Lumepirone pharmaceutical composition, long-acting microsphere sustained-release preparation and preparation method of long-acting microsphere sustained-release preparation

Abstract

The invention discloses a composition containing a lumepirone active component, a long-acting sustained-release preparation and a preparation method of the long-acting sustained-release preparation, and belongs to the field of pharmaceutical preparations. The composition containing the lumepirone active ingredient, which can be slowly released for a long time, is obtained by particularly limiting medicinal polymer auxiliary materials; according to the preparation method, the lumepirone is taken as a raw material, and preparation process conditions are further controlled, so that the long-acting sustained-release preparation containing the lumepirone active ingredient is obtained, sustained release of the lumepirone for 1 week to 2 months is realized, and the compliance of a patient can be effectively improved compared with a common preparation (such as a capsule); and on the premise of ensuring the safety and the effectiveness of the medicine, the clinical requirement of stable release of the medicine is met at the same time.

Description

Lumiperone pharmaceutical composition, long-acting microsphere sustained-release preparation and preparation method thereof 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, and in particular to a lumiperone pharmaceutical composition, a long-acting microsphere sustained-release preparation and a preparation method thereof. Background Art

[0002] Mental illness generally refers to psychological disorders, specifically abnormal psychological processes, personality traits, and behavioral patterns caused by physiological, psychological, or social factors. These disorders manifest as an inability to act in socially acceptable ways, resulting in behaviors that are maladaptive to both the individual and society. Antipsychotic medications are often used to treat or alleviate these symptoms.

[0003] Among them, the representative first-generation antipsychotics involved include chlorpromazine, fluphenazine, haloperidol, penfluridol, etc., which effectively relieve positive symptoms by blocking dopamine receptors, but are almost ineffective for negative symptoms and impaired cognitive function; the representative second-generation antipsychotics include risperidone, clozapine, olanzapine, aripiprazole, quetiapine, ziprasidone, etc., which can block dopamine receptors and 5-hydroxytryptamine receptors. Compared with most first-generation drugs, the incidence of extrapyramidal adverse reactions is lower, but most second-generation drugs can cause weight gain and lipid metabolism disorders (obesity); in the past two years, a new multi-target antipsychotic drug, lumepirone, CAS number: 313368-91-1, English name: ITI-722 or Lumateperone, was disclosed. It was approved for marketing in the United States in December 2019 for the treatment of schizophrenia in adults. Unlike first- and second-generation antipsychotics, which generally target only serotonin and dopamine neurotransmitters, lumepirone also targets glutamine neurotransmitters. This allows it to improve not only the positive symptoms of schizophrenia (delusions, hallucinations, and behavioral abnormalities), but also negative symptoms (flat affect, impoverished speech, and decreased arousal) and depression. Furthermore, compared to second-generation antipsychotics, lumepirone overcomes the drawbacks of weight gain and glucose and lipid metabolism disturbances, reducing the risk of weight gain. Studies have shown that lumepirone reduces the risk of weight gain by 13% compared to the commonly used antipsychotic risperidone.

[0004] Currently, patients' inability to adhere to regular medication use with existing antipsychotics is one of the main causes of relapse. Clinical trials have demonstrated that long-acting injectable antipsychotics significantly reduce hospitalization and treatment discontinuation rates compared to oral antipsychotics, making them an important treatment for relapse prevention. Regular injections reduce the need for patients to worry about forgetting to take medication, reducing their daily burden. They also protect their privacy and prevent drug abuse by minimizing the risk of others discovering their medication use. Currently, long-acting injectable second-generation antipsychotics are used as first-line treatment for patients with acute and maintenance schizophrenia. Available long-acting injectable second-generation antipsychotics in my country include risperidone microspheres for injection every two weeks, paliperidone palmitate for monthly injections, and paliperidone palmitate for three-monthly injections. However, the development of a long-acting, extended-release formulation of lumepirone is still under development.

[0005] Prior art CN113473988A and CN114072150A disclose that lumepirone, in free form or in pharmaceutically acceptable salt form, can be administered by any suitable route, including oral, parenteral, transdermal, or transmucosal administration, such as in the form of tablets, capsules, subcutaneous injections, long-acting injectables, or rapidly disintegrating oral tablets or films for sublingual or buccal administration. Regarding dosage and efficacy, the FDA specification states that the optimal oral dose is 42 mg / day, without the need for dose titration. This places stringent design requirements on lumepirone long-acting sustained-release injections: they must exhibit minimal burst release and stable and uniform release, which is one of the greatest challenges facing lumepirone long-acting sustained-release injections. Currently, no patents or publications disclose effective methods for preparing lumepirone long-acting sustained-release injections.

[0006] Therefore, developing a long-acting formulation of lumepirone with a small burst release and a smooth release to fully utilize the clinical advantages of lumepirone in the antipsychotic field (such as overcoming the disadvantages of weight gain and lipid metabolism disorders and improving safety; and being able to simultaneously improve the positive and negative symptoms (flat emotions, poor speech, decreased volitional activity, etc.) and depressive symptoms of schizophrenia patients) has become a technical problem that urgently needs to be solved.

[0007] SUMMARY OF THE INVENTION

[0008] Aiming to overcome the shortcomings of existing technologies, a lumepirone pharmaceutical composition, a long-acting microsphere sustained-release formulation, and a method for preparing the same are proposed. In this technical solution, by specifically limiting the pharmaceutical polymer excipients, a lumepirone pharmaceutical composition capable of long-term sustained-release is obtained. Furthermore, by further controlling the preparation process conditions, a long-acting microsphere sustained-release formulation is obtained, achieving sustained-release of lumepirone for one week to two months. Compared to conventional formulations (such as capsules), this can effectively improve patient compliance. Furthermore, the formulation ensures a smooth release, ensuring both safety and efficacy.

