Vortioxetine hydrobromide sustained-release microspheres as well as preparation, preparation method and application of votioxetine hydrobromide sustained-release microspheres

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a hydrobromic acid potioxetine sustained-release microsphere, a preparation thereof, a preparation method and application thereof. Compared with the prior art, the preparation method provided by the invention has the advantages that the drug loading capacity can be improved, the drug encapsulation efficiency can be improved, and the dosage of auxiliary materials is obviously reduced.

Description

Technical Field

[0001] The present disclosure belongs to the field of biomedical technologies, and particularly relates to a sustained-release microsphere of vortioxetine hydrobromide, its preparation, its preparation method and applications. Background Art

[0003] Vortioxetine is a new drug for treating depression. It mainly exerts its antidepressant effect by increasing the concentration of serotonin in the central nervous system. It was jointly developed by Lundbeck of Denmark and Takeda of Japan, and was approved for marketing by the US Food and Drug Administration (FDA) on September 30, 2013 for the treatment of major depressive disorder, with the trade name Brintellix and the dosage form of tablets. It was approved by the European Medicines Agency (EMA) in December of the same year, with the dosage forms of oral film-coated tablets and drops. Due to its status as a new drug with clinical value, it was given priority review in China, and its tablets were approved for marketing in China in 2017, with the trade name "Xindayue".

[0004] Currently, the marketed vortioxetine tablets need to be taken daily and for a long time. However, the compliance of patients taking antidepressants significantly decreases with the increase in the medication time, and it is easy to miss doses or resist taking medications, thus leading to the aggravation of the condition. Therefore, there is a clinical need for long-acting sustained-release injections to improve patient compliance and enhance the therapeutic effect.

[0005] CN109922806B discloses a long-acting sustained-release injection of vortioxetine hydrobromide, which prepares a suspension of vortioxetine hydrobromide to achieve the effect of long-acting drug release by controlling the particle size distribution. However, microcrystalline injections generally cause a large initial burst release in the body and have a short duration.

[0006] CN116850146B discloses a long-acting sustained-release preparation of vortioxetine free base or its medicinal salt and its preparation method, which prepares microspheres from vortioxetine and polylactide-glycolide copolymer to achieve long-acting sustained-release. However, the microspheres of vortioxetine free base have low hardness and are easy to break, and the basic group of vortioxetine reacts with the ester bond of the polylactide-glycolide copolymer to form multiple new impurities; while the microspheres of vortioxetine hydrobromide have a low drug loading, which does not meet the clinical medication requirements. In this method, the solubility of vortioxetine hydrobromide in the oil phase is low, and vortioxetine hydrobromide needs to be completely dissolved in the oil phase. To increase the drug loading, the amount of organic solvent needs to be increased, resulting in a lower concentration of the polylactide-glycolide copolymer in the oil phase. The prepared microspheres have a smaller particle size and a relatively loose spherical structure, and the sustained-release effect is poor. CN116850146B points out that the polylactide-glycolide copolymer can be dissolved in dichloromethane or a mixed solvent of dichloromethane and benzyl alcohol. However, in the examples, vortioxetine hydrobromide is dissolved in the mixed solvent mainly to increase the solubility of vortioxetine hydrobromide and improve the drug loading, but it cannot improve the drug encapsulation rate.

[0007] CN116919920B discloses a long-acting sustained-release microsphere composition of vilazodone hydrochloride and its preparation method. By using vilazodone hydrochloride and polylactide-glycolide copolymer to prepare long-acting sustained-release microspheres, the long-term medication effect can be achieved. This method forms a poorly soluble salt of vilazodone, increases its solubility in the organic solvent of the oil phase, and significantly reduces its solubility in the aqueous phase, thereby meeting the requirements of the O / W single emulsion-solvent evaporation method for microsphere preparation process, and helping to improve the drug loading and encapsulation rate. However, dimethyl sulfoxide or N-methylpyrrolidone in the preparation process of this method has a relatively high boiling point and is not easy to remove, and there will be a large amount of residue, which is harmful to health.

[0008] The present disclosure aims to provide a sustained-release microsphere of vilazodone hydrobromide, its preparation, its preparation method and application, which can improve the drug loading, improve the drug encapsulation rate, and significantly reduce the amount of excipients. Summary of the Invention

[0009] The technical problem to be solved by the present disclosure is that for the currently marketed vilazodone-related preparations with relatively low drug loading, low encapsulation rate or large amount of excipients, to develop a sustained-release microsphere of vilazodone hydrobromide, its preparation, and its preparation method, which can improve the drug loading and improve the drug encapsulation rate. Further, the sustained-release microsphere of vilazodone hydrobromide, its preparation, and its preparation method of the present disclosure can significantly reduce the amount of excipients.

[0010] To achieve the above technical objectives, the technical solutions adopted by the present disclosure are as follows:

[0011] On the one hand, the present disclosure provides a preparation method of a sustained-release microsphere of vilazodone hydrobromide, which includes the following steps: the pretreated vilazodone hydrobromide is used to obtain the sustained-release microsphere of vilazodone hydrobromide by the S / O / W double emulsion method; the pretreated vilazodone hydrobromide is the pulverized vilazodone hydrobromide.

[0012] Vilazodone hydrobromide can be obtained by purchasing in the market.

[0013] The preparation method of the sustained-release microsphere of vilazodone hydrobromide of the present disclosure can improve the drug loading. The preparation method of the sustained-release microsphere of vilazodone hydrobromide of the present disclosure can improve the drug encapsulation rate. Further, the preparation method of the sustained-release microsphere of vilazodone hydrobromide of the present disclosure can significantly reduce the amount of excipients.

[0014] In the embodiments of the present disclosure, vilazodone hydrobromide can be pulverized by pulverizing equipment such as a ball mill and a jet mill. The pulverizing equipment is not limited to the listed equipment. After pulverization, the minimum particle size can reach 0.1-0.5 μm. The smaller the particle size of vilazodone hydrobromide, the easier it is to disperse evenly when forming the oil phase, and the drug loading is more uniform and the spherical shape is better after forming the microspheres.

[0015] In the embodiments of the present disclosure, the particle size of the micronized vilazodone hydrobromide is 50 μm or less.

[0016] In some preferred embodiments of the present disclosure, the particle size of the micronized vilazodone hydrobromide is 30 μm or less.

[0017] In some preferred embodiments of the present disclosure, the particle size of the micronized vilazodone hydrobromide is 0.1 μm or more. In some preferred embodiments of the present disclosure, the particle size of the micronized vilazodone hydrobromide is 0.1 - 50 μm.

