or alkaline reagents provided by this invention had varying degrees of inhibitory effect on the increase of nitrosamine impurities in the formulation. In particular, when the antioxidants used were ascorbic acid, sodium sulfite, propyl gallate, etc., the increase of nitrosamine impurities in the corresponding formulations was the slowest.

[0096] Tables 1.2 and 1.3 show the results of the detection of nitrosamine impurity content and related substance content in the 1-month influencing factor test and accelerated test for each prescription.

[0097] Table 1.2: Inhibition effect of nitrosamine impurities in influencing factor test and accelerated test

[0099] Table 1.3: Results of related substance detection in influencing factor tests and accelerated tests:

[0100] ND: Indicates not detected. The limits for oxidation impurities, formylated impurities, acetylated impurities, disubstituted acetylated impurities, and the maximum unknown single impurity are all 0.2%, and the total impurity limit is 1.0%. As can be seen from the test results in Table 1.3, the formulations provided by this invention, which include antioxidants or alkaline reagents, show varying degrees of increase in related substances compared to the coated tablets prepared with the formulation of Example 1 without antioxidants or alkaline reagents. However, the changes in known impurities (oxidized impurities (CAS: 1429908-35-9), formylated impurities (CAS: 2135576-73-5), acetylated impurities (CAS: 1801352-86-2), disubstituted acetylated impurities (CAS: 2476761-84-7)), the maximum unknown single impurity, and the total impurity content are very small and all within the limits. Although the coated tablets prepared with the formulation of Example 6 containing sodium sulfite have a very good effect on inhibiting the growth of nitrosamine impurities, the related substances test showed a significant increase in oxidized impurities, the maximum unknown single impurity, and the total impurity content on day 0. Therefore, no further research was conducted.

[0101] Example 9 shows that the addition of anhydrous sodium carbonate has a very good inhibitory effect on nitrosamine impurities during the formulation preparation and storage process, but it leads to an increase in the content of related substances. In contrast, the formulation containing ascorbic acid, propyl gallate, and cysteine ​​hydrochloride not only has a good inhibitory effect on nitrosamine impurities, but also does not lead to a significant increase in the content of related substances.

[0102] The above experimental results show that the stable pharmaceutical composition provided by the present invention can maintain drug stability well and meet the requirements of drug production, packaging, and storage. Among them, the coated tablets prepared by the formulation of Example 4 (ascorbic acid group) and Example 5 (propyl gallate group) have better storage stability than those prepared by Example 9 (sodium carbonate group).

[0103] Test Example 2: Bioequivalence Study The effect of adding antioxidants or alkaline reagents on the in vitro dissolution of vortioxetine hydrobromide tablets was determined by in vitro dissolution testing.

[0104] Dissolution test method: The dissolution rate was determined according to the second method of the paddle method in General Chapter <0931 Determination of Dissolution and Release Rate> of the 2020 edition of the Chinese Pharmacopoeia.

[0105] pH 1.0 hydrochloric acid solution, paddle method, rotation speed 50 rpm, dissolution medium volume 900 mL, sampling time points: 5, 10, 15, 30, 45, 60 min; pH 4.5 acetate buffer, basket method, 100 rpm, dissolution medium volume 900 mL, sampling time points: 5, 10, 15, 30, 45, 60 min; pH 6.8 phosphate buffer, basket method, 100 rpm, dissolution medium volume 900 mL, sampling time points: 5, 10, 15, 30, 45, 60 min.

[0106] The vortioxetine hydrobromide tablets prepared in Examples 1 and 4 of this invention, as well as the reference formulation, were used as research subjects for testing. The test results showed that the in vitro dissolution curves of vortioxetine hydrobromide tablets prepared in Examples 4 and 1, and the reference formulation in pH 1.0, pH 4.5, and pH 6.8 media were similar to those of the reference formulation. f2 (All values ​​are greater than 70), indicating that there is no significant difference in bioequivalence between Examples 4 and 1 and the reference formulation. Therefore, the compositions with or without antioxidants are bioequivalent, and the pharmacokinetic profiles do not change after the addition of ascorbic acid.