[0009] In order to achieve the above technical objectives, the following technical solutions are proposed:

[0010] The first aspect of the present invention provides: a lumiperone pharmaceutical composition, which comprises a lumiperone active ingredient and a pharmaceutical polymer excipient, wherein the weight ratio of the lumiperone active ingredient to the pharmaceutical polymer excipient is 1: (1.5-19); wherein the pharmaceutical polymer excipient comprises a weight average molecular weight (M W ) is a glycolide-lactide copolymer (PLGA) with a molecular weight of 5,000 to 120,000 daltons; in the glycolide-lactide copolymer, the molar ratio of lactic acid units to glycolic acid units is 95:5 to 50:50. The present invention effectively controls the degradation rate of the glycolide-lactide copolymer and adjusts the sustained-release period, thereby achieving the desired sustained-release effect of the lumiperone pharmaceutical composition of the present invention.

[0011] Furthermore, the active ingredient of lumiperone includes lumiperone free base and its available salt forms (such as lumiperone p-toluenesulfonate).

[0012] As an example, the weight average molecular weight (M W ) is 5000 to 80000 Daltons; More preferably, the weight average molecular weight (M W ) is 40,000 to 80,000 Daltons, for example, 60,000 to 80,000 Daltons.

[0013] Preferably, in the glycolide-lactide copolymer, the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 50:50; more preferably, the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 75:25.

[0014] Preferably, the weight ratio of lumiperone active ingredient to pharmaceutical polymer excipient is 1:(1.5-10); for example, 1:(1.5-9), 1:(2-8), 1:(2-6), 1:(3-5), more specifically 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9.

[0015] The second aspect of the present invention provides: a long-acting sustained-release preparation, which includes a lumiperone active ingredient and a pharmaceutical polymer excipient, wherein the lumiperone active ingredient accounts for 5 to 40% of the total weight of the long-acting sustained-release preparation, and the pharmaceutical polymer excipient accounts for 60 to 95% of the total weight of the long-acting sustained-release preparation; wherein the pharmaceutical polymer excipient includes a glycolide-lactide copolymer having a weight-average molecular weight of 5,000 to 120,000 daltons; in the glycolide-lactide copolymer, the molar ratio of the lactic acid unit to the glycolic acid unit is 95:5 to 50:50.

[0016] Furthermore, the active ingredient of lumiperone includes lumiperone free base and its available salt forms (such as lumiperone p-toluenesulfonate).

[0017] As an example, the weight average molecular weight (M W ) is 5000 to 80000 Daltons; More preferably, the weight average molecular weight (M W ) is 40,000 to 80,000 Daltons, for example, 60,000 to 80,000 Daltons.

[0018] Preferably, in the glycolide-lactide copolymer, the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 50:50; more preferably, the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 75:25.

[0019] Preferably, the weight ratio of lumiperone active ingredient to pharmaceutical polymer excipient is 1:(1.5-19); more preferably, the weight ratio of lumiperone active ingredient to pharmaceutical polymer excipient is 1:(1.5-10); for example, 1:(1.5-9), 1:(2-8), 1:(2-6), 1:(3-5), more specifically 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9.

[0020] Furthermore, the long-acting sustained-release preparation is a long-acting sustained-release microgranule, which includes spherical particles with a particle size of 1 to 1000 μm and irregularly shaped particles. Preferably, the long-acting sustained-release microgranule prepared by microfluidics or homogeneous emulsification is spherical particles with a particle size of 20 to 200 μm, i.e., a long-acting microsphere sustained-release preparation.

[0021] For long-acting microsphere sustained-release preparations, the drug loading of the active ingredient of lumepirone can be 5-40%. More precisely, the drug loading of the active ingredient of lumepirone can be 10-30%.

[0022] The third aspect of the present invention provides: a method for preparing a long-acting microsphere sustained-release preparation, which adopts a homogenizing emulsification technology and specifically comprises the following steps:

[0023] A1. Preparation of the oil phase: The active ingredient Lumiperone and a pharmaceutical polymer excipient are dissolved in an organic solvent to obtain an oil phase and set aside;

[0024] B1. Preparation of the aqueous phase: Dissolve the surfactant in water to obtain an aqueous phase and set aside;

[0025] C1. Emulsification: Take a certain volume of the aqueous phase obtained in step B1 as the external aqueous phase I; start high-speed shearing, add the oil phase obtained in step A1 to the external aqueous phase I, and continue shearing to obtain an incompletely solidified emulsion or suspension;

[0026] D1. Solvent evaporation: Take a certain volume of the aqueous phase obtained in step B1 as the external aqueous phase II; start stirring, place the uncured emulsion or suspension obtained in step C1 into the external aqueous phase II, and continue stirring until the solvent evaporates to obtain crude microspheres;

[0027] E1. Post-treatment: The crude microspheres obtained in step D1 are washed with pure water, sieved to collect the microspheres, and dried to obtain a long-acting microsphere sustained-release preparation.

[0028] Preferably, the method comprises the following steps:

[0029] A1. Preparation of the oil phase: Dissolve the active ingredient (active drug) of lumiperone and the pharmaceutical polymer excipient (molecular backbone) in an organic solvent and completely dissolve by stirring, vortexing, or sonication to form a transparent solution, i.e., the oil phase. Store at 4-10°C until ready to use.

[0030] B1. Preparation of the aqueous phase: Dissolve the surfactant in water to obtain an aqueous phase, temporarily store at 4 to 10 ° C and set aside;

[0031] C1. Emulsification: Take a certain volume of the aqueous phase obtained in step B1, designated as external aqueous phase I (W1). Using a homogenizer at high shear speed (e.g., 1000-3000 rpm), slowly and evenly add the oil phase obtained in step A1 to the external aqueous phase I. Continue shearing until a partially solidified emulsion or suspension is obtained.

[0032] D1. Solvent Evaporation: Take a certain volume of the aqueous phase obtained in step B1, designated as external aqueous phase II (W2); start stirring (e.g., at a speed of 50-1000 rpm), place the partially solidified emulsion or suspension obtained in step C1 into the external aqueous phase II, and continue stirring at temperature T1 until the solvent evaporates, thereby obtaining crude microspheres;

[0033] E1. Post-treatment: The crude microspheres obtained in step D1 are washed with pure water, sieved to collect the microspheres, and dried to obtain a long-acting microsphere sustained-release preparation.

