Long-acting brexpiprazole microsphere and preparation method therefor

Abstract

The present invention belongs to the field of pharmaceutical preparations, and relates to a long-acting brexpiprazole microsphere and a preparation method therefor. The method comprises the following steps: (1) dissolving brexpiprazole and a degradable polymer in an organic solvent to obtain a drug-containing polymer solution as an oil phase; (2) mixing the drug-containing polymer solution with a polyvinyl alcohol solution by means of a microfluidic technique to obtain an oil-in-water emulsion; and (3) under stirring, solidifying, washing and freeze-drying the oil-in-water emulsion to obtain the long-acting brexpiprazole microsphere. In the present invention, the in-vitro release rate of the final microsphere is adjusted by means of adjusting the volatilization and stirring time during the formation of the O / W primary emulsion, thereby screening microspheres with no burst release or lag period, and exhibiting sustained release. The long-acting brexpiprazole microsphere provided in the present invention has a simple preparation process, is readily scalable for industrial production, exhibits high encapsulation efficiency, high drug loading capacity, uniform microsphere particle size distribution, spherical morphology, good flowability, good syringeability and injectability, has a significant sustained-release effect, and can be used to reduce fluctuations in blood drug level and effectively improve the compliance of patients with psychiatric diseases.

Description

A long-acting biriperazole microsphere and its preparation method Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and particularly relates to a long-acting birepiperazole microsphere and its preparation method. Background Technology

[0002] Brepiperazole is an atypical antipsychotic drug that regulates the monoaminergic neurotransmission system in the brain. It is a partial agonist of serotonin (5-HT1A) and dopamine D2 receptors, an antagonist of serotonin (5-HT2A) and dopamine α1 / 2 receptors, and has broad binding affinity for other central monoaminergic receptor subtypes. Its structure is shown in the figure below. Compared with typical antipsychotics, brepiperazole has reduced extrapyramidal reactions. Compared with the atypical antipsychotic aripiprazole, brepiperazole has increased affinity for 5-HT receptors, reduced activity on D2 receptors, better tolerability, and a lower incidence of akathisia as a side effect. Clinically, it has shown a trend towards better efficacy in treating negative symptoms and cognitive function in schizophrenia, and when used as adjunctive therapy for depression, it has a faster onset of action.

[0003] Currently, the only marketed formulations of iriperazole are tablets and orally disintegrating tablets, with a target dose of 2-4 mg once daily. Since its launch, global sales of iriperazole have increased year by year, from US$0.51 billion in 2015 to US$1.374 billion in 2020. However, due to the specific nature of mental illnesses and the relatively long treatment process, patient compliance is often poor, making it difficult to administer medication regularly and reducing treatment efficacy. Furthermore, iriperazole tablets have an increased incidence of cerebrovascular adverse reactions (such as stroke and transient ischemic attack) in elderly patients with Alzheimer's disease, which may be related to the fact that conventional oral immediate-release formulations tend to reach higher required concentrations, resulting in larger fluctuations in blood drug concentrations. Therefore, the development of long-acting iriperazole microspheres is of great significance in order to improve patient compliance, reduce side effects, and expand the range of patients for its use.

[0004] Patent WO 2023036003 A1 discloses a long-acting formulation of birepiperazole for injection and its preparation method, specifically a microcrystalline injection. The drug crystals are dispersed in a micron-sized suspension. This dosage form has a wide particle size distribution, and the uneven particle size easily leads to large fluctuations in blood drug concentration, making it difficult to maintain a stable blood drug concentration. Furthermore, the preparation process of this patent is complex, making it difficult to achieve industrial-scale production.

[0005] Patent CN 116531379 A discloses an ibuprofen sustained-release composition, its preparation method, and its application. Using dichloromethane as an organic solvent, polylactic acid, polylactic acid-glycolic acid copolymer, and polycaprolactone are mixed in a certain proportion as a carrier. The ibuprofen sustained-release composition is prepared using an emulsification solvent evaporation method. The dichloromethane solvent used in this formulation is highly toxic to humans, and ibuprofen has very low solubility in dichloromethane. Using dichloromethane as a solvent in the oil phase makes it impossible to prepare microspheres with high drug loading. Furthermore, the carrier component, polycaprolactone, has a collagen-stimulating effect, which can cause local tissue induration, posing uncontrollable side effects for patients with immune diseases.

