Lumateperone pharmaceutical composition, long-acting microsphere sustained-release formulation and method for preparing same

Abstract

The present invention relates to the field of pharmaceutical formulations. It discloses a composition containing lumateperone as an active ingredient, as well as a long-acting sustained-release formulation and a method for preparing the same. A composition containing lumateperone as an active ingredient capable of achieving a long-acting sustained-release formulation can be obtained by specifically defining pharmaceutical polymer excipient auxiliary materials. By further controlling the preparation process conditions, a long-acting sustained-release formulation containing lumateperone as an active ingredient can be obtained, which satisfies the sustained release of lumateperone for 1 week to 2 months and effectively improves patient compliance compared with common formulations (e.g., capsules). This satisfies the clinical requirement for stable drug release while ensuring drug safety and efficacy.

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical preparations, and relates to an antipsychotic sustained-release pharmaceutical preparation and a preparation method thereof, in particular to a lumateperone pharmaceutical composition, and a long-acting microsphere sustained-release preparation and a preparation method thereof. [Background technology]

[0002] Mental illness generally refers to a mental disorder, specifically a variety of abnormal mental processes, abnormal personality traits, and abnormal behavioral patterns caused by physical, mental, or social reasons. It means that a person is unable to behave in a socially acceptable and appropriate manner, and as a result, their behavior is inappropriate for both themselves and society. Therefore, antipsychotic drugs are often used to treat and alleviate symptoms.

[0003] Representative first-generation antipsychotics include chlorpromazine, perphenazine, haloperidol, and penfluridol. These drugs can effectively alleviate positive symptoms by blocking dopamine receptors, but have little effect on negative symptoms or cognitive impairment. Representative second-generation antipsychotics include risperidone, clozapine, olanzapine, aripiprazole, quetiapine, and ziprasidone. These drugs block dopamine and 5-hydroxytryptamine receptors and are associated with fewer extrapyramidal adverse events than most first-generation drugs. However, most second-generation drugs cause weight gain and impaired glucose and lipid metabolism (obesity). Over the past two years, lumateperone (CAS No. 313368-91-1, also known as ITI-722), a novel antipsychotic with multitarget effects, was introduced and approved for the treatment of adult schizophrenia in the United States in December 2019. Unlike first- and second-generation antipsychotics, it generally targets only two neurotransmitters: 5-hydroxytryptamine and dopamine. Because lumateperone also acts on glutamate neurotransmission, it is effective not only in improving positive symptoms (delusions, hallucinations, behavioral abnormalities, etc.) in schizophrenia patients, but also in negative symptoms (affective blunting, language impairment, and decreased motivation, etc.) and depression. Furthermore, compared to second-generation antipsychotics, lumateperone overcomes the drawbacks of weight gain and impaired glucose and lipid metabolism, reducing the likelihood of weight gain. Research has shown that lumateperone can reduce the risk of weight gain by 13% compared to the currently used antipsychotic, risperidone.

[0004] Currently, one of the major reasons for relapse in antipsychotic medication practice is patients' inability to adhere to regular medication schedules. Clinical trials have confirmed that existing long-acting injectable antipsychotics can significantly reduce patient hospitalization and treatment discontinuation rates compared with oral antipsychotics, making them an important treatment method for preventing relapse. Regular injections reduce the daily burden on patients by eliminating the need to worry about forgetting to take their medication. Furthermore, they effectively protect privacy in daily life and work, eliminating the need for others to know about their medication. Furthermore, they can prevent drug abuse. Currently, second-generation long-acting injectable antipsychotics are used as first-line medications for the acute and maintenance phases of schizophrenia. Second-generation long-acting injectable antipsychotics available on the market in China include risperidone microsphere injections administered once every two weeks, paliperidone palmitate injections administered once a month, and paliperidone palmitate injections administered once every three months. Development of a long-acting sustained-release formulation of lumateperone is still in its early stages.

[0005] Prior art CN113473988A and CN114072150A disclose that lumateperone, in free form or in the form of a pharmaceutically acceptable salt, can be administered by any suitable route, including orally, parenterally, transdermally, or transmucosally, for example, in the form of a tablet, capsule, subcutaneous injection, long-acting injection, or an orally rapidly disintegrating tablet or film for sublingual or buccal administration. Regarding dosage and efficacy, the FDA's instructions stipulate that the optimal oral dosage is 42 mg / day without dose escalation, and strict design requirements are imposed on lumateperone long-acting sustained-release injections: they must have minimal burst release and stable, uniform release characteristics, which is one of the biggest challenges for current lumateperone long-acting sustained-release injections. Currently, there are no patents or publications disclosing an effective method for preparing lumateperone sustained-release injections.

[0006] Therefore, there is an urgent need to develop a long-acting formulation of lumateperone that minimizes burst release, provides stable release, and maximizes the clinical advantages of lumateperone in the field of antipsychotic drugs (overcoming the drawbacks of weight gain and glucose and lipid metabolism disorders, improving safety, and at the same time improving positive and negative symptoms (blunted affect, language impairment, decreased willpower, etc.) and depressive symptoms in schizophrenic patients). Summary of the Invention

[0007] To overcome the shortcomings of the prior art, a lumateperone pharmaceutical composition, a long-acting microsphere sustained-release formulation, and a preparation method thereof are provided. In this technical solution, a long-acting lumateperone pharmaceutical composition is obtained by specifically limiting the pharmaceutical polymer excipients; and a long-acting microsphere sustained-release formulation is obtained by further controlling the preparation process conditions, thereby achieving a sustained release of lumateperone for 1 week to 2 months. Compared with common formulations (e.g., capsules), this effectively improves patient compliance, ensures stable release of the formulation, and satisfies the safety and efficacy of the drug.

[0008] To achieve the above technical objectives, the following technical solutions are provided:

[0009] In a first aspect, the present invention provides a lumateperone pharmaceutical composition comprising a lumateperone active ingredient and a pharmaceutical polymeric excipient in a mass ratio of 1:(1.5-19); wherein the pharmaceutical polymeric excipient has a weight average molecular weight (M W ) comprises a glycolide-lactide copolymer (PLGA) of 5,000 to 120,000 daltons; and in the glycolide-lactide copolymer, the molar ratio of lactic acid units to glycolic acid units is 95:5 to 50:50. According to the present invention, the sustained-release period is adjusted by effectively controlling the degradation rate of the glycolide-lactide copolymer, and the lumateperone pharmaceutical composition of the present invention has the desired sustained-release effect.

