Brexpiprazole sustained-release microsphere and preparation method thereof

Abstract

The invention relates to the field of medicines, in particular to a brexpiprazole sustained-release microsphere and a preparation method thereof. The brexpiprazole sustained-release microsphere is prepared by adopting an emulsion solvent evaporation method, and the pH value of an external water phase is adjusted to be alkaline. The brexpiprazole sustained-release microsphere disclosed by the invention can realize high drug loading capacity and good balling property.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a brexpiprazole sustained-release microsphere and a preparation method thereof. BACKGROUND

[0002] Brexpiprazole, also known as asenapine and praziprazole, is an atypical antipsychotic drug. Brexpiprazole has a regulatory effect on the monoaminergic neurotransmission system in the brain, and is a partial agonist of 5-hydroxytryptamine (5-HT1A) and dopamine D2 receptors, an antagonist of 5-hydroxytryptamine (5-HT2A) receptors and dopamine alpha1 / 2 receptors, and has a wide binding affinity to other central monoamine receptor subtypes.

[0003] Brexpiprazole was jointly developed by Denmark's Nordmark and Japan's Otsuka Pharmaceutical Co., Ltd. It was first approved for marketing by the FDA in July 2015 for the treatment of major depressive disorder (MDD) and schizophrenia, and has since been approved in Japan and the European Union. In May 2023, it was approved for the treatment of agitation associated with Alzheimer's disease dementia. It was approved in China on June 25, 2024.

[0004] The traditional administration route is to directly orally administer brexpiprazole solid tablets or to orally administer brexpiprazole prepared into an oral dissolving film. This not only fails to maintain a stable blood drug concentration and produces more adverse reactions, but also requires frequent administration, which greatly reduces the patient's compliance. In addition, schizophrenic patients need long-term medication, and patients are prone to hiding their medication. Therefore, it is necessary to prescribe brexpiprazole long-acting sustained-release preparations.

[0005] Therefore, the present application is proposed. SUMMARY

[0006] Since the administration dose of brexpiprazole is high, if a high drug loading can be achieved, it will be beneficial to improve the clinical adaptability and avoid the increase in pain caused by the blockage of the needle due to too much drug powder. At the same time, since brexpiprazole is a poorly soluble drug, it is difficult to achieve a high drug loading for microspheres of such a drug, and problems such as poor ball forming may occur.

[0007] Therefore, the present application is proposed.

[0008] The specific technical solutions are as follows:

[0009] A brexpiprazole sustained-release microsphere is prepared by an emulsion solvent evaporation method, wherein the pH of the external water phase is adjusted to be alkaline, and preferably the pH of the external water phase is adjusted to be 8-12.

[0010] The present invention also provides a bripiprazole sustained-release microsphere, which is prepared by an O / W emulsification-solvent evaporation method, wherein the preparation of the oil phase includes: completely dissolving the bripiprazole or its salt and polymer in an organic solvent, and the resulting solution is used as the oil phase.

[0011] The present invention also provides bripiprazole sustained-release microspheres, which are prepared by an O / W emulsion solvent evaporation method, wherein the mass ratio of bripiprazole or its salt to organic solvent in the oil phase is 1:10 to 1:30, preferably 12 to 22, and more preferably 1:14 to 1:20.

[0012] The present invention also provides a bripiprazole sustained-release microsphere, which is prepared by an O / W emulsification-solvent evaporation method, wherein the mass ratio of organic solvent to external aqueous phase in the oil phase is 1:20 to 200, preferably 1:40 to 1:160.

[0013] The present invention also provides a method for preparing bripiprazole sustained-release microspheres, comprising the following steps: (1) dissolving bripiprazole or its salt and polymer in an organic solvent, and the resulting solution is used as an oil phase; (2) dissolving a water-soluble polymer in water, and using it as an external aqueous phase; (3) mixing and dispersing the oil phase and the external aqueous phase, and solidifying them to obtain microspheres.

[0014] The present invention also provides a pharmaceutical composition comprising the above-described birepiperazole sustained-release microspheres and pharmaceutically acceptable excipients.

[0015] The present invention also provides the use of the above-mentioned birepiperazole sustained-release microspheres or composition in the preparation of medicaments for treating depression (including major depressive disorder), schizophrenia, Alzheimer's disease, and post-traumatic stress disorder.

[0016] The beneficial effects achieved by this invention are at least as follows:

[0017] I. This invention adjusts the pH of the external aqueous phase to alkaline, which can improve the drug loading of birepiperazole sustained-release microspheres, especially enabling the preparation of birepiperazole sustained-release microspheres with good sphericity and high drug loading. Studies have shown that if the pH is neutral, once the theoretical drug loading exceeds 50%, the sphericity of the microspheres is very poor. However, adjusting the pH to alkaline allows for drug loading of 30-80% as needed without affecting the sphericity of the microspheres.

[0018] II. In the preparation of bripiprazole sustained-release microspheres, controlling the mass ratio of bripiprazole or its salt to organic solvent in the oil phase is crucial for improving the morphology of the microspheres. When the mass ratio of bripiprazole or its salt to organic solvent is controlled at 1:10 to 1:30, the morphology of the microspheres can be effectively improved, resulting in microspheres with good spherical shape, smooth and round surface, and uniform particle size.