[0034] Depending on the design objectives, the mass fraction of the active ingredient lumiperone in the oil phase can be 2-15%, the concentration of the pharmaceutical polymer excipient in the oil phase can be 5-25%, and the mass fraction of the surfactant in the aqueous phase can be 0.5-5%, preferably 0.5-2%.

[0035] Preferably, in step A1, the organic solvent comprises one or a mixture of any two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, chloroform, ether, benzyl alcohol, N,N-dimethylformamide and N,N-dimethylacetamide.

[0036] Preferably, in step B1, the surfactant comprises one or a mixture of any two or more of Pluronic F-127, sodium lauryl sulfonate, sodium lauryl sulfate and polyvinyl alcohol (PVA).

[0037] 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.

[0038] 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, the volume ratio of the oil phase to the external aqueous phase II is 1:10 to 1:100.

[0039] Preferably, step D1 is performed at a temperature T1 of 0 to 40°C, wherein the temperature T1 can be a constant temperature or a temperature gradient within the range. More preferably, the temperature T1 is 3 to 30°C.

[0040] The fourth aspect of the present invention provides: a method for preparing a long-acting microsphere sustained-release preparation, which adopts microfluidic technology and specifically comprises the following steps:

[0041] A2. Preparation of the oil phase: The active ingredient Lumiperone and a pharmaceutical polymer excipient are dissolved in an organic solvent to obtain an oil phase and set aside;

[0042] B2. Preparation of the aqueous phase: dissolve the surfactant in water to obtain an aqueous phase and set aside;

[0043] C2. The oil phase obtained in step A2 and a portion of the aqueous phase obtained in step B2 were separately injected into the microfluidic device using syringe pumps, with the flow rates of the oil phase and the aqueous phase controlled to obtain an oil-in-water emulsion. The emulsion was collected and temporarily stored in a receiver containing the portion of the aqueous phase obtained in step B2, thereby obtaining semi-solidified microspheres.

[0044] D2 solvent evaporation: The semi-cured microspheres obtained in step C2 of the receiver are placed in a volatilizer and stirred continuously until the solvent evaporates to obtain fully cured microspheres;

[0045] E2. Post-treatment: The fully solidified microspheres obtained in step D2 are washed with pure water, collected by sieving, and dried to obtain a long-acting microsphere sustained-release preparation.

[0046] Preferably, the method comprises the following steps:

[0047] A2. Preparation of the oil phase: Dissolve the active ingredient (active drug) of lumiperone and the pharmaceutical polymer excipient (molecular skeleton) in an organic solvent and completely dissolve them by stirring, vortexing, or sonication to form a transparent solution, i.e., the oil phase. Store at 4 to 10°C until ready to use.

[0048] B2: Preparation of aqueous phase: Dissolve the surfactant in water to obtain the aqueous phase, and store it at 4-10°C for later use;

[0049] C2. 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 separately injected into the microfluidic device using syringe pumps, with the flow rates of the oil phase and the aqueous phase being controlled. Ultimately, an oil-in-water emulsion is obtained. The emulsion is collected and temporarily stored in a receiver containing the portion of the aqueous phase obtained in step B2, thereby obtaining semi-solidified microspheres.

[0050] D2 solvent evaporation: The receiver obtained in step C2 semi-cured microspheres are placed in a evaporator and stirred continuously at a temperature T2 until the solvent evaporates to obtain fully cured microspheres;

[0051] E2. Post-treatment: The fully solidified microspheres obtained in step D2 are washed with pure water, collected by sieving, and dried to obtain a long-acting microsphere sustained-release preparation.

[0052] According to the design objectives, the mass fraction of the active ingredient lumepirone in the oil phase can be 2-15%, the concentration (mass fraction) of the pharmaceutical polymer excipient in the oil phase can be 5-25%, and the mass fraction of the surfactant in the aqueous phase can be 0.5-5%, preferably 0.5-2%.

[0053] Preferably, in step A2, the organic solvent comprises one or a mixture of any two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, chloroform, ether, benzyl alcohol, N,N-dimethylformamide and N,N-dimethylacetamide.

[0054] Preferably, in step B2, the surfactant comprises one or a mixture of any two or more of Pluronic F-127, sodium lauryl sulfonate, sodium lauryl sulfate and polyvinyl alcohol (PVA).

[0055] Preferably, in step C2, the temperature in the microfluidic device is controlled to be 4-10° C. to ensure the effective formation of the oil-in-water emulsion and the formation of semi-solidified microspheres in the receiver.

[0056] Preferably, in step C2, the flow rate ratio between the oil phase and the water phase is controlled to be 1:2 to 1:200. More preferably, the flow rate ratio between the oil phase and the water phase is 1:10 to 1:100.

[0057] Preferably, step D2 is performed at a temperature T2 of 3 to 40°C. The temperature T2 may be a constant temperature or a temperature gradient within the range. More preferably, the temperature T2 is 3 to 35°C.

[0058] In this article, the terms used include:

[0059] Lumiperone active ingredient: refers to lumiperone free base or its available salt form.

[0060] Available salt forms: refers to pharmaceutically acceptable salts of lumepirone free base, such as, 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.

[0061] Drug loading: refers to the amount of drug loaded per unit weight or volume of microspheres, of which the amount of drug that can be released is the effective drug loading. Unless the drug is irreversibly bound to the matrix, drug loading can be considered the drug content of the microspheres.

[0062] Encapsulation rate: refers to the percentage of the encapsulated substance (such as a drug) in the total drug input, reflecting the degree to which the drug is encapsulated by the carrier.