[0010] Additionally, the lumateperone active ingredient includes lumateperone free base and its available salt forms (eg, lumateperone p-toluenesulfonate).

[0011] Preferably, the glycolide-lactide copolymer has a weight average molecular weight (M) of 5,000 to 80,000 daltons. W ), and more preferably the glycolide-lactide copolymer has a weight average molecular weight (M) of 40,000 to 80,000 daltons, for example 60,000 to 80,000 daltons. W )

[0012] Preferably, in the glycolide-lactide copolymer, the molar ratio of lactic acid units to glycolic acid units is 85:15 to 50:50; more preferably, the molar ratio of lactic acid units to glycolic acid units is 85:15 to 75:25.

[0013] Preferably, the mass ratio of the lumateperone active ingredient to the pharmaceutical polymeric excipient is 1:(1.5-10); for example, 1:(1.5-9), 1:(2-8), 1:(2-6) or 1:(3-5), more specifically, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 or 1:9.

[0014] In a second aspect, the present invention provides a long-acting sustained-release formulation comprising a lumateperone active ingredient and a pharmaceutical polymeric excipient, wherein the lumateperone active ingredient accounts for 5-40% of the total mass of the long-acting sustained-release formulation, and the pharmaceutical polymeric excipient accounts for 60-95% of the total mass of the long-acting sustained-release formulation; wherein the pharmaceutical polymeric excipient comprises a glycolide-lactide copolymer having a weight-average molecular weight of 5,000-120,000 daltons; and wherein the molar ratio of lactic acid units to glycolic acid units in the glycolide-lactide copolymer is 95:5-50:50.

[0015] Additionally, the lumateperone active ingredient includes lumateperone free base and its available salt forms (eg, lumateperone p-toluenesulfonate).

[0016] Preferably, the glycolide-lactide copolymer has a weight average molecular weight (M) of 5,000 to 80,000 daltons. W ), and more preferably the glycolide-lactide copolymer has a weight average molecular weight (M) of 40,000 to 80,000 daltons, for example 60,000 to 80,000 daltons. W )

[0017] Preferably, in the glycolide-lactide copolymer, the molar ratio of lactic acid units to glycolic acid units is 85:15 to 50:50; more preferably, the molar ratio of lactic acid units to glycolic acid units is 85:15 to 75:25.

[0018] Preferably, the mass ratio of the lumateperone active ingredient to the pharmaceutical polymer excipient is 1:(1.5-10); more preferably, the mass ratio of the lumateperone active ingredient to the pharmaceutical polymer excipient is 1:(1.5-10); for example, 1:(1.5-9), 1:(2-8), 1:(2-6) or 1:(3-5), more specifically, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 or 1:9.

[0019] Furthermore, the long-acting sustained-release formulation is a long-acting sustained-release microsphere formulation. The long-acting sustained-release microsphere formulation comprises spherical granules and irregular granules having a particle size of 1 to 1,000 μm. Preferably, the long-acting sustained-release microgranule formulation is prepared by a microfluidic method or a homogeneous emulsification method and is a spherical granule having a particle size of 20 to 200 μm, i.e., a long-acting microsphere sustained-release formulation.

[0020] For long-acting microsphere sustained-release formulations, the drug loading of the lumateperone active ingredient can be 5-40%. More precisely, the drug loading of the lumateperone active ingredient is 10-30%.

[0021] In a third aspect, the present invention provides a method for preparing a long-acting microsphere sustained-release formulation, which employs a homogeneous emulsification technique and specifically includes the steps of: A1. Preparation of oil phase: Dissolve lumateperone active ingredient and pharmaceutical polymer excipients in an organic solvent to obtain an oil phase for later use; B1. Preparation of aqueous phase: dissolving surfactant in water to obtain aqueous phase for later use; C1. Emulsification: A certain amount of the aqueous phase obtained in step B1 is taken as external aqueous phase I; high-speed shearing is started, and the oil phase obtained in step A1 is added to external aqueous phase I, and the shearing is continued to obtain an incompletely solidified emulsion or suspension; D1. Solvent evaporation: A certain amount of the aqueous phase obtained in step B1 is designated as external aqueous phase II; stirring is started, and the incompletely solidified emulsion or suspension obtained in step C1 is added to external aqueous phase II, and stirring is continued until the solvent evaporation is completed to obtain coarse microspheres; and E1. Post-treatment: Washing the crude microspheres obtained in step D1 with pure water, sieving, collecting and drying the microspheres to obtain a long-acting microsphere sustained-release formulation.

[0022] Preferably, the method comprises the steps of: A1. Preparation of oil phase: Dissolve lumateperone active ingredient (active drug) and pharmaceutical polymer excipient (molecular framework) in an organic solvent, and then completely dissolve the lumateperone active ingredient and pharmaceutical polymer excipient by stirring, vortexing, ultrasonic treatment, etc. to obtain a transparent solution, i.e., oil phase, and temporarily store this oil phase at a temperature of 4-10°C for later use; B1. Preparation of aqueous phase: dissolving surfactant in water to obtain aqueous phase, and temporarily storing this aqueous phase at a temperature of 4-10°C for later use; C1. Emulsification: A certain amount of the aqueous phase obtained in step B1 is designated as external aqueous phase I (W1); start a homogenizing emulsifier for high-speed shearing (for example, at a speed of 1,000 to 3,000 rpm), and slowly add the oil phase obtained in step A1 to the external aqueous phase I at a constant speed, and continuously shear until an incompletely solidified emulsion or suspension is obtained; D1. Solvent evaporation: A certain amount of the aqueous phase obtained in step B1 is designated as external aqueous phase II (W2); start stirring (for example, at a rotation speed of 50 to 1,000 rpm), add the incompletely solidified emulsion or suspension obtained in step C1 to external aqueous phase II, and continue stirring at a temperature of T1 until the solvent evaporation is completed to obtain coarse microspheres; and E1. Post-treatment: Washing the crude microspheres obtained in step D1 with pure water, sieving, collecting and drying to obtain a long-acting microsphere sustained-release formulation.