[0107] Examples 10-17: Vortioxetine hydrobromide tablets and their preparation methods The effects of different amounts of ascorbic acid, propyl gallate, cysteine ​​hydrochloride, and α-tocopherol on nitrosamine impurities and related substances were studied.

[0108] Table 2.1: Prescriptions for Examples 10-17

[0109] The preparation methods of tablets and coated tablets of the formulations in Examples 10-17 are the same as those of the formulations in Examples 4-9, including the preparation process and coating process.

[0110] Following the method of Test Example 1, the coated tablets prepared according to the formulations of Examples 10-17 were subjected to stability tests. The test results showed that in the formulations with added antioxidants, the total ascorbic acid content was 0.01-0.1% by weight, the propyl gallate content was 0.1-0.25% by weight, particularly 0.1-0.2% by weight, the α-tocopherol content was 0.1-0.5% by weight, and the cysteine ​​hydrochloride content was 0.01-0.05% by weight. The nitrosamine impurities detected in the coated tablets prepared according to these formulations were significantly lower than those in Example 1 during the influencing factor test and accelerated testing, and the contents of related substances were all within the limits. This indicates that the solid pharmaceutical composition provided by the present invention has a good effect on inhibiting the growth of nitrosamine impurities during the storage of the formulation and has little impact on changes in the contents of related substances. Table 2.2 below shows the nitrosamine impurity content in the formulations detected in the influencing factor test and accelerated testing of Examples 10-12.

[0111] Table 2.2 Influencing Factors: Nitrosamine Impurity Suppression Effect and Related Substance Content in Accelerated and Accelerated Tests

[0112] Note: The limits for oxidized impurities, formylated impurities, acetylated impurities, disubstituted acetylated impurities, and the maximum unknown single impurity are all 0.2%, and the total impurity limit is 1.0%.

[0113] Further stability studies showed that while adding alkaline reagents such as sodium carbonate to the formulation effectively inhibited the increase of nitrosamine impurities during the preparation and storage of the pharmaceutical formulation, it also led to a significant increase in related substances, particularly oxidative impurities, affecting product safety. Ascorbic acid and cysteine ​​hydrochloride are preferred nitrosamine inhibitors in this invention. Studies on the inhibition effect of nitrosamine impurities found that the higher the content of ascorbic acid and cysteine ​​hydrochloride in the formulation, the better the inhibitory effect on the growth of nitrosamine impurities. However, excessively high levels of ascorbic acid and cysteine ​​hydrochloride can lead to an increase in related substances in the pharmaceutical formulation, causing product safety issues. Regarding quality and safety issues, in this invention, the preferred pharmaceutical composition contains 0.001% to 0.1% ascorbic acid and 0.01% to 0.05% cysteine ​​hydrochloride. Within this range, the growth of nitrosamine impurities during the preparation and storage of the pharmaceutical formulation can be effectively inhibited without causing a significant increase in the content of related substances. Furthermore, pharmaceutical compositions containing 0.001% to 0.1% ascorbic acid or 0.01% to 0.05% cysteine ​​hydrochloride exhibit higher in vitro dissolution similarity to the reference formulation compared to those containing other antioxidants or alkaline reagents.

[0114] The above embodiments are only used to illustrate the technical solution and beneficial effects of the present invention in detail. Those skilled in the art can make some modifications or improvements based on the present invention. Such modifications or improvements made without departing from the spirit of the present invention are all within the protection scope of the present invention.

Claims

1. A stable solid pharmaceutical composition, characterized in that, Include: (a) Vortioxetine or a pharmaceutically acceptable salt thereof, (b) Selected from one or more antioxidants and basic reagents, Optionally, it also includes (c) one or more pharmaceutical excipients selected from diluents, binders, disintegrants and lubricants; The antioxidant is selected from one or more of the following: ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, ascorbyl palmitate, sodium ascorbate phosphate, magnesium ascorbate phosphate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), di-tert-butylhydroquinone, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium dithionite, potassium metabisulfite, and thymol. The alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.

