Coated granules, solid dispersions and formulations containing vortioxetine hydrobromide for oral taste masking

Abstract

This application discloses coated granules, solid dispersions, combinations and formulations for oral taste masking, which have been shown to improve the taste masking effect of vortioxetine hydrobromide and increase patient compliance and tolerability.

Description

[Technical Field]

[0001] The present application relates to the technical field of pharmaceuticals, and in particular to coated granules, solid dispersions, compositions and formulations for oral taste masking. [Background technology]

[0002] Vortioxetine is a multi-target antidepressant, with 5-HT3 receptor antagonism and 5-HT 1A It also has receptor agonist effects and is used to treat major depressive disorder. Currently, vortioxetine hydrobromide is used clinically as the active ingredient. It was jointly developed by Takeda Pharmaceutical Company and Lundbeck, and was approved by the FDA on September 30, 2013, and is now on the market under the trade name Trintellix. It is available in 5 mg, 10 mg, 15 mg, and 20 mg film-coated tablets.

[0003] The chemical name of vortioxetine hydrobromide is 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide, and its molecular formula is C 18 H 22 NS·HBr. US9562024B2 also lists the hemihydrobromide compound of vortioxetine, i.e., every two vortioxetine molecules share one hydrobromide molecule, with the molecular formula C 18 H 22 N2S·1 / 2HBr is disclosed. 18 H 22 NS HBr and C 18 H 22 The structural formula of NS·1 / 2HBr is: [ka]

[0004] Depression is a common illness with high clinical demand. However, depressed patients often refuse or fail to cooperate with treatment when symptoms appear, and often spit out medication without medical staff or family caregivers noticing. Conventional tablets and capsules are "monolithic tablets," which pose a risk of esophageal blockage when taken by psychiatric patients, elderly people, and long-term bedridden patients. Therefore, there is a clinical need for more appropriate dosage forms to improve patient compliance and compliance. Orally dispersible formulations allow drugs to be present in the oral cavity in particulate form (e.g., granules, powders, suspensions, dry suspensions) or liquid form (e.g., oral suspensions), or can be rapidly converted to particulate or liquid form in the oral cavity (e.g., orally disintegrating tablets, orally dispersible tablets). Orally dispersible formulations are the most appropriate technical means to improve compliance in depressed patients, and orally disintegrating tablets are the optimal dosage form due to their ease of use, portability, and stable quality. For example, alprazolam orally disintegrating tablets, olanzapine orally disintegrating tablets, and risperidone orally disintegrating tablets.

[0005] Due to various reasons, including the physical and chemical properties of the vortioxetine drug substance and clinical suitability, few other dosage forms have been marketed to date.

[0006] The hydrobromide salt of vortioxetine and the lactate salt sold in Europe are both highly irritating to the oral mucosa, causing discomfort to users when exposed to the oral cavity, particularly on the tongue, which can persist for more than half a day even after rinsing. This affects compliance and limits its application in oral formulations exposed to the oral cavity. Therefore, to address the issue of mucosal irritation, it is necessary to prepare oral formulations in an orally dispersible dosage form other than film-coated tablets.

[0007] Two approaches are typically used to overcome the unpleasant taste of drugs. The first approach is to reduce the drug's solubility and thereby reduce its exposure in the oral cavity. The other approach is to alter the drug's ability to interact with taste receptors, which can potentially lead to unknown toxicity and side effects due to the effects on taste-related receptors. Therefore, the first approach is safer for patients. To reduce oral irritation caused by drugs, it is necessary to reduce the drug's exposure in the oral cavity and slow its dissolution rate. However, slowing the drug's dissolution rate also slows drug absorption, which affects the absorption and metabolic rates of immediate-release dosage forms and thus affects the efficacy and safety of the drug. This technical contradiction is the main technical obstacle preventing the product from being sold as an oral taste-masking immediate-release dosage form. In particular, when a patient's condition improves and they cooperate with their medication and switch to a regular immediate-release coated tablet, the different dissolution, absorption, and metabolic rates of the two dosage forms can cause potential physiological and pathological problems for the patient after switching to a regular immediate-release coated tablet.

[0008] Correcting the taste using flavoring agents is one way to adjust the unpleasant texture of the active ingredient, such as its bitterness, but flavoring agents are very ineffective in improving the irritation caused by vortioxetine.

[0009] The currently approved oral solution of vortioxetine lactate has not received market approval even after many years on the market due to its strong irritant properties. Therefore, a new oral exposure, taste-masking, immediate-release formulation suitable for patients with depression must be developed as soon as possible to meet the clinical individualized dosing needs. Summary of the Invention

[0010] To address the issues of vortioxetine irritation to the oral mucosa and tongue surface and its unpleasant texture, one or more embodiments of the present application provide a taste-masked formulation of vortioxetine in an immediate release dosage form, which, by employing appropriate auxiliary materials and manufacturing methods, improves patient compliance and tolerance.

[0011] According to one or more embodiments of the present application, the vortioxetine hemihydrobromide orodispersible formulation comprises vortioxetine hemihydrobromide and pharmaceutically acceptable excipients.

[0012] In one or more embodiments of the present application, the orally dispersible formulation of the present application is a tablet, granule, capsule, powder, suspension, dry suspension, or solution.

[0013] In one or more embodiments of the present application, the tablet is an orally disintegrating tablet or an orally dispersible tablet.

[0014] According to one or more embodiments of the present application, the orally dispersible taste-masked formulation of vortioxetine hemi- or monohydrobromide comprises vortioxetine hemi- or monohydrobromide and a pharmaceutically acceptable taste-masking aid.

[0015] In one or more embodiments of the present application, in the orally dispersible taste-masked formulation of the present application, the vortioxetine hemi- or monohydrobromide is coated with the taste-masking aid to form coated granules.

[0016] In one or more embodiments of the present application, the taste-masking auxiliary material in the coated granules is a cellulose acetate-based material, an ethyl cellulose-based material, a hydroxypropyl cellulose-based material, a methacrylic acid copolymer-based material, a chitosan-based material, a copolyvidone, or a polyvinyl alcohol.

[0017] In one or more embodiments of the present application, the taste-masking adjunct material in the coated granules comprises an alkaline adjunct material.

[0018] In one or more embodiments of the present application, the coated granules include an anti-sticking agent.

[0019] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide in the orally dispersible taste-masked formulation is dispersed in a taste-masking aid material to form a solid dispersion.

[0020] In one or more embodiments of the present application, the taste-masking auxiliary material in the solid dispersion is a cellulose acetate-based material, an ethyl cellulose-based material, a hydroxypropyl cellulose-based material, a methacrylic acid copolymer-based material, a chitosan-based material, a copolyvidone, a crospovidone, a polyvinyl alcohol-based material, or a polyethylene glycol-based material.

[0021] In one or more embodiments of the present application, the taste-masking adjunct material in the solid dispersion comprises an alkaline adjunct material.

[0022] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide in the solid dispersion is mixed with an alkaline auxiliary material.

[0023] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide salt in the solid dispersion is mixed with at least one of trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine to form a composition.

[0024] In one or more embodiments of the present application, the taste-masking coated granules of vortioxetine hemi- or monohydrobromide may comprise a taste-masking coating auxiliary material selected from the group consisting of cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, methacrylic acid copolymer, chitosan, copolyvidone, and polyvinyl alcohol.

[0025] In one or more embodiments of the present application, the taste-masking coating auxiliary material comprises an alkaline auxiliary material.

[0026] In one or more embodiments of the present application, the taste-masking coating aid material comprises an anti-sticking agent.

[0027] In one or more embodiments of the present application, in the taste-masking solid dispersion of vortioxetine hemi- or monohydrobromide, the taste-masking aid material is cellulose acetate-based, ethyl cellulose-based, hydroxypropyl cellulose-based, methacrylic acid copolymer-based, chitosan-based, copolyvidone, crospovidone, polyvinyl alcohol or polyethylene glycol-based.

[0028] In one or more embodiments of the present application, the taste-masking adjunct material comprises an alkaline adjunct material.

[0029] According to one or more embodiments of the present application, the taste-masking composition for vortioxetine hemi- or monohydrobromide comprises vortioxetine hemi- or monohydrobromide, an alkaline auxiliary material.

[0030] In one or more embodiments of the present application, the alkaline auxiliary material of the taste-masking composition is at least one of trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine.

[0031] In one or more embodiments of the present application, the methacrylic acid copolymer system in the orally dispersible taste-masking formulation, the taste-masking coated granules, or the taste-masking solid dispersion is a polyacrylic acid resin.

[0032] In one or more embodiments of the present application, the polyacrylic acid resin in the orally dispersible taste-masking formulation, the taste-masking coated granules, or the taste-masking solid dispersion is polyacrylic acid resin II or polyacrylic acid resin IV.

[0033] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide in the orally dispersible taste-masked formulation or the taste-masking coated granules is coated with a taste-masking auxiliary material to form coated granules, which are further dispersed in a taste-masking auxiliary material to form a solid dispersion, and the formed solid dispersion is further mixed with an alkaline auxiliary material.

[0034] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide in the orally dispersible taste-masked formulation or solid dispersion is dispersed in a taste-masking aid to form a solid dispersion, the solid dispersion is further coated with a taste-masking aid to form coated granules, and the formed coated granules are further mixed with an alkaline aid.

[0035] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide in the orally dispersible taste-masked formulation or the taste-masking coated granules is coated with a taste-masking auxiliary material to form coated granules, and the formed coated granules are further mixed with an alkaline auxiliary material.

[0036] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide in the orally dispersible taste-masked formulation or solid dispersion is dispersed in a taste-masking auxiliary material to form a solid dispersion, and the formed solid dispersion is further mixed with an alkaline auxiliary material.

[0037] In one or more embodiments of the present application, the taste-masking coating auxiliary material in the orally dispersible taste-masking formulation or taste-masking coated granules is a cellulose acetate-based, ethyl cellulose-based, hydroxypropyl cellulose-based, methacrylic acid copolymer-based, chitosan-based, copolyvidone-based, or polyvinyl alcohol-based material.

[0038] According to one or more embodiments of the present application, the taste-masking auxiliary material in the orally dispersible taste-masking formulation or the taste-masking solid dispersion is a cellulose acetate-based material, an ethyl cellulose-based material, a hydroxypropyl cellulose-based material, a methacrylic acid copolymer-based material, a chitosan-based material, a copolyvidone, a crospovidone, a polyvinyl alcohol-based material, or a polyethylene glycol-based material.

[0039] In one or more embodiments of the present application, the alkaline auxiliary material in the orally dispersible taste-masking formulation or taste-masking composition is at least one of trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine.

[0040] In one or more embodiments of the present application, the weight ratio of vortioxetine hemi- or monohydrobromide in the orally dispersible taste-masked formulation, taste-masking coated granules, taste-masking solid dispersion or taste-masking composition to the drug-acceptable taste-masking auxiliary material forming the coating or solid dispersion is 1:0.1 to 1:5, for example 1:0.3 to 1:3, 1:0.5 to 1:1.5, or for example 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4 or 1:5.

[0041] In one or more embodiments of the application, the weight ratio of vortioxetine hemi- or monohydrobromide to the pharmaceutically acceptable alkaline auxiliary material is 1:0.01 to 1:1.1, such as 1:0.01 to 1:1, or such as 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.5, 1:1, 1:1.1.

[0042] In one or more embodiments of the present application, the orally dispersible taste-masking formulation, the taste-masking coated granule, the taste-masking solid dispersion or the taste-masking composition of the present application is crystalline or amorphous.

[0043] In one or more embodiments of the present application, the orally dispersible taste-masking formulation, taste-masking coated granule, taste-masking solid dispersion or taste-masking composition of the present application comprises a filler, a flavoring agent, a release-modifying agent, a plasticizer, an anti-adherent agent, and / or a disintegrant.

[0044] In one or more embodiments of the present application, the anti-adherent agent is talc and comprises 5% to 25%, for example, 10% to 20%, or for example, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the total weight of the taste-masking coated granules.

[0045] In one or more embodiments of the present application, the taste masking agent is neotame, and accounts for 0.05% to 0.5%, for example, 0.1%, 0.2%, or 0.3%, of the total weight of the orally dispersible taste-masking formulation.

[0046] In one or more embodiments of the present application, the release-modifying agent is polyethylene glycol or an alkaline auxiliary material.

[0047] In one or more embodiments of the present application, the disintegrant is sodium carboxymethyl starch, croscarmellose sodium, crospovidone, or a combination thereof, and accounts for 1% to 8%, preferably 2% to 6%, of the total weight of the orally dispersible taste-masking formulation.

[0048] In one or more embodiments of the present application, the orally dispersible taste-masking formulation, taste-masking coated granules, taste-masking solid dispersion or taste-masking composition is prepared into a tablet, granule, capsule, powder, suspension, dry suspension or solution.

[0049] In one or more embodiments of the present application, the tablet is an orally disintegrating or dispersible tablet.

[0050] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide in the orodispersible formulation, orodispersible taste-masked formulation, taste-masking coated granules, taste-masking solid dispersion or taste-masking composition is amorphous or crystalline.

[0051]

[0010] One or more embodiments of the present application provide a use of vortioxetine hemihydrobromide in the manufacture of an orodispersible agent, taste-masking coated granules, taste-masking solid dispersion, taste-masking composition, or orodispersible taste-masking formulation. In one or more embodiments of the present application, the orodispersible agent or orodispersible taste-masking formulation produced is a tablet, granule, capsule, powder, suspension, dry suspension, or solution. In one or more embodiments of the present application, the tablet is an orally disintegrating tablet or a dispersible tablet.

[0052] One or more embodiments of the present application provide a use of vortioxetine monohydrobromide in the manufacture of an orodispersible agent, taste-masking coated granules, taste-masking solid dispersion, taste-masking composition, or orodispersible taste-masking formulation. In one or more embodiments of the present application, the orodispersible agent or orodispersible taste-masking formulation to be manufactured is a tablet, granule, capsule, powder, suspension, dry suspension, or solution. In one or more embodiments of the present application, the tablet is an orally disintegrating tablet or a dispersible tablet.

[0053] According to one or more embodiments of the present application, a method for producing taste-masked coated vortioxetine hemi- or monohydrobromide granules or formulations thereof comprises: (1) milling vortioxetine hemi- or monohydrobromide to obtain vortioxetine hemi- or monohydrobromide powder; (2a) dispersing a taste-masking aid in a solvent and subjecting the vortioxetine hemi- or mono-hydrobromide powder to a fluidized bed treatment to coat the vortioxetine hemi- or mono-hydrobromide with the taste-masking aid, and after removing the solvent, obtaining vortioxetine hemi- or mono-hydrobromide coated with the taste-masking aid; or adding the vortioxetine hemi- or monohydrobromide powder and taste-masking aid to a solvent to form a vortioxetine hemi- or monohydrobromide suspension, and removing the solvent by fluidized bed, spray drying or evaporation to obtain vortioxetine hemi- or monohydrobromide coated with taste-masking aid (2b); Optionally, step (3) of manufacturing the coated vortioxetine hemi- or monohydrobromide into a formulation.

[0054] In one or more embodiments of the present application, vortioxetine hemi- or monohydrobromide is milled and then sieved through a 20-300 mesh sieve, for example a 100, 150 or 200 mesh sieve.

[0055] In one or more embodiments of the present application, the taste-masking aid and the release-modifying agent are dispersed in a solvent.

[0056] In one or more embodiments of the present application, the release-modifying agent is polyethylene glycol or an alkaline auxiliary material.

[0057] In one or more embodiments of the present application, the solvent is water, ethanol, or dichloromethane.

[0058] Preferably, the vortioxetine hemi- or monohydrobromide powder, taste-masking aid, release modifier and plasticizer are added to a solvent to form a vortioxetine hemi- or monohydrobromide suspension, more preferably the plasticizer is polyethylene glycol or triethyl citrate, and preferably the solvent is water, ethanol or dichloromethane.

[0059] According to one or more embodiments of the present application, a method for producing a solid dispersion of vortioxetine hemi- or monohydrobromide or a formulation thereof comprises: (1) milling vortioxetine hemi- or monohydrobromide to obtain vortioxetine hemi- or monohydrobromide powder; (2a) mixing the vortioxetine hemi- or monohydrobromide powder with a taste-masking auxiliary material, heating to soften or liquefy at 50 to 150°C, cooling to solidify, and pulverizing to obtain a powder; or (2b) dissolving the vortioxetine hemi- or mono-hydrobromide powder and a taste-masking aid in a solvent and removing the solvent by distillation, fluidized bed or spray drying to obtain a powder; Optionally, step (3) of manufacturing the powder obtained in step (2a) or (2b) into a formulation.

[0060] In one or more embodiments of the present application, vortioxetine hemi- or monohydrobromide is milled and then sieved through a 20-300 mesh sieve, for example a 100, 150 or 200 mesh sieve.

[0061] In one or more embodiments of the present application, the vortioxetine hemi- or monohydrobromide powder, a taste-masking aid and a release-modifying agent are mixed together.

[0062] In one or more embodiments of the present application, the solvent is water, ethanol, or dichloromethane.

[0063] In one or more embodiments of the present application, the taste-masking auxiliary material is a cellulose acetate-based material, an ethyl cellulose-based material, a hydroxypropyl cellulose-based material, a methacrylic acid copolymer-based material, a chitosan-based material, a copolyvidone-based material, a crospovidone-based material, a polyvinyl alcohol-based material, or a polyethylene glycol-based material.