[0023] According to the design purpose, the mass percentage of the lumateperone active ingredient in the oil phase can be 2-15%, and the concentration of the pharmaceutical polymer excipient in the oil phase can be 5-25%. The mass percentage of the surfactant in the aqueous phase is 0.5-5%; preferably, the mass percentage of the surfactant in the aqueous phase is 0.5-2%.

[0024] Preferably, in step A1, the organic solvent comprises one or a mixture of two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, trichloromethane, diethyl ether, benzyl alcohol, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0025] Preferably, in step B1, the surfactant comprises one or a mixture of two or more of Pluronic F-127, sodium dodecyl sulfonate, sodium dodecyl sulfate, and polyvinyl alcohol (PVA).

[0026] Preferably, in step C1, the volume ratio of the oil phase to the external aqueous phase I is 1:5 to 1:50. More preferably, the volume ratio of the oil phase to the external aqueous phase I is 1:10 to 1:20.

[0027] Preferably, in step D1, the volume ratio of the oil phase to the external aqueous phase II is 1:10 to 1:200, more preferably 1:10 to 1:100.

[0028] Preferably, step D1 is carried out at a temperature T1 of 0 to 40°C, where T1 may be a constant temperature or a temperature gradient within this range. More preferably, T1 is 3 to 30°C.

[0029] In a fourth aspect, the present invention provides a method for preparing a long-acting microsphere sustained release formulation, which employs microfluidic technology and specifically comprises the steps of: A2. Preparation of oil phase: dissolving lumateperone active ingredient and pharmaceutical polymer excipients in an organic solvent to obtain an oil phase for later use; B2. Preparation of aqueous phase: dissolving surfactant in water to obtain aqueous phase for later use; C2. Using a syringe pump, the oil phase obtained in step A2 and a portion of the aqueous phase obtained in step B2 are injected into a microfluidic device while controlling the flow rates of the oil phase and the aqueous phase, to finally obtain an oil-in-water emulsion, which is collected in a receiver containing a portion of the aqueous phase obtained in step B2, and temporarily stored to obtain semi-solid microspheres; D2. Solvent evaporation: The semi-solid microspheres obtained in step C2 are transferred from the receiver to an evaporator and continuously stirred until the solvent evaporation is completed to obtain completely solidified microspheres; and E2. Post-treatment: Washing the completely solidified microspheres obtained in step D2 with pure water, sieving, collecting and drying the microspheres to obtain a long-acting microsphere sustained-release formulation.

[0030] Preferably, the method comprises the steps of: A2. Preparation of oil phase: Dissolve lumateperone active ingredient (active drug) and pharmaceutical polymer excipient (molecular framework) in an organic solvent, and then completely dissolve the lumateperone active ingredient and pharmaceutical polymer excipient by stirring, vortexing, ultrasonic treatment, etc. to form a transparent solution, i.e., oil phase, and temporarily store this oil phase at a temperature of 4-10°C for later use; B2. Preparation of aqueous phase: dissolving surfactant in water to obtain aqueous phase, and temporarily storing this aqueous phase at 4-10°C for later use; C2. Using a syringe pump, the oil phase (i.e., dispersed phase) obtained in step A2 and a portion of the aqueous phase (i.e., continuous phase) obtained in step B2 are injected into a microfluidic device while controlling the flow rates of the oil phase and the aqueous phase, to finally obtain an oil-in-water emulsion, which is collected in a receiver containing a portion of the aqueous phase obtained in step B2, thereby obtaining semi-solidified microspheres; D2. Solvent evaporation: The semi-solidified microspheres obtained in step C2 are transferred from the receiver to an evaporator and continuously stirred at a temperature T2 until the solvent evaporation is completed to obtain completely solidified microspheres; and E2. Post-treatment: Washing the completely solidified microspheres obtained in step D2 with pure water, sieving, collecting and drying the microspheres to obtain a long-acting microsphere sustained-release formulation.

[0031] According to the design objective, the mass percentage of the lumateperone active ingredient in the oil phase is 2-15%, the concentration (mass percentage) of the pharmaceutical polymer excipient in the oil phase is 5-25%, and the mass percentage of the surfactant in the aqueous phase is 0.5-5%; preferably, the mass percentage of the surfactant in the aqueous phase is 0.5-2%.

[0032] Preferably, in step A2, the organic solvent comprises one or a mixture of two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, trichloromethane, diethyl ether, benzyl alcohol, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0033] Preferably, in step B2, the surfactant comprises one or a mixture of two or more of Pluronic F-127, sodium dodecyl sulfonate, sodium dodecyl sulfate, and polyvinyl alcohol (PVA).

[0034] Preferably, in step C2, the temperature in the microfluidic device is controlled between 4 and 10° C. to ensure effective formation of the oil-in-water emulsion and subsequent formation of semi-solid microspheres in the receiver.

[0035] Preferably, in step C2, the flow rate ratio between the oil phase and the aqueous phase is controlled to be 1:2 to 1:200, more preferably 1:10 to 1:100.

[0036] Preferably, step D2 is carried out at a temperature T2 of 3 to 40°C, where T2 may be a constant temperature or a temperature gradient within this range. More preferably, T2 is 3 to 35°C.

[0037] The terms used in this invention include the following:

[0038] Lumateperone active ingredient: refers to lumateperone free base or its available salt forms.

[0039] Available Salt Forms: refers to pharmaceutically acceptable salts of lumateperone free base, including, but not limited to, hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, citrate, acetate, oxalate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts.

[0040] Drug loading: refers to the amount of drug loaded per unit mass or volume of a microsphere, and the amount of drug that can be released is considered to be the effective drug loading. Unless the drug is irreversibly bound to the matrix, drug loading can be considered as the drug content of the microsphere.

[0041] Encapsulation efficiency: refers to the proportion of encapsulated material (e.g., drug) in the total formulation, and reflects the degree to which the drug is encapsulated by the carrier.

