Vortioxetine hydrobromide sustained-release microspheres, their formulations, preparation methods, and applications

Abstract

This disclosure belongs to the field of biomedical technology, specifically relating to vortioxetine hydrobromide sustained-release microspheres, their formulations, preparation methods, and applications. This disclosure has the following advantages: the preparation method of vortioxetine hydrobromide sustained-release microspheres provided in this disclosure can increase drug loading, improve drug encapsulation efficiency, and significantly reduce excipient usage.

Description

Technical Field

[0001] This disclosure belongs to the field of biomedical technology, specifically relating to vortioxetine hydrobromide sustained-release microspheres, their formulations, their preparation methods, and their applications. Background Technology

[0002] Vortioxetine is a new drug for the treatment of depression. It exerts its antidepressant effect mainly by increasing the concentration of serotonin in the central nervous system. It was jointly developed by Lundbeck Pharmaceuticals of Denmark and Takeda Pharmaceutical of Japan. It was approved by the U.S. Food and Drug Administration (FDA) on September 30, 2013, for the treatment of major depressive disorder. Its brand name is Brintellix and it is available in tablet form. In December of the same year, it was approved by the European Medicines Agency (EMA) in the form of oral film-coated tablets and drops. Because it is a new drug with clinical value, it was given priority review in China. Its tablet form was approved for marketing in China in 2017 and is available in the brand name "Xindayue".

[0003] Currently available vortioxetine tablets require daily and long-term use. However, patient adherence to antidepressants decreases significantly over time, leading to missed doses, medication refusal, and ultimately, worsening of the condition. Therefore, long-term sustained-release injectable formulations are needed clinically to increase patient adherence and improve treatment efficacy.

[0004] CN109922806B discloses a long-acting sustained-release injection of vortioxetine hydrobromide, which prepares vortioxetine hydrobromide into a suspension and achieves a long-acting drug release effect by controlling the particle size distribution. However, microcrystalline injections generally cause a large burst release in vivo with a short duration.

[0005] CN116850146B discloses a long-acting sustained-release formulation of vortioxetine free base or its pharmaceutical salt and its preparation method. Microspheres are prepared from vortioxetine and lactide-glycolic acid copolymer to achieve a long-acting sustained-release effect. However, the vortioxetine free base microspheres have low hardness and are easily broken. Furthermore, the basic groups of vortioxetine react with the ester bonds of the lactide-glycolic acid copolymer, forming various new impurities. The drug loading of the vortioxetine hydrobromide microspheres is also low, failing to meet clinical requirements. In this method, vortioxetine hydrobromide has low solubility in the oil phase, requiring complete dissolution. Increasing the drug loading necessitates increasing the amount of organic solvent, resulting in a lower concentration of the lactide-glycolic acid copolymer in the oil phase. Consequently, the resulting microspheres have small particle sizes, a loose structure, and poor sustained-release effect. CN116850146B indicates that lactide-glycolic acid copolymer can be dissolved in dichloromethane or a mixed solvent of dichloromethane and benzyl alcohol. However, in the examples, vortioxetine hydrobromide is dissolved in a mixed solvent, mainly to increase the solubility of vortioxetine hydrobromide and increase the drug loading, but it cannot improve the drug encapsulation efficiency.

[0006] CN116919920B discloses a long-acting sustained-release microsphere composition of vortioxetine sineoxate and its preparation method. The method uses vortioxetine sineoxate and lactide-glycolic acid copolymer to prepare long-acting sustained-release microspheres, achieving a long-term medication effect. This method increases the solubility of sineoxate in oil-phase organic solvents and significantly reduces its solubility in aqueous phase by forming a poorly soluble salt, thus meeting the requirements of the O / W single-emulsion-solvent evaporation method for microsphere preparation and helping to improve drug loading and encapsulation efficiency. However, the high boiling points of dimethyl sulfoxide or N-methylpyrrolidone generated during the preparation process make them difficult to remove, resulting in significant residues that may pose health risks.

[0007] The present disclosure aims to provide a sustained-release microsphere of vortioxetine hydrobromide, its formulation, its preparation method and application, which can improve drug loading, improve drug encapsulation efficiency and significantly reduce excipient usage. Summary of the Invention

[0008] The technical problem this disclosure aims to solve is that current vortioxetine formulations on the market have low drug loading, low encapsulation efficiency, or high excipient usage. This disclosure provides a vortioxetine hydrobromide sustained-release microsphere, its formulation, and its preparation method, which can improve drug loading and encapsulation efficiency. Furthermore, the vortioxetine hydrobromide sustained-release microsphere, its formulation, and its preparation method disclosed in this disclosure can significantly reduce excipient usage.

[0009] To achieve the above-mentioned technical objectives, the technical solution adopted in this disclosure is as follows:

[0010] On the one hand, this disclosure provides a method for preparing vortioxetine hydrobromide sustained-release microspheres, the method comprising the following steps: pretreated vortioxetine hydrobromide is used to obtain vortioxetine hydrobromide sustained-release microspheres by S / O / W double emulsion method; wherein the pretreated vortioxetine hydrobromide is pulverized vortioxetine hydrobromide.

[0011] Vortioxetine hydrobromide is available for purchase on the market.

[0012] The method for preparing vortioxetine hydrobromide sustained-release microspheres disclosed herein can improve drug loading. The method for preparing vortioxetine hydrobromide sustained-release microspheres disclosed herein can improve drug encapsulation efficiency. Furthermore, the method for preparing vortioxetine hydrobromide sustained-release microspheres disclosed herein can significantly reduce the amount of excipients required.

[0013] In the embodiments disclosed herein, vortioxetine hydrobromide can be obtained by pulverizing using equipment such as ball mills or air jet mills. The pulverizing equipment is not limited to the listed equipment, and the particle size after pulverization can be as small as 0.1-0.5 μm. The smaller the particle size of vortioxetine hydrobromide, the easier it is to disperse evenly when forming an oil phase, resulting in a more uniform drug loading and better spherical shape after spherical formation.

[0014] In embodiments of this disclosure, the pulverized vortioxetine hydrobromide has a particle size of less than 50 μm.

[0015] In some preferred embodiments of this disclosure, the pulverized vortioxetine hydrobromide has a particle size of less than 30 μm.