[0063] The beneficial technical effects brought about by adopting the present invention are:

[0064] First, the present invention provides a lumiperone pharmaceutical composition by specifically limiting pharmaceutical polymer excipients. Furthermore, by further controlling the preparation process conditions, a long-acting sustained-release preparation, particularly long-acting sustained-release microspheres, is obtained. These microspheres can achieve sustained release of lumiperone for one week to two months, effectively improving patient compliance compared to conventional preparations (e.g., capsules). Furthermore, the preparation ensures a smooth release, ensuring both safety and efficacy.

[0065] Second, the present invention provides a method for preparing a long-acting microsphere sustained-release preparation based on homogeneous emulsification technology. The prepared long-acting microsphere sustained-release preparation achieves a stable sustained-release period of 1 week to 2 months compared to general oral preparations, effectively improving patient compliance and enhancing clinical treatment effects.

[0066] 3. The present invention is based on microfluidic technology to prepare microspheres with uniform size and good morphology. By controlling the flow rate ratio between the oil phase and the water phase and the conditions in the microfluidic device, the microfluidic lumepirone microspheres are ensured to be closer to zero-order release and have a smooth release, meeting the requirements of drug safety and efficacy and solving the problem of unstable release of homogeneous emulsified microspheres. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] FIG1 is a schematic structural diagram of the lumepirone long-acting sustained-release microspheres of the present invention (left: lumepirone long-acting sustained-release microspheres prepared by a microfluidic method; right: lumepirone long-acting sustained-release microspheres prepared by a homogeneous emulsification method);

[0068] FIG2 shows the results of in vitro release testing of the lumiperone long-acting sustained-release microspheres obtained in Example 2-4;

[0069] FIG3 shows the results of in vitro release testing of the lumepirone long-acting sustained-release microspheres obtained in Examples 5-7;

[0070] FIG4 shows the results of in vitro release testing of the lumepirone long-acting sustained-release microspheres obtained in Examples 8-10.

[0071] FIG5 is a SEM image of the lumepirone long-acting sustained-release microspheres obtained in Example 17.

[0072] FIG6 is a cross-sectional SEM image of the lumepirone long-acting sustained-release microspheres obtained in Example 17.

[0073] FIG7 shows the in vivo release results of the lumepirone long-acting sustained-release microspheres obtained in Examples 14, 15, 17 and 18 in mice.

[0074] FIG8 shows the in vivo release results of the lumepirone long-acting sustained-release microspheres obtained in Examples 16 and 19-21 in mice. Example

[0075] The present invention is further described below by way of examples. The examples of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention. Those skilled in the art may make some non-essential improvements and adjustments without violating the spirit of the present invention, which still fall within the scope of protection of the present invention.

[0076] Example 1

[0077] This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing a lumepirone-type drug. The preparation method comprises the following steps:

[0078] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 95:5, molecular weight 78,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0079] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and preserving it at 10° C.;

[0080] 3) Take 90 mL of the aqueous phase as the external aqueous phase I and start the high-speed shear of the homogenizer at 2000 rpm. Transfer the oil phase to a 20 mL syringe and use a syringe pump to pump the oil phase into the external aqueous phase I at a constant speed (0.3 mL / s). The entire process takes about 30 seconds. Continue shearing for 180 seconds, when emulsification is complete, to obtain a suspension.

[0081] 4) Taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and evaporating at 4°C for 2 h, then raising the temperature to 25°C and stirring and evaporating for 2 h to obtain microspheres;

[0082] 5) The microspheres obtained in step 4) are filtered through a sieve, washed, collected, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0083] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release test, and the actual drug loading of the microspheres was found to be 16.34%, and the encapsulation efficiency was 81.7%.

[0084] Example 2

[0085] This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing a lumepirone-type drug. The preparation method comprises the following steps:

[0086] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 50:50, molecular weight 61000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0087] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0088] 3) Take 90 mL of the aqueous phase as the external aqueous phase I and start the high-speed shear of the homogenizer at 2000 rpm. Transfer the oil phase to a 20 mL syringe and use a syringe pump to pump the oil phase into the external aqueous phase I at a constant speed (0.3 mL / s). The entire process takes about 30 seconds. Continue shearing for 180 seconds, when emulsification is complete, to obtain a suspension.

[0089] 4) Taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and evaporating at 4°C for 2 h, then raising the temperature to 25°C and stirring and evaporating for 2 h to obtain microspheres;

[0090] 5) The microspheres obtained in step 4) are filtered through a sieve, washed, collected, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0091] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release test, and the actual drug loading of the microspheres was found to be 16.02%, with an encapsulation efficiency of 80.1%.

[0092] Example 3

[0093] This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing a lumepirone-type drug. The preparation method comprises the following steps:

[0094] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 74,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0095] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0096] 3) Take 90 mL of the aqueous phase as the external aqueous phase I and start the homogenizer at 2000 rpm. Transfer the oil phase to a 20 mL syringe and use a syringe pump to pump the oil phase into the external aqueous phase I at a constant speed (0.3 mL / s). The entire process takes about 30 seconds. Continue shearing for 180 seconds, at which point the emulsification is complete to obtain a suspension.

[0097] 4) Taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and evaporating at 10°C for 2 h, then raising the temperature to 25°C and stirring and evaporating for 2 h to obtain microspheres;

[0098] 5) The microspheres obtained in step 4) are filtered through a sieve, washed, collected, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0099] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, resulting in an actual drug loading of 16.46% and an encapsulation efficiency of 82.3%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG2 .

[0100] Example 4

[0101] This embodiment adopts homogenization emulsification technology to prepare a long-acting sustained-release microsphere containing a lumepirone-type drug. The preparation method comprises the following steps:

[0102] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 85:15, molecular weight 72,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0103] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0104] 3) Take 90 mL of the aqueous phase as the external aqueous phase I and start the homogenizer at 2000 rpm. Transfer the oil phase to a 20 mL syringe and use a syringe pump to pump the oil phase into the external aqueous phase I at a constant speed (0.3 mL / s). The entire process takes about 30 seconds. Continue shearing for 180 seconds, at which point the emulsification is complete to obtain a suspension.