[0018] In some preferred embodiments of the present disclosure, the particle size of the micronized vilazodone hydrobromide is 0.1 - 30 μm.

[0019] In some preferred embodiments of the present disclosure, the particle size of the micronized vilazodone hydrobromide is 0.3 - 30 μm.

[0020] In the embodiments of the present disclosure, the particle size of the micronized vilazodone 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, 30 μm.

[0021] In some preferred embodiments of the present disclosure, the content of vilazodone hydrobromide in the sustained-release microspheres of vilazodone hydrobromide accounts for 10% - 80% of the total weight of the microspheres, preferably 20% - 65%, and more preferably 30% - 50%.

[0022] In some preferred embodiments of the present disclosure, wherein the S / O / W multiple emulsion method includes a step of emulsifying an oil phase containing pretreated vilazodone hydrobromide with an aqueous phase to form an S / O / W emulsion droplet suspension. The difference between S / O / W and O / W: 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, thus not being limited by solubility; the fact that S / O / W is not limited by solubility is the main reason for increasing the drug loading.

[0023] In some preferred embodiments of the present disclosure, the aqueous phase includes an aqueous solution of an emulsifier and a buffer salt. The buffer salt can reduce the solubility in the aqueous phase and thus significantly improve the encapsulation efficiency.

[0024] In some preferred embodiments of the present disclosure, the preparation step of the oil phase containing pretreated vilazodone hydrobromide includes dissolving a biodegradable polymer in an organic solvent, then adding micronized vilazodone hydrobromide, and mixing evenly to obtain the oil phase. The micronized vilazodone hydrobromide can be directly dispersed in the oil phase to form S / O without the need for dissolution.

[0025] In some preferred embodiments of the present disclosure, the buffer salt includes any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or sodium dihydrogen phosphate.

[0026] In some preferred embodiments of the present disclosure, the concentration of the buffer salt in the aqueous phase is 1 - 500 mM, preferably 1 - 300 mM, more preferably 2 - 200 mM.

[0027] In some preferred embodiments of the present disclosure, the aqueous solution of the emulsifier is selected from any one or more of an aqueous solution of polyvinyl alcohol, an aqueous solution of poloxamer, and an aqueous solution of polyethylene glycol.

[0028] In some preferred embodiments of the present disclosure, the aqueous solution of the emulsifier is an aqueous solution of polyvinyl alcohol.

[0029] In some preferred embodiments of the present disclosure, the concentration of the emulsifier in the aqueous solution of the emulsifier is 0.05% - 5% w / v; preferably, the concentration of the emulsifier in the aqueous solution of the emulsifier is 0.05% - 3% w / v; preferably, the concentration of the emulsifier in the aqueous solution of the emulsifier is 0.1% - 2% w / v.

[0030] In some preferred embodiments of the present disclosure, the biodegradable polymer is selected from any one or more of lactide - glycolide copolymer (PLGA), polylactic acid, polyglycolic acid, polycaprolactone, poly (L - lactic acid - co - glycolic acid), polyanhydride, polyorthoester, polyphosphazene, polyphosphate ester, polyamide, chitosan, dextran, alginate, or hyaluronic acid.

[0031] In some preferred embodiments of the present disclosure, the biodegradable polymer is a lactide - glycolide copolymer.

[0032] In some preferred embodiments of the present disclosure, the molar ratio of lactide to glycolide in the lactide - glycolide copolymer is 85:15 - 25:75, preferably 80:20 - 40:60, more preferably 75:25 - 50:50.

[0033] In some preferred embodiments of the present disclosure, the weight - average molecular weight of the lactide - glycolide copolymer is 5000 - 200000 Daltons, preferably 8000 - 160000 Daltons, more preferably 20000 - 60000 Daltons.

[0034] In some preferred embodiments of the present disclosure, the intrinsic viscosity of the lactide - glycolide copolymer is 0.05 - 2 dl / g, preferably 0.08 - 1.5 dl / g, more preferably 0.1 - 0.6 dl / g.

[0035] In some preferred embodiments of the present disclosure, the organic solvent is selected from any one or more of dichloromethane, chloroform, carbon tetrachloride, dichloroethane, dichloropropane, trichloroethane, and ethyl acetate.

[0036] In some preferred embodiments of the present disclosure, the organic solvent is dichloromethane;

[0037] In some preferred embodiments of the present disclosure, the volume ratio of the organic solvent to the aqueous emulsifier solution is 1:30 to 1:500, preferably 1:40 to 1:400, preferably 1:50 to 1:300, and preferably 1:50 to 1:200.

[0038] In some preferred embodiments of the present disclosure, the following step is further included: after removing the organic solvent from the S / O / W emulsion droplet suspension, it is freeze-dried to obtain the sustained-release microspheres of vilazodone hydrobromide.

[0039] On the other hand, the present disclosure provides the sustained-release microspheres of vilazodone hydrobromide obtained by the preparation method as described above.

[0040] On the other hand, the present disclosure provides a kind of sustained-release microspheres of vilazodone hydrobromide, wherein the content of vilazodone hydrobromide in the sustained-release microspheres of vilazodone hydrobromide accounts for 10% to 80% of the total weight of the microspheres, preferably 20% to 65%, and preferably 30% to 50%.

[0041] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the pretreated vilazodone hydrobromide is obtained by the S / O / W double emulsion method, and the pretreated vilazodone hydrobromide is the pulverized vilazodone hydrobromide.

[0042] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the particle size of the pulverized vilazodone hydrobromide is below 50 μm, preferably below 30 μm.

[0043] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the sustained-release microspheres of vilazodone hydrobromide include vilazodone hydrobromide and a biodegradable polymer.

[0044] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the S / O / W double emulsion method includes the step of emulsifying the oil phase containing the pretreated vilazodone hydrobromide with the aqueous phase to form an S / O / W emulsion droplet suspension.

[0045] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the aqueous phase includes an aqueous emulsifier solution and a buffer salt.

[0046] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the preparation step of the oil phase containing pretreated vilazodone hydrobromide includes dissolving a biodegradable polymer in an organic solvent, and then adding the pulverized vilazodone hydrobromide, and mixing uniformly to obtain the oil phase.

[0047] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the buffer salt is selected from any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or sodium dihydrogen phosphate.