[0064] In one or more embodiments of the present application, the methacrylic acid copolymer system is a polyacrylic acid resin.

[0065] In one or more embodiments of the present application, the polyacrylic acid resin is polyacrylic acid resin II or polyacrylic acid resin IV.

[0066] One or more embodiments of the present application relate to a method for preparing a taste-masked composition of vortioxetine hemi- or monohydrobromide or a formulation thereof, comprising: (1) milling vortioxetine hemi- or monohydrobromide to obtain vortioxetine hemi- or monohydrobromide powder; (2) mixing the vortioxetine hemi- or monohydrobromide powder with an alkaline auxiliary material to obtain a taste-masking composition; Optionally, step (3) of manufacturing the taste-masking composition into a formulation.

[0067] Preferably, vortioxetine hemi- or monohydrobromide is pulverized and then sieved through a 50-300 mesh sieve, more preferably a 100-200 mesh sieve.

[0068] Preferably, the alkaline auxiliary material is trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine.

[0069] In one or more embodiments of the present application, the powder can be manufactured into a conventional formulation using methods common in the art.

[0070] In one or more embodiments of the present application, the weight ratio of vortioxetine hemi- or mono-hydrobromide to the pharmaceutically acceptable taste-masking adjunct is 1:0.1 to 1:5, such as 1:0.5 to 1:1.5, 1:0.3 to 1:1.5, 1:0.3 to 1:1.3, or such as 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4 or 1:5, and the weight ratio of vortioxetine hemi- or mono-hydrobromide to the pharmaceutically acceptable alkaline adjunct is 1:0.01 to 1:1.1, preferably 1:0.01 to 1:1.

[0071] In one or more embodiments of the present application, in a solid dispersion comprising vortioxetine hemihydrobromide and polyacrylic acid resin IV, the weight ratio of said vortioxetine hemihydrobromide salt to polyacrylic acid resin IV is 1:0.1 to 1:5, such as 1:0.3 to 1:2, 1:0.5 to 1:1.5, or for example 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4 or 1:5.

[0072] In one or more embodiments of the present application, the solid dispersion comprising vortioxetine monohydrobromide and polyacrylic acid resin IV may have a weight ratio of vortioxetine hemihydrobromide to polyacrylic acid resin IV of 1:0.1 to 1:5, 1:0.3 to 1:2, 1:0.5 to 1:1.5, or for example, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4 or 1:5. In one or more embodiments of the present application, the solid dispersion comprising vortioxetine hemihydrobromide and polyacrylic acid resin IV has the characteristic peaks shown in Figure 20.

[0073] In one or more embodiments of the present application, the solid dispersion comprising vortioxetine monohydrobromide and polyacrylic acid resin IV has the characteristic peaks shown in Figure 22.

[0074] In one or more embodiments of the present application, the X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, for the solid dispersion comprising vortioxetine hemihydrobromide and polyacrylic acid resin IV, or the solid dispersion formed with vortioxetine monohydrobromide and polyacrylic acid resin IV has characteristic peaks at the following positions: 4.2±0.2°, 14.5±0.2°, 17.4±0.2°, 19.2±0.2° and 22.6±0.2°.

[0075] In one or more embodiments of the present application, the X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, for the solid dispersion comprising vortioxetine hemihydrobromide and polyacrylic acid resin IV, or the solid dispersion formed with vortioxetine monohydrobromide and polyacrylic acid resin IV, has characteristic peaks at the following positions: 4.2±0.2°, 14.5±0.2°, 16.6±0.2°, 17.4±0.2°, 19.2±0.2°, 21.5±0.2°, 22.6±0.2°, 24.4±0.2°, 26.0±0.2°, 28.2±0.2° and 29.0±0.2°.

[0076] In one or more embodiments of the present application, the solid dispersion comprising vortioxetine hemihydrobromide and polyacrylic acid resin IV, or the solid dispersion formed with vortioxetine monohydrobromide and polyacrylic acid resin IV, further comprises at least one of PEG 4000, PEG 6000 and PEG 8000.

[0077] In one or more embodiments of the present application, the weight ratio of the polyacrylic acid resin IV to at least one of PEG 4000, PEG 6000, and PEG 8000 is 1:0.05 to 1:2, for example, 1:0.05, 1:0.1, 1:0.5, 1:1, 1:1.5, or 1:2.

[0078] One or more embodiments of the present application provide the use of the orally dispersible taste-masked formulation, taste-masking coated granules, taste-masking solid dispersion or taste-masking composition of vortioxetine hemi- or monohydrobromide salt of the present application in the manufacture of an antidepressant.

[0079] According to one or more embodiments of the present application, the orally dispersible taste-masked formulation, taste-masking coated granules, taste-masking solid dispersion and taste-masking composition of vortioxetine hemi- or mono-hydrobromide salt of the present application may be used for the treatment of depression or for the manufacture of an antidepressant.

[0080] A method for treating depression according to one or more embodiments of the present application comprises administering to a subject in need thereof an orally dispersible taste-masked formulation, taste-masking coated granules, taste-masking solid dispersion or taste-masking composition of vortioxetine hemi- or monohydrobromide as defined in any one of the preceding claims.

[0081] MODE FOR CARRYING OUT THE INVENTION In one or more embodiments of the present application, the orally dispersible formulation allows the drug to be present in the oral cavity in the form of a particulate formulation (e.g., granules, powders, suspensions, dry suspensions) or a liquid formulation (e.g., oral suspension), or can be rapidly converted into a particulate or liquid form in the oral cavity (e.g., orally disintegrating tablets, orally dispersible tablets).

[0082] In one or more embodiments of the present application, vortioxetine hydrobromide powder is embedded or coated with a suitable taste-masking polymeric auxiliary material to obtain coated granules, which are then manufactured into an orally dispersible formulation by known methods for manufacturing oral formulations.

[0083] In one or more embodiments of the present application, the orodispersible formulation of vortioxetine hydrobromide comprises vortioxetine hydrobromide, a taste-masking polymer, one of chitosan and deacetylated chitosan, and other auxiliary materials, in a weight ratio of vortioxetine hydrobromide:polymer containing dimethylaminoethyl units, chitosan, or deacetylated chitosan=1:0.1 to 1:5, for example, 0.3 to 1:3.

[0084] In one or more embodiments of the present application, the orally dispersible formulation of vortioxetine hydrobromide further comprises an anti-adherent agent in a formulation ratio (percentage of the total weight of the taste masking granules) of 5% to 25% to prevent adhesion during the manufacturing process of the taste masking coated granules. The anti-adherent agent may be talc.

[0085] In one or more embodiments of the present application, the orodispersible formulation of vortioxetine hydrobromide further comprises a flavoring agent in a formulation ratio (percentage of the total weight of the formulation) of 0.05% to 0.5%, which may be neotame.

[0086] One or more embodiments of the present application provide a second solution in which vortioxetine hydrobromide and suitable polymeric excipients are prepared into a crystalline or amorphous solid dispersion, which is then subsequently manufactured into an orally dispersible formulation using known methods for manufacturing oral formulations.

[0087] In one or more embodiments of the present application, the orally dispersible, taste-masked formulation of vortioxetine hydrobromide comprises vortioxetine hydrobromide, a taste-masking polymer, chitosan, or one of deacetylated chitosan, and other auxiliary materials, in a weight ratio of vortioxetine hydrobromide to polymer containing dimethylaminoethyl units, chitosan, or deacetylated chitosan of 1:0.3 to 1:5.

[0088] In one or more embodiments of the present application, the orally dispersible, taste-masked formulation of vortioxetine hydrobromide further comprises a flavoring agent in a formulation ratio (percentage of the total weight of the formulation) of 0.05% to 0.5%, which may be neotame.

[0089] One or more embodiments of the present application provide a third solution by using a weakly alkaline auxiliary material to quickly change the pH environment in which the drug disperses in the oral cavity, so that the drug dissolution in the oral cavity is below the irritation threshold and returns to an acidic pH environment in gastric juice, thereby solving the problems of exposure in the oral cavity, dissolution in the digestive tract, and absorption and metabolism.

[0090] In one or more embodiments of the present application, the orally dispersible, taste-masked formulation of vortioxetine hydrobromide comprises vortioxetine hydrobromide, an alkaline or weakly alkaline taste-masking agent, and a flavoring agent, in a weight ratio of vortioxetine hydrobromide:flavoring agent=1:(0.0001-0.01), for example, 1:(0.0009-0.009).

[0091] In one or more embodiments of the present application, the taste-masking agent in the orally dispersible, taste-masked formulation of vortioxetine hydrobromide is a medicinal alkaline auxiliary material, including, but not limited to, trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide or methylamine phosphate.

[0092] In one or more embodiments of the present application, the taste masking agent in the orodispersible taste-masked formulation of vortioxetine hydrobromide is a medicinal taste masking agent, including but not limited to neotame.

[0093] In one or more embodiments of the present application, the taste-masked coated granules or taste-masked solid dispersion of vortioxetine hydrobromide may be prepared into an orally dispersible formulation of vortioxetine hydrobromide.

[0094] In one or more embodiments of the present application, the oral exposure or dispersion formulation of the taste-masked coated granules or taste-masked solid dispersion of vortioxetine hydrobromide includes, but is not limited to, those that are present in the oral cavity in the form of a particulate formulation (e.g., granules, powders, suspensions, dry suspensions) or a liquid formulation (e.g., oral liquid), or that can be rapidly converted into a particulate or liquid form in the oral cavity (e.g., orally disintegrating tablets, orally dispersible tablets).

[0095] According to one or more embodiments of the present application, a method for producing a taste-masked formulation of the drug vortioxetine hydrobromide includes at least the following three methods, Method 1 to Method 3.

[0096] Method one: (1) milling vortioxetine hydrobromide to obtain vortioxetine hydrobromide powder, and preferably sieving the powder through a 20-300 mesh sieve, more preferably through a 100-200 mesh sieve, Step (2a) of dispersing a taste-masking aid in a solvent, coating the vortioxetine hydrobromide powder with the taste-masking aid in a fluidized bed, and after removing the solvent, obtaining vortioxetine hydrobromide coated with the taste-masking aid, preferably dispersing the taste-masking aid and the release modifier in a solvent, more preferably the release modifier is polyethylene glycol or an alkaline aid, and preferably the solvent is water, ethanol or dichloromethane; or Step (2b) of adding the vortioxetine hydrobromide powder and taste-masking aid to a solvent to form a suspension, and removing the solvent by fluidized bed, spray drying or evaporation to obtain vortioxetine hydrobromide coated with taste-masking aid, preferably adding the vortioxetine hydrobromide powder, taste-masking aid, and / or release modifier and plasticizer to a solvent to form a vortioxetine hydrobromide suspension, preferably the plasticizer is polyethylene glycol or triethyl citrate, and preferably the solvent is water, ethanol or dichloromethane; Optionally, step (3) of manufacturing the coated vortioxetine hydrobromide into a formulation.

[0097] Method two: (1) milling vortioxetine hydrobromide to obtain vortioxetine hydrobromide powder, and preferably sieving the powder through a 20-300 mesh sieve, more preferably through a 100-200 mesh sieve, (2a) mixing the vortioxetine hydrobromide powder with a taste-masking adjuvant, heating to soften or liquefy at 50-150°C, cooling to solidify, and pulverizing to obtain a powder, preferably mixing the vortioxetine hydrobromide powder with a taste-masking adjuvant and a release-modifying agent; or Step (2b) of dissolving the vortioxetine hydrobromide powder and taste-masking aid in a solvent and removing the solvent by distillation, fluidized bed or spray drying to obtain a powder, preferably wherein the solvent is water, ethanol or dichloromethane; Optionally, step (3) of manufacturing the powder obtained in step (2a) or (2b) into a formulation.

[0098] Method three: (1) milling vortioxetine hemi- or monohydrobromide to obtain vortioxetine hemi- or monohydrobromide powder, and preferably sieving the powder through a 50-300 mesh sieve, more preferably through a 100-200 mesh sieve, Step (2) mixing the vortioxetine hemi- or monohydrobromide powder with an alkaline auxiliary material to obtain a taste-masking composition, preferably the alkaline auxiliary material being trisodium phosphate, disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, tripotassium citrate, sodium acetate, calcium hydroxide or meglumine; Optionally, step (3) of manufacturing the taste-masking composition into a formulation.

[0099] In one or more embodiments of the present application, the method may use vortioxetine hemi- or monohydrobromide, or may use amorphous or crystalline vortioxetine hemi- or monohydrobromide.

[0100] In one or more embodiments of the present application, the three manufacturing methods may be carried out independently, in combination with each other, or in combination based on known manufacturing processes for formulations.

[0101] In one or more embodiments of the present application, the release-modifying agent in the manufacturing method includes, but is not limited to, mannitol, sorbitol, polyethylene glycol, polyethylene glycol, hydroxypropyl cellulose, and / or hypromellose.

[0102] In one or more embodiments of the present application, the plasticizer in the manufacturing method includes, but is not limited to, polyethylene glycol and / or triethyl citrate.

[0103] In one or more embodiments of the present application, the orally dispersible, taste-masked formulation of vortioxetine hydrobromide can be prepared by co-dissolving one or more pharmaceutically acceptable resins and vortioxetine hydrobromide in one or more pharmaceutically acceptable solvents to obtain a true solution, and then removing the solvent from the solution by rotary evaporation, spray drying or fluidized bed granulation to obtain a solid dispersion of microcrystalline vortioxetine hydrobromide in the limited space of the polymer. Other well-known auxiliary materials can then be added in appropriate amounts according to a conventional formulation process, and the taste can then be masked with a low-molecular-weight alkaline material to produce an orally dispersible, taste-masked formulation of vortioxetine hydrobromide for oral exposure.

[0104] In one or more embodiments of the present application, polyacrylic acid resin IV and vortioxetine hemi- or monohydrobromide are dissolved in a solvent, and the weight ratio of vortioxetine hemi- or monohydrobromide to polyacrylic acid resin IV is 1:0.1 to 1:5, preferably 1:0.3 to 1:2, and more preferably 1:0.5 to 1:1.5. After removing the solvent, a solid dispersion is obtained, and the characteristic peaks of powder crystal diffraction are 4.2±0.2°, 14.5±0.2°, 17.4±0.2°, 19.2±0.2° and 22.6±0.2°, and the characteristic peaks of powder crystal diffraction are 4.2±0.2°, 14.5±0.2°, 16.6±0.2°, 17.4±0.2°, 19.2±0.2°, 21.5±0.2°, 22.6±0.2°, 24.4±0.2°, 26.0±0.2°, 28.2±0.2° and 29.0±0.2°. Stability studies have shown that the solid dispersion has stable dissolution, stable impurities and stable crystallinity.

[0105] In one or more embodiments of the present application, the method for preparing the taste-masked orally dispersible formulation of vortioxetine includes co-dissolving one or more pharmaceutically acceptable resins and vortioxetine hydrobromide in one or more pharmaceutically acceptable solvents, subsequently reducing the solubility of the solution or removing the solvent, causing vortioxetine and the resin to form a solid dispersion and granules thereof. Other well-known auxiliary materials may be added in appropriate amounts according to common formulation processes to prepare the taste-masked orally dispersible formulation of vortioxetine hydrobromide, in which vortioxetine exists in the resin in an ionic or molecular state and interacts with functional groups in the resin, allowing it to dissociate slowly in the oral environment and then rapidly dissociate into vortioxetine in the gastrointestinal tract after passing through the gastric environment.

[0106] In one or more embodiments of the present application, one or more pharmaceutically acceptable resins and vortioxetine hemi- or mono-hydrobromide are co-dissolved in one or more pharmaceutically acceptable solvents, and then the solubility of the solution is reduced (e.g., by adding an anti-solvent or lowering the temperature) or the solvent is removed to obtain a solid dispersion of amorphous vortioxetine hydrobromide. Based on a common formulation process, other well-known auxiliary materials can be added in a prescribed amount, and alkaline auxiliary materials can be selectively added and mixed with the additional auxiliary materials. The alkaline auxiliary materials can change the microenvironment of the receptors in the mucosa and taste buds to reduce irritation, and vortioxetine hydrobromide exists in an amorphous aggregated state.

[0107] In one or more embodiments of the present application, the resin is a polyacrylic acid resin type (L, S type or II, III, IV type), -NH2, NR2, -COOH, -COO - , -SO3H, or -SO3 - Examples of suitable polymeric materials include, but are not limited to, linear polymeric materials such as methacrylic acid resins, divinylbenzene resins, and polystyrene resins containing the functional group:

[0108] In one or more embodiments of the present application, the method for preparing the taste-masked orally dispersible formulation of vortioxetine hydrobromide comprises homogeneously mixing one or more pharmaceutically acceptable taste-masking aids, one or more pharmaceutically acceptable release modifiers, and vortioxetine hydrobromide, followed by hot-melt granulation and hot-melt extrusion to prepare a solid dispersion. Other well-known adjuvants may then be added in a suitable amount according to a typical formulation process, and the solid dispersion may be further mixed with an alkaline taste-masking aid or coated with the taste-masking aid. The taste-masked orally dispersible formulation of vortioxetine hydrobromide is slowly or not released in the oral environment, and after passing through the gastric environment, rapidly dissociates into vortioxetine in the gastrointestinal tract for absorption.

