Lumepirone long-acting microsphere sustained-release preparation without release stagnation period in early stage and preparation method of Lumepirone long-acting microsphere sustained-release preparation

Abstract

The invention discloses a lumepirone long-acting microsphere sustained-release preparation without a release stagnation period in an early stage, which comprises a lumepirone active ingredient and a medicinal polymer auxiliary material in a mass ratio of (1: 4)-(1: 1), the medicinal polymer auxiliary material is at least one of glycolide-lactide copolymers with the weight-average molecular weight of 5000-150000 Da, and the molar ratio of lactic acid units to glycolic acid units of the glycolide-lactide copolymers is (50: 50)-(95: 5). The lumepirone long-acting microsphere sustained-release preparation without a release arrest phase in the early stage is obtained by specially limiting drying conditions in liquid and medicinal polymer auxiliary materials, the release of the lumepirone long-acting microsphere sustained-release preparation can be maintained for 2 weeks to 1 month without oral administration of the long-acting sustained-release microspheres of lumepirone capsules, the safety and effectiveness of the medicine are met, and the sustained-release preparation is suitable for clinical application. Meanwhile, the problems of early-stage long-time stagnant release and early-stage burst release of the long-acting microsphere preparation can be solved, the compliance can be effectively improved, convenience is provided for patients to the maximum extent, and the economic cost is reduced.

Description

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a long-acting microsphere sustained-release formulation of rumepiride with no initial release lag period and its preparation method. Background Technology

[0002] Bipolar disorder (BD), formerly known as manic-depressive illness, is a paroxysmal mood disorder characterized by manic or hypomanic episodes. Two subtypes have been identified: Bipolar I and Bipolar II. Bipolar I is characterized by manic episodes, characterized by a marked and sustained elevation of mood, either arrogant or irritable, accompanied by abnormal and sustained increases in energy or activity, lasting at least one week. While a lifetime of major depressive episodes is not a necessary diagnostic criterion, most individuals with Bipolar I will experience a major depressive episode at some point in their lives. Bipolar II is characterized by a current or past history of both hypomanic and major depressive episodes. Hypomanic episodes are similar in symptoms to mania but cause less damage and are shorter in duration (at least four consecutive days). Currently, antipsychotic medications are commonly used to treat or alleviate these symptoms.

[0003] According to the National Guidelines for the Prevention and Treatment of Bipolar Disorder, medications for this type of disorder include: Representative first-generation antipsychotics include chlorpromazine, perphenazine, haloperidol, and penfluridone, which effectively relieve positive symptoms by blocking dopamine receptors, but are almost ineffective for negative symptoms and cognitive impairment, and have significant adverse reactions; Representative second-generation antipsychotics include risperidone, clozapine, olanzapine, aripiprazole, quetiapine, and ziprasidone, which can block dopamine and serotonin receptors. Compared with most first-generation drugs, the incidence of extrapyramidal adverse reactions is lower, but most second-generation drugs can lead to weight gain and glucose and lipid metabolism disorders (obesity).

[0004] Lumateperone is a small molecule drug (CAS: 313368-91-1) that selectively and simultaneously modulates three neurotransmitter pathways involved in serious illness: serotonin, dopamine, and glutamate. Unlike existing schizophrenia medications, lumateperone is a dopamine receptor phosphoprotein modulator (DPPM), acting as a presynaptic partial agonist and postsynaptic antagonist at the D2 receptor. It is the first and only drug with these indications for treating bipolar I or II-related depressive episodes in adults. Previously, quetiapine, olflurane, lurasidone, and caliprazine had all been approved by the FDA for the treatment of bipolar depression, but their scope of application was not as broad as that of lumateperone. Intra Cellular Therapies' lumateperone capsules (brand name Caplyta®) were approved for marketing in 2019 for the treatment of schizophrenia in adults.

[0005] Currently, for existing BD medication use, the inability of patients to adhere to regular medication is one of the main reasons for disease relapse. Clinical trials have confirmed that existing long-acting BD injections significantly reduce hospitalization and treatment interruption rates compared to oral BD, making them an important treatment method for preventing relapse. Injecting only periodically eliminates the need for patients to worry about forgetting to take their medication, reducing daily burden, and protecting their privacy from others discovering their medication use in daily life and work. It also helps prevent drug abuse. Currently, second-generation long-acting BD injections are used as first-line treatment for patients with acute and maintenance schizophrenia. Second-generation long-acting BD injections already marketed in my country include: risperidone microspheres injected every two weeks, paliperidone palmitate injected monthly, and paliperidone palmitate ester injected every three months. However, the development of long-acting sustained-release formulations of rumepiride is still in its infancy, and long-acting sustained-release microspheres often have a long initial release cessation period. Furthermore, the FDA instructions indicate that rumepiride has low oral bioavailability, only 4.4%.