[0048] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the concentration of the buffer salt in the aqueous phase is 1 to 500 mM, preferably 1 to 300 mM, more preferably 2 to 200 mM. The aqueous phase includes an emulsifier aqueous solution and a buffer salt. The concentration of the buffer salt in the aqueous phase in the present 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 being fully dissolved, an aqueous phase with a buffer concentration of 1 to 500 mM, preferably 1 to 300 mM, more preferably 2 to 200 mM is formed.

[0049] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present 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; preferably, the emulsifier aqueous solution is a polyvinyl alcohol aqueous solution.

[0050] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present 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.

[0051] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the biodegradable polymer is selected from any one or more of lactide-glycolide copolymer (PLGA), polylactic acid, polyglycolic acid, polycaprolactone, poly (L-lactic acid-co-glycolic acid), polyanhydride, polyorthoester, polyphosphazene, polyphosphate ester, polyamide, chitosan, dextran, alginate, or hyaluronic acid.

[0052] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the biodegradable polymer is lactide-glycolide copolymer.

[0053] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 85:15 to 25:75, preferably 80:20 to 40:60, and more preferably 75:25 to 50:50.

[0054] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the weight-average molecular weight of the lactide-glycolide copolymer is 5000 to 200000 Daltons, preferably 8000 to 160000 Daltons, and more preferably 20000 to 60000 Daltons.

[0055] In some preferred embodiments of the present disclosure, for the sustained-release microspheres of vilazodone hydrobromide according to the present disclosure, the intrinsic viscosity of the lactide-glycolide 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.

[0056] On the other hand, the present disclosure provides a sustained-release microsphere preparation of vilazodone hydrobromide, which comprises the sustained-release microspheres of vilazodone hydrobromide obtained by the preparation method as described above, and the sustained-release microspheres of vilazodone hydrobromide as described above.

[0057] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the content of vilazodone hydrobromide in the sustained-release microspheres thereof accounts for 10% to 80% of the total weight of the microspheres, preferably 20% to 65%, and more preferably 30% to 50%.

[0058] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the pretreated vilazodone hydrobromide in the sustained-release microspheres thereof is obtained by the S / O / W double emulsion method, and the pretreated vilazodone hydrobromide is pulverized vilazodone hydrobromide.

[0059] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the particle size of the pulverized vilazodone hydrobromide is 50 μm or less, preferably 30 μm or less.

[0060] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the particle size of the pulverized vilazodone hydrobromide is 0.1 μm or more, preferably 0.1 - 50 μm, and more preferably 0.1 - 30 μm.

[0061] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the sustained-release microspheres thereof comprise vilazodone hydrobromide and a biodegradable polymer.

[0062] In some preferred embodiments of the present disclosure, for the sustained-release microsphere formulation of vilazodone hydrobromide according to the present disclosure, the S / O / W double emulsion method includes the step of emulsifying an oil phase containing pretreated vilazodone hydrobromide with an aqueous phase to form a suspension of S / O / W emulsion droplets.

[0063] In some preferred embodiments of the present disclosure, for the sustained-release microsphere formulation of vilazodone hydrobromide according to the present disclosure, the aqueous phase includes an aqueous solution of an emulsifier and a buffer salt.

[0064] In some preferred embodiments of the present disclosure, for the sustained-release microsphere formulation of vilazodone hydrobromide according to the present disclosure, the preparation step of the oil phase containing pretreated vilazodone hydrobromide includes dissolving a biodegradable polymer in an organic solvent, and then adding comminuted vilazodone hydrobromide, and mixing evenly to obtain the oil phase.

[0065] In some preferred embodiments of the present disclosure, for the sustained-release microsphere formulation of vilazodone hydrobromide according to the present disclosure, the buffer salt is selected from any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate.

[0066] In some preferred embodiments of the present disclosure, for the sustained-release microsphere formulation of vilazodone hydrobromide according to the present disclosure, the concentration of the buffer salt in the aqueous phase is 1 - 500 mM, preferably 1 - 300 mM, more preferably 2 - 200 mM. The aqueous phase includes an aqueous solution of an emulsifier and a buffer salt. The concentration of the buffer salt in the aqueous phase in the present invention refers to the concentration of the buffer salt in the aqueous phase after adding the buffer salt to the aqueous solution of the emulsifier. In one embodiment, the buffer solution is added to the aqueous solution of the emulsifier in solid form, and after complete dissolution, an aqueous phase with a buffer concentration of 1 - 500 mM, preferably 1 - 300 mM, more preferably 2 - 200 mM is formed.

[0067] In some preferred embodiments of the present disclosure, for the sustained-release microsphere formulation of vilazodone hydrobromide according to the present disclosure, the aqueous solution of the emulsifier is selected from any one or more of an aqueous solution of polyvinyl alcohol, an aqueous solution of poloxamer, and an aqueous solution of polyethylene glycol; preferably, the aqueous solution of the emulsifier is an aqueous solution of polyvinyl alcohol.

[0068] In some preferred embodiments of the present disclosure, for the sustained-release microsphere formulation of vilazodone hydrobromide according to the present disclosure, the concentration of the emulsifier in the aqueous solution of the emulsifier is 0.05% - 5% w / v; preferably, the concentration of the emulsifier in the aqueous solution of the emulsifier is 0.05% - 3% w / v; preferably, the concentration of the emulsifier in the aqueous solution of the emulsifier is 0.1% - 2% w / v.

[0069] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the biodegradable polymer is selected from any one or more of polylactide-co-glycolide (PLGA), polylactic acid, polyglycolic acid, polycaprolactone, poly(lactic-co-glycolic acid), polyanhydride, polyorthoester, polyphosphazene, polyphosphate ester, polyamide, chitosan, dextran, alginate or hyaluronic acid.

[0070] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the biodegradable polymer is polylactide-co-glycolide.

[0071] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the molar ratio of lactide to glycolide in the polylactide-co-glycolide is 85:15 to 25:75, preferably 80:20 to 40:60, and more preferably 75:25 to 50:50.

[0072] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the weight-average molecular weight of the polylactide-co-glycolide is 5000 to 200000 Daltons, preferably 8000 to 160000 Daltons, and more preferably 20000 to 60000 Daltons.

[0073] In some preferred embodiments of the present disclosure, for the sustained-release microsphere preparation of vilazodone hydrobromide according to the present disclosure, the intrinsic viscosity of the polylactide-co-glycolide 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.

[0074] On the other hand, the present disclosure provides the use of the vilazodone hydrobromide sustained-release microspheres obtained by the preparation method as described above, the vilazodone hydrobromide sustained-release microspheres as described above, or the vilazodone hydrobromide sustained-release microsphere preparation as described above in the preparation of a sustained-release preparation of a medicament for treating depression.