[0105] 4) Taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and evaporating at 10°C for 2 h, then raising the temperature to 25°C and stirring and evaporating for 2 h to obtain microspheres;

[0106] 5) The microspheres obtained in step 4) are filtered through a sieve, washed, collected, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0107] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, resulting in an actual drug loading of 16.69% and an encapsulation efficiency of 83.4%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG2 .

[0108] Example 5

[0109] This embodiment uses microfluidic technology to prepare a long-acting sustained-release microsphere containing a lumepirone-type drug. The preparation method includes the following steps:

[0110] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 50:50, molecular weight 61000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0111] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0112] 3) Injecting the oil phase (dispersed phase) fluid and the aqueous phase (continuous phase) fluid into the microfluidic device using syringe pumps, adjusting the oil phase flow rate to 100 μL / h and the aqueous phase flow rate to 2000 μL / h. The dispersed phase is sheared by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, which is collected and placed in a receiver containing the aqueous phase. The temperature is controlled at 10°C throughout the process.

[0113] 4) After the receiver is full, the semi-cured microspheres obtained in step 3) are transferred to a volatilizer and stirred; a temperature control program is started (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours) to evaporate the organic solvent to obtain fully cured microspheres;

[0114] 5) The fully cured microspheres obtained in step 4) are washed with pure water, filtered, and the finished wet microspheres are collected and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0115] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, resulting in an actual drug loading of 18.75% and an encapsulation efficiency of 93.7%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG3 .

[0116] Example 6

[0117] This embodiment uses microfluidic technology to prepare a long-acting sustained-release microsphere containing a lumepirone-type drug. The preparation method includes the following steps:

[0118] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 74,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0119] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0120] 3) Injecting the oil phase (dispersed phase) fluid and the aqueous phase (continuous phase) fluid into the microfluidic device using syringe pumps, adjusting the oil phase flow rate to 100 μL / h and the aqueous phase flow rate to 2000 μL / h. The dispersed phase is sheared by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, which is collected and placed in a receiver containing the aqueous phase. The temperature is controlled at 10°C throughout the process.

[0121] 4) After the receiver is full, the semi-cured microspheres obtained in step 3) are transferred to a volatilizer and stirred; a temperature control program is started (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours) to evaporate the organic solvent to obtain fully cured microspheres;

[0122] 5) The fully solidified microspheres obtained in step 4) are washed with pure water, filtered, and the finished wet microspheres are collected. After freeze-drying, the finished microspheres are obtained, i.e., lumepirone long-acting sustained-release microspheres.

[0123] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, resulting in an actual drug loading of 19.30% and an encapsulation of 96.5%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG3 .

[0124] Example 7

[0125] This embodiment uses microfluidic technology to prepare a long-acting sustained-release microsphere containing a lumepirone-type drug. The preparation method includes the following steps:

[0126] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 85:15, molecular weight 72,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0127] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0128] 3) Injecting the oil phase (dispersed phase) fluid and the aqueous phase (continuous phase) fluid into the microfluidic device using syringe pumps, adjusting the oil phase flow rate to 100 μL / h and the aqueous phase flow rate to 2000 μL / h. The dispersed phase is sheared by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, which is collected and placed in a receiver containing the aqueous phase. The temperature is controlled at 10°C throughout the process.

[0129] 4) After the receiver is full, the semi-cured microspheres obtained in step 3) are transferred to a volatilizer and stirred; a temperature control program is started (4°C for 1 hour, 15°C for 1 hour, and 25°C for 2 hours) to evaporate the organic solvent to obtain fully cured microspheres;

[0130] 5) The fully cured microspheres obtained in step 4) are washed with pure water, filtered, and the finished wet microspheres are collected and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0131] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, resulting in an actual drug loading of 18.98% and an encapsulation of 94.9%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG3 .

[0132] Example 8

[0133] In this example, ester-terminated PLGA with a molecular weight of 74,000 was used to prepare lumepirone long-acting sustained-release microspheres using a homogenization emulsification technique, with the remaining steps being the same as in Example 3. This completes the discussion on PLGA end group screening and further illustrates this technical solution.

[0134] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, resulting in an actual drug loading of 18.92% and an encapsulation of 94.6%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG4 .

[0135] Example 9

[0136] In this example, PLGA with a molecular weight of 49,000 was selected and homogenized and emulsified, with the remaining steps being the same as in Example 3, to prepare lumepirone long-acting sustained-release microspheres. This completes the discussion on low molecular weight screening of PLGA and further illustrates this technical solution.

[0137] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, resulting in an actual drug loading of 19.42% and an encapsulation of 97.1%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG4 .

[0138] Example 10

[0139] In this example, PLGA with a molecular weight of 116,000 was selected and homogenized and emulsified, with the remaining steps being the same as in Example 3, to prepare lumepirone long-acting sustained-release microspheres. This completes the discussion on high molecular weight screening of PLGA and further illustrates this technical solution.

[0140] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, resulting in an actual drug loading of 18.04% and an encapsulation efficiency of 90.2%. The obtained lumepirone long-acting sustained-release microspheres were subjected to in vitro release testing, and the results are shown in FIG4 .

[0141] Example 11

[0142] In this example, 0.11 g of lumepirone was added, and homogenization and emulsification were used, with the remaining steps being the same as in Example 3, to prepare lumepirone long-acting sustained-release microspheres. This completes the discussion on low-dosage screening of lumepirone, and this technical solution is further explained.

[0143] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is about 0.11 / (0.11+2.08)=5%, and the actual drug loading of the microspheres is 4.76%, with an encapsulation efficiency of 95.2%.

[0144] Example 12

[0145] In this example, 1.39 g of lumepirone was added, and homogenization and emulsification were used, with the remaining steps being the same as in Example 3, to prepare lumepirone long-acting sustained-release microspheres. This completes the discussion on high-feed-rate screening of PLGA, and this technical solution is further explained.

[0146] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is about 1.39 / (1.39+2.08)=40%, and the actual drug loading of the microspheres is 30.48%, with an encapsulation efficiency of 76.2%.