[0006] Therefore, there is an urgent need to find a long-acting microsphere sustained-release formulation of rumepiride with no initial release lag period and a preparation method thereof. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a long-acting microsphere sustained-release formulation of rumepiride with no initial release stagnation period. This formulation solves the problem of no initial release stagnation period in existing long-acting sustained-release microsphere formulations of rumepiride, while also achieving no burst release phenomenon.

[0008] A long-acting microsphere sustained-release formulation of rumepiride with no initial release lag period, comprising the active ingredient rumepiride and pharmaceutical polymeric excipients, is prepared by the following method: (1) Dissolve the active ingredient of lumepirocin and the pharmaceutical polymer excipient in an organic solvent, stir and sonicate to obtain an oil phase; dissolve the surfactant in water to obtain an aqueous phase; (2) Take a portion of the aqueous phase obtained in step (1) as external aqueous phase I, and prepare a lumepimide sustained-release microsphere suspension by using a single emulsion method or a membrane emulsification method; (3) Take the remaining aqueous phase from step (1) as external aqueous phase II, add the lumepirolen sustained-release microsphere suspension obtained in step (2) to external aqueous phase II, and continue heating and stirring to dry in the liquid until the organic solvent is completely evaporated. After filtration, washing and sieving, collect the lumepirolen sustained-release microspheres, freeze-dry and obtain the long-acting lumepirolen microsphere sustained-release formulation with no release stagnation period in the early stage. The mass ratio of the active ingredient rumeperone to the pharmaceutical polymeric excipient is 1:4 to 1:1; The pharmaceutical polymeric excipient is a glycolide-lactide copolymer (PLGA) with a weight-average molecular weight of 5,000 to 150,000 Da, wherein the molar ratio of lactic acid units (LA) to glycolic acid units (GA) in the glycolide-lactide copolymer is 50:50 to 95:5.

[0009] In this invention, by specifying the pharmaceutical polymeric excipient as a glycolide-lactide copolymer with a weight-average molecular weight of 5000-150000 Da and a molar ratio of lactic acid units (LA) to glycolic acid units (GA) of 50:50-95:5, and by using one or more of the above-mentioned glycolide-lactide copolymers, the effective time of the prepared lumepirox long-acting microsphere sustained-release formulation is ≥2 weeks. Combined with the liquid drying treatment method, the dissolution rate of the active ingredient of lumepirox in the early stage of injection is controlled, thereby achieving the effect of no burst release and no release stagnation period in the early stage. At the same time, it can ensure that the effective time of the lumepirox long-acting microsphere sustained-release formulation can reach 2 weeks to 1 month.

[0010] Preferably, the effective time of the lumepirocin long-acting microsphere sustained-release formulation is ≥2 weeks.

[0011] Preferably, the active ingredient of lumepirozol is lumepirozol free base or its salt.

[0012] Preferably, the pharmaceutical polymeric excipient is at least one of glycolide-lactide copolymer (PLGA) with a weight average molecular weight of 6000-60000 Da, and the molar ratio of lactic acid unit (LA) to glycolic acid unit (GA) of the glycolide-lactide copolymer is 50:50 to 75:25.

[0013] Preferably, in step (3), the liquid drying includes room temperature drying and staged heating drying. The staged heating drying involves first drying at 25~35 ℃ for 1~3 h, and then heating to 35~45 ℃ for 3~5 h.

[0014] More preferably, the staged heating and drying conditions are: drying at 35 ℃ for 1-3 hours, followed by heating to 40 ℃ for 3-5 hours.

[0015] In this invention, different liquid drying conditions significantly affect the in vitro release of microspheres, thus influencing in vivo results. The longer the liquid drying heating time, the higher the aging degree of the PLGA material. Appropriately extending the liquid drying time can effectively reduce the burst release behavior of the lumepone long-acting microsphere sustained-release formulation in vivo. However, excessive aging of the PLGA can cause the lumepone long-acting microsphere sustained-release formulation to fail to release in vivo initially.

[0016] More preferably, in step (1), the pharmaceutical polymeric excipient is a glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 50:50.

[0017] In this invention, a single type of glycolide-lactide copolymer is used as a pharmaceutical polymeric excipient. By controlling the drying conditions in the liquid, a long-acting microsphere sustained-release formulation of rumepiride without burst release and without an initial release stagnation period can be prepared. The effective time of the formulation can reach 2 weeks.