[0075] In some preferred embodiments of the present disclosure, the method for preparing vilazodone hydrobromide sustained-release microspheres comprises the following steps:

[0076] (1) Vilazodone hydrobromide is pulverized;

[0077] (2) The polylactide-co-glycolide (PLGA) is dissolved in an organic solvent. After complete dissolution, the pulverized vilazodone hydrobromide is added, and then high-shear mixing is carried out to make it uniform, serving as the oil phase;

[0078] (3) An aqueous solution of polyvinyl alcohol (PVA) with a certain concentration is prepared, and a buffer salt is added and completely dissolved to serve as the water phase;

[0079] (4) Use a high - shear emulsifier to shear - emulsify the oil phase and the water phase into an S / O / W emulsion droplet suspension;

[0080] (5) Stir at a low speed, volatilize and remove the organic solvent; after solidification, collect, wash, and lyophilize to obtain the sustained - release microspheres of vilazodone hydrobromide.

[0081] In some preferred embodiments of the present disclosure, the method for preparing the sustained - release microspheres of vilazodone hydrobromide comprises the following steps:

[0082] (1) Pulverize vilazodone hydrobromide; control the particle size of the pulverized vilazodone hydrobromide to be below 30 μm;

[0083] (2) Dissolve the poly(lactide - co - glycolide) (PLGA) in an organic solvent, and after complete dissolution, add the pulverized vilazodone hydrobromide, and then perform high - shear mixing to make it uniform as the oil phase; wherein, the molar ratio of lactide to glycolide in the poly(lactide - co - glycolide) is 75:25 to 50:50; the weight - average molecular weight of the poly(lactide - co - glycolide) is 20000 to 60000 Daltons; the intrinsic viscosity of the poly(lactide - co - glycolide) is 0.1 to 0.6 dl / g; the organic solvent is dichloromethane;

[0084] (3) Prepare an aqueous solution of polyvinyl alcohol (PVA) with a certain concentration, add a buffer salt, and dissolve it completely as the water phase; the concentration of the polyvinyl alcohol aqueous solution is 0.1% - 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 water phase is 2 - 200 mM; the volume ratio of the organic solvent to the polyvinyl alcohol solution is 1:50 to 1:300;

[0085] (4) Use a high - shear emulsifier to shear - emulsify the oil phase and the water phase into an S / O / W emulsion droplet suspension;

[0086] (5) Stir at a low speed, volatilize and remove the organic solvent; after solidification, collect, wash, and lyophilize to obtain the sustained - release microspheres of vilazodone hydrobromide. The content of vilazodone hydrobromide in the sustained - release microspheres of vilazodone hydrobromide accounts for 30% - 65% of the total weight of the microspheres.

[0087] The present disclosure has the following advantages:

[0088] (1) The method for preparing the sustained - release microspheres of vilazodone hydrobromide provided by the present disclosure can increase the drug - loading capacity.

[0089] (2) The method for preparing the sustained - release microspheres of vilazodone hydrobromide provided by the present disclosure can increase the drug entrapment efficiency, which helps to increase the drug - loading capacity.

[0090] (3) The preparation method of the vortioxetine hydrobromide sustained-release microspheres provided by the present disclosure can significantly reduce the dosage of excipients and further improve the drug use safety.

[0091] (4) The preparation method of the vortioxetine hydrobromide sustained-release microspheres provided by the present disclosure has good sphericity.

[0092] (5) The vortioxetine hydrobromide sustained-release microspheres or the vortioxetine hydrobromide sustained-release microsphere preparation provided by the present disclosure can increase the compliance of patients and improve the treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] In order to more clearly illustrate the specific embodiments of the present disclosure or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present disclosure. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts. The drawings herein are incorporated into the specification and form a part of the specification, showing the embodiments in line with the specification, and are used together with the specification to explain the principles of the specification.

[0094] Figure 1 Shows the electron microscope images of vortioxetine hydrobromide before and after airflow pulverization in Example 1.

[0095] Figure 2 Shows the electron microscope image of the microspheres obtained in Example 4.

[0096] Figure 3 Shows the in vitro release curve of the microspheres obtained in Example 4.

[0097] Figure 4 Shows the electron microscope image of the microspheres obtained in Example 10.

[0098] Figure 5 Shows the electron microscope image of the microspheres obtained in Comparative Example 1.

[0099] Figure 6 Shows the liquid chromatography diagram of the microspheres obtained in Comparative Example 1.

[0100] Figure 7 Shows the first-level mass spectrum 1 of the microspheres obtained in Comparative Example 1.

[0101] Figure 8 Shows the first-level mass spectrum 2 of the microspheres obtained in Comparative Example 1.

[0102] Figure 9 Shows the electron microscope image of the microspheres obtained in Comparative Example 4. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0103] Definitions and Explanations

[0104] To facilitate a better understanding of the present disclosure, certain technical and scientific terms are specifically defined below. In the present disclosure, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Moreover, the terms related to cell and tissue culture, microbiology, and laboratory operation procedures used herein are all terms widely used in the corresponding fields and conventional procedures. Meanwhile, to better understand the present disclosure, the definitions and explanations of relevant terms are provided below. It should be understood that the present disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, and of course, changes can be made thereto. It should also be understood that the terms used in this application are only for describing specific embodiments and are not intended to be limiting.

[0105] Unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" as used in this specification and the appended claims include plural referents.

[0106] 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 comprises a series of steps is not limited to the listed steps or modules, but optionally further includes steps not listed, or optionally further includes other steps inherent to these processes, methods, products, or devices.

[0107] In the description herein, reference to "some embodiments", "some implementations", or "some embodiments" describes a subset of all possible embodiments. However, it is understood that "some embodiments" can be the same subset or different subsets of all possible embodiments and can be combined with each other without conflict.

[0108] Solid-in-oil-in-water (S / O / W) is a complex emulsion in which drug powder is suspended in an organic phase to form a suspension (i.e., a solid-oil dispersion), and then this suspension is dispersed into an aqueous phase to form an S / O / W multiple emulsion.

[0109] dl / g, i.e., deciliter per gram, is the unit of intrinsic viscosity.

[0110] Method for detecting the drug loading of the sustained-release microspheres of vilazodone hydrobromide:

[0111] Test sample solution: Weigh approximately 13 mg of the sustained-release microspheres of vilazodone hydrobromide into a 20 mL volumetric flask, dissolve it in 4 mL of acetonitrile by ultrasonic treatment, then add methanol to dissolve and make up to the scale, shake well, filter through a 0.22 μm PTFE filter membrane, and take the subsequent filtrate for detection.