[0006] Patent CN 118477048 A discloses a bripiprazole sustained-release microsphere and its preparation method. The emulsification and evaporation time exceeds 4 hours, and both evaporation and solidification require control at different temperatures, making the process complex and resulting in low production efficiency. The preparation process employs a stator-rotor shear emulsification method, which is limited by batch variations during scale-up. Different batches lead to different shear mixer parameters, easily causing problems of uneven stirring / shearing with large quantities during scale-up production. This significantly reduces the encapsulation rate and microsphere yield, making scale-up a major challenge. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention uses a benzyl alcohol / ethyl acetate system, which is safer than dichloromethane, as the organic solvent. Instead of using polylactic acid and polycaprolactone, it uses only polylactic acid-glycolic acid copolymer, a safer and more biodegradable polymer, as the drug carrier, thus avoiding certain uncontrollable risks. Simultaneously, microfluidic technology is employed to prepare uniformly sized injectable birepiperazole sustained-release microspheres. These microspheres are easier to inject due to their spherical shape, good flowability, and good needle penetration. Furthermore, the preparation method is simple, significantly improving the encapsulation efficiency and drug loading of traditional methods. More importantly, this invention allows for adjustment of the microsphere release rate by controlling the stirring and evaporation time, resulting in microspheres with no burst release, no hysteresis, and a slow release period of two months or more.

[0008] The first objective of this invention is to provide a method for preparing birepiperazole long-acting microspheres, comprising the following steps:

[0009] Step (1): Dissolve biriperazole and the biodegradable polymer in an organic solvent at a mass ratio of 1:1 to 1:10 to obtain a drug-containing polymer solution, which is used as the oil phase;

[0010] Step (2): Dissolve polyvinyl alcohol in water to obtain a first aqueous phase with a concentration of 0.1-1.5%. Using microfluidic technology, mix the oil phase and the first aqueous phase described in step (1) at a volume ratio of 1:1 to 1:45. The flow rate ratio of the oil phase and the first aqueous phase is 1:1 to 1:45. After obtaining the primary emulsion, evaporate the organic solvent and control the evaporation ratio to 0-20% to obtain an oil-in-water emulsion.

[0011] Step (3): The oil-in-water emulsion described in step (2) is added to the second aqueous phase as the curing phase for curing. The volume of the curing phase is 0.05-1.0 L / g microspheres, and the curing time is 2-6 h. After curing, the microspheres are washed and dried to obtain the bripiprazole long-acting microspheres.

[0012] In step (1), the degradable polymer is polylactic acid-glycolic acid copolymer or polylactic acid;

[0013] In step (1), the organic solvent that forms the oil phase is a benzyl alcohol-ethyl acetate mixed solvent system.

[0014] As a further optimization, in step (1), bripiprazole is dissolved in benzyl alcohol to obtain a bripiprazole solution; polylactic acid-glycolic acid copolymer or polylactic acid is dissolved in ethyl acetate to obtain a polymer solution; then the bripiprazole solution and the polymer solution are mixed and vortexed to obtain the oil phase.

[0015] As a further optimization, in step (1), the mass concentration of the buriperazole solution is 2% to 20%; and the mass concentration of the degradable polymer solution is 4% to 35%.

[0016] As a further optimization, in step (1), the mixing ratio of bripiprazole solution and polymer solution is controlled so that the mass ratio of bripiprazole to degradable polymer is 1:1 to 1:5.

[0017] As a further optimization, in step (2), the concentration of the polyvinyl alcohol solution is 0.1% to 1%.

[0018] As a further optimization, in step (2), the oil-in-water emulsion is obtained by pumping the oil phase and the first aqueous phase into a microfluidic reactor for mixing.