[0109] In one or more embodiments of the present application, the alkaline linear polymeric material includes, but is not limited to, a polyacrylic acid resin system (e.g., type II or type IV), chitosan, or an amino sugar polymer.

[0110] In one or more embodiments of the present application, the release-modifying agent includes, but is not limited to, mannitol, sorbitol, polyethylene glycol, polyethylene glycol, hydroxypropyl cellulose, or hypromellose.

[0111] The inventors have developed a vortioxetine hemi-salt (C 18 H 22 N2S·1 / 2HBr) is vortioxetine monosalt (C 18 H 22 It has clearly less irritating properties than N2S·HBr, and has exactly the same C 18 H 22Surprisingly, we found that the amount of N2S was also reduced. In a sodium acetate medium with a pH of 6.8 that simulates the oral environment, the difference in solubility between the two is not significant (as determined by the standard method in the United States Pharmacopoeia, the solubility of vortioxetine monosalt is 0.15 mg / ml and that of vortioxetine hemi-salt is 0.14 mg / ml), but the irritation of vortioxetine hemi-salt is significantly reduced.

[0112] Vortioxetine hemi-salt is less irritating to the mouth and tongue, and when prepared into a solid dispersion with polymeric auxiliary materials, it can significantly improve the dissolution rate and total dissolution amount of vortioxetine in the gastrointestinal tract while ensuring no oral irritation.

[0113] Disintegration rate is an important clinical index for orally disintegrating tablets, and pharmacopoeias in various countries recommend a rate within one minute. For drugs with poor patient tolerance, the faster the better. Freeze-dried orally disintegrating tablets use freeze-drying technology, where the active ingredient in powder or solution is uniformly dispersed in the framework solution, then dispensed and freeze-dried. The resulting product can disintegrate within five seconds, but the process is complicated and difficult to commercialize. Compressed orally disintegrating tablets can achieve the one-minute disintegration time limit by using conventional tablet manufacturing techniques, an effective disintegrant, and reduced pelleting pressure. However, reduced pelleting pressure significantly affects tablet strength, resulting in wear and tear during production, transportation, and use. Researchers have combined various disintegrants to create composite disintegrants that ensure the finished product is within the normal tablet strength range and disintegrates within 10 seconds.

[0114] In one or more embodiments of the present application, the composite disintegrants include, but are not limited to, sodium carboxymethyl starch, croscarmellose sodium, and crospovidone.

[0115] In one or more embodiments of the present application, the weight ratio of carboxymethyl starch sodium, croscarmellose sodium, and crospovidone is 1:1:1, and the weight ratio in the formulation is 1% to 8%, for example, 2% to 6%.

[0116] In one or more embodiments of the present application, the present application uses a polymer known to be safe. Currently known molded products of this type of polymer mainly include polyacrylic acid resin type II and polyacrylic acid resin type IV (Eudragit type E). Eudragit type E, commonly known as Amino Methacrylate Copolymer, is listed in the United States Pharmacopoeia USP40-NF35 edition. The FDA has clarified that the maximum daily dose of this polymer used for taste masking of orally disintegrating tablets is 214.28 mg, which can meet the taste masking needs of vortioxetine hydrobromide and its analogue, Youshaku E100 (trade name of a Chinese pharmaceutical), which has the same chemical structure, physical and chemical properties, and quality standards as its counterpart.

[0117] In one or more embodiments of the present application, flavoring agents are selectively added to correct the taste, thereby improving the taste and providing a variety of flavors. One of the flavoring agents used in this technology is neotame, which is listed in the United States Pharmacopoeia USP40-NF35 edition and is widely used as a food additive.

[0118] In one or more embodiments of the present application, the use of a taste masking agent for the alkaline auxiliary material can clearly reduce the irritation to the tongue and reduce the irritation to a level that is clinically administrable.

[0119] In one or more embodiments of the present application, the taste-masking agent used is a medicament-acceptable adjuvant material.

[0120] The formulations according to one or more embodiments of the present application may improve patient compliance and compliance, enhance the dissolution of vortioxetine hydrobromide, potentially improve the bioavailability of the drug, and overcome the drawback of the prior art oral formulations of vortioxetine being a single dosage form that does not meet the needs of clinical differentiation and individualized dosing.

[0121] The inventors of the present application conducted a study on commercially available film-coated tablets of vortioxetine hydrobromide as follows: Single-dose tablets of 20 mg, 10 mg, and 5 mg were found to have a pronounced bitter taste and a long-lasting, strong, delayed irritation after dispersion in the oral cavity. The oral irritation has limited the development and clinical application of oral formulations other than film-coated tablets. [Brief explanation of the drawings]

[0122] [Figure 1] Figure 10: X-ray powder diffraction pattern of vortioxetine hemihydrobromide. [Figure 2] Figure 1 shows the X-ray powder diffraction pattern of vortioxetine monohydrobromide (α form). [Figure 3] Figure 1 shows the X-ray powder diffraction pattern of vortioxetine monohydrobromide (β form). [Figure 4] 1 shows the X-ray powder diffraction pattern of E100:PEG6000=1:0.23 after spray drying. [Figure 5] X-ray powder diffraction pattern of vortioxetine hemihydrobromide:solvent E100:PEG6000=1:0.3:0.07 taste-masked powder. [Figure 6] X-ray powder diffraction pattern of vortioxetine monohydrobromide alpha form: PEG 6000 (1:0.3:0.07 taste-masked powder). [Figure 7] X-ray powder diffraction pattern of vortioxetine monohydrobromide beta form: E100:PEG6000=1:0.3:0.07 taste-masked powder. [Figure 8]Figure 1 shows an ultraviolet scan of vortioxetine monohydrobromide in 0.1N hydrochloric acid. [Figure 9] FIG. 1 is an ultraviolet scan of Eudragit E PO in 0.1 N hydrochloric acid. [Figure 10] Figure 1 shows an ultraviolet scan of a powder mixture of vortioxetine monohydrobromide:Eudragit E PO=1:0.5 in 0.1N hydrochloric acid. [Figure 11] Figure 1 shows an ultraviolet scan of a hot melt powder mixture of vortioxetine monohydrobromide:Eudragit E PO=1:0.5 in 0.1N hydrochloric acid. [Figure 12] Figure 1 shows an ultraviolet scan of vortioxetine hemihydrobromide in 0.1N hydrochloric acid. [Figure 13] Figure 1 shows an ultraviolet scan of a powder mixture of vortioxetine hemihydrobromide:Eudragit E PO=1:1.5 in 0.1N hydrochloric acid. [Figure 14] Figure 1 shows an ultraviolet scan of a hot melt powder mixture of vortioxetine hemihydrobromide:Eudragit E PO=1:1.5 in 0.1N hydrochloric acid. [Figure 15] Figure 1 shows an ultraviolet scan of a vortioxetine hemihydrobromide:Eudragit E PO=1:5 powder mixture in 0.1N hydrochloric acid. [Figure 16] Figure 1 shows an ultraviolet scan of a vortioxetine hemihydrobromide:Eudragit E PO=1:5 hot melt powder mixture in 0.1N hydrochloric acid. [Figure 17] FIG. 1 is an ultraviolet scan of polyacrylic acid resin IV in 0.1N hydrochloric acid. [Figure 18] Figure 1 shows an ultraviolet scan of a powder mixture of vortioxetine monohydrobromide:polyacrylic acid resin IV=1:1.5 in 0.1N hydrochloric acid. [Figure 19] UV scan of hot melt powder of vortioxetine monohydrobromide:polyacrylic acid resin IV=1:1.5 in 0.1N hydrochloric acid. [Figure 20]X-ray powder diffraction pattern of a solid dispersion of vortioxetine hemihydrobromide-polyacrylic acid resin IV. [Figure 21] 1 is an X-ray powder diffraction pattern of polyacrylic acid resin IV after spray drying. [Figure 22] X-ray powder diffraction pattern of vortioxetine monohydrobromide-polyacrylic acid resin IV solid dispersion. [Figure 23] X-ray powder diffraction pattern of a solid dispersion of vortioxetine monohydrobromide:polyacrylic acid resin II=1:1.5. [Figure 24] 1 is an X-ray powder diffraction pattern of polyacrylic acid resin II (ethanol rotary evaporation). [Figure 25] X-ray powder diffraction pattern of a solid dispersion of vortioxetine hemihydrobromide:polyacrylic acid resin II=1:1.5. DETAILED DESCRIPTION OF THE INVENTION

[0123] Example Hereinafter, the embodiments of the present application will be described in detail with reference to specific examples. However, those skilled in the art should understand that the examples are merely for the purpose of illustrating the present application and should not be construed as limiting the scope of the present application.

[0124] In the examples, unless specific conditions are specified, the procedures are carried out according to general conditions or conditions recommended by the manufacturer or supplier. Unless the manufacturer and specific model of the reagents or equipment used are specified, they are all general products available on the market.

[0125] The polyacrylic acid resin II of the present application is designated as Methyl methacrylate-methacrylic acid copolymer (1:1) by the European Pharmacopoeia, as Methacrylic Acid Copolymer Type A by the United States Pharmacopoeia, and as "Pu Bing Huo Dilute Acid Resin II" by the Chinese Pharmacopoeia, and may be purchased, for example, from suppliers such as ROHM Corporation (for example, under the trade names Eudragit L, Eudragit L100, and Eudragit L PO) or Anhui Shanhe Pharmaceutical Supplements Co., Ltd. (for example, under the product name Pu Bing Huo Dilute Acid Resin II).

[0126] The polyacrylic acid resin IV of the present application is designated as Amino Methacrylate Copolymer by the United States Pharmacopoeia and as "Jubinghuo Dilute Acid Resin IV" by the Chinese Pharmacopoeia, and may be purchased, for example, from suppliers such as Rohm Company (e.g., trade names Eudragit E100, Eudragit E PO), Guangzhou Maofeng Pharmaceutical Supplements Co., Ltd. (e.g., trade names Yousha E, Yousha E100), or Anhui Shanhe Pharmaceutical Supplements Co., Ltd. (e.g., product name Jubinhuo Dilute Acid Resin IV).

[0127] Other polyacrylic acid resins may be purchased, for example, from Rohm Company, under the trade names Eudragit RL100, Eudragit L100, Eudragit RS PO, and Eudragit S100. The auxiliary materials used in the examples are not auxiliary materials related to the present application, and when preparing formulations using the present application, other known general functional pharmaceutical auxiliary materials may be used depending on the dosage form, formulation stability, and clinical use requirements. In the examples, when no specific crystalline form is specified for vortioxetine monohydrobromide, it indicates that any of crystalline forms α, β, or γ can be used.

[0128] Equipment used in the experiment: The X-ray powder diffraction (XRD) instrument used was a D / max-2200 / pc equipped with a RINT2000 vertical goniometer, MO monochromator, and scintillation counter detector. The acquisition software was XG operation. The instrument was calibrated using a silicon single crystal standard. The detection conditions were a 2θ scan angle range of 3–40° or 3–50°, a step size of 0.02°, and a speed of 6° / min. The detection process utilized Kα X-rays with a copper target wavelength of 1.54 nm, operating at 40 kV and 20 mA, and testing samples at room temperature. The required samples were placed on a SiP anti-reflection plate. The samples were sieved before detection.

[0129] UV-visible spectrophotometer: UV-2600, Shimadzu, Japan.

[0130] Analytical balance: AUW120D, SHIMADZU.

[0131] Rotary evaporator: R205, Taizhou Xinli Electronic Equipment Co., Ltd.

[0132] Hot air circulation oven: DHG-9070A, Shanghai Yheng Scientific Instruments Co., Ltd.

[0133] Vortex mixer: Vortex-2, Shanghai Cosmetics Industry Co., Ltd.

[0134] Multifunctional fluidized bed: BWF-1G, Chongqing Yingge Granulation Packaging Technology Co., Ltd.

[0135] Vacuum freeze dryer: FD-2D, Beijing BoMikang Experimental Equipment Co., Ltd.

[0136] Rotary tablet press: ZP8, Shanghai Xinyuan Pharmaceutical Machinery Co., Ltd.

[0137] High efficiency coating machine: Labcoating IV, Shenzhen Xinyi Special Technology Co., Ltd.

[0138] Dry granulator: GL-5B, Setsue Meiten Machinery Co., Ltd.

[0139] Graining machine: P100, Shenzhen Xinyi Special Technology Co., Ltd.

[0140] Portable pH meter: STARTER 300.

[0141] Freezer dryer: SCIENT2-30F, Ningbo New Lawn Materials Technology Co., Ltd.

[0142] Flatbed blister packaging machine; Setsue Jiangmingtian Machinery Co., Ltd.

[0143] How we collect relevant data: Detection method for pH value and exposure amount (based on vortioxetine): Take one tablet of this product (or powder equivalent to 20 mg of vortioxetine), add 5.0 g of purified water, seal and shake to disperse at 36 ± 2°C, incubate for 5 minutes, cool to room temperature, detect the pH value of the suspension, filter through a 0.22 μm Millipore filter, take 2.0 ml of the filtrate and dilute it to 10 ml with purified water to use as the test solution, and further dilute it quantitatively with purified water to a 10 μg / ml (based on vortioxetine) solution to use as the control solution. Detect the absorbance at a wavelength of 226 nm using the UV method, and calculate the dissolution concentration and relative dissolution amount of vortioxetine.

[0144]

number

[0145] Control absorbance x 20 Determination of bromine content in vortioxetine hydrobromide by titration: First, prepare a 0.1 mol / L silver nitrate titrant solution, then prepare a 5 mg / ml eosin Y test solution. Take a 0.3 g sample, add 60 mL of methanol to dissolve it, then add 20 mL of water, 20 mL of glacial acetic acid, and 8 drops of eosin Y test solution, and titrate with silver nitrate titrant solution until the end point (pink) appears. Carry out a blank test. The calculation formula is as follows: Br%=[(Vs-Vb)xNx7.990] / [0.1xWx(1-Water%)]x100% where: V S = volume of 0.1 mol / mL silver nitrate titrant consumed by the sample, mL V b = volume consumed in blank test, mL N = normality of silver nitrate titrant W = sample weight, mg Water % = water content of the sample 7.990 = each mL of 0.1 mol / mL silver nitrate titrant corresponds to 7.990 mg of Br In the examples, the taste masking effect is evaluated based on the subject's sensitivity to the bitterness and irritation of the test sample to the oral cavity and tongue.

[0146] Texture and spiciness ratings tested by subjects: 0-1 minute instantaneous stimulation Delayed stimulation Bitterness +++ Strong, almost unbearable 1-15 minute delay Tolerable ++ Stinging, but tolerable 15-30 minute delay Tolerable + Little to no stimulation Delay of more than 30 minutes Unacceptable The average value is calculated after 5-10 subjects have completed the test.

[0147] Preparation Example 1 Preparation of vortioxetine free base Vortioxetine was synthesized by referring to the manufacturing method described in Example 24 of Patent Document WO2007 / 144005A1. Specifically, under a nitrogen atmosphere, 200 mL of toluene, 40.76 g of sodium tert-butoxide, 0.33 g of Pd(dba)2 [bis(dibenzylideneacetone)palladium(0)], and 0.68 g of rac-BINAP (2,2'-bis(diphenylphosphine)-1,1'-binaphthyl) were added in this order to a 500 mL four-neck flask, and stirring was started. Then, 19.54 g of 2,4-dimethylthiophene was added to the flask. To the mixture was added 42.00 g of 2-bromoiodobenzene, which was heated to reflux for 5 hours, cooled to room temperature, filtered to remove insoluble materials, and the filtrate was returned to a 500 mL four-neck flask. 42.20 g of anhydrous piperazine, 40.76 g of sodium tert-butoxide, 0.33 g of Pd(dba)2, and 0.68 g of rac-BINAP were added, and the mixture was refluxed for 2 hours, at which point the reaction was complete.

[0148] The solution was cooled to room temperature and extracted with 100 mL of water. The organic phase was filtered and the filtrate was washed with 3 x 80 mL of saturated brine. The organic phase was heated to 70°C, 16.50 mL of 48% hydrobromic acid (145.9 mmol) and 8.3 mL of water were added, stirred for 30 minutes, cooled to room temperature, kept warm for 2 hours, filtered, washed with toluene and sucked dry. The filter cake was dried in vacuo at 50°C for 10 hours to give 40.18 g of white solid 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide, i.e., vortioxetine hydrobromide, with a molar yield of 75%.

[0149] 40.18 g of vortioxetine hydrobromide obtained in the previous step was dissolved in 200 mL of water, 200 mL of dichloromethane was added, the pH was adjusted to 9-10 with 15% aqueous sodium hydroxide, the mixture was incubated for 30 minutes, and the mixture was allowed to stand for layer separation. The aqueous phase was extracted once with 100 mL of dichloromethane, combined with the organic phase and washed with 100 mL of water. The organic phase was separated and dried with 5 g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 29.7 g of white crystalline 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine, i.e., vortioxetine free base, with a molar yield of 94.0%.