[0018] More preferably, in step (1), the pharmaceutical polymeric excipient is a composition of a glycolide-lactide copolymer (PLGA5050) with a molar ratio of lactic acid units to glycolic acid units of 50:50 and a glycolide-lactide copolymer (PLGA7525) with a molar ratio of lactic acid units to glycolic acid units of 75:25. In the composition, the mass ratio of the glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 50:50 and the glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 75:25 is 1:9 to 5:5.

[0019] In this invention, two types of glycolide-lactide copolymers are used as pharmaceutical polymeric excipients. By controlling the drying conditions in the liquid, a long-acting microsphere sustained-release formulation of rumepiride without burst release and without an initial release stagnation period can be prepared. The effective time of the formulation can reach one month.

[0020] More preferably, in the composition, the mass ratio of the glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 50:50 and the glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 75:25 is 2:8.

[0021] Preferably, in step (1), the organic solvent is at least one of dichloromethane, dimethyl sulfoxide, ethyl acetate, acetone, chloroform, benzyl alcohol, diethyl ether, and N,N-dimethylformamide.

[0022] Preferably, in step (1), the surfactant is at least one of polyvinyl alcohol, sodium carboxymethyl cellulose, poloxamer, Tween 80, and sodium dodecyl sulfonate.

[0023] Preferably, in step (2), the single emulsion method is as follows: the oil phase is added to the external aqueous phase I, and after high-speed shearing, a lumepirocin sustained-release microsphere suspension is obtained; wherein the volume ratio of the oil phase to the external aqueous phase I is 1:20~100.

[0024] Preferably, in step (2), the membrane emulsification method is as follows: the oil phase is slowly and uniformly added to the external aqueous phase I to obtain an emulsion, and the emulsion is passed through a membrane tube under pressure to obtain a lumepimeperone sustained-release microsphere suspension; wherein the volume ratio of the oil phase to the external aqueous phase I is 1:5~50.

[0025] More preferably, the membrane tube has a pore size of 10~150 µm and a pressure of 0.01~0.1 MPa.

[0026] In this invention, the membrane emulsification method produces a more uniform particle size of the long-acting microsphere sustained-release formulation of rumepiride than the single emulsion method. By controlling the pore size of the membrane tube and membrane emulsification, a long-acting microsphere sustained-release formulation of rumepiride with a particle size of 2~120 μm is obtained.

[0027] Preferably, the particle size of the lumepirocin long-acting microsphere sustained-release formulation is 2~120 μm.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) This invention, through specific limitations on the drying conditions in the liquid and the pharmaceutical polymeric excipients, yields a long-acting microsphere sustained-release formulation of rumepiride with no initial release stagnation period. Addressing the issue of long-acting sustained-release microspheres having a prolonged initial release stagnation period, we further control the preparation process and use two or more pharmaceutical polymeric excipients in combination to obtain a long-acting sustained-release microsphere with no initial release stagnation period, eliminating the need for oral rumepiride capsules and maintaining release for 2 weeks to 1 month. This invention maintains stable blood drug concentrations, ensuring drug safety and efficacy, while simultaneously solving the problem of prolonged initial release stagnation in long-acting microsphere formulations. It effectively improves patient compliance, maximizes patient convenience, and reduces economic costs. (2) This invention, based on the single-emulsion method, provides a method suitable for the preparation of long-acting microsphere sustained-release formulations by specifically limiting the drying conditions in the liquid and the pharmaceutical polymer excipients. The prepared rumeperone long-acting microsphere sustained-release formulation achieves stable sustained release for 2 weeks compared with general oral formulations, and can solve the problem of long-term stagnant release in the early stage of long-acting microsphere formulations, effectively improving patient compliance and enhancing clinical treatment efficacy; (3) Based on membrane emulsification technology, this invention prepares a long-acting microsphere sustained-release formulation of rumepiride with uniform size and good morphology by controlling the conditions inside the membrane emulsification device, so as to ensure a more stable release of rumepiride and meet the requirements of drug safety and efficacy.

[0029] (4) Based on the membrane emulsification method, the present invention improves and optimizes the preparation process conditions. By using two or more pharmaceutical polymer excipients in combination and by specifically limiting the proportion of two or more pharmaceutical polymers, a one-month long-acting microsphere sustained-release formulation of rumeperone with no release stagnation period in the early stage is prepared. This can effectively improve compliance, provide maximum convenience for patients, and reduce economic costs. Attached Figure Description

[0030] Figure 1 The images show SEM images of the long-acting sustained-release microsphere formulations of lumepirocin prepared in Examples 1 and 3. The upper image shows the long-acting sustained-release microsphere formulation of lumepirocin prepared in Example 3 using the membrane emulsification method, and the lower image shows the long-acting sustained-release microsphere formulation of lumepirocin prepared in Example 1 using the single emulsion method.