[0147] Example 13

[0148] This example uses homogenization emulsification technology to prepare long-acting sustained-release microspheres containing lumepirone as an active ingredient. The preparation method includes the following steps:

[0149] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 95:5, molecular weight 42,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0150] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0151] 3) Take 90 mL of the aqueous phase as the external aqueous phase I and start the high-speed shear of the homogenizer at 1500 rpm. Transfer the oil phase to a 10 mL syringe and use a syringe pump to pump the oil phase into the external aqueous phase I at a constant speed (0.3 mL / s). The entire process takes about 30 seconds. Continue shearing for 180 seconds, completing the emulsification process and obtaining a crude emulsion.

[0152] 4) Taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the crude emulsion obtained in step 3) into the external aqueous phase II, stirring and evaporating at 4°C for 2 hours, then raising the temperature to 25°C and stirring and evaporating for 2 hours to obtain microspheres;

[0153] 5) The microspheres obtained in step 4) are filtered through a sieve, washed, collected, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0154] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, and the actual drug loading of the microspheres is 16.61%, the encapsulation efficiency is 83.05%, the particle size is 65.590 μm, and the span is 0.766.

[0155] Example 14

[0156] This example uses homogenization emulsification technology to prepare long-acting sustained-release microspheres containing lumepirone as an active ingredient. The preparation method includes the following steps:

[0157] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 50:50, molecular weight 28,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0158] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0159] 3) Take 90 mL of the aqueous phase as the external aqueous phase I and start the high-speed shear of the homogenizer at 2000 rpm. Transfer the oil phase to a 10 mL syringe and use a syringe pump to pump the oil phase into the external aqueous phase I at a constant speed (0.3 mL / s). The entire process takes about 30 seconds. Continue shearing for 180 seconds, when emulsification is complete, to obtain a suspension.

[0160] 4) Taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and evaporating at 4°C for 2 h, then raising the temperature to 25°C and stirring and evaporating for 2 h to obtain microspheres;

[0161] 5) The microspheres obtained in step 4) are washed and collected through a sieve, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0162] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, and the actual drug loading of the microspheres is 17.89%, with an encapsulation efficiency of 89.45%.

[0163] Example 15

[0164] This example uses homogenization emulsification technology to prepare long-acting sustained-release microspheres containing lumepirone as an active ingredient. The preparation method includes the following steps:

[0165] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 74,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0166] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0167] 3) Take 90 mL of the aqueous phase as the external aqueous phase I and start the homogenizer at 2000 rpm. Transfer the oil phase to a 10 mL syringe and use a syringe pump to pump the oil phase into the external aqueous phase I at a constant speed (0.3 mL / s). Continue shearing until emulsification is complete to obtain a suspension.

[0168] 4) Taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring continuously at 10°C, then raising the temperature to 25°C and continuing stirring to obtain microspheres;

[0169] 5) The microspheres obtained in step 4) are washed and collected through a sieve, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0170] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, and the actual drug loading of the microspheres is 17.09%, with an encapsulation efficiency of 85.47%.

[0171] Example 16

[0172] This example uses homogenization emulsification technology to prepare long-acting sustained-release microspheres containing lumepirone as an active ingredient. The preparation method includes the following steps:

[0173] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 85:15, molecular weight 42,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0174] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0175] 3) Take 90 mL of the aqueous phase as the external aqueous phase I and start the homogenizer at 2000 rpm. Transfer the oil phase to a 10 mL syringe and use a syringe pump to pump the oil phase into the external aqueous phase I at a constant speed (0.3 mL / s). The entire process takes about 30 seconds. Continue shearing for 180 seconds, completing the emulsification process and obtaining a suspension.

[0176] 4) Taking 540 mL of the aqueous phase as the external aqueous phase II and starting stirring; pouring the suspension obtained in step 3) into the external aqueous phase II, stirring and evaporating at 10°C for 2 h, then raising the temperature to 25°C and stirring and evaporating for 2 h to obtain microspheres;

[0177] 5) The microspheres obtained in step 4) are washed and collected through a sieve, and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0178] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, and the actual drug loading of the microspheres is 17.65%, with an encapsulation efficiency of 88.26%.

[0179] Example 17

[0180] This example uses homogenization emulsification technology to prepare long-acting sustained-release microspheres containing lumepirone as an active ingredient. The preparation method includes the following steps:

[0181] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 51,000, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0182] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0183] 3) The oil phase (dispersed phase) fluid and the water phase (continuous phase) fluid were injected into the emulsification device using syringe pumps, respectively. The oil phase flow rate was adjusted to 18 mL / min and the water phase flow rate was adjusted to 540 mL / min. The oil phase was sheared in an online shearing device serving as the emulsification device to obtain a crude emulsion.

[0184] 4) transferring the crude emulsion obtained in step 3) into a evaporator and stirring; starting a temperature control program (4° C. for 1 hour, 15° C. for 1 hour, and 25° C. for 2 hours) to evaporate the organic solvent to obtain fully cured microspheres;

[0185] 5) The fully cured microspheres obtained in step 4) are washed with pure water, filtered, and the finished wet microspheres are collected and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0186] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, and the actual drug loading of the microspheres is 17.51%, with an encapsulation efficiency of 87.53%.

[0187] Example 18

[0188] This embodiment adopts homogeneous emulsification technology to propose a method for preparing long-acting sustained-release microspheres containing lumepirone active ingredient, comprising the following steps:

[0189] 1) Weigh 0.52 g of lumepirone and 2.08 g of PLGA (LA:GA = 75:25, molecular weight 27,500, carboxyl-terminated), add 11.8 g of dichloromethane to dissolve to obtain a clear oil phase solution, and store at 10°C until ready for use;

[0190] 2) preparing a 0.5 wt% PVA aqueous solution as the aqueous phase and storing it at 10° C. for later use;

[0191] 3) The oil phase (dispersed phase) fluid and the water phase (continuous phase) fluid were injected into the emulsification device using syringe pumps, respectively. The oil phase flow rate was adjusted to 18 mL / min and the water phase flow rate was adjusted to 540 mL / min. The oil phase was sheared in an online shearing device serving as the emulsification device to obtain a crude emulsion.