[0150] Preparation Example 2: Preparation of vortioxetine hemihydrobromide Vortioxetine hemihydrobromide was prepared by referring to the synthetic method described in Example 1 of Patent US9562024B2. Specifically, 8.00 g (26.8 mmol) of vortioxetine was placed in a 250 mL round-bottom flask, 122 mL of ethanol was added, and the mixture was dissolved using ultrasonic waves. 2.70 g of hydrobromic acid (40% wt. concentration, 13.3 mmol) was added, 16 mL of ethanol was added, and the mixture was dissolved using ultrasonic waves. Under stirring, the ethanol solution of hydrobromic acid was slowly added dropwise to the ethanol solution of vortioxetine. During the addition, a solid precipitated, which was then rotary dried at 40°C and vacuum dried at 40°C for 24 hours to remove the solvent. 8.91 g (13.1 mmol) of white solid vortioxetine hemihydrobromide was obtained with a yield of 98.5%. The bromine content determined by titration was 11.60%.

[0151] Preparation Example 3 Preparation of vortioxetine monohydrobromide α crystalline form The α-crystalline form of vortioxetine monohydrobromide was synthesized according to the preparation method described in Example 4a of Patent Document WO 2007 / 144005 A1. Specifically, 2.0 g of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine was dissolved in 30 mL of hot ethyl acetate, and 0.73 mL of 48% wt aqueous hydrobromic acid solution was added. Since the reaction mixture became a thick solution, 10 mL of ethyl acetate was added to facilitate stirring, and the resulting solution was stirred at room temperature for 1 hour. The solution was filtered and dried overnight under vacuum (20°C) to produce 2.0 g of a white solid product, with a yield of 80%. The product was the α-crystalline form of vortioxetine monohydrobromide, and its bromine content measured by titration was 20.76%.

[0152] Preparation Example 4 Preparation of vortioxetine monohydrobromide β crystalline form The α-crystalline form of vortioxetine monohydrobromide was synthesized by following the preparation method described in Example 4c of Patent Document WO2007 / 144005A1. Specifically, 49.5 g of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine was dissolved in 500 mL of ethyl acetate, and 18.5 mL of 48% wt aqueous hydrobromic acid solution was added. The reaction mixture became a thick solution, which was stirred at room temperature overnight. After filtration and drying under vacuum (50°C) overnight, 29.6 g of a white solid product was obtained, with a yield of 47%. This product was the β-crystalline form of vortioxetine monohydrobromide. The bromine content measured by titration was 20.69%.

[0153] Preparation Example 5 Preparation of vortioxetine monohydrobromide gamma crystalline form The γ-crystalline form of vortioxetine monohydrobromide was synthesized by referring to the preparation method described in Example 4e of Patent Document WO2007 / 144005A1. Specifically, 1 g of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine was dissolved in 20 mL of water and heated to 85°C. When the reaction solution became essentially clear, one drop of aqueous HBr solution was added to clarify the solution. The aqueous HBr solution was added until a cloud point was observed. The solution was cooled to room temperature, filtered, and dried. The resulting product was the γ-crystalline form of vortioxetine monohydrobromide. The bromine content determined by titration was 20.73%.

[0154] Example 1: Preparation of a taste-masked powder of vortioxetine hydrobromide plus coating material 1a) Preparation of taste-masked powder of vortioxetine hemihydrobromide: E100:PEG6000 = 1:0.3:0.07 Add 30.00 g of E100 and 7.00 g of PEG 6000 to 470.02 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0155] 100.00 g of vortioxetine hemihydrobromide with a particle size of 100-200 mesh and 10.00 g of talc with a particle size of less than 325 mesh were placed in a BWF-1G multi-functional fluidized bed installed in the bottom spray coating mode. The materials were fluidized by adjusting the inlet air volume and the height of the draft tube. The inlet air temperature was set to 50-55°C, the hose pump rotation speed to 5 rpm, and the spray pressure to 1.0-1.5 atm. The resulting coating solution was sprayed onto the bed. After spraying, the material was allowed to fluidize for 30 minutes, after which heating was stopped. Once the material temperature had cooled to room temperature, the material was collected and sieved. 125.79 g of powder with a particle size of 60-150 mesh was obtained, with a yield of 85.57% and a measured powder content (based on vortioxetine) of 60.14%.

[0156] If the material sticks during the manufacturing process, an appropriate amount of talc can be added after the machine is stopped to ensure that the material is in a fluid state.

[0157] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have improved irritation compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0158] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0159] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0160] For more details, see Table 1.

[0161] [Table 1]

[0162] The X-ray powder diffraction pattern of the taste-masked powder of vortioxetine hemihydrobromide:E100:PEG6000 = 1:0.3:0.07 is shown in Figure 5, and the X-ray powder diffraction pattern of the spray-dried E100:PEG6000 = 1:0.23 is shown in Figure 4.

[0163] 1b) Preparation of taste-masked powder of vortioxetine monohydrobromide α-form: E100:PEG6000=1:0.3:0.07 Add 30.09g of E100 and 7.05g of PEG 6000 to 470.20g of pharmaceutical ethanol, stir to dissolve and then prepare for use.

[0164] 100.02 g of vortioxetine monohydrobromide alpha-form with a particle size of 100-200 mesh and 10.05 g of talc with a particle size of less than 325 mesh were placed in a BWF-1G multi-functional fluidized bed installed in the bottom spray coating mode. The materials were fluidized by adjusting the inlet air volume and the height of the draft tube. The inlet air temperature was set to 50-55°C, the hose pump rotation speed to 5 rpm, and the spray pressure to 1.0-1.5 atm. The resulting solution was sprayed onto the bed. After spraying, the material was allowed to fluidize for 30 minutes, after which heating was stopped. Once the material temperature had cooled to room temperature, the material was collected and sieved. 127.81 g of powder with a particle size of 60-150 mesh was obtained, with a yield of 86.82% and a measured powder content (based on vortioxetine) of 52.77%.

[0165] If the material sticks during the manufacturing process, an appropriate amount of talc can be added after the machine is stopped to ensure that the material is in a fluid state.

[0166] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have improved irritation compared to 100 mesh vortioxetine monohydrobromide alpha powder equivalent to 20 mg of vortioxetine.

[0167] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0168] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0169] For more details, see Table 2.

[0170] [Table 2]

[0171] The X-ray powder diffraction pattern of the taste-masked powder of vortioxetine monohydrobromide alpha form: modified E100:PEG6000 = 1:0.3:0.07 is shown in Figure 6, and the X-ray powder diffraction pattern of the modified E100:PEG6000 = 1:0.23 spray-dried powder is shown in Figure 4.

[0172] 1c) Preparation of taste-masked powder of vortioxetine monohydrobromide beta form: E100:PEG6000 = 1:0.3:0.07 Add 30.00 g of E100 and 7.00 g of PEG6000 to 470.20 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0173] 100.00 g of vortioxetine monohydrobromide alpha-form with a particle size of 100-200 mesh and 10.00 g of talc with a particle size of less than 325 mesh were placed in a BWF-1G multi-functional fluidized bed installed in the bottom spray coating mode. The materials were fluidized by adjusting the inlet air volume and the height of the draft tube. The inlet air temperature was set to 50-55°C, the hose pump rotation speed to 5 rpm, and the spray pressure to 1.0-1.5 atm. The resulting solution was sprayed onto the bed. After spraying, the material was allowed to fluidize for 30 minutes, after which heating was stopped. Once the material temperature had cooled to room temperature, the material was collected and sieved. 126.78 g of powder with a particle size of 60-150 mesh was obtained, with a yield of 86.24% and a measured powder content (based on vortioxetine) of 53.13%.

[0174] If the material sticks during the manufacturing process, an appropriate amount of talc can be added after the machine is stopped to ensure that the material is in a fluid state.

[0175] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have improved irritation compared to 100 mesh vortioxetine monohydrobromide beta powder equivalent to 20 mg of vortioxetine.

[0176] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0177] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0178] For more details, see Table 3.

[0179] [Table 3]

[0180] The X-ray powder diffraction pattern of the taste-masked powder of vortioxetine hydrobromide beta: modified E100:PEG6000 = 1:0.3:0.07 is shown in Figure 7, and the X-ray powder diffraction pattern of the modified E100:PEG6000 = 1:0.23 after spray drying is shown in Figure 4.

[0181] 1d) Preparation of taste-masked powder of vortioxetine hemihydrobromide: ethylcellulose N10: PEG6000 = 1:0.3:0.07 Add 150.00 g of ethylcellulose N10 and 3.50 g of PEG 6000 to 1500.00 g of pharmaceutical ethanol, stir to dissolve and then prepare for use.

[0182] 50.00 g of vortioxetine hemihydrobromide with a particle size of 100-200 mesh and 25.00 g of talc with a particle size of less than 325 mesh were placed in a BWF-1G multi-functional fluidized bed installed in the bottom spray coating mode. The materials were fluidized by adjusting the inlet air volume and the height of the draft tube. The inlet air temperature was set to 50-55°C, the hose pump rotation speed to 5 rpm, and the spray pressure to 1.0-1.5 atm. The resulting solution was sprayed onto the mixture. After spraying, the mixture was allowed to fluidize for 30 minutes, after which the residual ethanol was removed. The heating was stopped, and the mixture was allowed to cool to room temperature. The mixture was then collected and sieved to obtain 162.91 g of powder with a particle size of 60-150 mesh, for a yield of 71.30% and a measured powder content (based on vortioxetine) of 19.57%.

[0183] If the material sticks during the manufacturing process, an appropriate amount of talc can be added after the machine is stopped to ensure that the material is in a fluid state.

[0184] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have improved irritation compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0185] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0186] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0187] See Table 4 for details.

[0188] [Table 4]

[0189] 1e) Preparation of taste-masked powder of vortioxetine hemihydrobromide: Eudragit RL100: meglumine = 1:0.3:0.07 150.00 g of Eudragit RL100 and 3.50 g of meglumine are added to 1500.00 g of pharmaceutical grade ethanol, stirred to dissolve and then ready for use.

[0190] Place 50.00 g of vortioxetine hemihydrobromide with a particle size of 100-200 mesh and 25.00 g of talc with a particle size of less than 325 mesh into a BWF-1G multi-functional fluidized bed installed in bottom spray coating mode. Adjust the inlet air volume and draft tube height to fluidize the materials. Set the inlet air temperature to 50-55°C, the hose pump rotation speed to 5 rpm, and the spray pressure to 1.0-1.5 atm to spray the prepared elution coating solution. After spraying, allow to fluidize for 30 minutes, remove any residual ethanol, stop heating, and allow the material to cool to room temperature. Collect the material and sieve it to obtain a powder with a particle size of 60-150 mesh.

[0191] If the material sticks during the manufacturing process, an appropriate amount of talc can be added after the machine is stopped to ensure that the material is in a fluid state.

[0192] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have improved irritation compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0193] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0194] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0195] See Table 5 for details.

[0196] [Table 5]

[0197] Example 2: Preparation of a taste-masked powder of vortioxetine hydrobromide plus coating material 2a) Preparation of taste-masked powder of vortioxetine hemihydrobromide:E100 = 1:0.7 Add 7.73g of E100 to 77.20g of pharmaceutical ethanol, stir to dissolve, and then prepare for use.

[0198] Add 10.02g of 200 mesh vortioxetine hemihydrobromide to the above solution, stir to disperse, pass through a 100 mesh stainless steel screen and collect the material, continuing to stir to prevent settling.

[0199] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The resulting suspension was sprayed and the condition of the material observed. 30 minutes after spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 7.81 g of taste-masking powder with a particle size of less than 80 mesh, for a yield of 43.98% and a measured powder content (based on vortioxetine) of 48.63%.

[0200] The remaining material was lightly crushed and then sieved to collect the powder with a particle size of less than 80 mesh to obtain 6.23 g of taste-masked powder, with a yield (based on vortioxetine) of 35.08% and a measured powder content (based on vortioxetine) of 49.38%.

[0201] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have significantly improved irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0202] After mixing the two taste-masking powders, five subjects took a portion of the taste-masking powder equivalent to 20 mg of vortioxetine and tested its texture. The results showed a significant improvement in irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0203] Homemade sample 1: Immediate irritation +, delayed irritation disappears within 1 to 15 minutes, bitterness is tolerable.

[0204] Homemade sample 2: Immediate irritation +, delayed irritation disappears within 1 to 15 minutes, bitterness is tolerable.

[0205] Homemade mixed sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0206] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0207] See Table 6 for details.

[0208] [Table 6]

[0209] 2b) Preparation of taste-masked powder of vortioxetine monohydrobromide: E100:PEG 6000 = 1:0.77 Add 7.70g of E100 to 77.10g of pharmaceutical ethanol, stir to dissolve, and then prepare for use.

[0210] Add 10.00 g of 200 mesh vortioxetine monohydrobromide to the above solution, stir to disperse, and pass through a 100 mesh stainless steel screen to collect the material, continuing to stir to prevent settling.

[0211] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The resulting suspension was sprayed and the condition of the material observed. 30 minutes after spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 6.98 g of taste-masking powder with a particle size of less than 80 mesh, for a yield of 39.44% and a measured powder content (based on vortioxetine) of 44.63%.

[0212] The remaining material was lightly crushed and then sieved to collect the powder with a particle size of less than 80 mesh to obtain 5.93 g of taste-masked powder, with a yield of 33.50% and a measured powder content (based on vortioxetine) of 45.38%.

[0213] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have significantly improved irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0214] After mixing the two taste-masking powders, five subjects took a portion of the taste-masking powder equivalent to 20 mg of vortioxetine and tested its texture. The results showed a significant improvement in irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0215] Homemade sample 1: Immediate irritation +, delayed irritation disappears within 1 to 15 minutes, bitterness is tolerable.

[0216] Homemade sample 2: Immediate irritation +, delayed irritation disappears within 1 to 15 minutes, bitterness is tolerable.

[0217] Homemade mixed sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0218] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0219] See Table 7 for details.

[0220] [Table 7]

[0221] 2c) Preparation of a taste-masked powder of vortioxetine hemihydrobromide:cellulose acetate:PEG6000 = 1:0.7:0.07 Add 7.00g of cellulose acetate and 0.70g of PEG6000 to 70.20g of pharmaceutical ethanol, stir to dissolve, and then prepare for use.

[0222] Add 10.00 g of 200 mesh vortioxetine hemihydrobromide to the above solution, stir to disperse, and pass through a 100 mesh stainless steel screen to collect the material, continuing to stir to prevent settling.

[0223] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The resulting suspension was sprayed and the condition of the material observed. 30 minutes after spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 6.97 g of taste-masking powder with a particle size of less than 80 mesh, for a yield of 40.76% and a measured powder content (based on vortioxetine) of 47.93%.

[0224] The remaining material was lightly crushed and the powder with a particle size of less than 80 mesh was sieved and collected to give 6.00 g of taste-masked powder with a yield of 33.90% (based on vortioxetine) and a powder content of 48.98% (based on vortioxetine).

[0225] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have significantly improved irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0226] After mixing the two taste-masking powders, five subjects took a portion of the taste-masking powder equivalent to 20 mg of vortioxetine and tested its texture. The results showed a significant improvement in irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0227] Homemade sample 1: Immediate irritation +, delayed irritation disappears within 1 to 15 minutes, bitterness is tolerable.

[0228] Homemade sample 2: Immediate irritation +, delayed irritation disappears within 1 to 15 minutes, bitterness is tolerable.

[0229] Homemade mixed sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0230] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0231] See Table 8 for details.

[0232] [Table 8]

[0233] 2d) Preparation of taste-masking powder of vortioxetine hemihydrobromide:polyvinyl alcohol (low viscosity) = 1:0.7 Add 7.00 g of polyvinyl alcohol (low viscosity) to 100.00 g of purified water, dissolve and stir in a 90 °C water bath, cool to room temperature, add 0.07 g of potassium citrate, stir and dissolve, and then prepare for use.

[0234] Add 10.00 g of 200 mesh vortioxetine hemihydrobromide to the above solution, stir to disperse, and pass through a 100 mesh stainless steel screen to collect the material, continuing to stir to prevent settling.

[0235] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 30-33m 3 The inlet air temperature was set to 60-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The resulting suspension was sprayed and the condition of the material observed. 30 minutes after spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 12.79 g of taste-masking powder with a particle size of less than 80 mesh, for a yield of 75.24% and a measured powder content (based on vortioxetine) of 50.99%.

[0236] Five subjects tested the texture of a taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have significantly improved irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0237] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0238] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0239] See Table 9 for details.

[0240] [Table 9]

[0241] Example 3: Preparation of taste-masked powder with vortioxetine hemihydrobromide:coating material ratio of 1:1 3a) Preparation of taste-masked powder of vortioxetine hemihydrobromide: Eudragit E100: PEG6000 = 1:1:0.07 Add 10.00 g of Eudragit E100 and 0.70 g of PEG6000 to 70.00 g of pharmaceutical grade ethanol, stir to dissolve and then prepare for use.

[0242] Add 10.01 g of 200 mesh vortioxetine hemihydrobromide to the above solution, stir to disperse, and pass through a 100 mesh stainless steel screen to collect the material, continuing to stir to prevent settling.

[0243] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The resulting suspension was sprayed and the condition of the material observed. 30 minutes after spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 13.78 g of taste-masking powder with a particle size of less than 80 mesh, for a yield of 66.54% and a measured powder content (based on vortioxetine) of 41.79%.

[0244] Five subjects tested the texture of the taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have significantly improved irritation and virtually no irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0245] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0246] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0247] See Table 10 for more details.