[0019] III. In the preparation of bripiprazole sustained-release microspheres, controlling the mass ratio of organic solvent in the oil phase to the external aqueous phase is crucial for improving the morphology of the microspheres. When the mass ratio of organic solvent in the oil phase to the external aqueous phase is controlled at 1:20 to 200, the morphology of the microspheres can be effectively improved, resulting in microspheres with good spherical shape, smooth and round surface, and uniform particle size. Attached Figure Description

[0020] Figure 1 This is an electron microscope image of the microspheres from Example 1.

[0021] Figure 2 This is an electron microscope image of the microspheres from Example 2.

[0022] Figure 3 This is an electron microscope image of the microspheres from Example 3.

[0023] Figure 4 This is an electron microscope image of the microspheres from Example 4.

[0024] Figure 5 This is an electron microscope image of the microspheres from Example 5.

[0025] Figure 6 This is an electron microscope image of the microspheres from Example 6.

[0026] Figure 7 This is an electron microscope image of the microspheres from Example 7.

[0027] Figure 8 This is an electron microscope image of the microspheres from Example 8.

[0028] Figure 9 This is an electron microscope image of the microspheres from Example 9.

[0029] Figure 10 This is an electron microscope image of the microspheres from Example 10.

[0030] Figure 11 This is an electron microscope image of the microspheres from Example 11.

[0031] Figure 12 This is an electron microscope image of the microspheres from Example 12.

[0032] Figure 13 This is an electron microscope image of the microspheres from Example 13.

[0033] Figure 14 This is an electron microscope image of the microspheres from Example 14.

[0034] Figure 15 This is an electron microscope image of the microspheres from Example 15.

[0035] Figure 16 This is an electron microscope image of the microspheres from Example 16.

[0036] Figure 17 The image shows an electron microscope image of the microspheres from Example 17.

[0037] Figure 18 This is an electron microscope image of the microspheres from Example 18.

[0038] Figure 19 This is an electron microscope image of the microspheres from Example 19.

[0039] Figure 20 This is an electron microscope image of the microspheres from Example 20.

[0040] Figure 21 This is an electron microscope image of the microspheres from Example 21.

[0041] Figure 22 This is an electron microscope image of the microspheres from Example 22.

[0042] Figure 23 This is an electron microscope image of the microspheres from Example 23.

[0043] Figure 24 This is an electron microscope image of the microspheres from Example 24.

[0044] Figure 25 This is an electron microscope image of the microspheres from Example 25.

[0045] Figure 26 This is an electron microscope image of the microspheres in Comparative Example 1.

[0046] Figure 27 The results are for in vivo release in Examples 6, 7, and 8.

[0047] Figure 28 The results are for the in vitro release of Examples 4 and 12.

[0048] Figure 29 The results are for the in vitro release of Example 20. Detailed Implementation

[0049] Unless otherwise specified, the experimental methods described in the following embodiments of the present invention are generally performed under conventional conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the embodiments are commercially available products.

[0050] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0051] 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.

[0052] In this invention, "multiple" refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0053] As used in this disclosure, the term "solidification" refers to the process by which a substance is transformed from a low-molecular-weight substance into a high-molecular-weight substance.

[0054] As used in this disclosure, the term "freeze-drying" refers to freeze drying, a drying method that removes ice by rapidly freezing the material to be dried and then sublimating the ice into water vapor under high vacuum conditions.

[0055] As used in this disclosure, the term "microsphere" refers to a tiny spherical entity formed when a drug is dissolved or dispersed in a carrier excipient. Generally, particles with a diameter between 1 and 250 μm are called microspheres, particles with a diameter between 0.1 and 1 μm are called submicrospheres, and particles with a diameter between 10 and 100 nm are called nanospheres.

[0056] As used in this disclosure, the term "burst release" refers to the phenomenon of a large amount of drug being released within the first day after administration of an injectable microsphere sustained-release formulation, and its extent is generally measured by the cumulative drug release (%) over 24 hours.

[0057] Understandably, the pH value defined in this invention is allowed to fluctuate within the accuracy range of the instrument detection. Fluctuations are permitted within ranges such as ±0.5, ±0.4, ±0.3, ±0.2, and ±0.1.

[0058] In this application, % (w / w) and wt% both represent weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass-volume percentage. Unless otherwise specified, % refers to weight percentage.

[0059] On one hand, the present invention provides a bripiprazole sustained-release microsphere, which is prepared by an emulsification solvent evaporation method, wherein the pH of the external aqueous phase is adjusted to be alkaline, preferably adjusted to pH 8-12.

[0060] The inventors of this invention discovered that adjusting the pH of the external aqueous phase to alkaline can improve the drug loading of birepiperazole sustained-release microspheres, particularly enabling the preparation of birepiperazole sustained-release microspheres with good sphericity and high drug loading. Studies show that if the pH is 7, once the theoretical drug loading exceeds 50%, the microsphere sphericity becomes very poor. Adjusting the pH to alkaline allows for drug loading of 30-80% as needed without affecting the sphericity of the microspheres.

[0061] In some preferred embodiments, the pH is adjusted to 8-11, for example, the pH can be adjusted to 8, 9, 10, 11 and any two of the above.

[0062] The inventors of this invention have also discovered that when the pH is preferably adjusted to 8-11, the particle size range of the microspheres can be further reduced and the morphology of the microspheres can be improved, thereby enhancing the uniformity of microsphere size, reducing batch-to-batch differences, and improving the injection permeability.