2. The pharmaceutical composition according to claim 1, characterized in that, The antioxidant is selected from one or more of the following: ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, ascorbyl palmitate, sodium ascorbate phosphate, magnesium ascorbate phosphate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, sodium bisulfite, and thymol. Preferably, the antioxidant is selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, tocopheryl acetate, propyl gallate, gallic acid, octyl gallate, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, or sodium bisulfite.

3. The pharmaceutical composition according to claim 1, characterized in that, The alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate. Preferably, the alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The antioxidant content is 0.01~1% by weight, preferably 0.01~0.2% by weight; and / or, The content of the alkaline reagent is 0.5-3% by weight, preferably 0.5-1.5% by weight; wherein the weight percentage is relative to the total weight of (a), (b) and (c).

5. The solid pharmaceutical composition according to any one of claims 1 to 4, characterized in that, Component (b) is an antioxidant, wherein the antioxidant is selected from one or more of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbate, α-tocopherol, propyl gallate, gallic acid, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite, and the content of the antioxidant is 0.01~3% by weight, preferably 0.01~0.5% by weight, more preferably 0.01~0.25% by weight; or, Component (b) is an alkaline reagent selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate, and the content of the alkaline reagent is 0.5-2% by weight, preferably 0.5-1.2% by weight. Further preferably, component (b) is an antioxidant, selected from ascorbic acid, sodium ascorbate, isoascorbic acid, and sodium isoascorbate, with an antioxidant content of 0.01~0.1% by weight; or, the antioxidant is selected from cysteine ​​or cysteine ​​hydrochloride, with an antioxidant content of 0.01~0.05% by weight; or, the antioxidant is selected from propyl gallate or gallic acid, with an antioxidant content of 0.1~0.25% by weight. The weight percentages mentioned are relative to the total weight of (a), (b) and (c).

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that, The pharmaceutical composition further includes (c) one or more pharmaceutical excipients selected from diluents, binders, disintegrants and lubricants; The diluent is selected from one or more of mannitol, microcrystalline cellulose, lactose, sorbitol, sucrose, starch, and dicalcium phosphate; and / or, The adhesive is selected from one or more of hydroxypropyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, and polyvinylpyrrolidone; and / or, The disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; and / or, The lubricant is selected from one or more of the following: micronized silica gel, magnesium stearate, talc, stearic acid, and sodium stearate fumarate.

7. The pharmaceutical composition according to claim 6, characterized in that, The diluent is selected from one or more of mannitol, microcrystalline cellulose, and dicalcium phosphate; and / or, The adhesive is selected from one or more of hydroxypropyl cellulose and polyvinylpyrrolidone; and / or, The disintegrant is selected from one or more of sodium carboxymethyl starch and crospovidone; and / or The lubricant is selected from one or more of the following: micronized silica gel, magnesium stearate, talc, stearic acid, and sodium stearate fumarate.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, Include: (a) Vortioxetine or a pharmaceutically acceptable salt thereof, (b) Selected from one or more antioxidants and basic reagents, (c) Pharmaceutical excipients selected from one or more of diluents, binders, disintegrants and lubricants; The content of vortioxetine or a pharmaceutically acceptable salt thereof is 3-20% by weight, preferably 4-13% by weight; and / or The diluent content is 50-95% by weight, preferably 60-90% by weight; and / or, The adhesive content is 0.5-15% by weight, preferably 1-10% by weight; and / or, The content of the disintegrant is 0.1-10% by weight, preferably 1-5% by weight; and / or, The lubricant content is 1-5% by weight, preferably 1-3% by weight; The weight percentages mentioned are relative to the total weight of (a), (b) and (c).