[0248] [Table 10] 3b) Preparation of taste-masked powder of vortioxetine hemihydrobromide: Eudragit L100: PEG6000 = 1:1:0.07 Add 10.00 g of Eudragit L100 and 0.70 g of PEG6000 to 70.00 g of pharmaceutical ethanol, stir to dissolve and then prepare for use.

[0249] Add 10.00 g of 200 mesh vortioxetine hemihydrobromide to the above solution, stir to disperse, and pass through a 100 mesh stainless steel screen to collect the material, continuing to stir to prevent settling.

[0250] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The resulting suspension was sprayed and the condition of the material observed. 30 minutes after spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 14.14 g of taste-masking powder with a particle size of less than 80 mesh, for a yield of 68.31% and a measured powder content (based on vortioxetine) of 42.01%.

[0251] Five subjects tested the texture of the taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have significantly improved irritation and virtually no irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0252] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0253] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0254] See Table 11 for more details.

[0255] [Table 11]

[0256] 3c) Preparation of a taste-masked powder of vortioxetine hemihydrobromide:copolyvidone AV64 = 1:1 Add 10.00 g of Copolyvidone AV64 to 70.00 g of pharmaceutical ethanol, stir to dissolve, and then prepare for use.

[0257] Add 10.00 g of 200 mesh vortioxetine hemihydrobromide to the above solution, stir to disperse, and pass through a 100 mesh stainless steel screen to collect the material, continuing to stir to prevent settling.

[0258] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The resulting suspension was sprayed and the condition of the material observed. 30 minutes after spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 14.16 g of taste-masking powder with a particle size of less than 80 mesh, for a yield of 70.80% and a measured powder content (based on vortioxetine) of 42.78%.

[0259] Five subjects tested the texture of the taste-masking powder equivalent to 20 mg of vortioxetine, and it was found to have significantly improved irritation and virtually no irritation compared to 100 mesh vortioxetine hemihydrobromide equivalent to 20 mg of vortioxetine.

[0260] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0261] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0262] See Table 12 for more details.

[0263] [Table 12]

[0264] Example 4 Preparation of a 1:0.5 mixture of vortioxetine hydrobromide and Eudragit 4a) Preparation of a vortioxetine hemihydrobromide:Eudragit E PO = 1:0.5 mixture 5.00 g of vortioxetine hemihydrobromide and 2.50 g of Eudragit E PO were sieved through a 200-mesh stainless steel screen and placed in a clean, dry 50 ml screw-top glass bottle. The bottle was mixed for 5 minutes using a Vortex-2 vortex mixer, sieved through a 100-mesh stainless steel screen, and continued to mix for another 5 minutes. 0.50 g of the test sample was removed. The remaining material was collected, placed on a 75 mm diameter stainless steel tray, and placed in a DHG-9070A hot air circulating oven at 120-130°C for 30 minutes until the material reached a semi-fluid state. After cooling, the mixture was pulverized several times in a BJ-300A multi-purpose grinder and sieved through a 100-mesh stainless steel screen to obtain a 1:0.5 blend.

[0265] Five subjects tested the texture of a powder mixture equivalent to 20 mg of vortioxetine, which demonstrated improved irritation compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0266] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0267] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0268] See Table 13 for more details.

[0269] [Table 13]

[0270] 4b) Preparation of a vortioxetine monohydrobromide:Eudragit E PO = 1:0.5 mixture 5.00 g of vortioxetine monohydrobromide and 2.50 g of Eudragit E PO were sieved through a 200-mesh stainless steel screen and placed in a clean, dry 50 ml screw-top glass bottle. The bottle was mixed for 5 minutes using a Vortex-2 vortex mixer, sieved through a 100-mesh stainless steel screen, and continued to mix for another 5 minutes using a vortex mixer. 0.50 g of the test sample was removed. The remaining material was collected, placed on a 75 mm diameter stainless steel tray, and placed in a DHG-9070A hot air circulating oven at 120-130°C for 30 minutes until the material reached a semi-fluid state. After cooling, the mixture was pulverized several times in a BJ-300A multi-purpose grinder and sieved through a 100-mesh stainless steel screen to obtain a 1:0.5 blend.

[0271] Five subjects tested the texture of vortioxetine 20 mg mixed powder, demonstrating improved irritation compared to 100 mesh vortioxetine monohydrobromide powder equivalent to vortioxetine 20 mg.

[0272] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0273] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0274] See Table 14 for more information.

[0275] [Table 14]

[0276] UV scanning showed that the maximum absorption wavelength and peak intensity of vortioxetine did not change after treatment, and the results are shown in Figures 8, 9, 10, and 11.

[0277] 4c) Preparation of a vortioxetine monohydrobromide:Eudragit RS PO = 1:0.5 mixture 5.00 g of vortioxetine monohydrobromide and 2.50 g of Eudragit RS PO were sieved through a 200-mesh stainless steel screen and placed in a clean, dry 50 ml screw-top glass bottle. The bottle was mixed for 5 minutes using a Vortex-2 vortex mixer, sieved through a 100-mesh stainless steel screen, and continued to mix for another 5 minutes. 0.50 g of the test sample was removed. The remaining material was collected, placed on a 75 mm diameter stainless steel tray, and placed in a DHG-9070A hot air circulating oven at 120-130°C for 30 minutes until the material reached a semi-fluid state. After cooling, the mixture was pulverized several times in a BJ-300A multi-purpose grinder and sieved through a 100-mesh stainless steel screen to obtain a 1:0.5 blend.

[0278] Five subjects took a powder mixture equivalent to 20 mg of vortioxetine and tested the texture, which demonstrated improved irritation compared to 100 mesh vortioxetine monohydrobromide powder equivalent to 20 mg of vortioxetine.

[0279] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0280] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0281] See Table 15 for more information.

[0282] [Table 15]

[0283] Example 5 Preparation of a 1:1.5 mixture of vortioxetine hemihydrobromide:Eudragit E PO 5.00 g of vortioxetine hemihydrobromide and 7.50 g of Eudragit E PO were sieved through a 200-mesh stainless steel screen and placed in a clean, dry 50 ml screw-top glass bottle. The bottle was mixed for 5 minutes using a Vortex-2 vortex mixer, sieved through a 100-mesh stainless steel screen, and continued to mix for another 5 minutes. 0.50 g of the test sample was removed. The remaining material was collected, placed on a 75 mm diameter stainless steel tray, and placed in a DHG-9070A hot air circulating oven at 120-130°C for 30 minutes until the material reached a semi-fluid state. After cooling, the mixture was pulverized several times in a BJ-300A multi-purpose grinder and sieved through a 100-mesh stainless steel screen to obtain a 1:1.5 blend.

[0284] Five subjects tested the texture of a 1:1.5 powder mixture equivalent to 20 mg of vortioxetine, demonstrating a clear improvement in irritation compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0285] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0286] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0287] See Table 16 for more information.

[0288] [Table 16]

[0289] UV scanning showed that the maximum absorption wavelength and peak intensity of vortioxetine did not change after treatment, and the results are shown in Figures 9, 12, 13, and 14.

[0290] Example 6 Preparation of a 1:5 mixture of vortioxetine hemihydrobromide:Eudragit E PO 5.00 g of vortioxetine hemihydrobromide and 25.00 g of Eudragit E PO were sieved through a 200-mesh stainless steel screen and placed in a clean, dry 100 ml screw-top glass bottle. The bottle was mixed for 5 minutes using a Vortex-2 vortex mixer, sieved through a 100-mesh stainless steel screen, and continued to mix for another 5 minutes. 0.50 g of the test sample was removed. The remaining material was collected, placed on a 75 mm diameter stainless steel tray, and placed in a DHG-9070A hot air circulating oven at 120-130°C for 30 minutes until the material reached a semi-fluid state. After cooling, the mixture was pulverized several times in a BJ-300A multi-purpose grinder and sieved through a 100-mesh stainless steel screen to obtain a 1:5 blend, with a yield of 14.39% (based on vortioxetine).

[0291] A 1:5 powder mix equivalent to 20 mg of vortioxetine was tested by five subjects and proved to be significantly less irritating than 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0292] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0293] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0294] See Table 17 for more information.

[0295] [Table 17]

[0296] UV scanning showed that the maximum absorption wavelength and peak intensity of vortioxetine did not change after treatment, and the results are shown in Figures 9, 12, 15, and 16.

[0297] Example 7 Preparation of a mixture of vortioxetine hydrobromide:polyacrylic resin IV = 1:1.5 7a) Preparation of a vortioxetine hemihydrobromide:polyacrylic resin IV = 1:1.5 mixture 5.00 g of vortioxetine hemihydrobromide, sieved through a 200-mesh stainless steel screen, and 7.50 g of polyacrylic resin IV powder (100-mesh powder) were placed in a clean, dry 100 ml screw-top glass bottle and mixed for 5 minutes using a Vortex-2 vortex mixer. The mixture was then sieved through a 100-mesh stainless steel screen and vortexed for another 5 minutes, after which 0.50 g of test sample was removed. The remaining material was collected, placed on a 75 mm diameter stainless steel tray, and placed in a DHG-9070A hot air circulating oven at 120-130°C for 30 minutes until the mixture reached a semi-fluid state. After cooling, the mixture was ground several times in a BJ-300A multi-purpose grinder and sieved through a 100-mesh stainless steel screen to obtain 10.98 g of a 1:5 powder mixture. The yield was 87.84% and the measured powder content (based on vortioxetine) was 35.71%.

[0298] Five subjects tested the texture of a 1:1.5 powder mixture equivalent to 20 mg of vortioxetine, demonstrating a clear improvement in irritation compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0299] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0300] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0301] See Table 18 for more information.

[0302] [Table 18]

[0303] 7b) Preparation of a vortioxetine monohydrobromide:polyacrylic resin IV = 1:1.5 mixture 5.00 g of vortioxetine monohydrobromide (sieved through a 200-mesh stainless steel screen) and 7.50 g of polyacrylic resin IV (100-mesh powder) were placed in a clean, dry 100 ml screw-top glass bottle and mixed for 5 minutes using a Vortex-2 vortex mixer. The mixture was then sieved through a 100-mesh stainless steel screen and mixed for another 5 minutes using a vortex mixer. 0.50 g of the test sample was removed. The remaining material was collected, placed on a 75 mm diameter stainless steel tray, and placed in a DHG-9070A hot air circulating oven at 120-130°C for 30 minutes until the mixture reached a semi-fluid state. After cooling, the mixture was ground several times in a BJ-300A multi-purpose grinder and sieved through a 100-mesh stainless steel screen to obtain 11.23 g of a 1:5 powder mixture. The yield was 89.84% and the measured powder content (based on vortioxetine) was 31.12%.

[0304] Five subjects tested the texture of a 1:1.5 powder mixture equivalent to 20 mg of vortioxetine, demonstrating a clear improvement in irritation compared to 100 mesh vortioxetine monohydrobromide powder equivalent to 20 mg of vortioxetine.

[0305] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0306] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0307] See Table 19 for more details.

[0308] [Table 19]

[0309] UV scanning showed that the maximum absorption wavelength and peak intensity of vortioxetine did not change after treatment, and the results are shown in Figures 8, 17, 18, and 19.

[0310] Example 8 Preparation of a solid dispersion of vortioxetine hemihydrobromide:polyacrylic resin = 1:0.3 8a) Preparation of a solid dispersion of vortioxetine hemihydrobromide:polyacrylic resin IV = 1:0.3 Add 10.00 g of vortioxetine hemihydrobromide, 3.00 g of polyacrylic resin IV, and 0.70 g of PEG4000 to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0311] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The solution was sprayed, observing the condition of the material and adjusting the parameters appropriately to ensure normal spraying and drying. After 30 minutes of spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 10.29 g of powder with a particle size of less than 80 mesh, for a yield of 75.11% and a measured powder content (based on vortioxetine) of 62.97%.

[0312] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0313] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0314] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0315] See Table 20 for more information.

[0316] [Table 20]

[0317] 8b) Preparation of a solid dispersion of vortioxetine hemihydrobromide:polyacrylic resin II = 1:0.3 Add 10.00 g of vortioxetine hemihydrobromide and 3.00 g of polyacrylic resin II to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0318] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 Set the inlet air temperature to 50-55°C, the hose pump speed to 8 rpm, and the atomizing pressure to 1.0-1.5 atm. Spray the prepared solution, observing the condition of the material and adjusting the parameters appropriately to ensure normal atomization and drying. 30 minutes after spraying, stop heating. Once the material temperature has cooled to room temperature, collect the material and sieve it to obtain a powder with a particle size of less than 80 mesh.

[0319] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0320] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0321] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0322] See Table 21 for more details.

[0323] [Table 21]

[0324] Example 9 Preparation of a solid dispersion of vortioxetine hydrobromide:taste-masking aid = 1:0.7 9a) Preparation of a solid dispersion of vortioxetine hemihydrobromide:polyacrylic resin IV = 1:0.7 Add 10.00 g of vortioxetine hemihydrobromide and 7.70 g of polyacrylic resin IV (suppliers Eudragit E100 or Eudragit E PO from Rohm Company (Evonik Nutrition & Care GmbH), Youshaku E or Youshaku E100 from Guangzhou Maofeng Pharmaceutical Supplements Co., Ltd., or Polyacrylic resin IV from Anhui Shanhe Pharmaceutical Supplements Co., Ltd.) to 170.00 g of pharmaceutical-grade ethanol, heat to 50–55°C, stir, dissolve, and keep at 50–55°C for use.

[0325] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3The solution was sprayed with an inlet air temperature of 50-55°C, a hose pump speed of 8 rpm, and a spray pressure of 1.0-1.5 atm. The material was observed and the parameters adjusted appropriately to ensure proper spraying and drying. After 30 minutes of spraying, heating was stopped and the material cooled to room temperature. The material was collected and sieved to obtain 12.69 g of powder with a particle size of less than 80 mesh, for a yield of 71.69% and a measured powder content (based on vortioxetine) of 49.47%.

[0326] A texture test of 20 mg of vortioxetine equivalent solid dispersion was conducted by five subjects and compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, it was found that the unprocessed material had obvious irritation and was barely tolerable, and the processed vortioxetine solid dispersion was barely irritating.

[0327] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0328] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0329] See Table 22 for more information.

[0330] [Table 22] The X-ray powder diffraction pattern of the vortioxetine hemihydrobromide:polyacrylic resin IV = 1:0.7 solid dispersion is shown in Figure 20, and the X-ray powder diffraction pattern of polyacrylic resin IV after spray drying is shown in Figure 21.

[0331] The stability of the solid dispersion of 9a) was tested in accordance with the requirements of the 2015 edition of the People's Republic of China Pharmacopoeia (accelerated 6-month test at 40±2°C and 75%±5% humidity), and the stability was found to be good. The solubility of the solid dispersion of 9a) in 0.1N hydrochloric acid and pH 4.5 acetate buffer (paddle method, 50 rpm) showed a fast dissolution rate (10-minute data) and complete dissolution (30-minute data). The results are shown in Table 23.

[0332] [Table 23]

[0333] 9b) Preparation of a solid dispersion of vortioxetine monohydrobromide:polyacrylic resin IV = 1:0.77 Add 10.00 g of vortioxetine monohydrobromide and 7.70 g of polyacrylic resin IV (suppliers Eudragit E100 or Eudragit E PO from Rohm Company (Evonik Nutrition & Care GmbH), Youshaku E or Youshaku E100 from Guangzhou Maofeng Pharmaceutical Supplements Co., Ltd., or Polyacrylic resin IV from Anhui Shanhe Pharmaceutical Supplements Co., Ltd.) to 300.00 g of pharmaceutical ethanol, stir to dissolve, and then prepare for use.

[0334] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The solution was sprayed, observing the material and adjusting the parameters appropriately to ensure proper spraying and drying. After 30 minutes of spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 11.73 g of powder with a particle size of less than 80 mesh. This gave a yield of 66.27%, a measured powder content (based on vortioxetine) of 44.47%, and a measured bromine content of vortioxetine hydrobromide in the solid dispersion of 11.83%.

[0335] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine monohydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0336] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0337] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0338] See Table 24 for details.

[0339] [Table 24]

[0340] The X-ray powder diffraction pattern of the vortioxetine monohydrobromide:polyacrylic resin IV = 1:0.77 solid dispersion is shown in Figure 22, and the X-ray powder diffraction pattern of polyacrylic resin IV after spray drying is shown in Figure 21.

[0341] The stability of the solid dispersion of 9b) was tested in accordance with the requirements of the 2015 edition of the People's Republic of China Pharmacopoeia (accelerated 6-month test at 40±2°C and 75%±5% humidity), and the stability was found to be good. The solubility of the solid dispersion of 9b) in 0.1N hydrochloric acid and pH 4.5 acetate buffer (paddle method, 50 rpm) showed a fast dissolution rate (10-minute data) and complete dissolution (30-minute data). The results are shown in Table 25.

[0342] [Table 25]

[0343] 9c) Preparation of a solid dispersion of vortioxetine hemihydrobromide:Eudragit RL100:PEG6000 = 1:0.7:0.07 Add 10.00g of vortioxetine hemihydrobromide, 7.00g of Eudragit RL100 and 0.70g of PEG6000 to 300.00g of pharmaceutical grade ethanol, stir to dissolve and then prepare for use.