[0031] Figure 2 The in vitro accelerated release curves of the long-acting sustained-release microspheres of rumeperone prepared in Example 1, Comparative Examples 1 and 2 are shown.

[0032] Figures 3-5 The following are, in order, the blood concentration curves of the long-acting sustained-release microsphere formulations of rumeperone prepared in rats according to Comparative Example 1, Example 1 and Comparative Example 2, Example 6 and Comparative Example 3. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0035] All raw materials used in this invention are commercially available.

[0036] Example 1 This embodiment uses the single-emulsion method and includes the following steps: (1) Weigh 1.5 g of lumepirozoline p-toluenesulfonate and 3.5 g of PLGA (LA:GA=50:50, molecular weight 35000, carboxyl-terminated), add 12 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use. (2) Take 500 mL of aqueous phase as external aqueous phase I, turn on the high-speed shear of the homogenizing emulsifier and control the speed to 6000 rpm; add the oil phase to the aqueous phase through a peristaltic pump with a peristaltic pump speed of 20 rpm, the whole process takes about 30 s; continue shearing for 30 s, the emulsification ends, and the Lumepiride sustained-release microsphere suspension is obtained. (3) Take 3500 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain a long-acting rumepiride microsphere sustained-release formulation with no release stagnation period in the early stage.

[0037] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 1.5 / (1.5+3.5)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 24.55%, with an encapsulation rate of 81.8%.

[0038] Example 2 This embodiment uses the single-emulsion method and includes the following steps: (1) Weigh 1.25 g of lumepirozoline p-toluenesulfonate and 1.25 g of PLGA (LA:GA=50:50, molecular weight 35000, carboxyl-terminated), add 6 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use. (2) Take 500 mL of aqueous phase as external aqueous phase I, turn on the high-speed shear of the homogenizing emulsifier and control the speed to 6000 rpm; add the oil phase to the aqueous phase through a peristaltic pump with a peristaltic pump speed of 20 rpm, the whole process takes about 30 s; continue shearing for 30 s, the emulsification ends, and the Lumepiride sustained-release microsphere suspension is obtained. (3) Take 3500 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain a long-acting rumepiride microsphere sustained-release formulation with no release stagnation period in the early stage.

[0039] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 1.25 / (1.25+1.25)=50%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 36.08% and the encapsulation rate was 72.2%.

[0040] Example 3 This embodiment uses membrane emulsification, and includes the following steps: (1) Weigh 0.3 g of lumepirozoline p-toluenesulfonate and 0.7 g of PLGA (PLGA with LA:GA=50:50, molecular weight 35000, carboxyl-terminated), add 3 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use. (2) Take 200 mL of aqueous phase as external aqueous phase I, and slowly and uniformly add oil phase to external aqueous phase I under mechanical stirring at 200 rpm. Install membrane tube with 50 μm pore size, turn on nitrogen pressure of 0.02 MPa in membrane emulsifier, and under this pressure, emulsion continuously passes through membrane tube. Repeat the cycle twice to obtain Lumepiride sustained-release microsphere suspension. (3) Take 800 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain a long-acting rumepiride microsphere sustained-release formulation with no release stagnation period in the early stage.

[0041] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 0.3 / (0.3+0.7)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 23.04%, with an encapsulation rate of 76.8%.

[0042] Example 4 This embodiment uses membrane emulsification, and includes the following steps: (1) Weigh 0.3 g of lumepirozoline p-toluenesulfonate and 0.7 g of PLGA (PLGA with LA:GA=50:50 (PLGA5050) and PLGA with LA:GA=75:25 (PLGA7525) have a mass ratio of 5:5, molecular weights of 35000 and 37000 respectively, and carboxyl-terminated), add 3 mL of dichloromethane to dissolve and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use. (2) Take 200 mL of aqueous phase as external aqueous phase I, and slowly and uniformly add oil phase to external aqueous phase I under mechanical stirring at 200 rpm. Install membrane tube with 50 μm pore size, turn on nitrogen pressure of 0.02 MPa in membrane emulsifier, and under this pressure, emulsion continuously passes through membrane tube. Repeat the cycle twice to obtain Lumepiride sustained-release microsphere suspension. (3) Take 800 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain a long-acting rumepiride microsphere sustained-release formulation with no release stagnation period in the early stage.

[0043] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 0.3 / (0.3+0.7)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 23.23% and the encapsulation rate was 77.4%.