[0019] As a further optimization, in step (2), the flow rate ratio of the oil phase and the first aqueous phase in the microfluidic reactor is 1:1 to 1:20.

[0020] As a further optimization, in step (2), the evaporation rate of organic solvents in the promulgated emulsion is controlled to be 0-15%.

[0021] As a further optimization, in step (3), the volume of the solidified phase is 0.1 to 0.5 L / g microspheres.

[0022] A second objective of this invention is to provide a long-acting birepiperazole microsphere prepared by the above method. The resulting long-acting birepiperazole microspheres have high encapsulation efficiency, large drug loading, uniform particle size distribution, and spherical shape, exhibiting good flowability and needle penetration, making them easier to inject.

[0023] The beneficial effects of this invention are as follows:

[0024] The preparation method of the present invention can obtain bripiprazole long-acting sustained-release microspheres with high encapsulation efficiency, large drug loading, uniform particle size, spherical shape, and excellent needle penetration, and the sustained-release effect can last for up to six months.

[0025] The buripiperazole sustained-release microspheres prepared by the method of the present invention not only have excellent performance, but also use a safer polylactic acid-glycolic acid copolymer as the carrier material. Furthermore, there is no need to add other polymers such as polycaprolactone or polylactic acid to adjust the ratio, making them safer and more friendly to the body.

[0026] The present invention also found that the release rate of microspheres can be adjusted by controlling the evaporation ratio of organic solvents, resulting in birepiperazole microspheres with no burst release, no release lag period, and an ideal release rate, without reducing the encapsulation efficiency and drug loading of the microspheres. Attached Figure Description

[0027] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings, wherein:

[0028] Figure 1 is a scanning electron microscope image of the sustained-release microspheres of Example 1 of the present invention.

[0029] Figure 2 is a scanning electron microscope image of the sustained-release microspheres of Example 4 of the present invention.

[0030] Figure 3 is a scanning electron microscope image of the sustained-release microspheres of Comparative Example 1 of the present invention.

[0031] Figure 4 is a scanning electron microscope image of the sustained-release microspheres of Comparative Example 2 of the present invention.

[0032] Figure 5 shows the in vitro release curves of sustained-release microspheres from Examples 1-6, 9, 10 and Comparative Example 2 of the present invention. Detailed Implementation

[0033] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0034] In this invention, unless otherwise stated, the raw materials used are existing products, and the specific preparation operations and performance tests are conventional techniques. For example, stirring is a conventional technique, and organic solvents are removed by conventional stirring and evaporation methods in a fume hood.

[0035] In this invention, unless otherwise stated, the freeze dryer used for freeze drying is model FDU-2110.

[0036] Example 1

[0037] 210 mg of biriperazole was dissolved in 3 mL of benzyl alcohol to obtain a biriperazole solution. 420 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 90 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The biriperazole solution and polymer solution were mixed and vortexed to obtain the oil phase. 7 mL of the oil phase and 35 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain biriperazole microsphere powder.

[0038] Example 2

[0039] 210 mg of bripiprazole was dissolved in 3 mL of benzyl alcohol to obtain a bripiprazole solution. 420 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 130 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 7 mL of the oil phase and 35 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0040] Example 3

[0041] 210 mg of bripiprazole was dissolved in 3 mL of benzyl alcohol to obtain a bripiprazole solution. 420 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 130 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 7 mL of the oil phase and 35 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 9.5% of its weight. The dispersion was then poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0042] Example 4

[0043] 210 mg of bripiprazole was dissolved in 3 mL of benzyl alcohol to obtain a bripiprazole solution. 420 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 130 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 7 mL of the oil phase and 35 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was not stirred or evaporated, but directly poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the emulsion was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0044] Example 5

[0045] 200 mg of biriperazole was dissolved in 4 mL of benzyl alcohol to obtain a biriperazole solution. 400 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 130 kDa) was dissolved in 6 mL of ethyl acetate to obtain a polymer solution. The biriperazole solution and polymer solution were mixed and vortexed to obtain the oil phase. 10 mL of the oil phase and 50 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 2% of its weight. The dispersion was then poured into 160 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain biriperazole microsphere powder.