[0016] In some preferred embodiments of this disclosure, the pulverized vortioxetine hydrobromide has a particle size of 0.1 μm or larger. In some preferred embodiments of this disclosure, the pulverized vortioxetine hydrobromide has a particle size of 0.1-50 μm.

[0017] In some preferred embodiments of this disclosure, the pulverized vortioxetine hydrobromide has a particle size of 0.1-30 μm.

[0018] In some preferred embodiments of this disclosure, the pulverized vortioxetine hydrobromide has a particle size of 0.3-30 μm.

[0019] In the embodiments of this disclosure, the particle size of the pulverized vortioxetine hydrobromide is 0.3, 0.5, 0.8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 μm.

[0020] In some preferred embodiments of this disclosure, the content of vortioxetine hydrobromide in the sustained-release microspheres accounts for 10% to 80% of the total weight of the microspheres, preferably 20% to 65%, and more preferably 30% to 50%.

[0021] In some preferred embodiments of this disclosure, the S / O / W double emulsification method includes the step of emulsifying an oil phase containing pretreated vortioxetine hydrobromide with an aqueous phase to form an S / O / W emulsion droplet suspension. The difference between S / O / W and O / W is that in O / W, the drug needs to be completely dissolved in the oil phase, so the drug loading is limited by solubility; while in S / O / W, the drug does not need to be dissolved, and therefore is not limited by solubility. The fact that S / O / W is not limited by solubility is the main reason for its increased drug loading.

[0022] In some preferred embodiments of this disclosure, the aqueous phase comprises an aqueous emulsifier solution and a buffer salt. The buffer salt can reduce its solubility in the aqueous phase, thereby significantly improving the encapsulation efficiency.

[0023] In some preferred embodiments of this disclosure, the preparation step of the oil phase containing pretreated vortioxetine hydrobromide includes dissolving a biodegradable polymer in an organic solvent, adding pulverized vortioxetine hydrobromide, and mixing thoroughly to form the oil phase. The pulverized vortioxetine hydrobromide can be directly dispersed in the oil phase to form S / O without the need for dissolution.

[0024] In some preferred embodiments of this disclosure, the buffer salt comprises any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or sodium dihydrogen phosphate.

[0025] In some preferred embodiments of this disclosure, the concentration of the buffer salt in the aqueous phase is 1–500 mM, preferably 1–300 mM, and more preferably 2–200 mM.

[0026] In some preferred embodiments of this disclosure, the emulsifier aqueous solution is selected from any one or more of polyvinyl alcohol aqueous solution, poloxamer aqueous solution, and polyethylene glycol aqueous solution.

[0027] In some preferred embodiments of this disclosure, the emulsifier aqueous solution is a polyvinyl alcohol aqueous solution.

[0028] In some preferred embodiments of this disclosure, the concentration of the emulsifier in the aqueous emulsifier solution is 0.05% to 5% w / v; preferably, the concentration of the emulsifier in the aqueous emulsifier solution is 0.05% to 3% w / v; preferably, the concentration of the emulsifier in the aqueous emulsifier solution is 0.1% to 2% w / v.

[0029] In some preferred embodiments of this disclosure, the biodegradable polymer is selected from any one or more of lactide-glycolic acid copolymer (PLGA), polylactic acid, polyglycolic acid, polycaprolactone, L-polylactic acid-glycolic acid copolymer, polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyamide, chitosan, dextran, alginate, or hyaluronic acid.

[0030] In some preferred embodiments of this disclosure, the biodegradable polymer is a lactide-glycolic acid copolymer.

[0031] In some preferred embodiments of this disclosure, the molar ratio of lactide to glycolide in the lactide-glycol copolymer is 85:15 to 25:75, preferably 80:20 to 40:60, and more preferably 75:25 to 50:50.

[0032] In some preferred embodiments of this disclosure, the weight-average molecular weight of the lactide-glycolic acid copolymer is 5,000 to 200,000 Daltons, preferably 8,000 to 160,000 Daltons, and more preferably 20,000 to 60,000 Daltons.

[0033] In some preferred embodiments of this disclosure, the intrinsic viscosity of the lactide-glycolic acid copolymer is 0.05 to 2 dl / g, preferably 0.08 to 1.5 dl / g, and more preferably 0.1 to 0.6 dl / g.

[0034] In some preferred embodiments of this disclosure, the organic solvent is selected from any one or more of dichloromethane, trichloromethane, tetrachloromethane, dichloroethane, dichloropropane, trichloroethane, and ethyl acetate.

[0035] In some preferred embodiments of this disclosure, the organic solvent is dichloromethane;

[0036] In some preferred embodiments of this disclosure, the volume ratio of the organic solvent to the aqueous emulsifier is 1:30 to 1:500, preferably 1:40 to 1:400, preferably 1:50 to 1:300, and more preferably 1:50 to 1:200.

[0037] In some preferred embodiments of this disclosure, the following step is also included: after removing the organic solvent from the S / O / W emulsion droplet suspension, it is freeze-dried to obtain vortioxetine hydrobromide sustained-release microspheres.

[0038] On the other hand, this disclosure provides vortioxetine hydrobromide sustained-release microspheres prepared by the method described above.

[0039] On the other hand, this disclosure provides vortioxetine hydrobromide sustained-release microspheres, wherein the content of vortioxetine hydrobromide in the sustained-release microspheres accounts for 10% to 80% of the total weight of the microspheres, preferably 20% to 65%, and more preferably 30% to 50%.

[0040] In some preferred embodiments of this disclosure, the vortioxetine hydrobromide sustained-release microspheres of this disclosure are obtained by pre-treating vortioxetine hydrobromide using an S / O / W double emulsion method, wherein the pre-treated vortioxetine hydrobromide is pulverized vortioxetine hydrobromide.

[0041] In some preferred embodiments of this disclosure, the pulverized vortioxetine hydrobromide sustained-release microspheres of this disclosure have a particle size of less than 50 μm, preferably less than 30 μm.

[0042] In some preferred embodiments of this disclosure, the vortioxetine hydrobromide sustained-release microspheres of this disclosure comprise vortioxetine hydrobromide and a biodegradable polymer.

[0043] In some preferred embodiments of this disclosure, the S / O / W double emulsification method according to the vortioxetine hydrobromide sustained-release microspheres of this disclosure includes the step of emulsifying an oil phase containing pretreated vortioxetine hydrobromide with an aqueous phase to form an S / O / W emulsion droplet suspension.