9. A stable solid pharmaceutical composition, characterized in that, It contains the following components: (a) Vortioxetine hydrobromide, wherein the content of vortioxetine hydrobromide is 3-20% by weight, preferably 4-13% by weight; (b) At least one of an antioxidant and an alkaline reagent, wherein the antioxidant is present in an amount of 0.001 to 1% by weight, preferably 0.01 to 0.25% by weight, and / or the alkaline reagent is present in an amount of 0.5 to 3% by weight, preferably 0.5 to 1.5% by weight. (c) a diluent, a binder, a disintegrant, and a lubricant, wherein the diluent is present in a concentration of 50-95% by weight, preferably 60-90% by weight; the binder is present in a concentration of 0.5-15% by weight, preferably 1-10% by weight; the disintegrant is present in a concentration of 0.1-10% by weight, preferably 1-5% by weight; and the lubricant is present in a concentration of 1-5% by weight, preferably 1-3% by weight. The weight percentages mentioned are relative to the total weight of (a), (b) and (c); Further preferably, the antioxidant is selected from one or more of ascorbic acid, α-tocopherol, propyl gallate, gallic acid, cysteine, cysteine ​​hydrochloride, butylated hydroxytoluene, butylated hydroxyanisole, sodium sulfite, and sodium bisulfite; the alkaline reagent is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. The diluent is selected from one or more of mannitol, microcrystalline cellulose, and dicalcium phosphate. The adhesive is selected from one or more of hydroxypropyl cellulose and polyvinylpyrrolidone; The disintegrant is selected from one or more of sodium carboxymethyl starch and crospovidone; The lubricant is selected from one or more of the following: micronized silica gel, magnesium stearate, talc, stearic acid, and sodium stearate fumarate. Preferably, the antioxidant is selected from ascorbic acid or sodium ascorbate, and the content of the antioxidant is 0.01~0.1% by weight; or, The antioxidant is selected from cysteine ​​or cysteine ​​hydrochloride, and the content of the antioxidant is 0.01~0.05% by weight; or, The antioxidant is selected from propyl gallate or gallic acid, and the content of the antioxidant is 0.1~0.25% by weight.

10. The solid pharmaceutical composition according to any one of claims 1 to 9, characterized in that, The solid pharmaceutical composition is a tablet, and optionally, the solid pharmaceutical composition further includes a coating material, preferably a film-coating premix.

11. The solid pharmaceutical composition according to any one of claims 1 to 10, characterized in that, When placed at 40℃±2℃ and 75%±5%RH for at least 1 month, or at least 3 months, or at least 6 months, the nitrosamine impurities in the pharmaceutical composition are controlled at a level of ≤20ppm. Further preferred, the content of oxidative impurities and the maximum unknown single impurity in the pharmaceutical composition is within the limit range of ≤0.2%, and the total impurities are within the limit range of ≤1.0%. Further preferably, the nitrosamine impurity is N-nitrosovothioxine.

12. A method for preparing the solid composition according to any one of claims 1 to 10, characterized in that, Including method (A) or (B): Method (A) involves first adding the prescribed amounts of diluent, antioxidant and / or alkaline reagent, vortioxetine or its pharmaceutically acceptable salt to a wet granulator, mixing thoroughly, then adding a pre-prepared binder for granulation; followed by drying, granulation to obtain dry granules, then mixing the dry granules thoroughly with a disintegrant and lubricant, and finally compressing to obtain tablets; or, Method (B) involves first adding the prescribed amount of diluent and vortioxetine or its pharmaceutically acceptable salt to a wet granulator, mixing them thoroughly, then adding a pre-prepared aqueous binder solution containing antioxidants and / or alkaline reagents to granulate; then drying and granulating to obtain dry granules, then mixing the dry granules thoroughly with disintegrants and lubricants, and then compressing them into tablets. Optionally, the method (A) or (B) further includes the step of coating the uncoated tablets obtained by compression with a coating material to obtain coated tablets.

Images