[0046] Example 6

[0047] 160 mg of bripiprazole was dissolved in 4 mL of benzyl alcohol to obtain a bripiprazole solution. 480 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 130 kDa) was dissolved in 8 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 12 mL of the oil phase and 60 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 225 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0048] Example 7

[0049] 120 mg of bripiprazole was dissolved in 3 mL of benzyl alcohol to obtain a bripiprazole solution. 240 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 130 kDa) was dissolved in 3 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 6 mL of the oil phase and 30 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 90 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0050] Example 8

[0051] 120 mg of bripiprazole was dissolved in 2 mL of benzyl alcohol to obtain a bripiprazole solution. 360 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 12 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 6 mL of the oil phase and 30 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 12 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 90 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0052] Example 9

[0053] 480 mg of bripiprazole was dissolved in 4 mL of benzyl alcohol to obtain a bripiprazole solution. 480 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 90 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and polymer solution were mixed and vortexed to obtain the oil phase. 8 mL of the oil phase and 40 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred until 5% of its weight evaporated. The dispersion was then poured into 135 mL of ultrapure water and allowed to solidify for 2 hours. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0054] Example 10

[0055] 160 mg of bripiprazole was dissolved in 4 mL of benzyl alcohol to obtain a bripiprazole solution. 480 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 12 kDa) was dissolved in 8 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 12 mL of the oil phase and 60 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 8.5% of its weight. The dispersion was then poured into 225 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0056] Example 11

[0057] 4g of bripiprazole was dissolved in 20g of benzyl alcohol to obtain a bripiprazole solution; 8g of polylactic acid was dissolved in 16g of ethyl acetate to obtain a polymer solution; the bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. The oil phase and a 1% polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 using a horizontal flow pump. The resulting emulsion was poured into 6000mL of ultrapure water, solidified for 6 hours, filtered, washed three times with water, and freeze-dried to obtain bripiprazole microsphere powder.

[0058] Example 12

[0059] 4g of bripiprazole was dissolved in 16g of benzyl alcohol to obtain a bripiprazole solution; 20g of polylactic acid-glycolic acid copolymer was dissolved in 37g of ethyl acetate to obtain a polymer solution; the bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. The oil phase and a 0.1% polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:20 using a horizontal flow pump. The resulting emulsion was stirred to evaporate 15% of its weight. The dispersion was then poured into 2400mL of ultrapure water and allowed to solidify for 6 hours. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0060] Comparative Example 1

[0061] 120 mg of bripiprazole was dissolved in 2 mL of benzyl alcohol to obtain a bripiprazole solution. 240 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 90 kDa) was dissolved in 2 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and polymer solution were mixed and vortexed to obtain the oil phase. The oil phase was then added dropwise to 20 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution. The resulting emulsion was stirred until 5% of its weight evaporated. The dispersion was then poured into 120 mL of ultrapure water and stirred for 2 hours. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0062] Comparative Example 2

[0063] Weigh 40 mg of bripiprazole and dissolve it in 1 mL of benzyl alcohol to obtain a bripiprazole solution. Dissolve 120 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 12 kDa) in 2 mL of ethyl acetate to obtain a polymer solution. Mix the bripiprazole solution and the polymer solution together and vortex disperse to obtain the oil phase. Add the oil phase dropwise to 15 mL of 0.01 g / mL polyvinyl alcohol aqueous solution. Stir the resulting emulsion to evaporate 5% of its weight. Pour the dispersion into 90 mL of ultrapure water, stir for 2 h, filter, wash three times with water, and freeze-dry to obtain bripiprazole microsphere powder.