[0112] Reference solution: Weigh 5 mg of vilazodone hydrobromide into a 20 mL volumetric flask, dissolve it in 4 mL of acetonitrile by ultrasonic treatment, then make up to the scale with methanol, shake well, filter through a 0.22 μm PTFE filter membrane, and inject the subsequent filtrate.

[0113] Mobile phase: 0.05% TFA-aqueous solution, 0.035% TFA-acetonitrile;

[0114] Chromatographic column: an octadecylsilyl-bonded silica gel packing chromatographic column;

[0115] Flow rate: 0.7 mL / min;

[0116] Detection wavelength: 254 nm;

[0117] Column temperature: 60 °C;

[0118] Sample injection volume: 10 μL.

[0119] The formula used for detecting the drug loading amount is as follows:

[0120] Drug loading amount (%) = (mass of the drug contained in the microspheres) / (total mass of the microspheres) * 100%

[0121] Theoretical drug loading amount (%) = (drug dosage) / (total weight of the microspheres) * 100%

[0122] Entrapment efficiency (%) = (actual drug loading amount of the microspheres) / (theoretical drug loading amount of the microspheres) * 100%

[0123] Method for detecting the particle size of the vortioxetine hydrobromide sustained-release microspheres:

[0124] Sample preparation: Take an appropriate amount of the sample in a vial, add 5 mL of 1% SDS dispersion medium, ultrasonicate for 2 min, place it in a HydroEV dispersion system, rotate at 2100 rpm, after deducting the background, add the sample to a beaker, and use a Mastersizer 3000 laser particle size analyzer to measure the particle size.

[0125] The formula used for detecting the particle size of the microspheres is as follows:

[0126] Distance between diameters (also known as distribution span, Span): It is a measure of the width of the particle size distribution of the sample.

[0127] Span = (D 90 -D 10 ) / D 50 , the closer the value is to 1, the narrower the distribution, the more uniform the particle size, and the subsequent clinical needle clogging will be reduced. However, the main advantage of the microspheres depends on the release, and it has nothing to do with the particle size. Generally, the distance between diameters less than 1.8 is acceptable, and the more uniform the particle size that can achieve the same release, the better.

[0128] D 50 (median diameter) refers to the particle size value when the particle distribution cumulative reaches 50%, indicating that in the particle distribution curve, 50% of the particle sizes are less than or equal to D 50 . D50 It is often used to represent the average particle size of particles.

[0129] D 90 refers to the particle size value when the particle size distribution accumulates to 90%, indicating that in the particle size distribution curve, 90% of the particle sizes are less than or equal to D 90 .

[0130] D 10 refers to the particle size value when the particle size distribution accumulates to 10%, indicating that in the particle size distribution curve, 10% of the particle sizes are less than or equal to D 10 .

[0131] Particle size detection method for pulverized vilazodone hydrobromide:

[0132] Dry method detection is adopted: 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 air flow, and calculate the particle size of the sample after deducting the background.

[0133] In this patent, the particle size of pulverized vilazodone hydrobromide is the average particle size, that is, D 50 , which refers to the particle size value when the particle size distribution accumulates to 50%, indicating that in the particle size distribution curve, 50% of the particle sizes are less than or equal to D 50 .

[0134] Example

[0135] To make the objectives, technical solutions, and advantages of the embodiments of the present disclosure clearer, the technical solutions in the embodiments of the present disclosure will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present disclosure. Obviously, the described embodiments are some, but not all, of the embodiments of the present disclosure. The following is only a further description of the present disclosure, and the protection scope of the present disclosure is not limited thereto.

[0136] Example 1

[0137] Preparation of vilazodone hydrobromide sustained-release microspheres 1:

[0138] Vortioxetine hydrobromide was subjected to air jet milling; 3 g of poly(lactic-co-glycolic acid) (PLGA5050 2.5A) was dissolved in 9 mL of dichloromethane. After complete dissolution, 1.286 g of the milled vortioxetine hydrobromide (particle size 9.551 μm) was added, and then high-shear mixing was carried out to make it uniform as the oil phase; 1.2 L of 0.1% polyvinyl alcohol (PVA) aqueous solution was prepared, and 32 g of potassium dihydrogen phosphate was added and completely dissolved as the water phase (concentration of potassium dihydrogen phosphate 196 mM); the oil phase and the water phase were sheared and emulsified into an S / O / W emulsion droplet suspension using a high-shear emulsifier; low-speed stirring was carried out to volatilize and remove the organic solvent; after curing, it was collected, washed, and freeze-dried to obtain vortioxetine hydrobromide sustained-release microspheres 1.

[0139] 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 microspheres 1 were detected. The detection results of the drug loading and encapsulation efficiency of vortioxetine hydrobromide sustained-release microspheres 1 are shown in Table 1.

[0140] Table 1. Detection results of drug loading and encapsulation efficiency of vortioxetine hydrobromide sustained-release microspheres 1

[0141] Theoretical drug loading Actual drug loading Entrapment efficiency 30％ 26.87％ 90％

[0142] Referring to the aforementioned method for detecting the particle size of vortioxetine hydrobromide sustained-release microspheres, the particle size of vortioxetine hydrobromide sustained-release microspheres 1 was detected. The measurement results are shown in Table 2.

[0143] Table 2. Detection results of particle size of vortioxetine hydrobromide sustained-release microspheres 1

[0144] <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Diameter distance 11.929 21.708 37.615 1.183

[0145] From the data in Table 2 of Example 1, it can be seen that the closer the span value is to 1, the narrower the distribution, the more uniform the particle size, and the subsequent needle clogging phenomenon in clinical practice can be reduced.

[0146] Examples 2 - 9

[0147] Examples with different PLGA models:

[0148] Vortioxetine hydrobromide was subjected to air flow pulverization; 3 g of poly(lactic-co-glycolic acid) (PLGA) was dissolved in 9 mL of dichloromethane. After complete dissolution, 2 g of pulverized vortioxetine hydrobromide (particle size 19.325 μm) was added, and then high-shear mixing was carried out to make it uniform as the oil phase; 900 mL of 0.5% polyvinyl alcohol (PVA) aqueous solution was prepared, and 5.9 g of disodium hydrogen phosphate was added and completely dissolved as the aqueous phase (disodium hydrogen phosphate concentration 46 mM); the oil phase and the aqueous phase were sheared and emulsified into an S / O / W emulsion droplet suspension using a high-shear emulsifier; stirred at low speed, and the organic solvent was volatilized and removed; after curing, it was collected, washed, and freeze-dried to obtain 2-9 vortioxetine hydrobromide sustained-release microspheres, and the test results are shown in Table 3 and Table 4.