[0063] In some preferred embodiments, the external aqueous phase is a water-soluble polymer solution, preferably with a concentration of 0.01% to 5%, more preferably 0.01% to 3%, and even more preferably 0.01% to 1%. For example, it can be 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, and any range between the above.

[0064] In some preferred embodiments, the water-soluble polymer is selected from at least one of polyvinyl alcohol (PVA), polyethylene glycol (PEG), and poloxamer.

[0065] In some preferred embodiments, the components or raw materials of the birepiperazole sustained-release microspheres include birepiperazole or its salts, and a polymer; preferably, the weight content of birepiperazole or its salts is 20% to 85%, more preferably 28% to 85% or 20% to 75%, more preferably 30% to 80%, and even more preferably 30% to 75%. For example, it can be 20%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, and any range between the above.

[0066] In some preferred embodiments, the polymer content by weight is 15-80%, preferably 15-72%, more preferably 20-70% or 25-80%, and even more preferably 25-70%. For example, it can be 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 72%, 75%, 80%, 85%, and any range between the above.

[0067] In some preferred embodiments, the polymer is selected from at least one of lactide-glycolic acid copolymer, polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), and polylactide-glycolic acid copolymer (PLCG).

[0068] In some preferred embodiments, the molar ratio of lactide to glycolide in the lactide-glycol copolymer is 90:10 to 10:90. Preferably, it is 85:15 to 15:85, and more preferably 80:20 to 45:55. For example, it can be 90:10, 85:15, 80:20, 75:25, 55:45, 50:50, 45:55, and any range between the above.

[0069] In some preferred embodiments, the molecular weight of the lactide-glycolic acid copolymer is 5,000 to 100,000; preferably 10,000 to 60,000, more preferably 15,000 to 55,000, and even more preferably 20,000 to 50,000. For example, it can be 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, and any range between the above.

[0070] In some preferred embodiments, the emulsification solvent evaporation method is an O / W emulsification-solvent evaporation method; wherein the preparation of the oil phase includes: dissolving the buriperazole or its salt and polymer in an organic solvent, and the resulting solution is used as the oil phase.

[0071] In some preferred embodiments, the organic solvent is at least one selected from dichloromethane, ethyl acetate, dodecanol, acetone, and chloroform.

[0072] Understandably, dissolution refers to the dissolution of buripiperazole or its salts in an organic solvent to obtain a solution free of buripiperazole or its salt solid particles. Understandably, if buripiperazole or its salts are difficult to completely dissolve in an organic solvent at room temperature, conventional methods in the art can be used to promote dissolution, such as heating to dissolve, stirring to dissolve, crushing the solid to dissolve, adding a solubilizer or co-solvent to dissolve, or a combination of the above methods.

[0073] In some preferred embodiments, the mass ratio of birepiperazole or its salt to the organic solvent in the oil phase is 1:10 to 1:30, preferably 1:12 to 1:22, and more preferably 1:14 to 1:20. For example, it can be 1:10, 1:12, 1:14, 1:15, 1:15.8, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:25, 1:30, and any range between the two mentioned above.

[0074] In some preferred embodiments, the mass ratio of the organic solvent in the oil phase to the external aqueous phase is 1:20 to 1:200, preferably 1:40 to 1:160, more preferably 1:40 to 1:140 or 1:40 to 1:130. For example, it can be 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:71, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, and any range between the two.

[0075] In some preferred embodiments, the average particle size of the buripiperazole microspheres ranges from 5 to 50 micrometers, preferably from 5 to 35 micrometers, and more preferably from 5 to 30 micrometers.

[0076] On the other hand, the present invention also provides bripiprazole sustained-release microspheres, which are prepared by an O / W emulsification-solvent evaporation method, wherein the preparation of the oil phase includes: dissolving the bripiprazole or its salt and polymer in an organic solvent, and the resulting solution is used as the oil phase.

[0077] The inventors of this invention discovered in their research that dissolving birepiperazole or its salt in an organic solvent, compared to using an oil phase suspension containing birepiperazole or its salt solid, can improve the batch stability of microsphere formulations, which is beneficial for large-scale production, avoids large release fluctuations caused by uneven distribution of the sustained-release matrix and drug, and ensures slow and stable drug release.

[0078] In some embodiments, the organic solvent is selected from at least one of dichloromethane, ethyl acetate, dodecanol, acetone, and chloroform.

[0079] In some embodiments, the pH of the external aqueous phase is adjusted to be alkaline, preferably to 8-12.

[0080] In some preferred embodiments, the pH is adjusted to 8-11, for example, the pH can be adjusted to 8, 9, 10, 11 and any two of the above.

[0081] In some preferred embodiments, the external aqueous phase is a water-soluble polymer solution, preferably with a concentration of 0.01% to 5%, more preferably 0.01% to 3%, and even more preferably 0.01% to 1%. For example, it can be 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, and any range between the above.

[0082] In some preferred embodiments, the water-soluble polymer is selected from at least one of polyvinyl alcohol, polyethylene glycol (PEG), and poloxamer.

[0083] In some preferred embodiments, the components or raw materials of the birepiperazole sustained-release microspheres include birepiperazole or its salts, and a polymer; preferably, the weight content of birepiperazole or its salts is 20% to 85%, more preferably 28% to 85% or 20% to 75%, more preferably 30% to 80%, and even more preferably 30% to 75%. For example, it can be 20%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, and any range between the above.