[0064] Comparative Example 3

[0065] 40 mg of bripiprazole was dissolved in 1 mL of benzyl alcohol to obtain a bripiprazole solution. 120 mg of polylactic acid-glycolic acid copolymer (carboxyl-terminated lactide to glycolide molar ratio = 75:25, Mw = 12 kDa) was dissolved in 2 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and polymer solution were mixed and vortexed to obtain the oil phase. The oil phase was then added dropwise to 15 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution. The resulting emulsion was stirred until 5% of its weight evaporated. The dispersion was then poured into 90 mL of ultrapure water and stirred for 2 hours. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0066] Comparative Example 4

[0067] Weigh 40 mg of bripiprazole and dissolve it in 1 mL of benzyl alcohol to obtain a bripiprazole solution. Dissolve 120 mg of polylactic acid-glycolic acid copolymer (carboxyl-terminated lactide to glycolide molar ratio = 50:50, Mw = 12 kDa) in 2 mL of ethyl acetate to obtain a polymer solution. Mix the bripiprazole solution and the polymer solution together and vortex disperse to obtain the oil phase. Add the oil phase dropwise to 15 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution. Stir the resulting emulsion to evaporate 5% of its weight. Pour the dispersion into 90 mL of ultrapure water, stir for 2 h, filter, wash three times with water, and freeze-dry to obtain bripiprazole microsphere powder.

[0068] Comparative Example 5

[0069] 120 mg of bripiprazole was dissolved in 1.3 mL of benzyl alcohol to obtain a bripiprazole solution. 120 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 90 kDa) was dissolved in 0.7 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and polymer solution were mixed and vortexed to obtain the oil phase. The oil phase was then added dropwise to 10 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution. The resulting emulsion was stirred until 5% of its weight evaporated. The dispersion was then poured into 60 mL of ultrapure water and stirred for 2 hours. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0070] Comparative Example 6

[0071] 120 mg of biriperazole was dissolved in 3 mL of benzyl alcohol to obtain a biriperazole solution. 360 mg of polylactic acid-glycolic acid copolymer (carboxyl-terminated lactide to glycolide molar ratio = 50:50, Mw = 12 kDa) was dissolved in 6 mL of ethyl acetate to obtain a polymer solution. The biriperazole solution and polymer solution were mixed and vortexed to obtain the oil phase. 9 mL of the oil phase and 45 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain biriperazole microsphere powder.

[0072] Comparative Example 7

[0073] 120 mg of bripiprazole was dissolved in 3 mL of benzyl alcohol to obtain a bripiprazole solution. 360 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 12 kDa) was dissolved in 6 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 9 mL of the oil phase and 27 mL of a 0.005 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:3 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0074] Comparative Example 8

[0075] 480 mg of bripiprazole was dissolved in 4 mL of benzyl alcohol to obtain a bripiprazole solution. 480 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 90 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and polymer solution were mixed and vortexed to obtain the oil phase. 8 mL of the oil phase and 40 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred until 5% of its weight evaporated. The dispersion was then poured into 135 mL of ultrapure water and allowed to solidify for 2 hours. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0076] Comparative Example 9

[0077] 200 mg of biriperazole was dissolved in 4 mL of benzyl alcohol to obtain a biriperazole solution. 400 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 12 kDa) was dissolved in 6 mL of ethyl acetate to obtain a polymer solution. The biriperazole solution and polymer solution were mixed and vortexed to obtain the oil phase. 10 mL of the oil phase and 50 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a co-current pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain biriperazole microsphere powder.

[0078] Comparative Example 10

[0079] 210 mg of biriperazole was dissolved in 3 mL of dimethyl sulfoxide to obtain a biriperazole solution. 420 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 130 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The biriperazole solution and polymer solution were mixed and vortexed to obtain the oil phase. 7 mL of the oil phase and 35 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain biriperazole microsphere powder.

[0080] Comparative Example 11

[0081] 210 mg of bripiprazole was dissolved in 3 mL of dichloromethane to obtain a bripiprazole solution. 420 mg of polylactic acid-glycolic acid copolymer (ester-terminated lactide to glycolide molar ratio = 75:25, Mw = 130 kDa) was dissolved in 4 mL of ethyl acetate to obtain a polymer solution. The bripiprazole solution and the polymer solution were mixed and vortexed to obtain the oil phase. 7 mL of the oil phase and 35 mL of a 0.01 g / mL polyvinyl alcohol aqueous solution were pumped into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20 mL / min using a horizontal flow pump. The resulting emulsion was stirred to evaporate 5% of its weight. The dispersion was then poured into 125 mL of ultrapure water and allowed to solidify for 2 h. After filtration, the mixture was washed three times with water and freeze-dried to obtain bripiprazole microsphere powder.