[0044] Example 5 This embodiment uses membrane emulsification, and includes the following steps: (1) Weigh 0.3 g of lumepiride p-toluenesulfonate and 0.7 g of PLGA (PLGA5050:PLGA7525=3:7, molecular weights of 35000 and 37000 respectively, carboxyl-terminated), add 3 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use. (2) Take 200 mL of aqueous phase as external aqueous phase I, and slowly and uniformly add oil phase to external aqueous phase I under mechanical stirring at 200 rpm. Install membrane tube with 50 μm pore size, turn on nitrogen pressure of 0.02 MPa in membrane emulsifier, and under this pressure, emulsion continuously passes through membrane tube. Repeat the cycle twice to obtain Lumepiride sustained-release microsphere suspension. (3) Take 800 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain a long-acting rumepiride microsphere sustained-release formulation with no release stagnation period in the early stage.

[0045] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 0.3 / (0.3+0.7)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 24.07%, with an encapsulation rate of 80.2%.

[0046] Example 6 This embodiment uses membrane emulsification, and includes the following steps: (1) Weigh 0.3 g of lumepiride p-toluenesulfonate and 0.7 g of PLGA (PLGA5050:PLGA7525=2:8, molecular weights of 35000 and 37000 respectively, carboxyl-terminated), add 3 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use; (2) Take 200 mL of aqueous phase as external aqueous phase I, and slowly and uniformly add oil phase to external aqueous phase I under mechanical stirring at 200 rpm. Install membrane tube with 50 μm pore size, turn on nitrogen pressure of 0.02 MPa in membrane emulsifier, and under this pressure, emulsion continuously passes through membrane tube. Repeat the cycle twice to obtain Lumepiride sustained-release microsphere suspension. (3) Take 800 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain a long-acting rumepiride microsphere sustained-release formulation with no release stagnation period in the early stage.

[0047] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 0.3 / (0.3+0.7)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 24.23%, with an encapsulation rate of 80.8%.

[0048] Example 7 This embodiment uses membrane emulsification, and includes the following steps: (1) Weigh 0.3 g of lumepirozoline p-toluenesulfonate and 0.7 g of PLGA (PLGA5050:PLGA7525=1:9, molecular weights of 35000 and 37000 respectively, carboxyl-terminated), add 3 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use; (2) Take 200 mL of aqueous phase as external aqueous phase I, and slowly and uniformly add oil phase to external aqueous phase I under mechanical stirring at 200 rpm. Install membrane tube with 50 μm pore size, turn on nitrogen pressure of 0.02 MPa in membrane emulsifier, and under this pressure, emulsion continuously passes through membrane tube. Repeat the cycle twice to obtain Lumepiride sustained-release microsphere suspension. (3) Take 800 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain a long-acting rumepiride microsphere sustained-release formulation with no release stagnation period in the early stage.

[0049] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 0.3 / (0.3+0.7)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 22.65% and the encapsulation rate was 75.5%.

[0050] Example 8 This embodiment uses membrane emulsification, and includes the following steps: (1) Weigh 0.3 g of lumepirozoline p-toluenesulfonate and 0.7 g of PLGA (PLGA5050:PLGA7525:PLGA7525=1:1:8, with molecular weights of 35000, 43000 and 37000 respectively, and carboxyl-terminated), add 3 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use; (2) Take 200 mL of aqueous phase as external aqueous phase I, and slowly and uniformly add oil phase to external aqueous phase I under mechanical stirring at 200 rpm. Install membrane tube with 50 μm pore size, turn on nitrogen pressure of 0.02 MPa in membrane emulsifier, and under this pressure, emulsion continuously passes through membrane tube. Repeat the cycle twice to obtain Lumepiride sustained-release microsphere suspension. (3) Take 800 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain a long-acting rumepiride microsphere sustained-release formulation with no release stagnation period in the early stage.

[0051] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 0.3 / (0.3+0.7)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 23.01%, with an encapsulation rate of 76.7%.

[0052] Comparative Example 1 This embodiment uses the single-emulsion method and includes the following steps: (1) Weigh 1.5 g of lumepirozoline p-toluenesulfonate and 3.5 g of PLGA (LA:GA=50:50, molecular weight 35000, carboxyl-terminated), add 12 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use. (2) Take 500 mL of the aqueous phase as the external aqueous phase I, turn on the high-speed shear of the homogenizing emulsifier and control the speed to 5000 rpm; add the oil phase to the aqueous phase through a peristaltic pump with a peristaltic pump speed of 20 rpm, and the whole process takes about 30 s; continue shearing for 30 s, and the emulsification ends, and a Lumepiride sustained-release microsphere suspension is obtained. (3) Take 1500 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumeperone sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 °C and stir continuously for 2 h to evaporate to obtain microspheres; wash and collect the obtained microspheres through a sieve, and dry them to obtain rumeperone long-acting microsphere sustained-release formulation.