[0084] In some preferred embodiments, the polymer content by weight is 15-80%, preferably 15-72%, more preferably 20-70% or 25-80%, and even more preferably 25-70%. For example, it can be 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 72%, 75%, 80%, 85%, and any range between the above.

[0085] In some preferred embodiments, the polymer is selected from at least one of lactide-glycolic acid copolymer, polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), and polylactide-glycolic acid copolymer (PLCG).

[0086] In some preferred embodiments, the molar ratio of lactide to glycolide in the lactide-glycol copolymer is 90:10 to 10:90. Preferably, it is 85:15 to 15:85, and more preferably 80:20 to 45:55. For example, it can be 90:10, 85:15, 80:20, 75:25, 55:45, 50:50, 45:55, and any range between the above.

[0087] In some preferred embodiments, the molecular weight of the lactide-glycolic acid copolymer is 5,000 to 100,000; preferably 10,000 to 60,000, more preferably 15,000 to 55,000, and even more preferably 20,000 to 50,000. For example, it can be 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, and any range between the above.

[0088] In some preferred embodiments, the mass ratio of birepiperazole or its salt to the organic solvent in the oil phase is 1:10 to 1:30, preferably 1:12 to 1:22, and more preferably 1:14 to 1:20. For example, it can be 1:10, 1:12, 1:14, 1:15, 1:15.8, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:25, 1:30, and any range between the two mentioned above.

[0089] In some preferred embodiments, the mass ratio of the organic solvent in the oil phase to the external aqueous phase is 1:20 to 1:200, preferably 1:40 to 1:160, more preferably 1:40 to 1:140 or 1:40 to 1:130. For example, it can be 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:71, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, and any range between the two.

[0090] In some preferred embodiments, the average particle size of the buripiperazole microspheres ranges from 5 to 50 micrometers, preferably from 5 to 35 micrometers, and more preferably from 5 to 30 micrometers.

[0091] Furthermore, the present invention also provides bripiprazole sustained-release microspheres, which are prepared by an emulsification solvent evaporation method, wherein the mass ratio of bripiprazole or its salt to organic solvent in the oil phase is 1:10 to 1:30, preferably 12 to 22, and more preferably 1:14 to 1:20. For example, it can be 1:10, 1:12, 1:14, 1:15, 1:15.8, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:25, 1:30, and any range between the above.

[0092] In some embodiments, the birepiperazole sustained-release microspheres are prepared using an O / W emulsification-solvent evaporation method, wherein the preparation of the oil phase includes dissolving the birepiperazole or its salt and polymer in an organic solvent, and the resulting solution is used as the oil phase.

[0093] In some embodiments, the organic solvent is selected from at least one of dichloromethane, ethyl acetate, dodecanol, acetone, and chloroform.

[0094] In some embodiments, the pH of the external aqueous phase is adjusted to be alkaline, preferably to 8-12.

[0095] In some preferred embodiments, the pH is adjusted to 8-11, for example, the pH can be adjusted to 8, 9, 10, 11 and any two of the above.

[0096] In some preferred embodiments, the external aqueous phase is a water-soluble polymer solution, preferably with a concentration of 0.01% to 5%, more preferably 0.01% to 3%, and even more preferably 0.01% to 1%. For example, it can be 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, and any range between the above.

[0097] In some preferred embodiments, the water-soluble polymer is selected from at least one of polyvinyl alcohol, polyethylene glycol (PEG), and poloxamer.

[0098] In some preferred embodiments, the components or raw materials of the birepiperazole sustained-release microspheres include birepiperazole or its salts, and a polymer; preferably, the weight content of birepiperazole or its salts is 20% to 85%, more preferably 28% to 85% or 20% to 75%, more preferably 30% to 80%, and even more preferably 30% to 75%. For example, it can be 20%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, and any range between the above.

[0099] In some preferred embodiments, the polymer content by weight is 15-80%, preferably 15-72%, more preferably 20-70% or 25-80%, and even more preferably 25-70%. For example, it can be 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 72%, 75%, 80%, 85%, and any range between the above.

[0100] In some preferred embodiments, the polymer is selected from at least one of lactide-glycolic acid copolymer, polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), and polylactide-glycolic acid copolymer (PLCG).

[0101] In some preferred embodiments, the molar ratio of lactide to glycolide in the lactide-glycol copolymer is 90:10 to 10:90. Preferably, it is 85:15 to 15:85, and more preferably 80:20 to 45:55. For example, it can be 90:10, 85:15, 80:20, 75:25, 55:45, 50:50, 45:55, and any range between the above.

[0102] In some preferred embodiments, the molecular weight of the lactide-glycolic acid copolymer is 5,000 to 100,000; preferably 10,000 to 60,000, more preferably 15,000 to 55,000, and even more preferably 20,000 to 50,000. For example, it can be 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, and any range between the above.

[0103] In some preferred embodiments, the mass ratio of the organic solvent in the oil phase to the external aqueous phase is 1:20 to 1:200, preferably 1:40 to 1:160. For example, it can be 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:71, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, and any range between the two mentioned above.

[0104] In some preferred embodiments, the average particle size of the buripiperazole microspheres ranges from 5 to 50 micrometers, preferably from 5 to 35 micrometers, and more preferably from 5 to 30 micrometers.