[0344] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 Set the inlet air temperature to 50-55°C, the hose pump speed to 8 rpm, and the atomizing pressure to 1.0-1.5 atm. Spray the prepared solution, observing the condition of the material and adjusting the parameters appropriately to ensure normal atomization and drying. 30 minutes after spraying, stop heating. Once the material temperature has cooled to room temperature, collect the material and sieve it to obtain a powder with a particle size of less than 80 mesh.

[0345] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0346] Homemade sample: Instantaneous stimulation ++, delayed stimulation disappears within 1-15 minutes, bitterness is tolerable.

[0347] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0348] See Table 26 for more information.

[0349] [Table 26]

[0350] 9d) Preparation of a solid dispersion of vortioxetine hemihydrobromide:Eudragit S100 = 1:0.7 Add 10.00g of vortioxetine hemihydrobromide and 7.00g of Eudragit S100 to 300.00g of pharmaceutical grade ethanol, stir to dissolve and then prepare for use.

[0351] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 Set the inlet air temperature to 50-55°C, the hose pump speed to 8 rpm, and the atomizing pressure to 1.0-1.5 atm. Spray the prepared solution, observing the condition of the material and adjusting the parameters appropriately to ensure normal atomization and drying. 30 minutes after spraying, stop heating. Once the material temperature has cooled to room temperature, collect the material and sieve it to obtain a powder with a particle size of less than 80 mesh.

[0352] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0353] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0354] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0355] See Table 27 for details.

[0356] [Table 27]

[0357] 9e) Preparation of a solid dispersion of vortioxetine hemihydrobromide:Eudragit L100 = 1:0.7 Add 10.00 g of vortioxetine hemihydrobromide and 7.00 g of Eudragit L100 to 300.00 g of pharmaceutical grade ethanol, stir to dissolve and then prepare for use.

[0358] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 Set the inlet air temperature to 50-55°C, the hose pump speed to 8 rpm, and the atomizing pressure to 1.0-1.5 atm. Spray the prepared solution, observing the condition of the material and adjusting the parameters appropriately to ensure normal atomization and drying. 30 minutes after spraying, stop heating. Once the material temperature has cooled to room temperature, collect the material and sieve it to obtain a powder with a particle size of less than 80 mesh.

[0359] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0360] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0361] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0362] See Table 28 for more information.

[0363] [Table 28]

[0364] Example 10 Preparation of a vortioxetine hemihydrobromide:polyacrylic resin IV=1:1 solid dispersion Add 10.00 g of vortioxetine hemihydrobromide, 10.00 g of polyacrylic resin IV, and 0.70 g of PEG6000 to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0365] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The solution was sprayed, observing the condition of the material and adjusting the parameters appropriately to ensure normal spraying and drying. After 30 minutes of spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 13.31 g of powder with a particle size of less than 80 mesh, for a yield of 64.30% and a measured powder content (based on vortioxetine) of 43.38%.

[0366] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0367] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0368] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0369] See Table 29 for more information.

[0370] [Table 29]

[0371] Example 11 Preparation of a solid dispersion of vortioxetine hydrobromide:taste-masking aid = 1:1.5 11a) Preparation of a solid dispersion of vortioxetine hemihydrobromide:polyacrylic resin IV = 1:1.5 Add 10.00 g of vortioxetine hemihydrobromide and 15.00 g of polyacrylic resin IV to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0372] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The solution was sprayed, observing the condition of the material and adjusting the parameters appropriately to ensure normal spraying and drying. After 30 minutes of spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 18.11 g of powder with a particle size of less than 80 mesh, for a yield of 72.44% and a measured powder content (based on vortioxetine) of 34.47%.

[0373] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0374] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0375] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0376] See Table 30 for details.

[0377] [Table 30]

[0378] 11b) Preparation of a solid dispersion of vortioxetine monohydrobromide:polyacrylic resin IV = 1:1.5 Add 10.00 g of vortioxetine monohydrobromide, 15.00 g of polyacrylic resin IV, and 0.70 g of PEG6000 to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0379] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The solution was sprayed, observing the condition of the material and adjusting the parameters appropriately to ensure normal spraying and drying. After 30 minutes of spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 17.17 g of powder with a particle size of less than 80 mesh, for a yield of 66.81% and a measured powder content (based on vortioxetine) of 30.57%.

[0380] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine monohydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0381] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0382] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0383] See Table 31 for more information.

[0384] [Table 31]

[0385] 11c) Preparation of a solid dispersion of vortioxetine monohydrobromide:ethylcellulose N10 = 1:1.5 Add 10.00 g of vortioxetine monohydrobromide and 15.00 g of ethylcellulose N10 to 300.0 g of pharmaceutical grade ethanol, add 1.00 g of potassium citrate that has been sieved through a 200 mesh sieve, stir and disperse evenly, continue stirring to prevent settling, and prepare for use.

[0386] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 Set the inlet air temperature to 50-55°C, the hose pump speed to 8 rpm, and the atomizing pressure to 1.0-1.5 atm. Spray the prepared solution, observing the condition of the material and adjusting the parameters appropriately to ensure normal atomization and drying. 30 minutes after spraying, stop heating. Once the material temperature has cooled to room temperature, collect the material and sieve it to obtain a powder with a particle size of less than 80 mesh.

[0387] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine monohydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0388] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0389] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0390] See Table 32 for more information.

[0391] [Table 32]

[0392] Example 12 Preparation of a solid dispersion of vortioxetine hemihydrobromide:taste-masking aid = 1:2 12a) Preparation of a vortioxetine hemihydrobromide:polyacrylic resin IV = 1:2 solid dispersion Add 10.00 g of vortioxetine hemihydrobromide, 20.00 g of polyacrylic resin IV, and 0.70 g of PEG6000 to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0393] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 Set the inlet air temperature to 50-55°C, the hose pump speed to 8 rpm, and the atomizing pressure to 1.0-1.5 atm. Spray the prepared solution, observing the condition of the material and adjusting the parameters appropriately to ensure normal atomization and drying. 30 minutes after spraying, stop heating. Once the material temperature has cooled to room temperature, collect the material and sieve it to obtain a powder with a particle size of less than 80 mesh.

[0394] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0395] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0396] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0397] See Table 33 for details.

[0398] [Table 33]

[0399] 12b) Preparation of a vortioxetine hemihydrobromide:cellulose acetate solid dispersion in a 1:2 ratio Add 10.00 g of vortioxetine hemihydrobromide, 20.00 g of cellulose acetate, and 0.70 g of PEG8000 to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0400] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 Set the inlet air temperature to 50-55°C, the hose pump speed to 8 rpm, and the atomizing pressure to 1.0-1.5 atm. Spray the prepared solution, observing the condition of the material and adjusting the parameters appropriately to ensure normal atomization and drying. 30 minutes after spraying, stop heating. Once the material temperature has cooled to room temperature, collect the material and sieve it to obtain a powder with a particle size of less than 80 mesh.

[0401] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0402] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0403] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0404] See Table 34 for details.

[0405] [Table 34]

[0406] Example 13 Preparation of a solid dispersion of vortioxetine hemihydrobromide plus a taste-masking aid 13a) Preparation of a vortioxetine hemihydrobromide:polyacrylic resin IV = 1:5 solid dispersion Add 10.00 g of vortioxetine hemihydrobromide and 50.00 g of polyacrylic resin IV to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0407] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The solution was sprayed with an inlet air temperature of 50-55°C, a hose pump speed of 8 rpm, and a spray pressure of 1.0-1.5 atm. The material was observed and the parameters adjusted appropriately to ensure proper spraying and drying. After 30 minutes of spraying, heating was stopped and the material cooled to room temperature. The material was collected and sieved to obtain 49.29 g of powder with a particle size of less than 80 mesh, for a yield of 82.15% and a measured powder content (based on vortioxetine) of 14.67%.

[0408] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0409] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0410] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0411] See Table 35 for details.

[0412] [Table 35]

[0413] 13b) Preparation of a vortioxetine hemihydrobromide:hydroxypropylcellulose LF=1:3 solid dispersion Add 10.00 g of vortioxetine hemihydrobromide, 30.00 g of hydroxypropylcellulose LF, and 1.00 g of meglumine to 300.0 g of pharmaceutical grade ethanol, stir to dissolve, and then prepare for use.

[0414] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 Set the inlet air temperature to 50-55°C, the hose pump speed to 8 rpm, and the atomizing pressure to 1.0-1.5 atm. Spray the prepared solution, observing the condition of the material and adjusting the parameters appropriately to ensure normal atomization and drying. 30 minutes after spraying, stop heating. Once the material temperature has cooled to room temperature, collect the material and sieve it to obtain a powder with a particle size of less than 80 mesh.

[0415] Five subjects took a solid dispersion equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the untreated material was obviously irritating with an almost unacceptable bitter taste, while the treated vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0416] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0417] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0418] See Table 36 for details.

[0419] [Table 36]

[0420] Example 14 Preparation of a solid dispersion of vortioxetine hydrobromide + polyacrylic resin 14a) Preparation of a vortioxetine hemihydrobromide:polyacrylic resin II solid dispersion at a ratio of 1:5 10.00 g of vortioxetine hemihydrobromide and 50.00 g of polyacrylic resin II were dissolved in ethanol up to 500.00 g by stirring in a water bath at 40-50°C. The mixture was filtered through a 0.45 μm Millipore filter, and the pH of the filtrate was adjusted with 5% (g / g) sodium hydroxide solution while stirring until no precipitate was observed (the pH was now 8.54). The ethanol was removed under vacuum using a rotary evaporator, and the resulting solid was lyophilized at 40-50°C to remove residual ethanol. It was then pulverized through a 100-mesh stainless steel sieve. 50.54 g of a vortioxetine-containing solid dispersion was obtained, with a yield of 84.23% and a measured powder content (based on vortioxetine) of 14.79%.

[0421] Five subjects took a powder mixture equivalent to 20 mg of vortioxetine and tested its texture, demonstrating that the irritation characteristic of vortioxetine was not felt compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0422] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0423] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0424] See Table 37 for details.

[0425] [Table 37]

[0426] 14b) Preparation of a solid dispersion of vortioxetine monohydrobromide:polyacrylic resin II = 1:1.5 10.00 g of vortioxetine monohydrobromide and 15.00 g of polyacrylic resin II were dissolved in ethanol up to 250.00 g by stirring in a water bath at 40-50°C. The mixture was filtered through a 0.45 μm Millipore filter, and the filtrate was stirred and adjusted to a pH of 8.32 with 5% (g / g) sodium hydroxide solution until no precipitate was observed. The ethanol was removed under vacuum using a rotary evaporator. The resulting solid was then lyophilized at 40-50°C to remove residual ethanol. It was then pulverized through a 100-mesh stainless steel sieve. 19.67 g of a vortioxetine-containing solid dispersion was obtained, with a yield of 78.68% and a measured powder content (based on vortioxetine) of 29.97%.

[0427] Five subjects took a powder mixture equivalent to 20 mg of vortioxetine and tested its texture, demonstrating that the irritation characteristic of vortioxetine was not felt compared to 100 mesh vortioxetine monohydrobromide powder equivalent to 20 mg of vortioxetine.

[0428] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0429] Control product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0430] See Table 38 for details.

[0431] [Table 38]

[0432] The X-ray powder diffraction pattern of the vortioxetine monohydrobromide:polyacrylic resin II = 1:1.5 solid dispersion is shown in Figure 23, and the X-ray powder diffraction pattern of polyacrylic resin II (ethanol rotary evaporation) is shown in Figure 24.

[0433] Example 15 Preparation of a solid dispersion of vortioxetine hemihydrobromide:polyacrylic resin II = 1:1.5 10.00 g of vortioxetine hemihydrobromide and 15.00 g of polyacrylic resin II were dissolved in ethanol up to 250.00 g by stirring in a water bath at 40-50 °C. The mixture was filtered through a 0.45 μm Millipore filter. The filtrate was then adjusted with 5% (g / g) sodium hydroxide solution while stirring until no precipitate was observed (the pH was now 8.47). The separated insoluble material was added to 400 g of purified water, homogenized at 40-50 °C, and passed through a 100-mesh screen. The mixture was then granulated in a WBF-1G multifunctional fluidized bed granulator fitted with a top-spray coating mode. The resulting powder was then milled through a 100-mesh stainless steel sieve. 12.94 g of vortioxetine-containing solid dispersion was obtained with a yield of 51.76% and a measured powder content (based on vortioxetine) of 35.77%.

[0434] Five subjects tested the texture of a solid dispersion equivalent to 20 mg of vortioxetine, and it was proven that the irritation characteristic of vortioxetine was not felt compared to 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine.

[0435] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0436] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0437] See Table 39 for details.

[0438] [Table 39]

[0439] The X-ray powder diffraction pattern of the vortioxetine hemihydrobromide:polyacrylic resin II = 1:1.5 solid dispersion is shown in Figure 25, and the X-ray powder diffraction pattern of polyacrylic resin II (ethanol rotary evaporation) is shown in Figure 24.

[0440] Example 16: Preparation of taste-masked granules using taste-masking coating powder Add 10.00 g of Eudragit RS100 to 150.00 g of ethanol, stir to dissolve and then prepare for use.

[0441] 10.00 g of the powder of Example 1d is taken and added to the above solution, and after stirring and dispersing, it is passed through a 60 mesh stainless steel screen, and stirring is continued to prevent sedimentation.

[0442] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The inlet air temperature was set to 50-55°C, the hose pump speed to 8 rpm, and the spray pressure to 1.0-1.5 atm. The solution was sprayed, observing the condition of the material and adjusting the parameters appropriately to ensure normal spraying and drying. After 30 minutes of spraying, heating was stopped and the material was allowed to cool to room temperature. The material was collected and sieved to obtain 15.87 g of powder with a particle size of less than 50 mesh, for a yield of 79.35% and a measured powder content (based on vortioxetine) of 25.47%.

[0443] Five subjects took granules equivalent to 20 mg of vortioxetine and tested their texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the unprocessed material was clearly irritating with an almost unacceptable bitter taste, while the processed vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0444] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0445] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0446] See Table 40 for details.

[0447] [Table 40]

[0448] Example 17: Preparation of a taste-masking coating powder using a solid dispersion Add 5.00 g of chitosan (deacetylation degree 85% or more) to 100.00 g of purified water, stir to dissolve, and then prepare for use.

[0449] 10.00 g of the powder of Example 9a is taken and added to the above solution, and after stirring and dispersing, it is passed through a 60 mesh stainless steel screen, and stirring is continued to prevent settling.

[0450] Placed on the BWF-1G multi-function fluidized bed mounted in top spray coating mode, with an air volume of 33 m 3 The solution was sprayed with an inlet air temperature of 60-55°C, a hose pump speed of 8 rpm, and a spray pressure of 1.0-1.5 atm. The material was observed and the parameters adjusted appropriately to ensure proper spraying and drying. After 30 minutes of spraying, heating was stopped and the material cooled to room temperature. The material was collected and sieved to obtain 11.11 g of powder with a particle size of less than 60 mesh, for a yield of 74.07% and a measured powder content (based on vortioxetine) of 35.17%.

[0451] Five subjects took powder equivalent to 20 mg of vortioxetine and tested its texture. Compared with 100 mesh vortioxetine hemihydrobromide powder equivalent to 20 mg of vortioxetine, the unprocessed material was clearly irritating with an almost unacceptable bitter taste, while the processed vortioxetine solid dispersion proved to be slightly irritating with an acceptable bitter taste.

[0452] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0453] Control product: Instant irritation ++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0454] See Table 41 for details.

[0455] [Table 41]

[0456] Example 18: Preparation of film-coated tablets of vortioxetine monohydrobromide, 10 mg / tablet The method for producing 100 0.152 g tablets is as follows: 2.25 g of powder prepared according to Example 9b (equivalent to 1.0 g of vortioxetine) Microcrystalline cellulose 4.15g Mannitol P100SD 8.00g Sodium carboxymethyl starch 0.70g Magnesium stearate 0.10g Gastric coating material (0.456g) Total 15.20g

[0457] Manufacturing method: (1) The powder of Example 9b, microcrystalline cellulose, mannitol P100SD, sodium carboxymethyl starch, and magnesium stearate were taken in the amounts prescribed in the recipe and placed in a clean, dry 50 ml screw-top glass reagent bottle. The bottle was mixed using a vortex mixer for 5 minutes, sieved through an 80-mesh sieve, and the mixture was continued to be mixed using a vortex mixer for another 5 minutes. The mixture was then removed and sieved through an 80-mesh sieve, and mixed for 5 minutes to obtain a premix for the next pelletization. (2) Using a ZP8 pelletizing machine, control the tablet weight to 147-157 mg / tablet and the hardness to 40-60 N in the 8 mm diameter mode to pelletize the tablets to obtain plain tablets. (3) Using purified water, prepare a suspension of the gastric coating material at a volumetric rate of approximately 10%, and continue stirring until ready for use. (4) The coating solution prepared in (3) is used to coat the plain tablets in a high-efficiency coating machine, and the actual weight gain of the tablets is about 1%.

[0458] The commercially available product (10 mg / tablet) and the product of the present application were each powdered, and 10 subjects tested the texture. The commercial product had a distinct irritating effect and was intolerant to the bitter taste, while the texture of the product of the present application was found to be acceptable.