[0042] The present invention has the following beneficial technical effects: 1. According to the present invention, a lumateperone pharmaceutical composition can be obtained by specifically limiting the pharmaceutical polymer excipients; and by further controlling the preparation process conditions, a long-acting sustained-release formulation, particularly a long-acting sustained-release microsphere, can be obtained, achieving a sustained release of lumateperone for 1 week to 2 months. Compared with common formulations (e.g., capsules), this effectively improves patient compliance, ensures stable release of the formulation, and satisfies the safety and efficacy of the drug. 2. The present invention provides a method for preparing long-acting microsphere sustained-release formulations based on homogeneous emulsification technology. Compared with conventional oral formulations, the prepared long-acting microsphere sustained-release formulations achieve stable sustained release for 1 week to 2 months, effectively improving patient compliance and clinical efficacy. 3. Microspheres with uniform size and good morphology are prepared using microfluidic technology. By controlling the flow rate ratio between the oil and aqueous phases and the conditions in the microfluidic device, the release of microfluidic lumateperone microspheres approaches zero-order kinetics and remains stable, thereby meeting the requirements for drug safety and efficacy. This approach effectively addresses the issue of unstable release observed with homogeneous emulsion microspheres. [Brief explanation of the drawings]

[0043] [Figure 1] FIG. 1 is a schematic diagram of the structure of the lumateperone long-acting sustained-release microspheres of the present invention (left: lumateperone long-acting sustained-release microspheres prepared by the microfluidic method; right: lumateperone long-acting sustained-release microspheres prepared by the homogeneous emulsification method). [Figure 2]FIG. 2 shows the results of an in vitro release test of the lumateperone long-acting sustained-release microspheres obtained in Examples 2 to 4. [Figure 3] FIG. 3 shows the results of an in vitro release test of the lumateperone long-acting sustained-release microspheres obtained in Examples 5 to 7. [Figure 4] FIG. 4 shows the results of an in vitro release test of the lumateperone long-acting sustained-release microspheres obtained in Examples 8 to 10. [Figure 5] FIG. 5 is a scanning electron microscope (SEM) image of the lumateperone long-acting sustained-release microspheres obtained in Example 17. [Figure 6] FIG. 6 is a cross-sectional SEM image of the lumateperone long-acting sustained-release microspheres obtained in Example 17. [Figure 7] FIG. 7 shows the in vivo release results of lumateperone long-acting sustained-release microspheres obtained in Examples 14, 15, 17 and 18 in mice. [Figure 8] FIG. 8 shows the in vivo release results of lumateperone long-acting sustained-release microspheres obtained in Examples 16 and 19-21 in mice. [Example]

[0044] The present invention will be further described by the following examples. The examples of the present invention are only used to explain the technical solutions of the present invention, and are not used to limit the scope of the present invention. Without violating the spirit of the present invention, those skilled in the art can make insubstantial improvements and adjustments, which also fall within the protection scope of the present invention.

[0045] Example 1 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 95:5, molecular weight 78,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a transparent oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt% aqueous solution of polyvinyl acetate (PVA) was prepared as the aqueous phase and stored at 10°C for later use; 3) 90 mL of the aqueous phase was used as the external aqueous phase I, and high-speed shearing was started using a homogenizer and emulsifier, with the rotation speed controlled at 2,000 rpm. The oil phase was transferred to a 20 mL syringe and injected into the external aqueous phase I at a constant speed (0.3 mL / s) using a syringe pump for approximately 30 seconds. The mixture was continuously sheared for 180 seconds, and a suspension was obtained after emulsification was completed. 4) 540 mL of the aqueous phase was designated as the external aqueous phase II, and stirring was initiated; the suspension obtained in step 3) was poured into the external aqueous phase II, and the mixture was continuously stirred at 4°C for 2 hours and evaporated, after which the temperature was raised to 25°C, and the mixture was continuously stirred for 2 hours and evaporated to obtain microspheres; and 5) The microspheres obtained in step 4) were filtered through a sieve, washed, collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0046] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, and in vitro release studies with the obtained lumateperone long-acting sustained-release microspheres showed an actual microsphere drug loading of 16.34% and an encapsulation efficiency of 81.7%.

[0047] Example 2 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 50:50, molecular weight 61,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) 90 mL of the aqueous phase was used as the external aqueous phase I, and high-speed shearing was started using a homogenizer and emulsifier, with the rotation speed controlled at 2,000 rpm. The oil phase was transferred to a 20 mL syringe and injected into the external aqueous phase I at a constant speed (0.3 mL / s) using a syringe pump for approximately 30 seconds. The mixture was continuously sheared for 180 seconds, and a suspension was obtained after emulsification was completed. 4) 540 mL of the aqueous phase was designated as the external aqueous phase II, and stirring was initiated; the suspension obtained in step 3) was poured into the external aqueous phase II, and the mixture was continuously stirred at 4°C for 2 hours and evaporated, after which the temperature was raised to 25°C, and the mixture was continuously stirred for 2 hours and evaporated to obtain microspheres; and 5) The microspheres obtained in step 4) were filtered through a sieve, washed, collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0048] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, and in vitro release studies with the obtained lumateperone long-acting sustained-release microspheres showed an actual drug loading of 16.02% and an encapsulation efficiency of 80.1%.

[0049] Example 3 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 74,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) 90 mL of the aqueous phase was used as the external aqueous phase I, and high-speed shearing was started using a homogenizer and emulsifier, with the rotation speed controlled at 2,000 rpm. The oil phase was transferred to a 20 mL syringe and injected into the external aqueous phase I at a constant speed (0.3 mL / s) using a syringe pump for approximately 30 seconds. The mixture was continuously sheared for 180 seconds, and a suspension was obtained after emulsification was completed. 4) 540 mL of the aqueous phase was designated as the external aqueous phase II, and stirring was initiated; the suspension obtained in step 3) was poured into the external aqueous phase II, and the mixture was continuously stirred at 10°C for 2 hours and evaporated, after which the temperature was raised to 25°C, and the mixture was continuously stirred for 2 hours and evaporated to obtain microspheres; and 5) The microspheres obtained in step 4) were filtered through a sieve, washed, collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0050] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 16.46%, and the encapsulation efficiency was 82.3%. The results of the in vitro release study on lumateperone long-acting sustained-release microspheres are shown in Figure 2.