[0149] Table 3. Test results of drug loading and encapsulation efficiency of microspheres

[0150] PLGA type Theoretical drug loading Actual drug loading Entrapment efficiency 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％

[0151] Table 4. Test results of microsphere particle size

[0152] <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Diameter 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

[0153] From the data in Table 3 and Table 4 of Examples 2-9, it can be seen that different PLGA models can all achieve a high encapsulation efficiency; the closer the distance value is to 1, the narrower the distribution, the more uniform the particle size, and the subsequent needle clogging phenomenon in clinical practice can be reduced.

[0154] Example 10

[0155] Example with reduced amount of raw material vortioxetine hydrobromide:

[0156] Vortioxetine hydrobromide was subjected to air flow pulverization; 2 g of poly(lactic-co-glycolic acid) (PLGA 5050 2.5A) was dissolved in 6 mL of dichloromethane. After complete dissolution, 0.5 g of pulverized vortioxetine hydrobromide (particle size 20.726 μm) was added, and then high-shear mixing was carried out to make it uniform as the oil phase; 600 mL of 0.5% polyvinyl alcohol (PVA) aqueous solution was prepared, and 4 g of disodium hydrogen phosphate was added and completely dissolved as the aqueous phase; the oil phase and the aqueous phase were sheared and emulsified into an S / O / W emulsion droplet suspension using a high-shear emulsifier; stirred at low speed, and the organic solvent was volatilized and removed; after curing, it was collected, washed, and freeze-dried to obtain vortioxetine hydrobromide sustained-release microspheres 10, and the test results are shown in Table 5.

[0157] Table 5. Test results of drug loading and encapsulation efficiency of microspheres

[0158] Theoretical drug loading Measured drug loading Entrapment efficiency 20％ 19.5％ 98％

[0159] From the data in Table 3 and Table 5 of Examples 2-9 and Example 10, it can be seen that when the amount of raw material vortioxetine hydrobromide in Example 10 is reduced, a high encapsulation efficiency can also be achieved; different drug loadings can also achieve a high encapsulation efficiency.

[0160] Example 11

[0161] Example where the amount of the starting material, vilazodone hydrobromide, is increased:

[0162] Vilazodone hydrobromide was subjected to airflow pulverization; 3 g of poly(lactide - co - glycolide) copolymer (PLGA 5050 2.5A) was dissolved in 10 mL of dichloromethane. After complete dissolution, 5.57 g of pulverized vilazodone hydrobromide (particle size 17.025 μm) was added, and then high - shear mixing was carried out to make it uniform as the oil phase; 1 L of 0.5% polyvinyl alcohol (PVA) aqueous solution was prepared, and 8.2 g of disodium hydrogen phosphate was added and completely dissolved as the water phase; a high - shear emulsifier was used to shear - emulsify the oil phase and the water phase into an S / O / W emulsion droplet suspension; low - speed stirring was carried out, and the organic solvent was volatilized and removed; after curing, it was collected, washed, and freeze - dried to obtain vilazodone hydrobromide sustained - release microspheres 11, and the test results are shown in Table 6.

[0163] Table 6. Test results of drug loading and encapsulation efficiency of microspheres

[0164] Theoretical drug loading Measured drug loading Entrapment efficiency 65％ 60.2％ 93％

[0165] From the data in Table 3 of Examples 2 - 9, Table 5 of Example 10, and Table 6 of Example 11, it can be seen that when the amount of the starting material, vilazodone hydrobromide, is increased in Example 11, a high encapsulation efficiency can also be achieved; this shows that high encapsulation efficiency can be achieved with different drug loadings.

[0166] Examples 12 - 15

[0167] Examples with different volume ratios of organic solvents to emulsifier aqueous solutions:

[0168] Vilazodone hydrobromide was subjected to airflow pulverization; 3 g of poly(lactide - co - glycolide) copolymer (PLGA 5050 2.5A) was dissolved in 9 mL of dichloromethane. After complete dissolution, 3 g of pulverized vilazodone hydrobromide (particle size 17.920 μm) was added, and then high - shear mixing was carried out to make it uniform as the oil phase; 0.5% polyvinyl alcohol (PVA) aqueous solutions of 450 mL, 900 mL, 1.8 L, and 2.7 L were prepared, and 2 mM - 200 mM of disodium hydrogen phosphate was added and completely dissolved as the water phase; a high - shear emulsifier was used to shear - emulsify the oil phase and the water phase into an S / O / W emulsion droplet suspension; low - speed stirring was carried out, and the organic solvent was volatilized and removed; after curing, it was collected, washed, and freeze - dried to obtain vilazodone hydrobromide sustained - release microspheres 12 - 15, and the test results are shown in Table 7.

[0169] Table 7. Test results of drug loading and encapsulation efficiency of microspheres

[0170]

[0171]

[0172] From the data in Table 7 of Examples 12 to 15, it can be seen that the ratios of organic solvents to the aqueous solution of emulsifier in Examples 12 to 15 are 1:50, 1:100, 1:200, and 1:300 respectively, and high encapsulation rates can be achieved with different ratios of organic solvents to the aqueous solution of emulsifier.

[0173] Example 16

[0174] In vitro release detection method:

[0175] Experimental sample: The microspheres prepared in Example 4;

[0176] Experimental method: Weigh approximately 20 mg of the microspheres prepared in Example 4, place them in a 100 ml centrifuge tube, add 50 ml of release medium, put it in a 37 °C shaker, and reciprocally shake at a frequency of 100 rpm. At the specified time points, take out the centrifuge tube from the shaker, let it stand for 10 min or centrifuge at high speed, take out 5 ml of the supernatant, filter (PTFE, 0.22 μm), discard 2 ml, and take the subsequent filtrate. And supplement an equal volume of fresh release medium. Control solution: Weigh 5 mg of vosoritide hydrobromide in a 20 mL volumetric flask, dissolve it with 4 ml of acetonitrile by ultrasonic treatment, then make up the volume to the mark with methanol, shake well, filter through a 0.22 μm PTFE filter membrane, and take the subsequent filtrate for injection. The release degree of the filtrate concentration is calculated by the external standard method. Among them, the cumulative release degree calculation formula is as follows:

[0177] Cumulative release degree calculation formula:

[0178] Cumulative release degree

[0179] In the formula:

[0180] V 0 is the volume of the release medium used, mL;

[0181] C t is the concentration of the drug contained in the release medium measured at the sampling time point, mg / mL;

[0182] V is the volume of each sampling, mL;

[0183] t is the sampling time point;

[0184] n = 1 means cumulative from the first time point;

[0185] c is the concentration of the release solution taken at the sampling point, mg / mL;

[0186] W is the total weight of the microspheres put in, mg;

[0187] X is the drug loading amount of the microspheres (%).