[0044] In some preferred embodiments of this disclosure, the aqueous phase of the vortioxetine hydrobromide sustained-release microspheres of this disclosure comprises an aqueous emulsifier and a buffer salt.

[0045] In some preferred embodiments of this disclosure, the preparation steps of the oil phase containing pretreated vortioxetine hydrobromide microspheres according to this disclosure include dissolving a biodegradable polymer in an organic solvent, adding pulverized vortioxetine hydrobromide, and mixing evenly to form the oil phase.

[0046] In some preferred embodiments of this disclosure, the buffer salt of the vortioxetine hydrobromide sustained-release microspheres of this disclosure is selected from any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or sodium dihydrogen phosphate.

[0047] In some preferred embodiments of this disclosure, according to the vortioxetine hydrobromide sustained-release microspheres of this disclosure, the concentration of the buffer salt in the aqueous phase is 1–500 mM, preferably 1–300 mM, and more preferably 2–200 mM. The aqueous phase comprises an emulsifier aqueous solution and the buffer salt. The concentration of the buffer salt in the aqueous phase according to this invention refers to the concentration of the buffer salt in the aqueous phase after adding the buffer salt to the emulsifier aqueous solution. In one embodiment, the buffer solution is added to the emulsifier aqueous solution in solid form, and after sufficient dissolution, forms an aqueous phase with a buffer concentration of 1–500 mM, preferably 1–300 mM, and more preferably 2–200 mM.

[0048] In some preferred embodiments of this disclosure, the emulsifier aqueous solution according to the vortioxetine hydrobromide sustained-release microspheres of this disclosure is selected from any one or more of polyvinyl alcohol aqueous solution, poloxamer aqueous solution, and polyethylene glycol aqueous solution; preferably, the emulsifier aqueous solution is a polyvinyl alcohol aqueous solution.

[0049] In some preferred embodiments of this disclosure, according to the vortioxetine hydrobromide sustained-release microspheres of this disclosure, the concentration of the emulsifier in the emulsifier aqueous solution is 0.05% to 5% w / v; preferably, the concentration of the emulsifier in the emulsifier aqueous solution is 0.05% to 3% w / v; preferably, the concentration of the emulsifier in the emulsifier aqueous solution is 0.1% to 2% w / v.

[0050] In some preferred embodiments of this disclosure, the biodegradable polymer of the vortioxetine hydrobromide sustained-release microspheres of this disclosure is selected from any one or more of lactide-glycolic acid copolymer (PLGA), polylactic acid, polyglycolic acid, polycaprolactone, L-polylactic acid-glycolic acid copolymer, polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyamide, chitosan, dextran, alginate, or hyaluronic acid.

[0051] In some preferred embodiments of this disclosure, the biodegradable polymer of the vortioxetine hydrobromide sustained-release microspheres of this disclosure is a lactide-glycolic acid copolymer.

[0052] In some preferred embodiments of this disclosure, according to the vortioxetine hydrobromide sustained-release microspheres of this disclosure, the molar ratio of lactide to glycolide in the lactide-glycolic acid copolymer is 85:15 to 25:75, preferably 80:20 to 40:60, and more preferably 75:25 to 50:50.

[0053] In some preferred embodiments of this disclosure, the weight-average molecular weight of the lactide-glycolic acid copolymer of the vortioxetine hydrobromide sustained-release microspheres of this disclosure is 5,000 to 200,000 Daltons, preferably 8,000 to 160,000 Daltons, and more preferably 20,000 to 60,000 Daltons.

[0054] In some preferred embodiments of this disclosure, the intrinsic viscosity of the lactide-glycolic acid copolymer of the vortioxetine hydrobromide sustained-release microspheres of this disclosure is 0.05 to 2 dl / g, preferably 0.08 to 1.5 dl / g, and more preferably 0.1 to 0.6 dl / g.

[0055] On the other hand, this disclosure provides a vortioxetine hydrobromide sustained-release microsphere formulation, comprising vortioxetine hydrobromide sustained-release microspheres obtained by the preparation method described above, and vortioxetine hydrobromide sustained-release microspheres as described above.

[0056] In some preferred embodiments of this disclosure, the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure comprises vortioxetine hydrobromide in a content of 10% to 80% of the total weight of the microspheres, preferably 20% to 65%, and more preferably 30% to 50%.

[0057] In some preferred embodiments of this disclosure, the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure comprises vortioxetine hydrobromide sustained-release microspheres pretreated with vortioxetine hydrobromide obtained by S / O / W double emulsion method, wherein the pretreated vortioxetine hydrobromide is pulverized vortioxetine hydrobromide.

[0058] In some preferred embodiments of this disclosure, the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure has a particle size of less than 50 μm, preferably less than 30 μm.

[0059] In some preferred embodiments of this disclosure, the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure has a particle size of 0.1 μm or more, preferably 0.1-50 μm, and more preferably 0.1-30 μm.

[0060] In some preferred embodiments of this disclosure, the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure comprises vortioxetine hydrobromide and a biodegradable polymer.

[0061] In some preferred embodiments of this disclosure, the S / O / W double emulsification method according to the sustained-release microsphere formulation of vortioxetine hydrobromide of this disclosure includes the step of emulsifying an oil phase containing pretreated vortioxetine hydrobromide with an aqueous phase to form an S / O / W emulsion droplet suspension.

[0062] In some preferred embodiments of this disclosure, the aqueous phase of the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure comprises an aqueous emulsifier solution and a buffer salt.

[0063] In some preferred embodiments of this disclosure, the preparation step of the oil phase containing pretreated vortioxetine hydrobromide according to the sustained-release microsphere formulation of this disclosure includes dissolving a biodegradable polymer in an organic solvent, adding pulverized vortioxetine hydrobromide, and mixing evenly to form the oil phase.

[0064] In some preferred embodiments of this disclosure, the buffer salt of the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure is selected from any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or sodium dihydrogen phosphate.