[0082] Test Example 1: Drug Loading and Encapsulation Efficiency of Microspheres

[0083] Octadecylsilane-bonded silica gel was used as the packing material; 0.15% phosphoric acid:acetonitrile (68:32) was used as the mobile phase, and the detection wavelength was 215 nm; 10 mg of bripiprazole microspheres prepared in Examples 1-10 and Comparative Examples 1-11 were weighed, dissolved in dimethyl sulfoxide, and then diluted to 100 mL with 0.15% phosphoric acid solution. The solution was shaken well, and a portion was centrifuged at 12500 rpm. The supernatant was then analyzed by HPLC to determine the total drug concentration. 10 mg of microspheres were weighed, diluted to 10 mL with 0.15% phosphoric acid solution, and the supernatant was analyzed by HPLC to determine the free drug concentration. The total drug amount minus the free drug amount is the encapsulated drug amount; the formulas for calculating drug loading and encapsulation efficiency are as follows:

[0084] Table 1. Drug loading and encapsulation efficiency of microspheres from different embodiments and comparative examples.

[0085] In Comparative Examples 1-5, this invention employed a method of dropwise addition of the oil phase to the aqueous phase followed by stirring to prepare bripiprazole microspheres. It was found that most samples prepared using this method achieved encapsulation efficiencies exceeding 95%, but significant differences remained overall. The process resulted in substantial drug loss, with the drug loading significantly lower than the theoretical loading. Despite attempts to modify various factors, such as using different amounts of raw materials, changing the polymer molecular weight, adjusting the solvent ratio, and using different polymer end-capping types, these attempts failed to completely resolve the issues with encapsulation efficiency and drug loading to achieve the desired results. Furthermore, the mass transfer process in this method is highly volume-dependent; once scaled up for production, the process parameters need to be readjusted, making scale-up production challenging.

[0086] In Examples 1-10 and Comparative Examples 6-11, this invention uses microfluidics to input two-phase solutions into a microfluidic device to prepare bripiprazole microspheres. Numerous process conditions, including flow rate ratio and total flow rate, stirring and evaporation time, polymer and formulation, solvent system, and curing conditions, were explored, and the following findings were made.

[0087] As shown in Table 1, Examples 2-4, which varied the degree of stirring and volatilization, had little effect on the microsphere encapsulation efficiency and drug loading, indicating that the process has good stability. Examples 1, 2, and 8 used polylactic acid-glycolic acid copolymers with different molecular weights, but these had little effect on the microsphere encapsulation efficiency and drug loading, indicating that within a certain range, changes in PLGA molecular weight are not a limiting factor. However, in Comparative Example 6, when the PLGA was changed to carboxyl-terminated and the molar ratio of lactide to glycolide was 50:50, a significant decrease in encapsulation efficiency and drug loading was observed, indicating that the end-capping groups of PLGA have a significant impact on the preparation of birepiperazole microspheres. In contrast, the scheme using ester-terminated PLGA with a lactide to glycolide molar ratio of 75:25 is more ideal. Furthermore, the use of dimethyl sulfoxide as the organic solvent in Comparative Example 10 resulted in a low encapsulation efficiency, while in Comparative Example 11, due to the limited solubility of birepiperazole in dichloromethane, a large amount of drug leakage occurred during the preparation process, resulting in very few microspheres collected, making effective testing impossible. In contrast, the benzyl alcohol / ethyl acetate solvent system helps to improve the solubility of buripiperazole and achieve higher encapsulation efficiency and drug loading.