[0188] Experimental results: The microspheres prepared in Example 4 showed a stable release and could effectively release for 25 days.

[0189] Comparative Example 1

[0190] Prepare microspheres according to the method of Example 1 in CN116850146B as follows:

[0191] Add 0.75 g of vilazodone and 3 g of poly(lactic-co-glycolic acid) (PLGA) to 9 mL of dichloromethane. After complete dissolution, an organic phase is formed. Prepare 1 L of 0.5% polyvinyl alcohol (PVA) aqueous solution as the aqueous phase; use a high-shear emulsifier to shear the organic phase and the aqueous phase into an O / W emulsion droplet suspension; stir at low speed to volatilize and remove the organic solvent; after curing, collect, wash, and lyophilize to obtain the microspheres. The test results are shown in Table 8. Figure 5 、 Figure 6 、 Figure 7 and Figure 8 。

[0192] Table 8. Test results of drug loading and encapsulation efficiency of microspheres

[0193] PLGA type Theoretical drug loading Actual drug loading Entrapment efficiency PLGA(5050 2.5A) 20％ 12.91％ 65％ PLGA(7525 5A) 20％ 13.92％ 70％

[0194] From the data in Table 8 of Comparative Example 1, it can be seen that the actual drug loading of the vilazodone microspheres obtained by the preparation method of CN116850146B is relatively low, and the encapsulation efficiency is relatively low.

[0195] Comparative Example 2

[0196] Comparative example using dichloromethane and ethanol as organic solvents:

[0197] Add 1.875 g of vilazodone hydrobromide and 6.25 g of poly(lactic-co-glycolic acid) (PLGA 5050 2.5A) to 26 mL of dichloromethane and 4 mL of ethanol. After complete dissolution, an organic phase is formed. Prepare 500 mL of 0.5% polyvinyl alcohol (PVA) aqueous solution as the aqueous phase; use a high-shear emulsifier to shear the organic phase and the aqueous phase into an O / W emulsion droplet suspension; stir at low speed to volatilize and remove the organic solvent; after curing, collect, wash, and lyophilize to obtain the microspheres. The test results are shown in Table 9.

[0198] Table 9. Test results of drug loading and encapsulation efficiency of microspheres

[0199] Theoretical drug loading Measured drug loading Entrapment efficiency 18％ 1.9％ 11％

[0200] As can be seen from the data in Table 9, the preparation method of Comparative Example 2 uses dichloromethane and ethanol as organic solvents, and the encapsulation efficiency of the obtained microspheres is relatively low. This is because vilazodone hydrobromide has a certain solubility in the aqueous solution of polyvinyl alcohol (PVA), and there is a certain amount of ethanol in the oil phase, resulting in the dissolution and loss of the active pharmaceutical ingredient with the continuous phase during the curing process. Therefore, the embedding effect of the microspheres is relatively poor and the encapsulation efficiency of the microspheres is relatively low.

[0201] Comparative Example 3

[0202] Comparative example without buffer salt in the aqueous phase:

[0203] Vilazodone hydrobromide was subjected to air flow pulverization; 3 g of poly(lactic-co-glycolic acid) (PLGA 5050 2.5A) was dissolved in 9 mL of dichloromethane. After complete dissolution, 1.286 g of pulverized vilazodone hydrobromide was added, and then high-shear mixing was carried out to make it uniform as the oil phase; 500 mL of 0.1% polyvinyl alcohol (PVA) aqueous solution was prepared as the aqueous phase; a high-shear emulsifier was used to shear the oil phase and the aqueous phase into an S / O / W emulsion droplet suspension; low-speed stirring was carried out to volatilize and remove the organic solvent; after curing, collection, washing, and freeze-drying were carried out to obtain the microspheres, and the test results are shown in Table 10.

[0204] Table 10. Test results of drug loading and encapsulation efficiency of microspheres

[0205] Theoretical drug loading Measured drug loading Entrapment efficiency 30％ 9.27％ 30.9％

[0206] As can be seen from the data in Table 10, the preparation method of Comparative Example 3 does not add buffer salt in the aqueous phase, and the obtained microspheres have a relatively low drug loading and a relatively low encapsulation efficiency. Comparing Examples 1 to 15 with Comparative Example 3 shows that the buffer salt in Examples 1 to 15 can reduce the solubility in the aqueous phase, thereby significantly increasing the drug loading and significantly increasing the encapsulation efficiency.

[0207] Comparative Example 4

[0208] Comparative example with a relatively large particle size of pulverized vilazodone hydrobromide:

[0209] 2 g of poly(lactic-co-glycolic acid) (PLGA 5050 2.5A) was dissolved in 6 mL of dichloromethane. After complete dissolution, 0.5 g of non-pulverized vilazodone hydrobromide (particle size: 63.260 μm) was added, and then high-shear mixing was carried out to make it uniform as the oil phase; 600 mL of 0.5% polyvinyl alcohol (PVA) aqueous solution was prepared and 4 g of disodium hydrogen phosphate was added and completely dissolved as the aqueous phase; a high-shear emulsifier was used to shear the oil phase and the aqueous phase into an S / O / W emulsion droplet suspension; low-speed stirring was carried out to volatilize and remove the organic solvent; after curing, collection was carried out to obtain the product.

[0210] Since the particle size of non-pulverized vilazodone hydrobromide is relatively large, it cannot be encapsulated into spheres, as Figure 9as shown

[0211] Through Figure 9 It can be seen from the data that when the particle size of vilazodone hydrobromide is large, it cannot be encapsulated into spheres, and sustained-release microspheres of vilazodone hydrobromide cannot be prepared.

[0212] The foregoing description of specific exemplary embodiments of the present disclosure is for purposes of illustration and exemplification. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it is apparent that many changes and variations are possible in light of the above teaching. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present disclosure and its practical applications, so that those skilled in the art can implement and utilize various different exemplary embodiments of the present disclosure, as well as various different selections and changes. The scope of the present 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: The following steps are involved: The pretreated vortioxetine hydrobromide is prepared by S / O / W double emulsion method to obtain vortioxetine hydrobromide sustained-release microspheres, wherein the pretreated vortioxetine hydrobromide is crushed vortioxetine hydrobromide.