[0459] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0460] Commercial product: Instant irritation +++, delayed irritation disappears after 30 minutes or more, bitterness is unacceptable.

[0461] See Table 42 for details.

[0462] [Table 42] The initial stability of the present product was tested in accordance with the requirements of the 2015 edition of the Pharmacopoeia of the People's Republic of China. Compared with the commercially available product, the solubility (paddle method, 50 rpm) of the present product in 0.1 N hydrochloric acid and pH 4.5 acetate buffer was found to be faster (10-minute data) and more complete (30-minute data) than the commercially available product. The results are shown in Table 43.

[0463] [Table 43]

[0464] Example 19: Preparation of orally disintegrating tablets (compressed tablets) of 20 mg / tablet 19a: A method for producing 100 0.088 g tablets of vortioxetine hemihydrobromide is as follows: Vortioxetine hemihydrobromide 2.28g (equivalent to 2.0g of vortioxetine) Mannitol P100SD 5.14g Sodium phosphate (anhydrous) 0.228g Crospovidone XL 0.352g Croscarmellose sodium 0.352g Sodium carboxymethyl starch 0.352g Magnesium stearate 0.044g Neotame 0.010g Iron oxide red 0.044g Total 8.802g

[0465] Manufacturing method: (1) Sift the neotame and iron oxide red through a 200-mesh sieve and the other ingredients through a 100-mesh sieve and prepare for use. (2) Take vortioxetine hemihydrobromide, sodium phosphate (anhydrous), mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium carboxymethyl starch, magnesium stearate, neotame, and iron oxide red in the amounts specified in the recipe, place in a 50 ml glass bottle, tighten the cap, mix in a vortex mixer for 5 minutes, pass through an 80 mesh sieve, continue mixing in the vortex mixer for another 5 minutes, remove, pass through an 80 mesh sieve, and mix for 5 minutes to obtain a premix for the next pelletization. (3) Using a ZP8 pelletizing machine, the tablets are pelletized in a shallow concave mode with a diameter of 6.0 mm, with the tablet weight controlled to 86-90 mg / tablet and the hardness controlled to 0.7-1.5 kG to obtain plain tablets.

[0466] 19b: A method for producing 100 0.088 g tablets of vortioxetine monohydrobromide is as follows: Vortioxetine monohydrobromide 2.54g (equivalent to 2.0g of vortioxetine) Mannitol P100SD 4.88g Sodium phosphate (anhydrous) 0.228g Crospovidone XL 0.352g Croscarmellose sodium 0.352g Sodium carboxymethyl starch 0.352g Magnesium stearate 0.044g Neotame 0.010g Iron oxide red 0.044g Total 8.802g

[0467] Manufacturing method: (1) Sift the neotame and iron oxide red through a 200-mesh sieve and the other ingredients through a 100-mesh sieve and prepare for use. (2) Take vortioxetine monohydrobromide, sodium phosphate (anhydrous), mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium carboxymethyl starch, magnesium stearate, neotame, and iron oxide red in the amounts specified in the recipe, place in a 50ml glass bottle, tighten the cap, mix in a vortex mixer for 5 minutes, pass through an 80-mesh sieve, continue mixing in the vortex mixer for another 5 minutes, remove, pass through an 80-mesh sieve, and mix for 5 minutes to obtain a premix for the next pelletization. (3) Using a ZP8 pelletizing machine, the tablets are pelletized in a shallow concave mode with a diameter of 6.0 mm, with the tablet weight controlled to 86-90 mg / tablet and the hardness controlled to 0.7-1.5 kG to obtain plain tablets.

[0468] Ten subjects tested the texture and found that two samples had no grittiness. The sample made with vortioxetine hemihydrobromide had almost no irritation and tasted good. The sample made with vortioxetine monohydrobromide had a stronger irritation than the sample made with vortioxetine hemihydrobromide, causing discomfort to the subjects.

[0469] Homemade sample 19a: Immediate irritation +, delayed irritation disappears within 1 to 15 minutes, bitterness is tolerable.

[0470] Homemade sample 19b: Instantaneous stimulation ++, delayed stimulation disappears after 30 minutes or more, bitterness is unacceptable.

[0471] See Table 44 for details.

[0472] [Table 44]

[0473] Example 20: Preparation of 20 mg / tablet orally disintegrating tablets (compressed tablets) The method for producing 100 0.152 g tablets of vortioxetine hemihydrobromide solid dispersion is as follows: 4.61 g of powder prepared in Example 10 (equivalent to 2.0 g of vortioxetine) Mannitol P100SD 8.30g Sodium phosphate (anhydrous) 0.304g Crospovidone XL 0.608g Croscarmellose sodium 0.608g Sodium carboxymethyl starch 0.608g Magnesium stearate 0.076g Neotame 0.015g Iron oxide red 0.076g Total 15.205g

[0474] Manufacturing method: (1) Sift the neotame and iron oxide red through a 200-mesh sieve and the other ingredients through a 100-mesh sieve and prepare for use. (2) Take the solid dispersion, sodium phosphate (anhydrous), mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium carboxymethyl starch, magnesium stearate, neotame, and iron oxide red in the amounts specified in the recipe, place them in a 50 ml glass bottle, tighten the cap, mix for 5 minutes using a vortex mixer, sieve through an 80 mesh sieve, continue mixing for another 5 minutes using the vortex mixer, remove the contents, sieve through an 80 mesh sieve, and mix for 5 minutes to obtain a premix for the next pelletization. (3) Using a ZP8 pellet molding machine, the tablets are pelletized in a shallow concave mode with a diameter of 8.0 mm, controlling the tablet weight to 145-149 mg / tablet and the hardness to 15-30 N to obtain plain tablets.

[0475] pH and relative exposure detection values: 8.92, 0.19% (7.5µg / ml) Ten subjects tested the texture and found that the sample dissolved in the mouth within 10 seconds, had no gritty feeling, was almost non-irritating, and tasted good.

[0476] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0477] See Table 45 for details.

[0478] [Table 45]

[0479] Example 21: Preparation of orally disintegrating tablets (lyophilized preparation) of 20 mg / tablet Manufacturing Method: Vortioxetine hemihydrobromide 0.912g Mannitol 1.876g Sorbitol 2.000g PEG4000 1.030g Sodium phosphate (anhydrous) 0.248g Medicinal Type B Gelatin 0.124g Neotame 0.001g Iron oxide red 0.003g Total 6.194g Purified water was added to 16 g to produce 40 tablets of approximately 0.4 g each, containing approximately 0.1548 g of solids.

[0480] Manufacturing method: (1) Pass vortioxetine hemihydrobromide and iron oxide red through a 100-mesh sieve and prepare for use. (2) Prepare the formulations of mannitol, sorbitol, PEG4000, medicated type B gelatin, neotame, etc. in the amounts prescribed and place them in a clean, dry 20ml screw-top glass bottle. Add approximately 8g of purified water, tighten the cap, and shake to dissolve at 50°C. Cool to room temperature. Prepare the formulations of vortioxetine hemihydrobromide, iron oxide red, and sodium phosphate in the amounts prescribed and shake to dissolve. Add purified water to the formulations and shake again to dissolve. Pass the suspension through an 80-mesh stainless steel screen three times and continue stirring to prevent settling. (3) Divide the suspension into portions at 0.4 g per well and freeze-dry. (4) The freeze-dried sample is heat-sealed to obtain an orally disintegrating tablet of the freeze-dried formulation.

[0481] pH value and relative exposure detected: 10.42, 0.27% (10.7 μg / ml) Ten subjects tested the texture and found that the sample dissolved in the mouth within 5 seconds, had no gritty feeling, and was very mild.

[0482] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0483] See Table 46 for details.

[0484] [Table 46]

[0485] Example 22: Preparation of orally disintegrating tablets (compressed tablets, freeze-dried preparations) of 20 mg / tablet 22a: The method for producing 100 0.152 g tablets with a micronized coated powder of vortioxetine hemihydrobromide is as follows: 4.79 g of powder of Example 3a prepared (equivalent to 2.0 g of vortioxetine) Mannitol P100SD 8.15g Sodium bicarbonate 0.304g Crospovidone XL 0.608g Croscarmellose sodium 0.608g Sodium carboxymethyl starch 0.608g Magnesium stearate 0.076g Neotame 0.015g Iron oxide red 0.076g Total 15.205g

[0486] Manufacturing method: (1) Sift the neotame and iron oxide red through a 200-mesh sieve and the other ingredients through an 80-mesh sieve and prepare for use. (2) The powder of Example 3a, sodium bicarbonate, mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium carboxymethyl starch, magnesium stearate, neotame, and iron oxide red were taken in the amounts specified in the recipe, placed in a 20 ml screw-top glass bottle, capped, mixed in a vortex mixer for 5 minutes, sieved through an 80-mesh sieve, continued mixing in the vortex mixer for another 5 minutes, removed, sieved through an 80-mesh sieve, and mixed for another 5 minutes to obtain a premix for the next pelletization. (3) Using a ZP8 pellet molding machine, the tablets are pelletized in a shallow concave mode with a diameter of 8.0 mm, controlling the tablet weight to 145-149 mg / tablet and the hardness to 15-30 N to obtain plain tablets.

[0487] 22b: Preparation of freeze-dried orally disintegrating tablets with micronized coating powder of vortioxetine hemihydrobromide Manufacturing Method: 1.914 g of powder of Example 3a prepared (equivalent to 0.8 g of vortioxetine) Mannitol 2.000g Sorbitol 2.000g PEG4000 1.030g Sodium bicarbonate 0.124g Medicinal Type B Gelatin 0.124g Neotame 0.001g Iron oxide red 0.003g Total 7.196g Purified water was added to 16 g to produce 40 tablets of approximately 0.4 g each, containing approximately 0.1799 g of solids.

[0488] Manufacturing method: (1) Prepare the raw materials for use by passing them through a 100 mesh sieve. (2) Add the prescribed amounts of mannitol, sorbitol, PEG4000, medicinal type B gelatin, neotame, etc. to a clean, dry 20ml screw-top glass bottle, add approximately 8g of purified water, tighten the cap, dissolve by shaking at 50°C, and cool to room temperature. Add the prepared powder of Example 3a and sodium bicarbonate to the prescribed amounts, shake to dissolve, add purified water up to the prescribed amount, shake again to dissolve, and pass the suspension through an 80-mesh stainless steel screen three times. Continue stirring to prevent settling. (3) Divide the suspension into portions at 0.4 g per well and freeze-dry. (4) The freeze-dried sample is heat-sealed to obtain freeze-dried orally disintegrating tablets.

[0489] Detected pH values ​​and relative exposure: Sample 22a: pH 8.02, 0.21% (8.3 μg / ml) Sample 22b: pH 9.79, 0.25% (9.9 μg / ml) Ten subjects tested the texture, and sample 22a dissolved in the mouth within 10 seconds, and sample 22b dissolved in the mouth within 10 seconds, without any gritty feeling and with very little irritation.

[0490] Sample 22a: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is acceptable.

[0491] Sample 22b: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is acceptable.

[0492] See Table 47 for details.

[0493] [Table 47]

[0494] Example 23: Preparation of orally disintegrating tablets (compressed tablets, freeze-dried preparations) of 20 mg / tablet 23a: The method for producing 100 0.152 g tablets with a micronized coated powder of vortioxetine hemihydrobromide is as follows: 5.60 g of powder prepared according to Example 7a (equivalent to 2.0 g of vortioxetine) Mannitol P100SD 7.31g Potassium phosphate (anhydrous) 0.304g Crospovidone XL 0.608g Croscarmellose sodium 0.608g Sodium carboxymethyl starch 0.608g Magnesium stearate 0.076g Neotame 0.015g Iron oxide red 0.076g Total 15.205g

[0495] Manufacturing method: (1) Sift the neotame and iron oxide red through a 200-mesh sieve and the other ingredients through an 80-mesh sieve and prepare for use. (2) The powder of Example 7a, potassium phosphate (anhydrous), mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium carboxymethyl starch, magnesium stearate, neotame, and iron oxide red were taken in the amounts specified in the recipe, placed in a 50 ml glass bottle, capped, mixed in a vortex mixer for 5 minutes, sieved through an 80-mesh sieve, continued mixing in the vortex mixer for another 5 minutes, removed, sieved through an 80-mesh sieve, and mixed for another 5 minutes to obtain a premix for the next pelletization. (3) Using a ZP8 pellet molding machine, the tablets are pelletized in a shallow concave mode with a diameter of 8.0 mm, controlling the tablet weight to 145-149 mg / tablet and the hardness to 15-30 N to obtain plain tablets.

[0496] 23b: Preparation of freeze-dried orally disintegrating tablets with micronized coating powder of vortioxetine hemihydrobromide Manufacturing Method: 2.240 g of powder prepared according to Example 7a (equivalent to 0.8 g of vortioxetine) Mannitol 2.000g Sorbitol 2.000g PEG4000 1.030g Potassium phosphate (anhydrous) 0.124g Medicinal Type B Gelatin 0.124g Neotame 0.001g Iron oxide red 0.003g Total 7.522g Purified water was added to 16 g to produce 40 tablets of approximately 0.4 g each, containing approximately 0.1799 g of solids.

[0497] Manufacturing method: (1) Prepare the raw materials for use by passing them through a 100 mesh sieve. (2) Add the ingredients listed in the recipe, such as mannitol, sorbitol, PEG4000, medicinal type B gelatin, and neotame, to a clean, dry 20ml screw-top glass bottle, add approximately 8g of purified water, tighten the cap, and dissolve by shaking at 50°C. Cool to room temperature. Add the powder of Example 7a, potassium phosphate (anhydrous), and iron oxide red to the recipe in the recipe, shake to dissolve, add purified water up to the recipe, shake again to dissolve, and pass the suspension through a 100-mesh stainless steel screen three times. Continue stirring to prevent settling. (3) Divide the suspension into portions at 0.4 g per well and freeze-dry. (4) The freeze-dried sample is heat-sealed to obtain freeze-dried orally disintegrating tablets.

[0498] Detected pH values ​​and relative exposure: Sample 23a: pH 8.02, 0.21% (8.3 μg / ml) Sample 23b: pH 9.79, 0.25% (9.9 μg / ml) Ten subjects tested the texture, and it was found that sample 23a dissolved in the mouth within 10 seconds, and sample 23b dissolved in the mouth within 5 seconds, with no gritty feeling and very little irritation.

[0499] Sample 23a: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is acceptable.

[0500] Sample 23b: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is acceptable.

[0501] See Table 48 for details.

[0502] [Table 48]

[0503] Example 24: Preparation of orally disintegrating tablets (compressed tablets, freeze-dried preparations) of 20 mg / tablet 24a: The method for producing 100 0.152 g tablets from vortioxetine hemihydrobromide solid dispersion powder is as follows: 5.80 g of powder prepared according to Example 11a (equivalent to 2.0 g of vortioxetine) Mannitol P100SD 7.140g Disodium hydrogen phosphate (anhydrous) 0.304g Crospovidone XL 0.608g Croscarmellose sodium 0.608g Sodium carboxymethyl starch 0.608g Magnesium stearate 0.076g Neotame 0.015g Iron oxide red 0.076g Total 15.235g

[0504] Manufacturing method: (1) Sift the neotame and iron oxide red through a 200-mesh sieve and the other ingredients through an 80-mesh sieve and prepare for use. (2) The powder of Example 11a, disodium hydrogen phosphate (anhydrous), mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium carboxymethyl starch, magnesium stearate, neotame, and iron oxide red were taken in the amounts specified in the recipe, placed in a 50 ml glass bottle, capped, mixed in a vortex mixer for 5 minutes, sieved through an 80 mesh sieve, continued mixing in the vortex mixer for another 5 minutes, removed, sieved through an 80 mesh sieve, and mixed for another 5 minutes to obtain a premix for the next pelletization step. (3) Using a ZP8 pelletizing machine, the tablets are pelletized in a shallow concave mode with a diameter of 8.0 mm, with the tablet weight controlled at 147-157 mg / tablet and the hardness controlled at 15-30 N to obtain plain tablets.

[0505] 24b: Preparation of freeze-dried orally disintegrating tablets from solid dispersion powder of vortioxetine hemihydrobromide Manufacturing Method: 2.321 g of powder of Example 11a prepared (equivalent to 0.8 g of vortioxetine) Mannitol 2.000g Sorbitol 2.000g PEG4000 1.030g Disodium hydrogen phosphate (anhydrous) 0.124g Medicinal Type B Gelatin 0.124g Neotame 0.001g Iron oxide red 0.003g Total 7.603g Purified water was added to 16 g to produce 40 tablets of approximately 0.4 g each, containing approximately 0.1901 g of solids.

[0506] Manufacturing method: (1) Sift the iron oxide red through a 100 mesh sieve and prepare for use. (2) Add the prescribed amounts of mannitol, sorbitol, PEG4000, medicinal type B gelatin, neotame, etc. to a clean, dry 20ml screw-top glass bottle, add approximately 8g of purified water, tighten the cap, dissolve by shaking at 50°C, and cool to room temperature. Add the prepared powder of Example 11a, disodium hydrogen phosphate, and iron oxide red to the prescribed amounts, shake to dissolve, add purified water up to the prescribed amounts, shake again to dissolve, and pass the suspension through a 100-mesh stainless steel screen three times. Continue stirring to prevent settling. (3) Divide the suspension into portions at 0.4 g per well and freeze-dry. (4) The freeze-dried sample is heat-sealed to obtain freeze-dried orally disintegrating tablets.