[0088] As shown in Table 1, from the perspective of encapsulation efficiency and drug loading, the optimal formulations are those of Examples 1-10, where the encapsulation efficiency of the prepared microspheres is all above 98%, and the drug loading is close to the theoretical drug loading. Among them, Example 9, with microfluidic technology, prepared microspheres with a drug loading ratio of 1:1, can achieve a drug loading of 42% and an encapsulation efficiency of over 98%. Despite a thorough search of relevant literature, patents, and market information, no birepiperazole microsphere product has yet been found that can achieve a drug loading of over 40% while maintaining such a high encapsulation efficiency.

[0089] As shown in Table 1, it was also found that the O / W pre-emulsion prepared using microfluidic technology in Example 4 did not require a stirring process and could be directly solidified to obtain microspheres with an encapsulation rate of over 99%, and the drug loading did not differ significantly from the theoretical drug loading. This method is particularly significant in terms of process simplification, greatly accelerating the production progress while ensuring quality, and is especially suitable for industrial production.

[0090] Test Example 2: Microsphere Particle Size

[0091] Take an appropriate amount of the microspheres prepared in Examples 1-10 and Comparative Examples 1-11, divide them into three portions, disperse them in water, and use a BT-2001 laser particle size analyzer to measure the particle size of the microspheres. The results are shown in Table 2.

[0092] Table 2 Microsphere particle size of different embodiments and comparative examples

[0093] As shown in Table 2, in Examples 6, 8, and 10, when the molecular weight of the polylactic acid-glycolic acid copolymer was relatively small, the microspheres prepared also had smaller particle sizes. Compared to other examples, collecting small-diameter microspheres requires smaller sieves, which easily clogs the sieves, making microsphere washing difficult and inefficient, thus unsuitable for industrial production. When the molecular weight of the polylactic acid-glycolic acid copolymer is above 90 kDa, microspheres with a particle size of 50-80 μm can be prepared using a flow control device, exhibiting uniform particle size and good needle penetration. Furthermore, the microspheres prepared by the direct droplet addition process, when the drug loading ratio was increased to 1:1 and 1:2 (Comparative Example 1 and Comparative Example 9), all had particle sizes greater than 100 μm, making them unsuitable for intramuscular injection. Therefore, from the perspective of particle size, Examples 1-5, 7, and 9 are the preferred formulations.

[0094] Test Example 3: Determination of Microsphere Morphology and Angle of Repose

[0095] Take appropriate amounts of the microspheres prepared in Examples 1 and 4 and Comparative Examples 1 and 2, and determine the morphology of the microspheres using scanning electron microscopy. The results are shown in Figures 1-4.

[0096] Table 3. Measurement of the angle of repose of microspheres in different embodiments and comparative examples.

[0097] The results of the angle of repose show that the birepiperazole microspheres prepared by microfluidic technology have a smaller angle of repose and better flowability.

[0098] Based on the results of scanning electron microscopy and repose angle measurements, the buripiperazole microspheres prepared by microfluidic technology are more spherical, have better flowability, better needle penetration, and are easier to inject.

[0099] Test Example 4: In vitro release rate of microspheres

[0100] Weigh 2g of sodium hydroxide and dissolve it in 500mL of water. Discard 105mL of the solution and add 6.8g of potassium dihydrogen phosphate and 605mL of water to dissolve it together. Then add 2g of hexadecyltrimethylammonium bromide to obtain a PBS solution containing 0.2% hexadecyltrimethylammonium bromide with a release medium of pH 7.4.

[0101] 12 mg of the bripiprazole microspheres prepared in Examples 1-6, 9, 10 and Comparative Example 2 were weighed into 100 mL stoppered conical flasks, and 100 mL of 0.2% hexadecyltrimethylammonium bromide in PBS solution was added. The flasks were placed in a 37°C water bath with a shaking incubator. 1 mL samples were taken at different time points (4 h, 1 d, 3 d, 5 d, 7 d…), centrifuged (8000 rpm, 5 min), and a small portion of the supernatant was collected for analysis. All old release medium for the remaining microspheres was removed, and fresh release medium was used for further sample collection. The samples were analyzed by high-performance liquid chromatography (HPLC), and the cumulative release percentage was calculated. A release rate curve of cumulative release percentage versus time was plotted. The results are shown in Figures 5-7.