[0065] In some preferred embodiments of this disclosure, according to the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure, the concentration of the buffer salt in the aqueous phase is 1–500 mM, preferably 1–300 mM, and more preferably 2–200 mM. The aqueous phase comprises an emulsifier aqueous solution and the buffer salt. The concentration of the buffer salt in the aqueous phase in this invention refers to the concentration of the buffer salt in the aqueous phase after adding the buffer salt to the emulsifier aqueous solution. In one embodiment, the buffer solution is added to the emulsifier aqueous solution in solid form, and after sufficient dissolution, forms an aqueous phase with a buffer concentration of 1–500 mM, preferably 1–300 mM, and more preferably 2–200 mM.

[0066] In some preferred embodiments of this disclosure, the emulsifier aqueous solution according to the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure is selected from any one or more of polyvinyl alcohol aqueous solution, poloxamer aqueous solution, and polyethylene glycol aqueous solution; preferably, the emulsifier aqueous solution is a polyvinyl alcohol aqueous solution.

[0067] In some preferred embodiments of this disclosure, according to the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure, the concentration of the emulsifier in the emulsifier aqueous solution is 0.05% to 5% w / v; preferably, the concentration of the emulsifier in the emulsifier aqueous solution is 0.05% to 3% w / v; preferably, the concentration of the emulsifier in the emulsifier aqueous solution is 0.1% to 2% w / v.

[0068] In some preferred embodiments of this disclosure, the biodegradable polymer of the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure is selected from any one or more of lactide-glycolic acid copolymer (PLGA), polylactic acid, polyglycolic acid, polycaprolactone, L-polylactic acid-glycolic acid copolymer, polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyamide, chitosan, dextran, alginate, or hyaluronic acid.

[0069] In some preferred embodiments of this disclosure, the biodegradable polymer in the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure is a lactide-glycolic acid copolymer.

[0070] In some preferred embodiments of this disclosure, according to the sustained-release microsphere formulation of vortioxetine hydrobromide of this disclosure, the molar ratio of lactide to glycolide in the lactide-glycolic acid copolymer is 85:15 to 25:75, preferably 80:20 to 40:60, and more preferably 75:25 to 50:50.

[0071] In some preferred embodiments of this disclosure, the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure has a weight-average molecular weight of 5,000 to 200,000 Daltons, preferably 8,000 to 160,000 Daltons, and more preferably 20,000 to 60,000 Daltons.

[0072] In some preferred embodiments of this disclosure, the intrinsic viscosity of the lactide-glycolic acid copolymer of the vortioxetine hydrobromide sustained-release microsphere formulation of this disclosure is 0.05 to 2 dl / g, preferably 0.08 to 1.5 dl / g, and more preferably 0.1 to 0.6 dl / g.

[0073] On the other hand, this disclosure provides the use of vortioxetine hydrobromide sustained-release microspheres obtained by the preparation method described above, vortioxetine hydrobromide sustained-release microspheres as described above, or vortioxetine hydrobromide sustained-release microsphere formulations as described above in the preparation of sustained-release formulations of drugs for treating depression.

[0074] In some preferred embodiments of this disclosure, the method for preparing vortioxetine hydrobromide sustained-release microspheres includes the following steps:

[0075] (1) Vortioxetine hydrobromide was pulverized;

[0076] (2) Dissolve lactide-glycolic acid copolymer (PLGA) in an organic solvent. After it is fully dissolved, add pulverized vortioxetine hydrobromide and mix it evenly under high shear to form the oil phase.

[0077] (3) Prepare a polyvinyl alcohol (PVA) aqueous solution of a certain concentration, add buffer salt, and fully dissolve it to form the aqueous phase;

[0078] (4) Use a high-shear emulsifier to shear emulsify the oil phase and the aqueous phase into an S / O / W emulsion droplet suspension;

[0079] (5) Stir at low speed to evaporate and remove organic solvent; collect after solidification, wash, freeze dry to obtain vortioxetine hydrobromide sustained-release microspheres.

[0080] In some preferred embodiments of this disclosure, the method for preparing vortioxetine hydrobromide sustained-release microspheres includes the following steps:

[0081] (1) Vortioxetine hydrobromide was pulverized; the particle size of the pulverized vortioxetine hydrobromide was controlled to be below 30 μm;

[0082] (2) Dissolve lactide-glycolic acid copolymer (PLGA) in an organic solvent. After complete dissolution, add pulverized vortioxetine hydrobromide and mix evenly under high shear to form the oil phase. The molar ratio of lactide to glycolide in the lactide-glycolic acid copolymer is 75:25 to 50:50. The weight-average molecular weight of the lactide-glycolic acid copolymer is 20,000 to 60,000 Daltons. The intrinsic viscosity of the lactide-glycolic acid copolymer is 0.1 to 0.6 dl / g. The organic solvent is dichloromethane.

[0083] (3) Prepare a polyvinyl alcohol (PVA) aqueous solution of a certain concentration, add a buffer salt, and dissolve it completely to form the aqueous phase; the concentration of the polyvinyl alcohol aqueous solution is 0.1% to 2% w / v; the buffer salt includes any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; the concentration of the buffer salt in the aqueous phase is 2 to 200 mM; the volume ratio of organic solvent to polyvinyl alcohol solution is 1:50 to 1:300;

[0084] (4) Use a high-shear emulsifier to shear emulsify the oil phase and the aqueous phase into an S / O / W emulsion droplet suspension;

[0085] (5) Stir at low speed to evaporate and remove organic solvent; collect after solidification, wash, and freeze-dry to obtain vortioxetine hydrobromide sustained-release microspheres. The content of vortioxetine hydrobromide in the vortioxetine hydrobromide sustained-release microspheres accounts for 30% to 65% of the total weight of the microspheres.

[0086] This disclosure has the following advantages:

[0087] (1) The preparation method of vortioxetine hydrobromide sustained-release microspheres provided in this disclosure can improve the drug loading.

[0088] (2) The preparation method of vortioxetine hydrobromide sustained-release microspheres provided in this disclosure can improve the drug encapsulation rate and help increase the drug loading.

[0089] (3) The preparation method of vortioxetine hydrobromide sustained-release microspheres provided in this disclosure can significantly reduce the amount of excipients used and further improve the safety of medication.

[0090] (4) The method for preparing vortioxetine hydrobromide sustained-release microspheres provided in this disclosure has good sphericity.