[0192] 4) transferring the crude emulsion obtained in step 3) into a evaporator and stirring; starting a temperature control program (4° C. for 1 hour, 15° C. for 1 hour, and 25° C. for 2 hours) to evaporate the organic solvent to obtain fully cured microspheres;

[0193] 5) The fully cured microspheres obtained in step 4) are washed with pure water, filtered, and the finished wet microspheres are collected and dried to obtain finished microspheres, i.e., lumepirone long-acting sustained-release microspheres.

[0194] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.52 / (0.52+2.08)=20%, and the actual drug loading of the microspheres is 18.18%, with an encapsulation efficiency of 90.89%.

[0195] Example 19

[0196] In this example, ester-terminated PLGA (LA:GA=85:15) with a molecular weight of 41,000 was selected, and the raw materials and auxiliary materials were weighed according to 0.26 g of lumepirone and 2.34 g of PLGA. The rest was the same as in Example 15 to prepare lumepirone long-acting sustained-release microspheres.

[0197] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.26 g / (0.26 g+2.34)=10%, and the actual drug loading of the microspheres is 9.06%, with an encapsulation efficiency of 90.6%.

[0198] Example 20

[0199] In this example, ester-terminated PLGA (LA:GA=85:15) with a molecular weight of 103,000 was selected. The raw materials and auxiliary materials were weighed according to 0.13 g of lumepirone and 2.47 g of PLGA. Then, a homogenization emulsification technique was used, and the rest of the process was the same as in Example 15 to prepare lumepirone long-acting sustained-release microspheres.

[0200] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 0.13 / (0.13+2.47)=5%, and the actual drug loading of the microspheres is 4.585%, with an encapsulation efficiency of 91.7%.

[0201] Example 21

[0202] In this example, ester-terminated PLGA (LA:GA=85:15) with a molecular weight of 43,000 was selected. The raw materials and auxiliary materials were weighed according to 1.04 g of lumepirone and 1.56 g of PLGA. Then, a homogenization emulsification technique was used, and the rest of the process was the same as in Example 15 to prepare lumepirone long-acting sustained-release microspheres.

[0203] The theoretical drug loading of the lumepirone long-acting sustained-release microspheres is 1.04 / (1.04+1.56)=40%, and the actual drug loading of the microspheres is 31.28%, with an encapsulation efficiency of 78.2%.

[0204] Example 22

[0205] In the drying process of Examples 1-21, freeze drying or vacuum drying can be specifically used, wherein the freeze drying procedures involved are shown in Table 1.

[0206] Table 1

[0207] Test Example 1

[0208] This test example conducts in vitro release testing of the lumepirone long-acting sustained-release microspheres prepared in Examples 1-12 [according to the provisions of the Pharmacopoeia of the People's Republic of China (P.473)] to further illustrate the present invention. Specifically, it includes:

[0209] 1. Prepare 0.01 mol / L physiological isotonic phosphate buffer solution, pH 7.4, containing 0.05% poloxamer and 0.05% sodium azide);

[0210] 2. Accurately weigh the lumepirone long-acting sustained-release microspheres prepared in Examples 1-12, place them in a test tube, add them to 30 mL of physiological isotonic phosphate buffer solution, and incubate them in a constant temperature shaker at 37°C;

[0211] 3. Take samples separately, filter the samples, and use HPLC-UV method to measure the active drug content in the sample liquid medium.

[0212] in conclusion:

[0213] 1) As can be seen from the examples of the present invention: Due to the characteristics of microfluidic technology itself (drugs and excipients are formed into microspheres within microchannels), there is almost no loss of active drug except for dissolution and a small amount of loss. Therefore, the encapsulation efficiency of lumepirone long-acting sustained-release microspheres prepared by microfluidic method is higher than that of homogeneous emulsification method;

[0214] 2) As shown in Figures 2-4, the homogenous emulsification and microfluidics methods provided in this protocol can be used to prepare long-acting, sustained-release microspheres of lumepirone with a sustained release of 1 to 6 weeks. The microfluidics-based products exhibit uniform size, good morphology (as shown in Figure 1), low burst release, and stable release. By controlling the process parameters, a sustained-release microsphere formulation of lumepirone with a low burst release and a stable release can be prepared.

[0215] 3) Figure 4 shows that, in the preparation of lumepirone long-acting sustained-release microspheres, there is little difference between using ester-terminated PLGA and carboxyl-terminated PLGA, and PLGA molecular weight has a significant impact on release. By specifically limiting the PLGA molecular weight, the sustained-release period and release profile of lumepirone long-acting sustained-release microspheres can be adjusted, ultimately allowing the preparation of microsphere formulations that meet clinical needs.

[0216] 4) In screening experiments using high (40% of theoretical drug loading) and low (5% of theoretical drug loading) dosages of the active ingredient lumiperone, it was found that although the low dosage ensured a high encapsulation efficiency, the PLGA content in the formulation was too high, which meant that the total amount of solids increased in clinical practice, which would cause pain. On the other hand, the high dosage had an adverse effect on the formulation, reducing the encapsulation efficiency and affecting the release behavior to a certain extent.

[0217] Test Example 2

[0218] Lumeperone microspheres from Examples 14-21 were selected for animal experiments. Male rats weighing approximately 250 g were screened and randomly divided into groups of 5. The samples were mixed uniformly with a vehicle (0.5% CMC-Na, 0.1% Tween-20, 0.9% NaCl). Examples 14-18 and Example 21 were administered intramuscularly at 10.5 mg / kg, while Examples 19 and 20 were administered intramuscularly at 21 mg / kg. Each dose was administered once. Venous blood was collected before and after administration, and the plasma concentration of lumeperone was determined.

[0219] As can be seen from Figures 7 and 8, the present invention has achieved a long-term sustained release effect ranging from 12 days to 63 days, with good burst release, almost no hysteresis period, and the blood drug concentration curve is normally distributed.