[0105] Furthermore, the present invention also provides bripiprazole sustained-release microspheres, which are prepared by an emulsification solvent evaporation method. The mass ratio of the organic solvent to the external aqueous phase in the oil phase is 1:20 to 200, preferably 1:40 to 1:160, more preferably 1:40 to 1:140 or 1:40 to 1:120. For example, it can be 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:71, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, and any range between the above.

[0106] In some preferred embodiments, the emulsification solvent evaporation method is an O / W emulsification-solvent evaporation method; wherein the preparation of the oil phase includes: dissolving the buriperazole or its salt and polymer in an organic solvent, and the resulting solution is used as the oil phase.

[0107] In some preferred embodiments, the organic solvent is at least one selected from dichloromethane, ethyl acetate, dodecanol, acetone, and chloroform.

[0108] In some embodiments, the pH of the external aqueous phase is adjusted to be alkaline, preferably to 8-12.

[0109] In some preferred embodiments, the pH is adjusted to 8-11, for example, the pH can be adjusted to 8, 9, 10, 11 and any two of the above.

[0110] In some preferred embodiments, the external aqueous phase is a water-soluble polymer solution, preferably with a concentration of 0.01% to 5%, more preferably 0.01% to 3%, and even more preferably 0.01% to 1%. For example, it can be 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, and any range between the above.

[0111] In some preferred embodiments, the water-soluble polymer is selected from at least one of polyvinyl alcohol, polyethylene glycol (PEG), and poloxamer.

[0112] In some preferred embodiments, the components or raw materials of the birepiperazole sustained-release microspheres include birepiperazole or its salts, and a polymer; preferably, the weight content of birepiperazole or its salts is 20% to 85%, more preferably 28% to 85% or 20% to 75%, more preferably 30% to 80%, and even more preferably 30% to 75%. For example, it can be 20%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, and any range between the above.

[0113] In some preferred embodiments, the polymer content by weight is 15-80%, preferably 15-72%, more preferably 20-70% or 25-80%, and even more preferably 25-70%. For example, it can be 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 72%, 75%, 80%, 85%, and any range between the above.

[0114] In some preferred embodiments, the polymer is selected from at least one of lactide-glycolic acid copolymer, polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), and polylactide-glycolic acid copolymer (PLCG).

[0115] In some preferred embodiments, the molar ratio of lactide to glycolide in the lactide-glycol copolymer is 90:10 to 10:90. Preferably, it is 85:15 to 15:85, and more preferably 80:20 to 45:55. For example, it can be 90:10, 85:15, 80:20, 75:25, 55:45, 50:50, 45:55, and any range between the above.

[0116] In some preferred embodiments, the molecular weight of the lactide-glycolic acid copolymer is 5,000 to 100,000; preferably 10,000 to 60,000, more preferably 15,000 to 55,000, and even more preferably 20,000 to 50,000. For example, it can be 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, and any range between the above.

[0117] In some preferred embodiments, the mass ratio of birepiperazole or its salt to the organic solvent in the oil phase is 1:10 to 1:30, preferably 1:12 to 1:22, and more preferably 1:14 to 1:20. For example, it can be 1:10, 1:12, 1:14, 1:15, 1:15.8, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:25, 1:30, and any range between the two mentioned above.

[0118] In some preferred embodiments, the average particle size of the buripiperazole microspheres ranges from 5 to 50 micrometers, preferably from 5 to 35 micrometers, and more preferably from 5 to 30 micrometers.

[0119] Furthermore, the present invention also provides a pharmaceutical composition comprising the above-described birepiperazole sustained-release microspheres and pharmaceutically acceptable excipients. Preferably, the pharmaceutically acceptable carrier is selected from self-suspending agents, pH adjusters, isotonic adjusters, surfactants, water, and physiological saline.

[0120] In some embodiments of this disclosure, the aforementioned suspending agent is selected from sodium carboxymethyl cellulose, poloxamer 188, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, or glycerin.

[0121] In some embodiments of this disclosure, the aforementioned isotonic regulator is selected from sodium chloride, glucose, mannitol, propylene glycol, or polysorbate.

[0122] In some embodiments of this disclosure, the aforementioned surfactant is a nonionic surfactant selected from the polysorbate series and the poloxamer series.

[0123] The technical solutions of this disclosure are further illustrated below through specific implementation methods. Those skilled in the art should understand that the embodiments described are merely illustrative of this disclosure and should not be construed as specific limitations thereof.

[0124] The present invention will be further described in detail below with reference to specific embodiments.

[0125] In vivo release assay: Nine male adult rats (Sprague-Dawley), weighing 250–350 g / week for 6–10 weeks, were randomly divided into three groups of three rats each, stratified by weight. The formulation was mixed with a special solvent and injected intramuscularly. Whole blood was collected after each administration and placed in anticoagulant centrifuge tubes. Plasma samples were obtained by centrifugation and then analyzed.

[0126] Method for determining drug loading: Accurately measure 8 mg of birepiperazole microspheres, add 20 ml of acetonitrile, sonicate until completely dissolved, and then add phosphate buffer to bring the volume to 50 ml. Inject the microspheres into a liquid chromatograph, record the chromatograms, and calculate the drug loading based on peak area using the external standard method.

[0127] Particle size determination method: Particle size and particle size distribution determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0982, Method III) was used for determination.