[0091] (5) The vortioxetine hydrobromide sustained-release microspheres or vortioxetine hydrobromide sustained-release microsphere formulations provided in this disclosure can increase patient compliance and improve treatment efficacy. Attached Figure Description

[0092] To more clearly illustrate the specific embodiments of this disclosure or the technical solutions in the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this disclosure. For those skilled in the art, other drawings can be obtained from these drawings without creative effort. The accompanying drawings are incorporated in and constitute a part of this specification, illustrating embodiments consistent with this specification, and together with the specification, are used to explain the principles of this specification.

[0093] Figure 1 Electron micrographs of vortioxetine hydrobromide before and after gas jet pulverization are shown in Example 1.

[0094] Figure 2 An electron microscope image of the microspheres obtained in Example 4 is shown.

[0095] Figure 3 The in vitro release curve of the microspheres obtained in Example 4 is shown.

[0096] Figure 4 An electron microscope image of the microspheres obtained in Example 10 is shown.

[0097] Figure 5 Electron micrographs of the microspheres obtained in Comparative Example 1 are shown.

[0098] Figure 6 The liquid chromatogram of the microspheres obtained in Comparative Example 1 is shown.

[0099] Figure 7 The first-order mass spectrum of the microspheres obtained in Comparative Example 1 is shown.

[0100] Figure 8 The first-order mass spectrum of the microspheres obtained in Comparative Example 1 is shown in Figure 2.

[0101] Figure 9 Electron micrographs of the microspheres obtained in Comparative Example 4 are shown. Detailed Implementation

[0102] Definitions and Explanations

[0103] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. In this disclosure, unless otherwise stated, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art. Furthermore, the cell and tissue culture, microbiology-related terms, and laboratory procedures used herein are all widely used terms and routine procedures in their respective fields. Meanwhile, to better understand this disclosure, definitions and explanations of relevant terms are provided below. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, and variations thereof are certainly possible. It should also be understood that the terminology used in this application is for describing specific embodiments only and is not intended to be limiting.

[0104] Unless otherwise expressly stated, the singular forms “a,” “an,” and “the” used in this specification and the appended claims include plural references.

[0105] As used herein, the terms “comprising” and “having”, and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0106] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0107] Water-in-oil-in-solid (S / O / W) emulsions are formed by suspending drug powder in an organic phase to form a suspension (i.e., a solid-oil dispersion), and then dispersing this suspension in an aqueous phase to form an S / O / W double emulsion.

[0108] dl / g, or deciliters per gram, is a unit of intrinsic viscosity.

[0109] Method for determining the drug loading of vortioxetine hydrobromide sustained-release microspheres:

[0110] Test sample solution: Weigh about 13 mg of vortioxetine hydrobromide sustained-release microspheres into a 20 mL volumetric flask, add 4 mL of acetonitrile to dissolve and sonicate, then add methanol to dissolve and dilute to the mark, shake well, filter through a 0.22 μm PTFE membrane, and take the filtrate for detection.

[0111] Reference solution: Weigh 5 mg of vortioxetine hydrobromide into a 20 mL volumetric flask, add 4 mL of acetonitrile to dissolve and sonicate, then dilute to the mark with methanol, shake well, filter through a 0.22 μm PTFE membrane, and inject the filtrate into the sample.

[0112] Mobile phase: 0.05% TFA-aqueous solution, 0.035% TFA-acetonitrile;

[0113] Column: An octadecylsilane-bonded silica gel column was used.

[0114] Flow rate: 0.7 mL / min;

[0115] Detection wavelength: 254nm;

[0116] Column temperature: 60℃;

[0117] Injection volume: 10 μL.

[0118] The formula used for drug loading detection is as follows:

[0119] Drug loading (%) = (Mass of drug contained in microspheres) / (Total mass of microspheres) * 100%

[0120] Theoretical drug loading (%) = (Drug dosage) / (Total weight of microspheres) * 100%

[0121] Encapsulation efficiency (%) = (Actual drug loading of microspheres) / (Theoretical drug loading of microspheres) * 100%

[0122] Method for determining the particle size of vortioxetine hydrobromide sustained-release microspheres:

[0123] Sample preparation: Take an appropriate amount of sample into a vial, add 5 ml of 1% SDS dispersion medium, sonicate for 2 min, place it into the HydroEV dispersion system, rotate at 2100 rpm, after background subtraction, add the sample into a beaker, and use a Mastersizer3000 laser particle size analyzer to determine the particle size.

[0124] The formula used for microsphere particle size determination is as follows:

[0125] Span (also known as distribution span): is a measure of the width of the particle size distribution in a sample.

[0126] Span = (D 90 -D 10 ) / D 50 A value closer to 1 indicates a narrower distribution and more uniform particle size, which will reduce needle blockage in subsequent clinical practice. However, the advantages of microspheres mainly depend on release, not particle size. Generally, a diameter spacing of less than 1.8 is sufficient, and the more uniform the particle size, the better for achieving the same release.

[0127] D 50 (Median diameter) refers to the particle size at which the cumulative particle distribution reaches 50%, indicating that in the particle distribution curve, 50% of the particles have a diameter less than or equal to D. 50 D50 It is often used to represent the average particle size.

[0128] D 90 This refers to the particle size value at which the cumulative particle distribution reaches 90%, indicating that in the particle distribution curve, 90% of the particles have a diameter less than or equal to D. 90 .

[0129] D 10 This refers to the particle size value at which the cumulative particle distribution reaches 10%, indicating that in the particle distribution curve, 10% of the particles have a diameter less than or equal to D. 10 .

[0130] Methods for determining the particle size of pulverized vortioxetine hydrobromide:

[0131] Dry method detection: Take an appropriate amount of sample and add it to the dry dispersion system of the Mastersizer 3000 laser particle size analyzer. Set the air pressure and injection speed to disperse the sample under the action of high-pressure airflow. After subtracting the background, calculate the sample particle size.

[0132] In this patent, the particle size of the pulverized vortioxetine hydrobromide is the average particle size, i.e., D. 50 This refers to the particle size value when the cumulative particle distribution reaches 50%, indicating that in the particle distribution curve, 50% of the particles have a particle size less than or equal to D. 50 .

[0133] Example

[0134] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. The following is merely a further description of this disclosure, and the protection scope of this disclosure is not limited thereto.