[0053] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 1.5 / (1.5+3.5)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 22.21%, with an encapsulation rate of 74.0%.

[0054] Comparative Example 2 This embodiment uses the single-emulsion method and includes the following steps: (1) Weigh 1.5 g of lumepirozoline p-toluenesulfonate and 3.5 g of PLGA (LA:GA=50:50, molecular weight 35000, carboxyl-terminated), add 12 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use. (2) Take 500 mL of the aqueous phase as the external aqueous phase I, turn on the high-speed shear of the homogenizing emulsifier and control the speed to 5000 rpm; add the oil phase to the aqueous phase through a peristaltic pump with a peristaltic pump speed of 20 rpm, and the whole process takes about 30 s; continue shearing for 30 s, and the emulsification ends, and a Lumepiride sustained-release microsphere suspension is obtained. (3) Take 3500 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumeperone sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 40 °C and stir continuously for 6 h to obtain microspheres; wash and collect the obtained microspheres through a sieve, and dry them to obtain rumeperone long-acting microsphere sustained-release formulation.

[0055] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 1.5 / (1.5+3.5)=30%. The content and in vitro release of the obtained long-acting sustained-release microsphere formulation of rumepiride were tested, and the actual drug loading of the microspheres was found to be 20.90% and the encapsulation rate was 69.7%.

[0056] Comparative Example 3 This embodiment uses membrane emulsification, and includes the following steps: (1) Weigh 0.3 g of lumepirozoline p-toluenesulfonate and 0.7 g of PLGA (LA:GA=75:25, molecular weight 37000, carboxyl-terminated), add 3 mL of dichloromethane to dissolve, and obtain a clear oil phase solution, which is stored at 2~8 ℃ for later use; prepare a 0.5 wt% PVA aqueous solution as the aqueous phase, which is stored at 2~8 ℃ for later use. (2) Take 200 mL of aqueous phase as external aqueous phase I, and slowly and uniformly add oil phase to external aqueous phase I under mechanical stirring at 200 rpm. Install membrane tube with 50 μm pore size, turn on nitrogen pressure of 0.02 MPa in membrane emulsifier, and under this pressure, emulsion continuously passes through membrane tube. Repeat the cycle 3 times to obtain Lumepiride sustained-release microsphere suspension. (3) Take 800 mL of aqueous phase as external aqueous phase II and start stirring; pour the rumepiride sustained-release microsphere suspension into external aqueous phase II and stir continuously at room temperature for 2 h to evaporate. Then, raise the temperature to 35 ℃ and stir continuously for 2 h to evaporate. Finally, raise the temperature to 40 ℃ and stir continuously for 4 h to evaporate to obtain microspheres. Wash and collect the obtained microspheres through a sieve and dry them to obtain the rumepiride long-acting microsphere sustained-release formulation.

[0057] The theoretical drug loading of the long-acting microsphere sustained-release formulation of rumepiride is 0.3 / (0.3+0.7)=30%. The content and in vitro release of the obtained long-acting sustained-release microspheres of rumepiride were tested, and the actual drug loading of the microspheres was found to be 22.93% and the encapsulation rate was 76.4%.

[0058] Sample Analysis I. Particle Size Analysis The long-acting sustained-release microsphere formulations of rumepiride prepared in Examples 1 and 3 were imaged using SEM, and the results are as follows: Figure 1 As shown. Figure 1 The figures show SEM images of the long-acting sustained-release microsphere formulations of rumepiride prepared in Examples 1 and 3. As shown in the figure, compared with the single emulsion method, the microspheres prepared by the membrane emulsification method have better morphology and more uniform particle size.

[0059] II. In vitro release detection Prepare a phosphate buffer solution with a pH of 7.4 containing 0.1% sodium dodecyl sulfate (SDS). Accurately weigh the lumepimeperone long-acting sustained-release microspheres prepared in Examples 1, 4-7, and Comparative Examples 1-3, place them in Erlenmeyer flasks, and add them to 40 mL of the above dissolution medium. Perform an in vitro accelerated release test on a shaker at 45 °C and 100 rpm. Take samples, centrifuge the samples at 8000 rpm for 5 min, and then perform HPLC analysis on the supernatant. The results are shown in the figure. Figure 2 and Figure 3 .