[0128] Example 1

[0129] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 38 g of dichloromethane by heating. A 2.3 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 8.13. The temperature was controlled at 8°C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product with an average particle size of 19 μm.

[0130] Electron microscopy results as follows Figure 1 As shown, the microspheres have good morphology, smooth and round surface, and uniform particle size. The burst release of the microspheres is low, with a release rate of 4.67% on the first day, a sustained release duration of 26 days, a drug loading of over 54%, a particle size of 3-66 μm, and an average particle size of 19 μm.

[0131] Example 2

[0132] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 38 g of dichloromethane by heating. A 2.3 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.02. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0133] Electron microscopy results as follows Figure 2As shown, the microspheres have good morphology, smooth and round surface, and uniform particle size. The burst release of the microspheres is low, with a first-day release of 1.53%, a sustained-release duration of 32 days, a drug loading of over 54%, a particle size of 3-59 μm, and an average particle size of 11 μm.

[0134] Example 3

[0135] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 38 g of dichloromethane by heating. A 2.3 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 10.05. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0136] As attached Figure 3 As shown, the microspheres have good morphology, smooth and round surface, and uniform particle size. The burst release is low, with a first-day release of 2.06%, a sustained-release duration of 33 days, a drug loading of over 54%, a particle size of 3-62 μm, and an average particle size of 11 μm.

[0137] Example 4

[0138] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 38 g of dichloromethane by heating. A 2.3 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 11.03. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0139] As attached Figure 4 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. Figure 28 As shown, the burst release is low, with a first-day release of 0.86%, a sustained-release duration of 35 days, a drug loading of 54%, a particle size of 1-48 μm, and an average particle size of 10 μm.

[0140] Example 5

[0141] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 38 g of dichloromethane by heating. A 2.3 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 12.01. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0142] As attached Figure 5 As shown, the microspheres are relatively round, with a rough and uneven surface, some of which are broken particles, and the particle size is relatively uniform. The drug loading is over 54%, the particle size is 2-86 μm, and the average particle size is 10 μm.

[0143] Example 6

[0144] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 43.2 g of dichloromethane by heating. A 2.6 L solution of 0.05% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.02. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0145] As attached Figure 6 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The drug loading is over 54%, the particle size is 3-67 μm, and the average particle size is 16 μm.

[0146] Example 7

[0147] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 45,000 and a molar ratio of lactide to glycolide of 75:25) were mixed and dissolved in 43.2 g of dichloromethane by heating. A 2.6 L solution of 0.05% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.03. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0148] As attached Figure 7 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The drug loading is above 54%, with a particle size of 2-50 μm and an average particle size of 21 μm. In vivo release is good and meets the requirements.

[0149] Example 8

[0150] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 49,000 and a molar ratio of lactide to glycolide of 55:45) were mixed and dissolved in 43.2 g of dichloromethane by heating. A 2.6 L solution of 0.05% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.01. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0151] As attached Figure 8 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The drug loading is above 54%, with a particle size of 4-58 μm and an average particle size of 20 μm. In vivo release is good and meets the requirements.

[0152] Example 9

[0153] 2.4 g of biriperazole and 5.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 41 g of dichloromethane by heating. A 3.7 L solution of 0.1% PVA was prepared, and sodium hydroxide was added to adjust the pH to 8.96. The temperature was controlled at 8°C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0154] As attached Figure 9 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The burst release is low, with 0.77% released on the first day and a sustained-release duration of 36 days. The drug loading is 29%, the particle size is 6-67 μm, and the average particle size is 15 μm.

[0155] Example 10

[0156] 2.4 g of biriperazole and 3.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 41 g of dichloromethane by heating. A 3.7 L solution of 0.1% PVA was prepared, and sodium hydroxide was added to adjust the pH to 8.93. The temperature was controlled at 8°C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0157] As attached Figure 10As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The burst release is low, with 1.09% released on the first day and a sustained-release duration of 34 days. The drug loading is 39%, the particle size is 5-72 μm, and the average particle size is 12 μm.

[0158] Example 11

[0159] 2.4 g of biriperazole and 2.4 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 41 g of dichloromethane by heating. A 3.7 L solution of 0.1% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.05. The temperature was controlled at 8 °C. The biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0160] As attached Figure 11 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The drug loading is 49%, the particle size is 4-66 μm, and the average particle size is 12 μm.

[0161] Example 12

[0162] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 38 g of dichloromethane by heating. A 2.7 L solution of 0.1% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.94. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0163] As attached Figure 12 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. Figure 28 As shown, the burst release is relatively small, with a release of 1.64% on the first day, and the release is stable. The drug loading is 54%, the particle size is 3-68 μm, and the average particle size is 20 μm.

[0164] Example 13

[0165] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 41 g of dichloromethane by heating. A 3.7 L solution of 0.1% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.97. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0166] As attached Figure 13 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The drug loading is 58%, the particle size is 2-64 μm, and the average particle size is 28 μm.

[0167] Example 14

[0168] 2.4 g of biriperazole and 1.3 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 41 g of dichloromethane by heating. A 3.7 L solution of 0.1% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.98. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0169] As attached Figure 14 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The drug loading is 63%, the particle size is 1-67 μm, and the average particle size is 25 μm.