[0135] Example 1

[0136] Preparation of vortioxetine hydrobromide sustained-release microspheres 1:

[0137] Vortioxetine hydrobromide was subjected to air jet milling; 3g of lactide-glycolic acid copolymer (PLGA5050 2.5A) was dissolved in 9mL of dichloromethane, and after complete dissolution, 1.286g of pulverized vortioxetine hydrobromide (particle size 9.551μm) was added, and the mixture was then subjected to high shear mixing to obtain the oil phase; 1.2L of 0.1% polyvinyl alcohol (PVA) aqueous solution was prepared, and 32g of potassium dihydrogen phosphate was added and completely dissolved to obtain the aqueous phase (potassium dihydrogen phosphate concentration 196mM); the oil phase and aqueous phase were shear emulsified into an S / O / W emulsion suspension using a high shear emulsifier; the organic solvent was removed by low-speed stirring and evaporation; after solidification, the mixture was collected, washed, and freeze-dried to obtain vortioxetine hydrobromide sustained-release microspheres 1.

[0138] Referring to the aforementioned method for detecting the drug loading of vortioxetine hydrobromide sustained-release microspheres, the drug loading and encapsulation efficiency of vortioxetine hydrobromide sustained-release microsphere 1 were tested. The test results of the drug loading and encapsulation efficiency of vortioxetine hydrobromide sustained-release microsphere 1 are shown in Table 1.

[0139] Table 1. Results of drug loading and encapsulation efficiency of vortioxetine hydrobromide sustained-release microspheres 1

[0140] Theoretical drug loading Actual drug loading Encapsulation rate 30％ 26.87％ 90％

[0141] Referring to the aforementioned method for detecting the particle size of vortioxetine hydrobromide sustained-release microspheres, the particle size of vortioxetine hydrobromide sustained-release microsphere 1 was detected, and the results are shown in Table 2.

[0142] Table 2. Microsphere size detection results of vortioxetine hydrobromide sustained-release microspheres 1

[0143] <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Distance 11.929 21.708 37.615 1.183

[0144] As shown in Table 2 of Implementation 1, the closer the diameter value is to 1, the narrower the distribution and the more uniform the particle size, which can reduce needle blockage in subsequent clinical practice.

[0145] Examples 2-9

[0146] Examples of different PLGA models:

[0147] Vortioxetine hydrobromide was subjected to air jet milling; 3g of lactide-glycolic acid copolymer (PLGA) was dissolved in 9mL of dichloromethane, and after complete dissolution, 2g of pulverized vortioxetine hydrobromide (particle size 19.325μm) was added, and the mixture was then subjected to high shear mixing to obtain the oil phase; 900mL of 0.5% polyvinyl alcohol (PVA) aqueous solution was prepared, and 5.9g of disodium hydrogen phosphate was added and completely dissolved to obtain the aqueous phase (disodium hydrogen phosphate concentration 46mM); the oil phase and aqueous phase were shear emulsified into an S / O / W emulsion suspension using a high shear emulsifier; the organic solvent was removed by low-speed stirring; after solidification, the mixture was collected, washed, and freeze-dried to obtain vortioxetine hydrobromide sustained-release microspheres 2-9. The test results are shown in Tables 3 and 4.

[0148] Table 3. Results of drug loading and encapsulation efficiency of microspheres

[0149] PLGA model Theoretical drug loading Actual drug loading Encapsulation rate Example 2 PLGA (5050 2.5A) 40％ 37.95％ 95％ Example 3 PLGA (7525 5A) 40％ 35.85％ 90％ Example 4 PLGA (5545PLG 6Glu) 40％ 38.6％ 97％ Example 5 PLGA (5050PLG 4.5E) 40％ 36.89％ 92％ Example 6 PLGA (7525 2CA) 40％ 38.14％ 95％ Example 7 PLGA(502H) 40％ 38.46％ 96％ Example 8 PLGA (7525 7E) 40％ 37.56％ 94％ Example 9 PLGA (7525 9E) 40％ 38.13％ 95％

[0150] Table 4. Microsphere particle size detection results

[0151] <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Distance Example 2 10.765 37.299 59.382 1.303 Example 3 18.326 40.66 72.057 1.321 Example 4 31.63 43.706 77.251 1.044 Example 5 31.12 57.597 95.049 1.110 Example 6 12.369 29.074 53.25 1.406 Example 7 14.138 33.694 61.795 1.414 Example 8 26.699 46.809 78.563 1.108 Example 9 21.777 37.4 61.657 1.066

[0152] The data from Tables 3 and 4 in sections 2-9 show that different PLGA models can achieve high encapsulation rates. The closer the diameter distance value is to 1, the narrower the distribution and the more uniform the particle size, which can reduce needle blockage in subsequent clinical practice.

[0153] Example 10

[0154] Example of reducing the amount of vortioxetine hydrobromide:

[0155] Vortioxetine hydrobromide was subjected to air jet milling; 2g of lactide-glycolic acid copolymer (PLGA 5050 2.5A) was dissolved in 6mL of dichloromethane, and after complete dissolution, 0.5g of pulverized vortioxetine hydrobromide (particle size 20.726μm) was added, and the mixture was then subjected to high shear mixing to form the oil phase; 600mL of 0.5% polyvinyl alcohol (PVA) aqueous solution was prepared, and 4g of disodium hydrogen phosphate was added and completely dissolved to form the aqueous phase; the oil phase and aqueous phase were shear emulsified into an S / O / W emulsion droplet suspension using a high shear emulsifier; the organic solvent was removed by low-speed stirring; after solidification, the mixture was collected, washed, and freeze-dried to obtain 10 vortioxetine hydrobromide sustained-release microspheres. The test results are shown in Table 5.

[0156] Table 5. Results of drug loading and encapsulation efficiency of microspheres

[0157] Theoretical drug delivery Actual measured drug loading Encapsulation rate 20％ 19.5％ 98％

[0158] Data from Examples 2-9 and Tables 3 and 5 of Example 10 show that a high encapsulation rate can be achieved even when the amount of vortioxetine hydrobromide in Example 10 is reduced; a high encapsulation rate can also be achieved with different drug loading amounts.