[0051] Example 4 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 85:15, molecular weight 72,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oily solution, which was then stored at 10°C for later use; 2) A 0.5 wt PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) 90 mL of the aqueous phase was used as the external aqueous phase I, and the homogenizer and emulsifier were started, controlling the rotation speed at 2,000 rpm; the oil phase was transferred to a 20 mL syringe and injected into the external aqueous phase I at a constant speed (0.3 mL / s) using a syringe pump for approximately 30 seconds; the mixture was continuously sheared for 180 seconds, and a suspension was obtained after emulsification was completed; 4) 540 mL of the aqueous phase was designated as the external aqueous phase II, and stirring was initiated; the suspension obtained in step 3) was poured into the external aqueous phase II, and the mixture was continuously stirred at 10°C for 2 hours and evaporated, after which the temperature was raised to 25°C, and the mixture was continuously stirred for 2 hours and evaporated to obtain microspheres; and 5) The microspheres obtained in step 4) were filtered through a sieve, washed, collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0052] The theoretical drug loading of the lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 16.69%, and the encapsulation efficiency was 83.4%. The results of the in vitro release test of the obtained lumateperone long-acting sustained-release microspheres are shown in Figure 2.

[0053] Example 5 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using microfluidic technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 50:50, molecular weight 61,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) The oil phase (dispersed phase) and the aqueous phase (continuous phase) were each injected into the microfluidic device using a syringe pump. The flow rates were set at 100 μL / h for the oil phase and 2,000 μL / h for the aqueous phase. Within the microfluidic device, the continuous phase sheared the dispersed phase, forming an oil-in-water emulsion. The semi-solidified microspheres were collected from this emulsion and subsequently placed into a receiver containing the aqueous phase. The temperature was carefully maintained at 10°C throughout the entire process; 4) After the receiver is full, the semi-solidified microspheres obtained in step 3) are transferred to an evaporator and stirring is started; a temperature control program (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours) is started to evaporate and remove the organic solvent, thereby obtaining completely solidified microspheres; and 5) The completely solidified microspheres obtained in step 4) were washed with purified water, filtered, and the completed wet microspheres were collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0054] The theoretical drug loading of the lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 18.75%, and the encapsulation efficiency was 93.7%. The results of the in vitro release test of the obtained lumateperone long-acting sustained-release microspheres are shown in Figure 3.

[0055] Example 6 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using microfluidic technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 74,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) The oil phase (dispersed phase) and the aqueous phase (continuous phase) were each injected into the microfluidic device using a syringe pump. The flow rates were set at 100 μL / h for the oil phase and 2,000 μL / h for the aqueous phase. Within the microfluidic device, the continuous phase sheared the dispersed phase, forming an oil-in-water emulsion. The semi-solidified microspheres were collected from this emulsion and subsequently placed into a receiver containing the aqueous phase. The temperature was carefully maintained at 10°C throughout the entire process; 4) After the receiver is full, the semi-solidified microspheres obtained in step 3) are transferred to an evaporator and stirring is started; a temperature control program (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours) is started to evaporate and remove the organic solvent, thereby obtaining completely solidified microspheres; and 5) The completely solidified microspheres obtained in step 4) were washed with purified water, filtered, and the completed wet microspheres were collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0056] The theoretical drug loading of the lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 19.30%, and the encapsulation efficiency was 96.5%. The results of the in vitro release test of the obtained lumateperone long-acting sustained-release microspheres are shown in Figure 3.

[0057] Example 7 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using microfluidic technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 85:15, molecular weight 72,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oily solution, which was then stored at 10°C for later use; 2) A 0.5 wt PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) The oil phase (dispersed phase) and the aqueous phase (continuous phase) were each injected into the microfluidic device using a syringe pump. The flow rates were set at 100 μL / h for the oil phase and 2,000 μL / h for the aqueous phase. Within the microfluidic device, the continuous phase sheared the dispersed phase, forming an oil-in-water emulsion. The semi-solidified microspheres were collected from this emulsion and subsequently placed into a receiver containing the aqueous phase. The temperature was carefully maintained at 10°C throughout the entire process; 4) After the receiver is full, the semi-solidified microspheres obtained in step 3) are transferred to an evaporator and stirring is started; a temperature control program (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours) is started to evaporate and remove the organic solvent, thereby obtaining completely solidified microspheres; and 5) The completely solidified microspheres obtained in step 4) were washed with purified water, filtered, and the completed wet microspheres were collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0058] The theoretical drug loading of the lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 18.98%, and the encapsulation efficiency was 94.9%. The results of the in vitro release test of the obtained lumateperone long-acting sustained-release microspheres are shown in Figure 3.

[0059] Example 8 In this example, lumateperone long-acting sustained-release microspheres were prepared in the same manner as in Example 3, except that ester-terminated PLGA with a molecular weight of 74,000 was selected and a homogeneous emulsification technique was used. This technical solution was used for further examples of screening the end groups of PLGA.

[0060] The theoretical drug loading of the lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 18.92%, and the encapsulation efficiency was 94.6%. The results of the in vitro release test of the obtained lumateperone long-acting sustained-release microspheres are shown in Figure 4.

[0061] Example 9 In this example, lumateperone long-acting sustained-release microspheres were prepared in the same manner as in Example 3, except that PLGA with a molecular weight of 49,000 was selected and homogeneous emulsification technology was used. This technical solution was used for further examples of screening low molecular weight PLGA.

[0062] The theoretical drug loading of the lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 19.42%, and the encapsulation efficiency was 97.1%. The results of the in vitro release test of the obtained lumateperone long-acting sustained-release microspheres are shown in Figure 4.

[0063] Example 10 In this example, lumateperone long-acting sustained-release microspheres were prepared in the same manner as in Example 3, except that PLGA with a molecular weight of 116,000 was selected and homogeneous emulsification technology was used. This technical solution was used for further examples of screening for high molecular weight PLGA.