2. The preparation method according to claim 1, wherein The particle size of the crushed vortioxetine hydrobromide is less than 50 μm, preferably less than 30 μm; Preferably, the content of vortioxetine hydrobromide in the vortioxetine hydrobromide sustained-release microspheres accounts for 10% to 80% of the total weight of the microspheres, preferably 20% to 65%, and preferably 30% to 50%.

3. The preparation method according to claim 1 or 2, wherein The S / O / W emulsion method comprises the steps of emulsifying the oil phase containing the pretreated vortioxetine hydrobromide with the water phase to form a S / O / W emulsion suspension; Preferably, the aqueous phase comprises an aqueous emulsifier solution and a buffer salt; Preferably, the step of preparing the oil phase containing the pretreated vortioxetine hydrobromide comprises dissolving the biodegradable polymer in an organic solvent, adding crushed vortioxetine hydrobromide, and mixing them uniformly to form the oil phase.

4. The preparation method according to claim 3, 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; Preferably, the concentration of the buffer salt in the aqueous phase is 1 to 500 mM, preferably 1 to 300 mM, preferably 2 to 200 mM; Preferably, the emulsifier aqueous solution is selected from any one or more of a polyvinyl alcohol aqueous solution, a poloxamer aqueous solution, and a polyethylene glycol aqueous solution; preferably, the emulsifier aqueous solution is a polyvinyl alcohol aqueous solution; Preferably, 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.

5. The preparation method according to claim 3 or 4, wherein The biodegradable polymer is selected from any one or more of lactide-co-glycolide (PLGA), polylactic acid, polyglycolic acid, polycaprolactone, poly(lactic acid-co-glycolide), polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyamide, chitosan, dextran, alginate or hyaluronic acid; preferably, the biodegradable polymer is lactide-co-glycolide; Preferably, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 85:15 to 25:75, preferably 80:20 to 40:60, preferably 75:25 to 50:50; Preferably, the weight average molecular weight of the lactide-glycolide copolymer is 5000 to 200000 Daltons, preferably 8000 to 160000 Daltons, preferably 20000 to 60000 Daltons; Preferably, the intrinsic viscosity of the lactide-glycolide copolymer is 0.05 to 2 dl / g, preferably 0.08 to 1.5 dl / g, preferably 0.1 to 0.6 dl / g; Preferably, the organic solvent is selected from any one or more of dichloromethane, chloroform, tetrachloromethane, dichloroethane, dichloropropane, trichloroethane, and ethyl acetate; preferably, the organic solvent is dichloromethane; Preferably, the volume ratio of the organic solvent to the aqueous emulsifier solution is 1:30 to 1:500, preferably 1:40 to 1:400, preferably 1:50 to 1:300, preferably 1:50 to 1:

200.

6. The preparation method according to any one of claims 1 to 5, wherein: The following steps are also included: After removing the organic solvent from the S / O / W emulsion suspension, the suspension is freeze-dried to obtain vortioxetine hydrobromide sustained-release microspheres.

7. Vortioxetine hydrobromide sustained-release microspheres obtained by the preparation method according to any one of claims 1 to 6.

8. A vortioxetine hydrobromide sustained-release microsphere, characterized in that: in, The content of vortioxetine hydrobromide in the vortioxetine hydrobromide sustained-release microspheres accounts for 10% to 80% of the total weight of the microspheres, preferably 20% to 65%, and preferably 30% to 50%; Preferably, the vortioxetine hydrobromide sustained-release microspheres are obtained by pre-treating the vortioxetine hydrobromide using an S / O / W double emulsion method, and the pre-treated vortioxetine hydrobromide is crushed vortioxetine hydrobromide; Preferably, the particle size of the crushed vortioxetine hydrobromide is less than 50 μm; Preferably, the vortioxetine hydrobromide sustained-release microspheres include vortioxetine hydrobromide and a biodegradable polymer; Preferably, the S / O / W emulsion method comprises the steps of emulsifying the oil phase containing the pretreated vortioxetine hydrobromide with the water phase to form a S / O / W emulsion suspension; Preferably, the aqueous phase comprises an aqueous emulsifier solution and a buffer salt; Preferably, the step of preparing the oil phase containing the pretreated vortioxetine hydrobromide comprises dissolving the biodegradable polymer in an organic solvent, adding crushed vortioxetine hydrobromide, and mixing them uniformly to form the oil phase; Preferably, the buffer salt is selected from any one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate; Preferably, the concentration of the buffer salt in the aqueous phase is 1 to 500 mM, preferably 1 to 300 mM, preferably 2 to 200 mM; Preferably, the emulsifier aqueous solution is selected from any one or more of a polyvinyl alcohol aqueous solution, a poloxamer aqueous solution, and a polyethylene glycol aqueous solution; preferably, the emulsifier aqueous solution is a polyvinyl alcohol aqueous solution; Preferably, 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; Preferably, the biodegradable polymer is selected from any one or more of lactide-co-glycolide (PLGA), polylactic acid, polyglycolic acid, polycaprolactone, poly(lactic acid-co-glycolide), polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyamide, chitosan, dextran, alginate or hyaluronic acid; preferably, the biodegradable polymer is lactide-co-glycolide; Preferably, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 85:15 to 25:75, preferably 80:20 to 40:60, preferably 75:25 to 50:50; Preferably, the weight average molecular weight of the lactide-glycolide copolymer is 5000 to 200000 Daltons, preferably 8000 to 160000 Daltons, preferably 20000 to 60000 Daltons; Preferably, the intrinsic viscosity of the lactide-glycolide copolymer is 0.05 to 2 dl / g, preferably 0.08 to 1.5 dl / g, and preferably 0.1 to 0.6 dl / g.

9. A vortioxetine hydrobromide sustained-release microsphere preparation, comprising the vortioxetine hydrobromide sustained-release microsphere obtained by the preparation method according to any one of claims 1 to 6, and the vortioxetine hydrobromide sustained-release microsphere according to claim 7 or 8.

10. Use of the vortioxetine hydrobromide sustained-release microspheres obtained by the preparation method according to any one of claims 1 to 6, the vortioxetine hydrobromide sustained-release microspheres according to claim 7 or 8, or the vortioxetine hydrobromide sustained-release microsphere preparation according to claim 9 in the preparation of a sustained-release preparation of a drug for treating depression.

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