[0159] Example 11

[0160] Example of increasing the amount of vortioxetine hydrobromide:

[0161] Vortioxetine hydrobromide was subjected to air jet milling; 3g of lactide-glycolic acid copolymer (PLGA 5050 2.5A) was dissolved in 10mL of dichloromethane, and after complete dissolution, 5.57g of pulverized vortioxetine hydrobromide (particle size 17.025μm) was added, and the mixture was then subjected to high shear mixing to form the oil phase; 1L of 0.5% polyvinyl alcohol (PVA) aqueous solution was prepared, and 8.2g of disodium hydrogen phosphate was added and completely dissolved to form the aqueous phase; the oil phase and aqueous phase were shear emulsified into an S / O / W emulsion droplet suspension using a high shear emulsifier; the organic solvent was removed by low-speed stirring; after solidification, the mixture was collected, washed, and freeze-dried to obtain vortioxetine hydrobromide sustained-release microspheres 11. The test results are shown in Table 6.

[0162] Table 6. Results of drug loading and encapsulation efficiency of microspheres

[0163] Theoretical drug delivery Actual drug loading Encapsulation rate 65％ 60.2％ 93％

[0164] Data from Tables 3 of Examples 2-9, Table 5 of Example 10, and Table 6 of Example 11 show that a high encapsulation rate can be achieved even when the amount of vortioxetine hydrobromide is increased in Example 11; this indicates that a high encapsulation rate can be achieved regardless of the amount of drug loaded.

[0165] Examples 12-15

[0166] Examples of different volume ratios of organic solvent to emulsifier aqueous solution:

[0167] Vortioxetine hydrobromide was subjected to air jet milling; 3g of lactide-glycolic acid copolymer (PLGA 5050 2.5A) was dissolved in 9mL of dichloromethane, and after complete dissolution, 3g of pulverized vortioxetine hydrobromide (particle size 17.920μm) was added, and the mixture was then subjected to high shear mixing to obtain the oil phase; 450mL, 900mL, 1.8L, and 2.7L of 0.5% polyvinyl alcohol (PVA) aqueous solution were prepared, and 2mM to 200mM disodium hydrogen phosphate was added and completely dissolved to obtain the aqueous phase; the oil phase and aqueous phase were shear emulsified into S / O / W droplet suspension using a high shear emulsifier; the organic solvent was removed by low-speed stirring; after solidification, the mixture was collected, washed, and freeze-dried to obtain 12-15 vortioxetine hydrobromide sustained-release microspheres. The test results are shown in Table 7.

[0168] Table 7. Results of drug loading and encapsulation efficiency of microspheres

[0169]

[0170]

[0171] As shown in Table 7 of Implementations 12-15, the ratios of organic solvent to emulsifier aqueous solution in Implementations 12-15 were 1:50, 1:100, 1:200, and 1:300, respectively. High encapsulation rates could be achieved with different ratios of organic solvent to emulsifier aqueous solution.

[0172] Example 16

[0173] In vitro release detection method:

[0174] Experimental sample: Microspheres prepared in Example 4;

[0175] Experimental Methods: Weigh approximately 20 mg of the microspheres prepared in Example 4 and place them in a 100 ml centrifuge tube. Add 50 ml of release medium and place the tube in a 37°C shaker at 100 rpm. At the specified time point, remove the centrifuge tube from the shaker, let it stand for 10 min or centrifuge at high speed, collect 5 ml of the supernatant, filter (PTFE, 0.22 μm), discard 2 ml, and collect the filtrate. Add an equal volume of fresh release medium. Reference Solution: Weigh 5 mg of vortioxetine hydrobromide into a 20 mL volumetric flask, add 4 ml of acetonitrile to dissolve and sonicate, then dilute to the mark with methanol, shake well, filter through a 0.22 μm PTFE membrane, and inject the filtrate. Calculate the release rate concentration of the filtrate using the external standard method. The cumulative release rate calculation formula is as follows:

[0176] Cumulative release rate calculation formula:

[0177] Cumulative release

[0178] In the formula:

[0179] V0 is the volume of the release medium used, in mL;

[0180] C t The concentration of the drug contained in the release medium was measured at the sampling time point, in mg / mL;

[0181] V represents the volume of each sample taken, in mL;

[0182] t is the sampling time point;

[0183] n=1 means accumulating from the first time point;

[0184] c represents the concentration of the released fluid taken from the sampling point, in mg / mL;

[0185] W represents the total weight of the microspheres added, in mg;

[0186] X represents the drug loading (%) of the microspheres.

[0187] Experimental results: The microspheres prepared in Example 4 released stably and could be effectively released for 25 days.

[0188] Comparative Example 1

[0189] Microspheres were prepared according to the method in Example 1 of CN116850146B, as follows:

[0190] 0.75 g of vortioxetine and 3 g of lactide-glycolic acid copolymer (PLGA) were added to 9 mL of dichloromethane and dissolved completely to form an organic phase. A 1 L solution of 0.5% polyvinyl alcohol (PVA) was prepared as the aqueous phase. The organic and aqueous phases were shear-emulsified into an O / W droplet suspension using a high-shear emulsifier. The suspension was stirred at low speed to evaporate and remove the organic solvent. After solidification, the suspension was collected, washed, and lyophilized to obtain microspheres. The test results are shown in Table 8. Figure 5 , Figure 6 , Figure 7 and Figure 8 .

[0191] Table 8. Results of drug loading and encapsulation efficiency of microspheres

[0192] PLGA model Theoretical drug loading Actual drug loading Encapsulation rate PLGA (5050 2.5A) 20％ 12.91％ 65％ PLGA (7525 5A) 20％ 13.92％ 70％

[0193] As can be seen from the data in Table 8 of Comparative Example 1, the vortioxetine microspheres prepared by the method of CN116850146B have a lower actual drug loading and a lower encapsulation efficiency.

[0194] Comparative Example 2

[0195] Comparative example using dichloromethane and ethanol as organic solvents:

[0196] 1.875 g of vortioxetine hydrobromide and 6.25 g of lactide-glycolic acid copolymer (PLGA 5050 2.5A) were added to 26 mL of dichloromethane and 4 mL of ethanol. After complete dissolution, an organic phase was formed. A 500 mL solution of 0.5% polyvinyl alcohol (PVA) was prepared as the aqueous phase. The organic and aqueous phases were shear emulsified into an O / W droplet suspension using a high-shear emulsifier. The organic solvent was removed by low-speed stirring and evaporation. After solidification, the microspheres were collected, washed, and lyophilized. The test results are shown in Table 9.