[0064] The theoretical drug loading of the lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 18.04%, and the encapsulation efficiency was 90.2%. The results of the in vitro release test of the obtained lumateperone long-acting sustained-release microspheres are shown in Figure 4.

[0065] Example 11 In this example, lumateperone long-acting sustained-release microspheres were prepared in the same manner as in Example 3, except that the lumateperone dosage was 0.11 g and homogeneous emulsification technology was used. This technical solution was used for further examples of screening low dosages of lumateperone.

[0066] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.11 / (0.11+2.08)=5%, the actual drug loading was 4.76%, and the encapsulation efficiency was 95.2%.

[0067] Example 12 In this example, lumateperone long-acting sustained-release microspheres were prepared in the same manner as in Example 3, except that the lumateperone dosage was 1.39 g and homogeneous emulsification technology was used. This technical solution was used for further examples of screening for high dosages of lumateperone.

[0068] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 1.39 / (1.39+2.08)=40%, the actual drug loading was 30.48%, and the encapsulation efficiency was 76.2%.

[0069] Example 13 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 95:5, molecular weight 42,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt% PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) 90 mL of the aqueous phase was used as the external aqueous phase I, and high-speed shearing was started using a homogenizer and emulsifier, with the rotation speed controlled at 1,500 rpm; the oil phase was transferred to a 10 mL syringe and injected into the external aqueous phase I at a constant speed (0.3 mL / s) using a syringe pump for approximately 30 seconds; the mixture was continuously sheared for 180 seconds, and after emulsification was completed, a crude emulsion was obtained; 4) 540 mL of the aqueous phase was designated as the external aqueous phase II, and stirring was initiated; the crude emulsion obtained in step 3) was poured into the external aqueous phase II, and the mixture was continuously stirred at 4°C for 2 hours and evaporated, after which the temperature was raised to 25°C, and the mixture was continuously stirred for 2 hours and evaporated to obtain microspheres; and 5) The microspheres obtained in step 4) were filtered through a sieve, washed, collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0070] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 16.61%, the encapsulation efficiency was 83.05%, the particle size was 65.590 μm, and the span was 0.776.

[0071] Example 14 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 50:50, molecular weight 28,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt% PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) 90 mL of the aqueous phase was used as the external aqueous phase I, and high-speed shearing was started using a homogenizer and emulsifier, with the rotation speed controlled at 2,000 rpm. The oil phase was transferred to a 10 mL syringe and injected into the external aqueous phase I at a constant speed (0.3 mL / s) using a syringe pump for approximately 30 seconds. The mixture was continuously sheared for 180 seconds, and a suspension was obtained after emulsification was completed. 4) 540 mL of the aqueous phase was designated as the external aqueous phase II, and stirring was initiated; the suspension obtained in step 3) was poured into the external aqueous phase II, and the mixture was continuously stirred at 4°C for 2 hours and evaporated, after which the temperature was raised to 25°C, and the mixture was continuously stirred for 2 hours and evaporated to obtain microspheres; and 5) The microspheres obtained in step 4) were filtered through a sieve, washed, collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0072] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 17.89%, and the encapsulation efficiency was 89.45%.

[0073] Example 15 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 74,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt% PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) 90 mL of the aqueous phase was used as the external aqueous phase I, and the homogenizer and emulsifier were started, controlling the rotation speed at 2,000 rpm; the oil phase was transferred to a 10 mL syringe and injected into the external aqueous phase I at a constant speed (0.3 mL / s) using a syringe pump for approximately 30 seconds; the mixture was continuously sheared for 180 seconds, and a suspension was obtained after emulsification was completed; 4) 540 mL of the aqueous phase was designated as the external aqueous phase II, and stirring was initiated; the suspension obtained in step 3) was poured into the external aqueous phase II, and the mixture was continuously stirred at 10°C and evaporated, after which the temperature was raised to 25°C, and the mixture was continuously stirred and evaporated to obtain microspheres; and 5) The microspheres obtained in step 4) were filtered through a sieve, washed, collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0074] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 17.09%, and the encapsulation efficiency was 85.47%.

[0075] Example 16 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 85:15, molecular weight 42,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt% PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) 90 mL of the aqueous phase was used as the external aqueous phase I, and high-speed shearing was started using a homogenizer and emulsifier, with the rotation speed controlled at 2,000 rpm. The oil phase was transferred to a 10 mL syringe and injected into the external aqueous phase I at a constant speed (0.3 mL / s) using a syringe pump for approximately 30 seconds. The mixture was continuously sheared for 180 seconds, and a suspension was obtained after emulsification was completed. 4) 540 mL of the aqueous phase was designated as the external aqueous phase II, and stirring was initiated; the suspension obtained in step 3) was poured into the external aqueous phase II, and the mixture was continuously stirred at 10°C for 2 hours and evaporated, after which the temperature was raised to 25°C, and the mixture was continuously stirred for 2 hours and evaporated to obtain microspheres; and 5) The microspheres obtained in step 4) were filtered through a sieve, washed, collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0076] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 17.65%, and the encapsulation efficiency was 88.26%.

[0077] Example 17 In this example, long-acting sustained-release microspheres containing lumateperone were prepared using homogeneous emulsification technology. The preparation method includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 51,000, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oil phase solution, which was stored at 10°C for later use; 2) A 0.5 wt% PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) The oil phase (dispersed phase) and the aqueous phase (continuous phase) were injected into the emulsification device using a syringe pump. The flow rates were set at 18 mL / min for the oil phase and 540 mL / min for the aqueous phase. The oil phase was sheared using an online shearing machine that also served as the emulsification device to obtain a crude emulsion. 4) The crude emulsion obtained in step 3) was transferred to an evaporator and stirring was started; and a temperature control program (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours) was started to remove the organic solvent by evaporation, and completely solidified microspheres were obtained; and 5) The completely solidified microspheres obtained in step 4) were washed with purified water, filtered, and the completed wet microspheres were collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0078] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 17.51%, and the encapsulation efficiency was 87.53%.