[0507] Detected pH values ​​and relative exposure: Sample 24a: pH 7.98, 0.29% (11.5 μg / ml) Sample 24b: pH 9.79, 0.35% (13.9 μg / ml) Ten subjects tested the texture, and sample 24a dissolved in the mouth within 10 seconds, and sample 24b dissolved in the mouth within 10 seconds, without any gritty feeling and with very little irritation.

[0508] Sample 24a: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is acceptable.

[0509] Sample 24b: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is acceptable.

[0510] See Table 49 for details.

[0511] [Table 49]

[0512] Example 25: Preparation of dispersible tablets of 20 mg / tablet The method for producing 100 0.152 g tablets is as follows: 4.61 g of the solid dispersion powder of Example 10 (equivalent to 2.0 g of vortioxetine) Microcrystalline cellulose 2.68g Mannitol P100SD 7.35g Calcium hydroxide 0.02g Sodium carboxymethyl starch 0.60g Neotame 0.01g Iron oxide red 0.05g Total 15.17g

[0513] Manufacturing method: (1) The solid dispersion powder of Example 10, microcrystalline cellulose, mannitol P100SD, calcium hydroxide, sodium carboxymethyl starch, neotame, and iron oxide red were taken in the amounts specified in the recipe and placed in a clean, dry 50 ml screw-top glass reagent bottle. The bottle was mixed using a vortex mixer for 5 minutes, sieved through an 80-mesh sieve, and further mixed using a vortex mixer for another 5 minutes. The bottle was then removed, sieved through an 80-mesh sieve, and further mixed for 5 minutes to obtain a premix for the next pelletization step. (2) Using a ZP8 pellet molding machine, the tablets are pelletized in a shallow concave mode with a diameter of 8.0 mm, with the tablet weight controlled at 147-157 mg / tablet and the hardness controlled at 50-80 N to obtain plain tablets.

[0514] pH value and relative exposure detected: pH 8.79, 0.45% (17.9 μg / ml) The sample was crushed and the powder equivalent to 20 mg of vortioxetine was tested by 10 subjects for texture and found to have a slight irritation within 1 minute and to be tolerable of the bitter taste of the product.

[0515] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0516] See Table 50 for details.

[0517] [Table 50]

[0518] Example 26: Preparation of dispersible tablets of 20 mg / tablet The method for producing 100 0.152 g tablets is as follows: 5.69 g of the taste-masking coated powder of Example 17 (equivalent to 2.0 g of vortioxetine) Microcrystalline cellulose 5.35g Mannitol P100SD 3.50g Sodium carboxymethyl starch 0.60g Neotame 0.01g Iron oxide red 0.05g Total 15.20g

[0519] Manufacturing method: (1) The taste masking coating powder of Example 17, microcrystalline cellulose, mannitol P100SD, sodium carboxymethyl starch, neotame, and iron oxide red were taken in the amounts described in the recipe and placed in a clean, dry 50 ml screw-top glass reagent bottle. The bottle was mixed in a vortex mixer for 5 minutes, sieved through an 80-mesh sieve, and further mixed in a vortex mixer for 5 minutes. The bottle was then removed, sieved through an 80-mesh sieve, and further mixed for 5 minutes to obtain a premix for subsequent pelletization. (2) Using a ZP8 pellet molding machine, the tablets are pelletized in a shallow concave mode with a diameter of 8.0 mm, with the tablet weight controlled at 147-157 mg / tablet and the hardness controlled at 50-80 N to obtain plain tablets.

[0520] pH value and relative exposure detected: pH 8.79, 0.45% (17.9 μg / ml) The sample was crushed and the powder equivalent to 20 mg of vortioxetine was tested by 10 subjects for texture and found to have a slight irritation within 1 minute and to be tolerable of the bitter taste of the product.

[0521] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0522] See Table 51 for details.

[0523] [Table 51]

[0524] Example 27: Preparation of granules or dry suspension (5 g per packet, containing 20 mg of vortioxetine) The method for producing 100 packets of 5g formulation is as follows: Vortioxetine hemihydrobromide 2.28g (equivalent to 2.0g of vortioxetine) Polyethylene glycol 180g Mannitol P100SD 180g Microcrystalline cellulose 104g Colloidal silicon dioxide 5g Carmellose sodium 5g Potassium citrate 2.5g Sodium carboxymethyl starch 20g Neotame 0.001g Magnesium stearate 1.0g Total 500.28g

[0525] Manufacturing method: (5) The raw material is passed through a 100 mesh sieve and prepared for use. (1) Take vortioxetine hemihydrobromide, polyethylene glycol, mannitol P100SD, microcrystalline cellulose, colloidal silicon dioxide, carmellose sodium, potassium citrate, carboxymethyl starch sodium, neotame, and magnesium stearate in the amounts prescribed and place them in a 2L stainless steel hopper. Attach the hopper to a mixer and mix for 10 minutes at 10 rpm. Remove a mixed sample. After sieving using a rotary sieving machine equipped with a 0.5mm stainless steel round-hole mesh plate, continue mixing in the mixer at 10 rpm for 10 minutes to obtain a premix for granulation. (2) The premix is ​​thinly sliced ​​in a dry granulator, sized using a 1.5 mm stainless steel round-hole mesh plate, and then passed through a 40 mesh stainless steel screen to produce fine powder, which is then returned to granulation again. 461.34 g of granules are obtained, with a yield of 92.2%. (3) The produced granules are packed into aluminum plastic heat-seal bags at 5g per bag and heat-sealed.

[0526] A sample was taken and dispersed in 20 ml of purified water, and 10 subjects were asked to taste it to determine whether the bitterness of the product was acceptable.

[0527] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0528] See Table 52 for details.

[0529] [Table 52]

[0530] Example 28 Preparation of Oral Suspension (5 ml per bottle, containing 20 mg vortioxetine) One hundred vials of vortioxetine hemihydrobromide solid dispersion are prepared as follows to produce a 5 ml oral suspension containing 20 mg of vortioxetine: 13.63 g of solid dispersion of Example 13a prepared (equivalent to 2.0 g of vortioxetine) Polyethylene glycol 50g Carmellose sodium 0.5g Sodium acetate 0.5g Add purified water to 500 ml.

[0531] Manufacturing method: (1) The solid dispersion of Example 13a, polyethylene glycol, carmellose sodium, and sodium acetate were taken in the amounts specified in the recipe, and 400 ml of purified water was added. The mixture was homogenized at 12,000 rpm for 2 minutes, stirred, and dissolved, and then the mixture was ready for use. (2) The suspension prepared by the above procedure is passed through a 100-mesh stainless steel sieve, and the pH value is adjusted to 8.0-8.5 with 1N hydrochloric acid or 1N sodium hydroxide solution. Purified water is added according to the recipe, and the suspension is stirred and dissolved before use. (3) Divide the suspension into vials, 5 ml per bottle, and seal the vials.

[0532] Samples are taken and 10 subjects test the texture and find that the bitterness of the product is tolerable.

[0533] Homemade sample: Immediate irritation +, delayed irritation disappears within 1-15 minutes, bitterness is tolerable.

[0534] See Table 53 for details.

[0535] [Table 53]

[0536] Comparative Example 1: Texture test of different salts 100-mesh vortioxetine lactate, vortioxetine monohydrobromide, or vortioxetine hemihydrobromide powder (each equivalent to 5 mg of vortioxetine) was placed directly on the tongue for one minute, and 10 subjects were randomly assigned to try each salt type three times. After trying one type, they rinsed their mouths and, once the irritation had subsided, tried another type. The bitterness and irritation were recorded, and after a few seconds, the subjects spat out the salt, rinsed their mouths, and recorded the time it took for the irritation to subside. After 1-1.5 hours, they ate a meal and recorded the sensation again. Table 54 shows a comparison of the texture of the different vortioxetine salts across 30 trials by 10 subjects.

[0537] [Table 54] Note: (1) The irritation is so strong that it is almost unbearable and does not go away even after repeated gargling. It takes more than an hour for the irritation to subside, even after eating. (2) No irritation after rinsing.

[0538] Comparative Example 2 Texture test of the present solid dispersion and a commercially available formulation The solid dispersion prepared in Example 9b, vortioxetine hemihydrobromide powder, and commercially available vortioxetine monohydrobromide tablets (each equivalent to 10 mg of vortioxetine) were powdered and passed through a 100-mesh sieve. Then, the tablets were placed directly on the tongue for one minute. Twenty subjects tried one of the salt types, rinsed their mouths, and tried another type once the irritation subsided. The bitterness and irritation were recorded, and the subjects were asked to expectorate the salt after a few seconds, rinse their mouths, and record the time it took for the irritation to subside. After 1 to 1.5 hours, they ate a meal and recorded the sensation again. Table 55 shows a comparison of the texture of the different vortioxetine powders by 20 subjects.

[0539] [Table 55] Note: (1) The irritation is so strong that it is almost unbearable and does not go away even after repeated gargling. It takes more than two hours for the irritation to subside, even after eating. (2) No irritation after rinsing.

Claims

1. An orally dispersible taste-masked formulation of vortioxetine hemihydrobromide in the form of a tablet, granule, capsule, powder, suspension or dry suspension, comprising a solid dispersion of vortioxetine hemihydrobromide, coated granules of vortioxetine hemihydrobromide or a mixture of vortioxetine hemihydrobromide and an alkaline auxiliary material, wherein the alkaline auxiliary material is at least one of trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide or meglumine.

2. the coated granules comprise vortioxetine hemihydrobromide coated with a taste-masking aid; Optionally, the coated granules include an anti-sticking agent; and The orally dispersible taste-masking formulation according to claim 1, comprising:

3. 3. The orally dispersible taste-masking formulation according to claim 2, wherein the taste-masking auxiliary material is cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, methacrylic acid copolymer, chitosan, copolyvidone, or polyvinyl alcohol.

4. 2. The orally dispersible taste-masking formulation according to claim 1, wherein the solid dispersion is formed by dispersing vortioxetine hemihydrobromide in a taste-masking aid material.

5. 5. The orally dispersible taste-masking formulation according to claim 4, wherein the taste-masking auxiliary material is cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, methacrylic acid copolymer, chitosan, copolyvidone, polyvinylpyrrolidone, polyvinyl alcohol or polyethylene glycol.

6. the solid dispersion of vortioxetine hemihydrobromide and the coated vortioxetine hemihydrobromide granules further comprise an alkaline auxiliary material; the alkaline auxiliary material is at least one of trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine; 2. The orally dispersible taste-masking formulation of claim 1, wherein

7. comprising an alkaline auxiliary material in the orally dispersible taste-masking formulation; the weight ratio of the vortioxetine hemihydrobromide to the taste-masking aid is 1:0.1 to 1:5; the weight ratio of the vortioxetine hemihydrobromide to the alkaline auxiliary material is 1:0.01 to 1:1.1; The orally dispersible taste-masking formulation according to claim 2, comprising:

8. comprising an alkaline auxiliary material in the orally dispersible taste-masking formulation; the weight ratio of the vortioxetine hemihydrobromide to the taste-masking aid is 1:0.1 to 1:5; the weight ratio of the vortioxetine hemihydrobromide to the alkaline auxiliary material is 1:0.01 to 1:1.1; The orally dispersible taste-masking formulation according to claim 4, comprising:

9. 7. The orally dispersible taste-masked formulation of claim 6, wherein the weight ratio of the vortioxetine hemihydrobromide to the alkaline auxiliary material is 1:0.01 to 1:1.

1.

10. The orally dispersible taste-masking formulation according to claim 7, further comprising a solid dispersion formed by dispersing the coated granules in a taste-masking auxiliary material.

11. The orally dispersible taste-masked formulation according to claim 8, wherein the solid dispersion further comprises coated granules coated with a taste-masking auxiliary material.

12. 2. The orally dispersible taste-masked formulation of claim 1, which has a crystalline form and an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, which has characteristic peaks at 4.2±0.2° and 17.4±0.2°.

13. further comprising a filler, a flavoring agent, a release modifier, a plasticizer, an anti-adherent, and / or a disintegrant; the anti-sticking agent is talc and accounts for 5% to 25% of the total weight of the coated granules; The orally dispersible taste-masking preparation according to any one of claims 1 to 5, comprising:

14. the anti-sticking agent is talc and accounts for 5% to 25% of the total weight of the coated granules; the disintegrant is sodium carboxymethyl starch, croscarmellose sodium, crospovidone, or a combination thereof, and accounts for 1% to 8% of the total weight of the orally dispersible taste-masking formulation; the flavoring agent is neotame and accounts for 0.05% to 0.5% of the total weight of the orally dispersible taste-masking formulation; 14. The orally dispersible taste-masking formulation according to claim 13, comprising:

15. (1a) dispersing a taste-masking aid in a solvent and coating vortioxetine hemi-hydrobromide powder with said taste-masking aid in a fluidized bed, and after removing the solvent, obtaining vortioxetine hemi-hydrobromide coated with the taste-masking aid; or adding the vortioxetine hemihydrobromide powder and taste-masking aid to a solvent to form a suspension, and removing the solvent by fluidized bed, spray drying or evaporation to obtain vortioxetine hemihydrobromide coated with taste-masking aid (1b); (2) preparing the coated vortioxetine hemihydrobromide granules into a formulation; Optionally, step (3) of mixing the coated vortioxetine hemihydrobromide with alkaline auxiliary materials and then preparing it into a formulation; 2. A method for preparing the orally dispersible taste-masked formulation of vortioxetine hemihydrobromide according to claim 1, comprising:

16. 16. A method for preparing an orally dispersible taste-masked formulation as claimed in claim 15, wherein in step (1a), the taste-masking aid and the release modifier are dispersed in a solvent, the vortioxetine hemi-hydrobromide powder is coated with the taste-masking aid in a fluidized bed, and after removing the solvent, vortioxetine hemi-hydrobromide coated with the taste-masking aid is obtained.

17. 17. The method for preparing an orally dispersible taste-masked formulation according to claim 16, wherein the release modifier is polyethylene glycol or an alkaline auxiliary material, and the solvent is water, ethanol or dichloromethane.

18. 16. A method for preparing an orally dispersible taste-masked formulation as claimed in claim 15, wherein in step (1b) the vortioxetine hemihydrobromide powder, taste-masking aid, release modifier and / or plasticizer are added to a solvent to form a vortioxetine hemihydrobromide suspension, and after removing the solvent by fluidized bed drying, spray drying or evaporation, vortioxetine hemihydrobromide coated with taste-masking aid is obtained.

19. 19. The method for producing an orally dispersible taste-masked formulation according to claim 18, wherein the plasticizer is polyethylene glycol or triethyl citrate, and the solvent is water, ethanol, or dichloromethane.

20. (1a) mixing vortioxetine hemihydrobromide powder with a taste-masking aid, heating to soften or liquefy at 50-150°C, cooling to solidify, and pulverizing to obtain a powder; or (1b) dissolving the vortioxetine hemihydrobromide powder and taste-masking aid in a solvent and removing the solvent by distillation, fluidized bed or spray drying to obtain a powder; Step (2) of preparing a formulation from the solid dispersion powder obtained in step (1a) or (1b); Optionally, step (3) of mixing the powder obtained in step (1a) or (1b) with an alkaline auxiliary material and then preparing it into a formulation.

2. A method for preparing the vortioxetine hemihydrobromide formulation of claim 1, comprising:

21. 21. A method for producing an orally dispersible taste-masked formulation as claimed in claim 20, wherein in step (1a), the vortioxetine hemihydrobromide powder, a taste-masking auxiliary material and a release-modifying agent are mixed, heated to 50 to 150°C to soften or liquefy, cooled to solidify, and pulverized to obtain a powder.

22. 22. The method for producing an orally dispersible masked formulation according to claim 20 or 21, wherein in step (1b), the solvent is water, ethanol or dichloromethane.

23. (1) mixing vortioxetine hemihydrobromide powder with an alkaline auxiliary material to obtain a taste-masking composition; (2) preparing the taste-masking composition into a formulation; 2. A method for preparing the orally dispersible taste-masked formulation of vortioxetine hemihydrobromide according to claim 1, comprising:

24. 24. The method for producing an orally dispersible taste-masked formulation according to claim 23, wherein in step (1), the alkaline auxiliary material is trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine.

25. The method of any one of claims 15 to 24, wherein the weight ratio of the vortioxetine hemihydrobromide to the pharmaceutically acceptable taste-masking adjunct material used in forming the coating or solid dispersion is 1:0.1 to 1:5, and the weight ratio of the vortioxetine hemihydrobromide to the pharmaceutically acceptable alkaline adjunct material is 1:0.01 to 1:1.

1.

26. 5. The orally dispersible taste-masked formulation of claim 4, comprising a solid dispersion formed of vortioxetine hemihydrobromide and amino methacrylate copolymer, wherein the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation has characteristic peaks at the positions of 4.2±0.2°, 14.5±0.2°, 17.4±0.2° and 22.6±0.2°.

27. 10. Use of the orodispersible taste-masked formulation of vortioxetine hemihydrobromide according to claim 1 in the preparation of a medicament used in the treatment of depressive affective disorder.

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