[0170] Example 15

[0171] 2.4 g of biriperazole and 0.8 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 41 g of dichloromethane by heating. A 3.7 L solution of 0.1% PVA was prepared, and sodium hydroxide was added to adjust the pH to 11.05. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0172] As attached Figure 15 As shown, the microspheres have good morphology, smooth and round surfaces, and uniform particle size. The burst release is low, with a first-day release of 3.32%. The drug loading is 73%, particle size ranges from 2 to 56 μm, and the average particle size is 18 μm.

[0173] Example 16

[0174] 2.4 g of biriperazole and 0.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 41 g of dichloromethane by heating. A 3.7 L solution of 0.1% PVA was prepared, and sodium hydroxide was added to adjust the pH to 11.13. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0175] As attached Figure 16 As shown, the microspheres have good morphology, with most having smooth and round surfaces and uniform particle size, and a small amount appearing as coated solids. The drug loading is 77%, the particle size is 1-77 μm, and the average particle size is 16 μm.

[0176] Example 17

[0177] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 28.8 g of dichloromethane by heating. A 2.3 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 11.25. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0178] As attached Figure 17 As shown, the microspheres have good morphology, with most having smooth and round surfaces and uniform particle size, and a small amount being coated solids. The drug loading is over 54%, the particle size is 8-68 μm, and the average particle size is 29 μm.

[0179] Example 18

[0180] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 33.6 g of dichloromethane by heating. A 2.7 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 11.06. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0181] As attached Figure 18 As shown, the microspheres have good morphology, with most having smooth and round surfaces and uniform particle size. The drug loading is over 58%, the particle size is 2-69 μm, and the average particle size is 30 μm.

[0182] Example 19

[0183] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 48 g of dichloromethane by heating. A 3.8 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 11.03. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0184] As attached Figure 19 As shown, the microspheres have good morphology, with most surfaces being smooth and round, and a small number of pores on the surface. The particle size is uniform. The drug loading is 57%, the particle size is 2-45 μm, and the average particle size is 12 μm.

[0185] Example 20

[0186] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 52.8 g of dichloromethane by heating. A 4.2 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 10.01. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0187] As attached Figure 20 As shown, the microspheres have good morphology, with most being perfectly round and having uniform particle size. The microspheres also exhibit a porous surface structure. Figure 29 As shown, the first-day release was 31.7%. The drug loading was 56%, the particle size was 1-76 μm, and the average particle size was 13 μm.

[0188] Example 21

[0189] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 41 g of dichloromethane by heating. A 1.2 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.10. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0190] As attached Figure 21As shown, the microspheres have poor morphology, with some being perfectly round and a large amount of unformed drug aggregated. The drug loading is 57%, the particle size is 2-80 μm, and the average particle size is 10 μm.

[0191] Example 22

[0192] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 43.2 g of dichloromethane by heating. A 2.16 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.07. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0193] As attached Figure 22 As shown, the microspheres have good morphology, are generally round, and have uniform particle size, although a small number of microspheres have pores on their surface. The drug loading is 56%, the particle size is 3-51 μm, and the average particle size is 26 μm.

[0194] Example 23

[0195] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 43.2 g of dichloromethane by heating. A 4.8 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.06. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0196] As attached Figure 23 As shown, the microspheres have good morphology, are generally round and have uniform particle size, with a small number of microspheres having pores on their surface. The drug loading is 54%, the particle size is 1-49 μm, and the average particle size is 12 μm.

[0197] Example 24

[0198] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 43.2 g of dichloromethane by heating. A 6.9 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.13. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 h, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0199] As attached Figure 24 As shown, the microsphere morphology is slightly unsatisfactory; the overall shape is round and the particle size is uniform, but a small number of microspheres have pores on their surface. The drug loading is 52%, the particle size is 5-58 μm, and the average particle size is 9 μm.

[0200] Example 25

[0201] 2.4 g of biriperazole and 1.6 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 43.2 g of dichloromethane by heating. A 7.78 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 9.26. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0202] As attached Figure 25 As shown, the microspheres have poor morphology; while the overall shape is round and the particle size is uniform, some are irregularly broken, and a small number of microspheres have pores on their surface. The drug loading is 40%, the particle size is 4-80 μm, and the average particle size is 6 μm.

[0203] Comparative Example 1

[0204] 2.4 g of biriperazole and 2.0 g of lactide-glycolic acid copolymer (with a weight-average molecular weight of 25,000 and a molar ratio of lactide to glycolide of 50:50) were mixed and dissolved in 38 g of dichloromethane by heating. A 2.3 L solution of 0.5% PVA was prepared, and sodium hydroxide was added to adjust the pH to 7.02. The temperature was controlled at 8 °C, and the biriperazole solution was dispersed into the PVA solution using a high-speed shear mixer or a static mixer. After curing for 4 hours, the microspheres were collected by filtration, freeze-dried, and dispersed to obtain the final product.

[0205] As attached Figure 26 As shown, the microspheres exhibit poor sphericity, with some remaining uncoated with drug. The initial release was 13.7%, with a sustained-release duration of 18 days. The drug loading was 52.9%, particle size ranged from 4 to 64 μm, and the average particle size was 11 μm.

[0206] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0207] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A sustained release microspheres of brexpiprazole, characterized by, The preparation of the brexpiprazole sustained-release microspheres by the emulsification-solvent evaporation method, wherein the pH of the external water phase is adjusted to be alkaline, preferably the pH of the external water phase is adjusted to be 8-12.