[0220] It can be seen from FIG5 and FIG6 that the microspheres of the present invention are round in shape, evenly distributed, and compact inside.

Claims

1. A lumiperone pharmaceutical composition, characterized in that The invention comprises a lumiperone active ingredient and a pharmaceutical polymer excipient, wherein the weight ratio of the lumiperone active ingredient to the pharmaceutical polymer excipient is 1:(1.5-19); wherein the pharmaceutical polymer 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 the lactic acid unit to the glycolic acid unit is 95:5-50:

50.

2. The lumiperone pharmaceutical composition according to claim 1, wherein The active ingredient of lumidperone includes lumidperone free base and its available salt form.

3. The lumiperone pharmaceutical composition according to claim 1, wherein The weight average molecular weight of the glycolide-lactide copolymer is 5,000 to 80,000 Daltons; in the glycolide-lactide copolymer, the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 50:

50.

4. A long-acting microsphere sustained-release preparation, characterized in that: The long-acting microsphere sustained-release preparation comprises a lumiperone active ingredient and a pharmaceutical polymer excipient, wherein the lumiperone active ingredient accounts for 5 to 40% of the total weight of the long-acting microsphere sustained-release preparation, and the pharmaceutical polymer excipient accounts for 60 to 95% of the total weight of the long-acting microsphere sustained-release preparation; wherein the pharmaceutical polymer excipient comprises a glycolide-lactide copolymer having a weight-average molecular weight 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; The long-acting microsphere sustained-release preparation is prepared by a microfluidics method or a homogeneous emulsification method, and the long-acting microsphere sustained-release preparation is spherical particles with a particle size of 20 to 200 μm.

5. The long-acting microsphere sustained-release preparation according to claim 4, characterized in that: The active ingredient of lumidperone includes lumidperone free base and its available salt form.

6. The long-acting microsphere sustained-release preparation according to claim 4, characterized in that: The weight average molecular weight of the glycolide-lactide copolymer is 5,000 to 80,000 Daltons; in the glycolide-lactide copolymer, the molar ratio of the lactic acid unit to the glycolic acid unit is 85:15 to 50:

50.

7. A method for preparing the long-acting microsphere sustained-release preparation according to any one of claims 4 to 6, characterized in that: The method adopts a homogenization emulsification method, comprising the following steps: A1. Preparation of the oil phase: The lumiperone active ingredient and the pharmaceutical polymer excipient are dissolved in an organic solvent to obtain an oil phase and set aside; B1. Preparation of the aqueous phase: Dissolve the surfactant in water to obtain an aqueous phase and set aside; C1. Emulsification: Take a certain volume of the aqueous phase obtained in step B1 as the external aqueous phase I; start high-speed shearing, add the oil phase obtained in step A1 to the external aqueous phase I, and continue shearing to obtain an incompletely solidified emulsion or suspension; Wherein, the volume ratio between the oil phase and the external aqueous phase I is 1:5 to 1:50; D1. Solvent evaporation: Take a certain volume of the aqueous phase obtained in step B1 as the external aqueous phase II; start stirring, place the incompletely solidified emulsion or suspension obtained in step C1 into the external aqueous phase II, and continue stirring until the solvent evaporates to obtain crude microspheres; Wherein, the volume ratio between the oil phase and the external aqueous phase II is 1:10 to 1:200; E1. Post-treatment: The crude microspheres obtained in step D1 are washed with pure water, sieved to collect the microspheres, and dried to obtain the long-acting microsphere sustained-release preparation.

8. The method for preparing the long-acting microsphere sustained-release preparation according to claim 7, characterized in that: In step A1, the organic solvent includes one or a mixture of any two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, chloroform, ethyl ether, benzyl alcohol, N,N-dimethylformamide and N,N-dimethylacetamide.

9. The method for preparing the long-acting microsphere sustained-release preparation according to claim 7, characterized in that: In step B1, the surfactant includes one or a mixture of any two or more of Pluronic F-127, sodium lauryl sulfonate, sodium lauryl sulfate and polyvinyl alcohol.

10. A method for preparing the long-acting microsphere sustained-release preparation according to any one of claims 4 to 6, characterized in that: The method adopts a microfluidic method and includes the following steps: A2. Preparation of the oil phase: The active ingredient Lumiperone and the pharmaceutical polymer excipients are dissolved in an organic solvent to obtain an oil phase and set aside; B2. Preparation of the aqueous phase: dissolve the surfactant in water to obtain an aqueous phase and set aside; C2. The oil phase obtained in step A2 and a portion of the aqueous phase obtained in step B2 are separately injected into a microfluidic device using a syringe pump, with the flow rate ratio between the oil phase and the aqueous phase controlled at 1:2 to 1:200, and the temperature in the microfluidic device controlled at 4°C to 10°C to obtain an oil-in-water emulsion. The emulsion is collected and temporarily stored in a receiver containing a portion of the aqueous phase obtained in step B2 to obtain semi-solidified microspheres. D2 solvent evaporation: the receiver in step C2 obtained in the semi-cured microspheres are placed in a evaporator, stirring continuously until the end of the solvent evaporation to obtain fully cured microspheres; E2. Post-treatment: The fully solidified microspheres obtained in step D2 are washed with pure water, sieved to collect the microspheres, and dried to obtain the long-acting microsphere sustained-release preparation.

11. The method for preparing the long-acting microsphere sustained-release preparation according to claim 10, characterized in that: In step A2, the organic solvent includes one or a mixture of any two or more of dichloromethane, dimethyl sulfoxide, methanol, ethyl acetate, chloroform, ether, benzyl alcohol, N,N-dimethylformamide and N,N-dimethylacetamide.

12. The method for preparing the long-acting microsphere sustained-release preparation according to claim 10, characterized in that: In step B2, the surfactant includes one or a mixture of any two or more of Pluronic F-127, sodium lauryl sulfonate, sodium lauryl sulfate and polyvinyl alcohol (PVA).

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