[0079] Example 18 In this example, a method for preparing long-acting sustained-release microspheres containing lumateperone active ingredient by applying homogeneous emulsification technology is provided, which includes the following steps: 1) 0.52 g of lumateperone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 27,500, carboxyl-terminated type) were weighed and dissolved in 11.8 g of dichloromethane to obtain a clear oily solution, which was then stored at 10°C for later use; 2) A 0.5 wt PVA aqueous solution was prepared as the aqueous phase and stored at 10°C for later use; 3) The oil phase (dispersed phase) and the aqueous phase (continuous phase) were injected into the emulsification device using a syringe pump. The flow rates were set at 18 mL / min for the oil phase and 540 mL / min for the aqueous phase. The oil phase was sheared using an online shearing machine that also served as the emulsification device to obtain a crude emulsion. 4) The crude emulsion obtained in step 3) was transferred to an evaporator and stirring was started; and a temperature control program (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours) was started to remove the organic solvent by evaporation, and completely solidified microspheres were obtained; and 5) The completely solidified microspheres obtained in step 4) were washed with purified water, filtered, and the completed wet microspheres were collected and dried to obtain the final microsphere product, i.e., lumateperone long-acting sustained-release microspheres.

[0080] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.52 / (0.52+2.08)=20%, the actual drug loading was 18.18%, and the encapsulation efficiency was 90.89%.

[0081] Example 19 In this example, lumateperone long-acting sustained-release microspheres were prepared in the same manner as in Example 15, except that ester-terminated PLGA (LA:GA=85:15) with a molecular weight of 41,000 was selected and 0.26 g of lumateperone and 2.34 g of PLGA were weighed out.

[0082] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.26 / (0.26+2.34)=10%, the actual drug loading was 9.06%, and the encapsulation efficiency was 90.6%.

[0083] Example 20 In this example, lumateperone long-acting sustained-release microspheres were prepared in the same manner as in Example 15, except that ester-terminated PLGA (LA:GA=85:15) with a molecular weight of 103,000 was selected, 0.13 g of lumateperone and 2.47 g of PLGA were weighed, and homogenization and emulsification techniques were employed.

[0084] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 0.13 / (0.13+2.47)=5%, the actual drug loading was 4.585%, and the encapsulation efficiency was 91.7%.

[0085] Example 21 In this example, lumateperone long-acting sustained-release microspheres were prepared in the same manner as in Example 15, except that ester-terminated PLGA (LA:GA=85:15) with a molecular weight of 43,000 was selected, 1.04 g of lumateperone and 1.56 g of PLGA were weighed, and a homogeneous emulsification technique was employed.

[0086] The theoretical drug loading of lumateperone long-acting sustained-release microspheres was 1.04 / (1.04+1.56)=40%, the actual drug loading was 31.28%, and the encapsulation efficiency was 78.2%.

[0087] Example 22 The drying procedures for Examples 1 to 21 can be freeze-drying or vacuum drying, and the freeze-drying procedures are shown in Table 1.

[0088] [Table 1]

[0089] Test Example 1 In this test example, the lumateperone long-acting sustained-release microspheres prepared in Examples 1 to 12 were subjected to in vitro release tests [as prescribed by the Chinese Pharmacopoeia (page 473)], which specifically include the following, to further illustrate the present invention: 1. A 0.01 mol / L physiological isotonic phosphate buffer solution (pH 7.4, containing 0.05% poloxamer and 0.05% sodium azide) was prepared; 2. The lumateperone long-acting sustained-release microspheres prepared in Examples 1 to 12 were accurately weighed and placed in a test tube, and 30 mL of physiological isotonic phosphate buffer solution was added. The test tube was then placed in a thermostatic shaker at 37°C and incubated; 3. Samples were taken and filtered, and the active drug content in the sample solution medium was determined by HPLC-UV detection method.

[0090] Conclusion: 1) As demonstrated in the examples of the present invention, due to the inherent properties of microfluidic technology (both drug and excipients form microspheres within the microchannels), loss of active drug is minimal, except for dissolution losses and minor losses. As a result, the microfluidic method provides higher encapsulation efficiency compared to the homogeneous emulsification method when preparing lumateperone long-acting sustained-release microspheres.

[0091] 2) From Figures 2-4, it is clear that the homogeneous emulsification method and microfluidic method described in this invention can be used to prepare lumateperone long-acting sustained-release microspheres that release over a period of 1 to 6 weeks. Microspheres prepared by the microfluidic method exhibit uniform size, good morphology (as shown in Figure 1), minimal burst release, and a stable release profile. By controlling the process conditions, lumateperone long-acting sustained-release microsphere formulations with reduced burst release and stable release can be achieved.

[0092] 3) Figure 4 shows that there is little difference between using ester-terminated PLGA and carboxyl-terminated PLGA in the preparation process of lumateperone long-acting sustained-release microspheres, and that the molecular weight of PLGA has a significant effect on release. By specifically limiting the molecular weight of PLGA, the sustained-release period and release curve of lumateperone long-acting sustained-release microspheres can be adjusted, ultimately resulting in the preparation of microsphere formulations that meet clinical requirements.

[0093] 4) In a screening experiment using a high dose (theoretical drug loading: 40%) and a low dose (theoretical drug loading: 5%) of the active ingredient lumateperone, it was found that although a high encapsulation efficiency could be achieved at a low dose, the PLGA content in the formulation was too high, which increased the total amount of solids in clinical practice and could cause pain; and that a high dose had a negative effect on the formulation, reduced encapsulation efficiency, and affected the release behavior to some extent.

[0094] Test Example 2 Lumateperone microspheres from Examples 14 to 21 were selected for animal experiments. Several male rats weighing approximately 250 g were selected and randomly divided into groups of five rats each. The samples were homogeneously mixed with a solvent (0.5% CMC-Na, 0.1% Tween-20, 0.9% NaCl). For Examples 14 to 18 and 21, 10.5 mg / kg of the drug was administered intramuscularly; for Examples 19 and 20, 21 mg / kg of the drug was administered intramuscularly. Each was administered once. Venous blood samples were collected before and after administration, and the lumateperone plasma concentrations after administration were measured.

[0095] As can be seen from Figures 7 and 8, the present invention achieved a long-acting sustained release effect lasting from 12 to 63 days, with minimal burst release, virtually no lag period, and a blood concentration curve following a normal distribution.