[0060] Figure 2 The in vitro accelerated release curves of the rumeperone long-acting sustained-release microspheres prepared in Example 1, Comparative Examples 1 and 2 are shown below. Figure 2 It is known that different liquid drying conditions will significantly affect the release of microspheres. The longer the liquid drying heating time, the higher the aging degree of the PLGA microsphere material, the lower the slope of the early stage of in vitro release, and the slower the release.

[0061] Figure 3 The in vitro accelerated release curves of the lumepone long-acting sustained-release microspheres prepared in Examples 4-7 and Comparative Example 3 are shown below. Figure 3 It can be seen that the use of different types of PLGA in proportion will affect the in vitro dissolution of the microsphere formulation in January. The higher the proportion of 7525 PLGA, the slower the dissolution and the lower the slope in the early stage. The higher the proportion of 5050 PLGA, the faster the dissolution and the higher the slope in the early stage.

[0062] III. In vivo release assay in SD rats The long-acting sustained-release microsphere formulations of rumeperone prepared in Examples 1 and 6, and Comparative Examples 1 to 3 were subjected to in vivo release tests in SD rats. Specifically, each group used three male SD rats, weighing approximately 200-250 g, as experimental animals. The SD rats were administered intramuscular injections. Before administration (0 hours) and at different time points after administration, 0.1 mL of blood was collected from the jugular vein of the SD rats and placed in centrifuge tubes containing sodium heparin. The tubes were centrifuged at 4000 rpm for 5 min, and the separated plasma was stored at -80 ℃ for later analysis. The sampling time points for the 2-week sustained-release microsphere formulation of rumepiride were 1 h, 2 h, 4 h, 8 h, 12 h, 1 d, 2 d, 3 d, 4 d, 5 d, 6 d, 7 d, 8 d, 9 d, 10 d, 12 d, 14 d, 16 d, and 18 d. The sampling time points for the 1-month sustained-release microsphere formulation of rumepiride were 1 h, 12 h, 1 d, 2 d, 4 d, 6 d, 8 d, 10 d, 12 d, and 14 d. Days 1, 16, 18, 20, 22, 24, 26, 28, 30, 32, and 34 were observed. Plasma concentrations of rumepiride were determined using a Waters ACQuity UPLC Class I plus, AB API 6500+ LC / MS / MS instrument. Results are as follows: Figures 3-5 As shown.

[0063] Figures 3-5 The following are, in order, the plasma concentration curves of rumeperone long-acting sustained-release microspheres prepared in Comparative Examples 1, 1, 2, 6, and 3 in rats. Figure 3 As shown, the long-acting sustained-release microsphere formulation of lumepirocin prepared in Comparative Example 1 exhibited a significant burst release phenomenon in SD rats, with a release period of approximately 2 weeks.

[0064] like Figure 4 As shown, the long-acting sustained-release microsphere formulation of rumepiride prepared in Example 1 showed no obvious burst release in SD rats, with a release period of approximately 2 weeks and no significant release stagnation in the early stage, effectively improving compliance, maximizing convenience for patients, and reducing economic costs. In contrast, the long-acting sustained-release microsphere formulation of rumepiride prepared in Comparative Example 2 also showed no obvious burst release, with a release period of approximately 2 weeks, but with a significant release stagnation in the early stage, during which oral rumepiride capsules were required to maintain efficacy.

[0065] like Figure 5As shown, the long-acting sustained-release microsphere formulation of rumepiride prepared in Comparative Example 3 showed no obvious burst release phenomenon, with a release period of approximately one month. However, there was a significant release stagnation period in the early stage, during which oral rumepiride capsules were required to maintain efficacy. The long-acting sustained-release microsphere formulation of rumepiride prepared in Example 6 showed no obvious burst release phenomenon, with a release period of approximately one month, and no significant release stagnation period in the early stage, effectively improving compliance, maximizing convenience for patients, and reducing economic costs.

[0066] In summary, combining Figure 1 , Figure 3 and Figure 4 As shown in Example 1 and Comparative Examples 1 and 2, the release of lumepirolimus long-acting sustained-release microspheres with a 2-week sustained-release cycle in SD rats exhibits a certain correlation with in vitro release. A higher initial slope of the in vitro release curve indicates a significant burst release in vivo, while a lower initial slope indicates a release stagnation period in vivo. Using the same PLGA material, different liquid drying conditions significantly affect the in vitro release of the microspheres, thus influencing in vivo results. Longer liquid drying heating times result in higher aging of the PLGA material, which can effectively reduce the burst release behavior of lumepirolimus microspheres in vivo. However, excessive PLGA aging can lead to a lack of initial release in vivo. Therefore, by effectively limiting the liquid drying step, the liquid drying conditions were determined to be 35 °C for 2 hours followed by 40 °C for 4 hours, resulting in a 2-week lumepirolimus long-acting sustained-release microsphere formulation without an initial release stagnation period in vivo.