[0197] Table 9. Results of drug loading and encapsulation efficiency of microspheres

[0198] Theoretical drug delivery Actual drug loading Encapsulation rate 18％ 1.9％ 11％

[0199] As shown in Table 9, the preparation method of Comparative Example 2, which uses dichloromethane and ethanol as organic solvents, resulted in a lower encapsulation rate of the microspheres. This is because vortioxetine hydrobromide has a certain solubility in polyvinyl alcohol (PVA) aqueous solution, and a certain amount of ethanol is present in the oil phase. As a result, the active pharmaceutical ingredient is dissolved and lost with the continuous phase during the curing process, thus the microsphere encapsulation effect is worse and the microsphere encapsulation rate is lower.

[0200] Comparative Example 3

[0201] Comparative example with no buffer salt added to the aqueous phase:

[0202] Vortioxetine hydrobromide was subjected to air jet milling; 3g of lactide-glycolic acid copolymer (PLGA 5050 2.5A) was dissolved in 9mL of dichloromethane, and after complete dissolution, 1.286g of milled vortioxetine hydrobromide was added, followed by high-shear mixing to obtain the oil phase; 500mL of 0.1% polyvinyl alcohol (PVA) aqueous solution was prepared as the aqueous phase; the oil phase and aqueous phase were shear emulsified into an S / O / W emulsion suspension using a high-shear emulsifier; the organic solvent was removed by low-speed stirring and evaporation; after solidification, the microspheres were collected, washed, and freeze-dried. The test results are shown in Table 10.

[0203] Table 10. Results of drug loading and encapsulation efficiency of microspheres

[0204] Theoretical drug delivery Actual measured drug loading Encapsulation rate 30％ 9.27％ 30.9％

[0205] As shown in Table 10, the preparation method of Comparative Example 3, which did not add buffer salt in the aqueous phase, resulted in microspheres with lower drug loading and encapsulation efficiency. Comparing Examples 1-15 with Comparative Example 3, it is evident that the buffer salt in Examples 1-15 can reduce solubility in the aqueous phase, thereby significantly increasing drug loading and encapsulation efficiency.

[0206] Comparative Example 4

[0207] Comparative examples of pulverized vortioxetine hydrobromide with larger particle sizes:

[0208] 2g of lactide-glycolic acid copolymer (PLGA 5050 2.5A) was dissolved in 6mL of dichloromethane. After complete dissolution, 0.5g of uncrushed vortioxetine hydrobromide (particle size 63.260μm) was added, and the mixture was then subjected to high shear mixing to obtain the oil phase. 600mL of 0.5% polyvinyl alcohol (PVA) aqueous solution was prepared, and 4g of disodium hydrogen phosphate was added and completely dissolved to obtain the aqueous phase. The oil phase and aqueous phase were shear emulsified into an S / O / W emulsion suspension using a high shear emulsifier. The organic solvent was removed by low-speed stirring, and the solidified product was collected, washed, and freeze-dried to obtain the final product.

[0209] Because the uncrushed vortioxetine hydrobromide particles are too large to form spheres, such as... Figure 9As shown.

[0210] pass Figure 9 Data shows that when the particle size of vortioxetine hydrobromide is large, it cannot be encapsulated into spheres, thus making it impossible to prepare sustained-release microspheres of vortioxetine hydrobromide.

[0211] The foregoing description of specific exemplary embodiments of this disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit this disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of this disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of this disclosure, as well as various different choices and variations. The scope of this disclosure is intended to be defined by the claims and their equivalents.

Claims

1. A method for preparing vortioxetine hydrobromide sustained-release microspheres, characterized in that, Includes the following steps: (1) Vortioxetine hydrobromide was pulverized; the particle size of the pulverized vortioxetine hydrobromide was controlled to be below 30 μm; (2) Dissolve lactide-glycolic acid copolymer (PLGA) in an organic solvent. After it is fully dissolved, add pulverized vortioxetine hydrobromide and mix it evenly under high shear to form the oil phase. The organic solvent is dichloromethane. (3) Prepare a polyvinyl alcohol (PVA) aqueous solution of a certain concentration, add buffer salt, and dissolve it completely to form the aqueous phase; the concentration of the polyvinyl alcohol aqueous solution is 0.1% to 2% w / v; the volume ratio of organic solvent to polyvinyl alcohol solution is 1:50 to 1:

300. (4) Use a high-shear emulsifier to shear emulsify the oil phase and the aqueous phase into an S / O / W emulsion droplet suspension; (5) Stir at low speed to evaporate and remove organic solvent; collect after solidification, wash, freeze dry to obtain vortioxetine hydrobromide sustained-release microspheres.

2. The preparation method according to claim 1, wherein, The vortioxetine hydrobromide sustained-release microspheres contain 30% to 65% vortioxetine hydrobromide by weight.

3. The preparation method according to claim 1, wherein, The buffer salt is selected from any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or sodium dihydrogen phosphate.

4. The preparation method according to claim 1, wherein, The concentration of the buffer salt in the aqueous phase is 2–200 mM.

5. The preparation method according to claim 1, wherein, The molar ratio of lactide to glycolide in the lactide-glycol copolymer is 75:25 to 50:

50.

6. The preparation method according to claim 1, wherein, The weight-average molecular weight of the lactide-glycolic acid copolymer is 20,000 to 60,000 Daltons.

7. The preparation method according to claim 1, wherein, The intrinsic viscosity of the lactide-glycolic acid copolymer is 0.1 to 0.6 dl / g.

8. The vortioxetine hydrobromide sustained-release microspheres obtained by the preparation method according to any one of claims 1 to 7.

9. A sustained-release microsphere formulation of vortioxetine hydrobromide, comprising the sustained-release microspheres of vortioxetine hydrobromide obtained by the preparation method according to any one of claims 1 to 7, and the sustained-release microspheres of vortioxetine hydrobromide according to claim 8.

10. The use of the vortioxetine hydrobromide sustained-release microspheres obtained by the preparation method according to any one of claims 1 to 7, the vortioxetine hydrobromide sustained-release microspheres according to claim 8, or the vortioxetine hydrobromide sustained-release microsphere formulation according to claim 9 in the preparation of sustained-release formulations of drugs for treating depression.

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