[0096] As shown in Figures 5 and 6, the microspheres of the present invention are spherical, uniformly dispersed internally, and highly compact.

Claims

1. A lumateperone pharmaceutical composition, comprising a lumateperone active ingredient and a pharmaceutical polymeric excipient in a mass ratio of 1:(1.5-19); the pharmaceutical polymeric excipient comprises a glycolide-lactide copolymer having a weight-average molecular weight of 5,000-120,000 daltons; and in the glycolide-lactide copolymer, the molar ratio of lactic acid units to glycolic acid units is 95:5-50:

50.

2. 2. The lumateperone pharmaceutical composition of claim 1, wherein the lumateperone active ingredient comprises lumateperone free base and its available salt forms.

3. 2. The lumateperone pharmaceutical composition of claim 1, wherein the glycolide-lactide copolymer has a weight average molecular weight of 5,000 to 80,000 daltons; and the molar ratio of lactic acid units to glycolic acid units in the glycolide-lactide copolymer is 85:15 to 50:

50.

4. A long-acting microsphere sustained-release formulation, comprising a lumateperone active ingredient and a pharmaceutical polymeric excipient, wherein the lumateperone active ingredient accounts for 5-40% of the total mass of the long-acting microsphere sustained-release formulation, and the pharmaceutical polymeric excipient accounts for 60-95% of the total mass of the long-acting microsphere sustained-release formulation; the pharmaceutical polymeric excipient comprises a glycolide-lactide copolymer having a weight-average molecular weight of 5,000-120,000 daltons; and in the glycolide-lactide polymer, the molar ratio of lactic acid units to glycolic acid units is 95:5-50:50; The long-acting microsphere sustained-release formulation is prepared by a microfluidic method or a homogeneous emulsification method, and the long-acting microsphere sustained-release formulation is characterized in that it is a spherical particle having a particle size of 20 to 200 μm.

5. 5. The long-acting microsphere sustained-release formulation of claim 4, wherein the lumateperone active ingredient comprises lumateperone free base and its available salt forms.

6. 5. The long-acting microsphere sustained-release formulation of claim 4, wherein the glycolide-lactide copolymer has a weight-average molecular weight of 5,000 to 80,000 daltons; and the molar ratio of lactic acid units to glycolic acid units in the glycolide-lactide copolymer is 85:15 to 50:

50.

7. A method for preparing the long-acting microsphere sustained-release formulation according to any one of claims 4 to 6, characterized in that the method employs a homogeneous emulsification method and comprises the following steps: A1. Preparation of oil phase: Dissolve lumateperone active ingredient and pharmaceutical polymer excipients in an organic solvent to obtain the oil phase to be used later; B1. Preparation of aqueous phase: Dissolve surfactant in water to obtain aqueous phase for later use; C1. Emulsification: A certain amount of the aqueous phase obtained in step B1 is designated as external aqueous phase I; start high-speed shearing, add the oil phase obtained in step A1 to external aqueous phase I, and continue shearing to obtain an incompletely solidified emulsion or suspension; wherein the volume ratio of the oil phase to the external aqueous phase I is 1:5 to 1:50; D1. Solvent evaporation: A certain amount of the aqueous phase obtained in step B1 is taken as external aqueous phase II; start stirring, add the incompletely solidified emulsion or suspension obtained in step C1 to external aqueous phase II, and continue stirring until the solvent evaporation is complete to obtain coarse microspheres; wherein the volume ratio of the oil phase to the external aqueous phase II is 1:10 to 1:200; and E1. Post-treatment: Washing the crude microspheres obtained in step D1 with pure water, sieving, collecting and drying the microspheres to obtain a long-acting microsphere sustained-release formulation.

8. 8. The method for preparing a long-acting microsphere sustained-release formulation according to claim 7, wherein in step A1, the organic solvent comprises one or a mixture of any two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, trichloromethane, diethyl ether, benzyl alcohol, N,N-dimethylformamide, and N,N-dimethylacetamide.

9. 8. The method for preparing a long-acting microsphere sustained-release formulation according to claim 7, wherein in step B1, the surfactant comprises one or a mixture of two or more of Pluronic F-127, sodium dodecyl sulfonate, sodium dodecyl sulfate, and polyvinyl alcohol.

10. A method for preparing the long-acting microsphere sustained-release formulation according to any one of claims 4 to 6, characterized in that the method employs a microfluidic method and comprises the following steps: A2. Preparation of oil phase: Dissolve lumateperone active ingredient and pharmaceutical polymer excipients in an organic solvent to obtain the oil phase to be used later; B2. Preparation of aqueous phase: Dissolve surfactant in water to obtain aqueous phase for later use; C2. Using a syringe pump, inject the oil phase obtained in step A2 and a portion of the aqueous phase obtained in step B2 into a microfluidic device while controlling the flow rate ratio of the oil phase to the aqueous phase to be 1:2 to 1:200 and controlling the temperature in the microfluidic device to be 4 to 10°C, to obtain an oil-in-water emulsion, recovering the oil-in-water emulsion, and temporarily storing the recovered oil-in-water emulsion in a receiver containing a portion of the aqueous phase obtained in step B2 to obtain semi-solidified microspheres; D2. Solvent evaporation: The semi-solidified microspheres obtained in step C2 are transferred from the receiver to an evaporator and stirred continuously until the solvent evaporation is completed to obtain completely solidified microspheres; and E2. Post-treatment: Washing the completely solidified microspheres obtained in step D2 with pure water, sieving, collecting and drying the microspheres to obtain a long-acting microsphere sustained-release formulation.

11. 11. The method for preparing a long-acting microsphere sustained-release formulation according to claim 10, wherein in step A2, the organic solvent comprises one or a mixture of any two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, trichloromethane, diethyl ether, benzyl alcohol, N,N-dimethylformamide, and N,N-dimethylacetamide.

12. 11. The method for preparing a long-acting microsphere sustained-release formulation according to claim 10, wherein in step B2, the surfactant comprises one or a mixture of two or more of Pluronic F-127, sodium dodecyl sulfonate, sodium dodecyl sulfate, and polyvinyl alcohol.

Images