[0067] Combination Figure 2 , Figure 5 As shown in Example 6 and Comparative Example 3, the release of the 1-month sustained-release lumepone long-acting sustained-release microsphere formulation in SD rats is somewhat correlated with its in vitro release. The higher the proportion of PLGA 7525, the slower the initial dissolution and the lower the slope, resulting in a release lag period in SD rats. By effectively limiting the ratio of the two different types of PLGA, controlling the ratio of PLGA5050 and PLGA7525 at 2:8, a 1-month lumepone long-acting sustained-release microsphere formulation without an initial release lag period in vivo can be obtained.

[0068] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. (1) Dissolve the active ingredient of lumepirocin and the pharmaceutical polymer excipient in an organic solvent, stir and sonicate to obtain an oil phase; dissolve the surfactant in water to obtain an aqueous phase; (2) Take a portion of the aqueous phase obtained in step (1) as external aqueous phase I, and prepare a lumepimide sustained-release microsphere suspension by using a single emulsion method or a membrane emulsification method; (3) Take the remaining aqueous phase from step (1) as external aqueous phase II, add the lumepirolen sustained-release microsphere suspension obtained in step (2) to external aqueous phase II, and continue heating and stirring to dry in the liquid until the organic solvent is completely evaporated. After filtration, washing and sieving, collect the lumepirolen sustained-release microspheres, freeze-dry and obtain the long-acting lumepirolen microsphere sustained-release formulation with no release stagnation period in the early stage. The mass ratio of the active ingredient rumeperone to the pharmaceutical polymeric excipient is 1:4 to 1:1; The pharmaceutical polymeric excipient is a glycolide-lactide copolymer with a weight-average molecular weight of 5,000 to 150,000 Da, wherein the molar ratio of lactic acid units to glycolic acid units in the glycolide-lactide copolymer is 50:50 to 95:

5.

2. The long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to claim 1, characterized in that, The liquid drying includes room temperature drying and staged temperature increase drying. The staged temperature increase drying involves first drying at 25~35 ℃ for 1~3 h, and then raising the temperature to 35~45 ℃ to continue drying for 3~5 h.

3. The method for preparing the long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to claim 2, characterized in that, The conditions for the staged heating and drying process are: drying at 35 ℃ for 1-3 hours, followed by heating to 40 ℃ for 3-5 hours.

4. The long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to claim 3, characterized in that, In step (1), the pharmaceutical polymeric excipient is a glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 50:

50.

5. The long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to claim 3, characterized in that, In step (1), the pharmaceutical polymeric excipient is a combination of a glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 50:50 and a glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 75:

25. In the composition, the mass ratio of the glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 50:50 and the glycolide-lactide copolymer with a molar ratio of lactic acid units to glycolic acid units of 75:25 is 1:9 to 5:

5.

6. The long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to claim 1, characterized in that, In step (1), the organic solvent is at least one of dichloromethane, dimethyl sulfoxide, ethyl acetate, acetone, chloroform, benzyl alcohol, diethyl ether, and N,N-dimethylformamide; The surfactant is at least one of polyvinyl alcohol, sodium carboxymethyl cellulose, poloxamer, Tween 80, and sodium dodecyl sulfonate.

7. The long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to claim 1, characterized in that, In step (2), the steps of the single emulsion method are as follows: the oil phase is added to the external aqueous phase I, and after high-speed shearing, a lumepirocin sustained-release microsphere suspension is obtained; wherein the volume ratio of the oil phase to the external aqueous phase I is 1:20~100.

8. The long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to claim 1, characterized in that, In step (2), the membrane emulsification method is as follows: the oil phase is slowly and uniformly added to the external aqueous phase I to obtain an emulsion, and the emulsion is passed through a membrane tube under pressure to obtain a lumepimeperone sustained-release microsphere suspension; wherein the volume ratio of the oil phase to the external aqueous phase I is 1:5~50; the pore size of the membrane tube is 10~150 µm, and the pressure is 0.01~0.1 MPa.

9. The long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to any one of claims 1 to 8, characterized in that, The particle size of the lumepirocin long-acting microsphere sustained-release formulation is 2~120 μm.

10. The long-acting microsphere sustained-release formulation of rumeperone with no initial release lag period according to any one of claims 1 to 8, characterized in that, The effective time of the aforementioned lumepirocin long-acting microsphere sustained-release formulation is ≥2 weeks.

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