2. The brexpiprazole sustained-release microspheres according to claim 1, wherein The pH of the external water phase is adjusted to be 8-11.

3. The brexpiprazole sustained-release microspheres according to claim 1, wherein The external water phase is a water-soluble polymer solution, preferably the concentration of the external water phase is 0.01%-5%, more preferably 0.01%-3%, further preferably 0.01%-1%; the water-soluble polymer is selected from at least one of polyvinyl alcohol (PVA), polyethylene glycol (PEG), and poloxamer.

4. The brexpiprazole sustained-release microspheres according to claim 1, wherein The components of the brexpiprazole sustained-release microspheres include brexpiprazole or a salt thereof, and a polymer; wherein the weight content of brexpiprazole or a salt thereof is 20%-85%, preferably 28%-85%; the weight content of the polymer is 15-80%, preferably 15-72%.

5. The brexpiprazole sustained-release microspheres according to claim 4, wherein The polymer is selected from at least one of poly(lactide-co-glycolide), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), and poly(lactide-co-lactide) (PLCG); preferably the molar ratio of lactide and glycolide in the poly(lactide-co-glycolide) is 90:10-10:90, preferably 80:20-45:

55.

6. The brexpiprazole sustained-release microspheres according to claim 5, wherein The molecular weight of the poly(lactide-co-glycolide) is 5000-100000; preferably 10000-60000, more preferably 15000-55000, further preferably 20000-50000.

7. The brexpiprazole sustained-release microspheres according to any one of claims 1 to 6, characterized by, The emulsification-solvent evaporation method is an O / W emulsification-solvent evaporation method; wherein the preparation of the oil phase includes: dissolving the brexpiprazole or a salt thereof and the polymer in an organic solvent, and the obtained solution is used as the oil phase.

8. The brexpiprazole sustained-release microspheres according to claim 7, wherein The organic solvent is selected from at least one of dichloromethane, ethyl acetate, dodecanol, acetone, and chloroform.

9. The brexpiprazole sustained-release microspheres according to claim 7, wherein The mass ratio of brexpiprazole or a salt thereof and the organic solvent in the oil phase is 1:10-1:30, preferably 1:12-1:22, further preferably 1:14-1:

20.

10. The brexpiprazole sustained-release microspheres according to claim 7, wherein The mass ratio of the organic solvent in the oil phase to the external water phase is 1:20-200, preferably 1:40-1:

160.

11. A sustained release microspheres of brexpiprazole, characterized by, The preparation of the brexpiprazole sustained-release microspheres by the O / W emulsification-solvent evaporation method, wherein the preparation of the oil phase includes: completely dissolving the brexpiprazole or a salt thereof and the polymer in an organic solvent, and the obtained solution is used as the oil phase.

12. The brexpiprazole sustained-release microspheres according to Claim 11, wherein The organic solvent is selected from at least one of dichloromethane, ethyl acetate, dodecanol, acetone, and chloroform.

13. The brexpiprazole sustained-release microspheres according to claim 11 or 12, characterized by, The pH of the external water phase is adjusted to be alkaline, preferably the pH is adjusted to be 8-12, preferably the pH is adjusted to be 8-11.

14. A sustained release microspheres of brexpiprazole, characterized by, The preparation of the brexpiprazole sustained-release microspheres by the O / W emulsification-solvent evaporation method, wherein the mass ratio of brexpiprazole or a salt thereof and the organic solvent in the oil phase is 1:10-1:30, preferably 1:12-1:22, further preferably 1:14-1:

20.

15. The brexpiprazole sustained release microspheres according to Claim 14, wherein The mass ratio of the organic solvent in the oil phase to the external water phase is 1:20-200, preferably 1:40-1:

160.

16. A sustained release microsphere of brexpiprazole, characterized by, The preparation of the brexpiprazole sustained-release microspheres by the O / W emulsification-solvent evaporation method, the mass ratio of the organic solvent in the oil phase to the external water phase is 1:20-200, preferably 1:40-1:

160.

17. The brexpiprazole sustained-release microspheres according to claim 16, wherein The mass ratio of brexpiprazole or a salt thereof to the organic solvent in the oil phase is 1:10 to 1:30, preferably 12 to 22, and further preferably 1:14 to 1:

20.

18. A method of preparing the brexpiprazole sustained-release microspheres according to any one of claims 1 to 17, characterized by, The method comprises the following steps: (1) dissolving brexpiprazole or a salt thereof and a polymer in an organic solvent to obtain a solution as an oil phase; (2) dissolving a water-soluble polymer in water as an external aqueous phase; and (3) mixing and dispersing the oil phase with the external aqueous phase, and solidifying to obtain microspheres.

19. A pharmaceutical composition comprising, The method comprises the following steps: (1) dissolving brexpiprazole or a salt thereof and a polymer in an organic solvent to obtain a solution as an oil phase; (2) dissolving a water-soluble polymer in water as an external aqueous phase; and (3) mixing and dispersing the oil phase with the external aqueous phase, and solidifying to obtain microspheres. Preferably, the pharmaceutically acceptable excipient is at least one selected from the group consisting of a suspending agent, a pH adjusting agent, a release adjusting agent, a lyophilization protecting agent, an isotonicity adjusting agent, and a surfactant.

20. Use of the brexpiprazole sustained-release microspheres according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating depression, schizophrenia, Alzheimer's disease, and post-traumatic stress disorder.

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