[0102] Figure 5 shows that the birepiperazole microspheres can achieve a sustained-release effect of 2 months or more. Examples 1 and 9 show that the greater the drug loading, the faster the release. Examples 3, 4, 6, and 9 indicate that the release rate varies with the stirring time during the formation of the O / W colostrum, which also demonstrates that the release rate can be adjusted by controlling the volatility of the organic solvent. Furthermore, the in vitro release curves of sustained-release microspheres prepared using the same formulation via a dropwise addition process (Comparative Example 2) and a microfluidic process (Example 6) reveal that the formulation using the microfluidic process exhibits a relatively slower release.

[0103] The above embodiments are exemplary and are intended to illustrate the technical concept and features of the present invention, so that those skilled in the art can understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing birepiperazole long-acting microspheres, characterized in that, Includes the following steps: Step (1): Dissolve biriperazole and the biodegradable polymer in an organic solvent at a mass ratio of 1:1 to 1:10 to obtain a drug-containing polymer solution, which is used as the oil phase; Step (2): Dissolve polyvinyl alcohol in water to obtain a first aqueous phase with a concentration of 0.1-1.5%. Using microfluidic technology, mix the oil phase and the first aqueous phase described in step (1) at a volume ratio of 1:1 to 1:

45. The flow rate ratio of the oil phase and the first aqueous phase is 1:1 to 1:

45. After obtaining the primary emulsion, evaporate the organic solvent and control the evaporation ratio to 0-20% to obtain an oil-in-water emulsion. Step (3): The oil-in-water emulsion described in step (2) is added to the second aqueous phase as the curing phase for curing. The volume of the curing phase is 0.05-1.0 L / g microspheres, and the curing time is 2-6 h. After curing, the microspheres are washed and dried to obtain the bripiprazole long-acting microspheres. In step (1), the degradable polymer is polylactic acid-glycolic acid copolymer or polylactic acid; In step (1), the organic solvent that forms the oil phase is a benzyl alcohol-ethyl acetate mixed solvent system.

2. The method for preparing birepiperazole long-acting microspheres according to claim 1, characterized in that, In step (1), bripiprazole is dissolved in benzyl alcohol to obtain a bripiprazole solution; polylactic acid-glycolic acid copolymer or polylactic acid is dissolved in ethyl acetate to obtain a polymer solution; then the bripiprazole solution and the polymer solution are mixed and vortexed to obtain the oil phase.

3. The method for preparing bripiprazole long-acting microspheres according to claim 2, characterized in that, In step (1), the mass concentration of the birepiperazole solution is 2% to 20%; the mass concentration of the degradable polymer solution is 4% to 35%.

4. The method for preparing birepiperazole long-acting microspheres according to claim 2, characterized in that, In step (1), the mixing ratio of bripiprazole solution and polymer solution is controlled so that the mass ratio of bripiprazole to degradable polymer is 1:1 to 1:

5.

5. The method for preparing birepiperazole long-acting microspheres according to claim 1, characterized in that, In step (2), the concentration of the polyvinyl alcohol solution is 0.1% to 1%.

6. The method for preparing birepiperazole long-acting microspheres according to claim 1, characterized in that, In step (2), the oil-in-water emulsion is obtained by pumping the oil phase and the first aqueous phase into a microfluidic reactor for mixing.

7. The method for preparing birepiperazole long-acting microspheres according to claim 6, characterized in that, In step (2), the flow rate ratio of the oil phase and the first aqueous phase in the microfluidic reactor is 1:1 to 1:

20.

8. The method for preparing birepiperazole long-acting microspheres according to claim 1, characterized in that, In step (2), the evaporation rate of organic solvents in the colostrum is controlled to be 0-15%.

9. The method for preparing birepiperazole long-acting microspheres according to claim 1, characterized in that, In step (3), the volume of the solidified phase is 0.1 to 0.5 L / g microspheres.

10. A long-acting biriperazole microsphere, characterized in that, Prepared by the method according to any one of claims 1 to 9.

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