Long-acting sustained release formulation composition of lurasidone and method of preparing the same

Abstract

The present application discloses a long-acting sustained-release formulation composition of lurasidone, which comprises lurasidone or a salt thereof and a high molecular material, wherein the mass ratio of lurasidone to the high molecular material is 0.5:9.5-5:5, the high molecular material comprises a main material polylactide and an optional release modifier, the mass of the release modifier is 0%-95% of the main material polylactide, and the release modifier is selected from polylactide or one or more mixtures of polylactide glycolide. The long-acting sustained-release formulation of the present application can achieve a sustained-release effect for 1 week to 3 months, can improve the compliance of patients, and has no obvious burst release in the early stage, no release lag period, smooth formulation release, and ensures the safety and effectiveness of drug release.

Description

Technical Field

[0001] This invention relates to a long-acting sustained-release formulation of rumepiride and its preparation method. Background Technology

[0002] Schizophrenia is a common, chronic, and highly disabling mental disorder affecting approximately 1% of the world's population. Antipsychotic medication is the primary treatment for schizophrenia; however, current drug therapy offers limited relief and is frequently accompanied by various adverse reactions. In December 2019, the U.S. Food and Drug Administration approved a novel antipsychotic drug—lumateperone. This drug has a unique mechanism of action and good safety and tolerability, effectively treating positive symptoms while improving negative symptoms, depressive symptoms, and social functioning.

[0003] Lumepiride is a novel small-molecule antipsychotic drug, first developed by Bristol-Myers Squibb and exclusively licensed to Intra-Cellular Therapies in 2005. It is a first-in-class drug that selectively modulates serotonin, dopamine (DA), and glutamate simultaneously. In December 2019, it was approved by the FDA in the United States for the treatment of schizophrenia in adults. In addition to schizophrenia, lumepimepiride has potential efficacy against bipolar depression, behavioral disorders associated with dementia and Alzheimer's disease, insomnia, and major depressive disorder (MDD), while also exhibiting better tolerability and fewer adverse reactions such as weight gain and dyslipidemia.

[0004] Currently, the only product on the market is Lumepiride p-toluenesulfonate capsules. This product is an oral preparation that needs to be administered daily to maintain its blood drug concentration. Frequent administration leads to poor patient adherence.

[0005] CN115671057A discloses a long-acting microsphere sustained-release formulation of rumepiride, which uses poly(lactic-co-glycolic acid) (PLGA) polymer material to prepare the microspheres. However, these microspheres have the following problems: i) the particle size distribution is narrow, resulting in overly concentrated microsphere release behavior, which is not conducive to maintaining a stable blood drug concentration during the dosing cycle; ii) there is a long lag period in vivo, resulting in unstable release; iii) the initial burst release is too high. Invention Overview

[0007] A first aspect of the present invention provides a long-acting sustained-release formulation composition of lumepirox omeprazole, comprising lumepirox omeprazole or a salt thereof and a polymeric material, wherein the mass ratio of lumepirox omeprazole to the polymeric material is 0.5:9.5 to 5:5, the polymeric material comprising a main material, polylactide (PLA), and optionally a release modifier, wherein the mass of the release modifier is 0% to 95% of the main material, polylactide, and the release modifier is selected from one or more mixtures of polylactide or polylactide glycolide.

[0008] In some embodiments of the present invention, the mass ratio of lumepone to polymeric material is 1:9 to 4:6; preferably, the mass ratio of lumepone to polymeric material is 1.5:8.5 to 3:7; preferably, the mass ratio of lumepone to polymeric material is 2:8 to 3:7; more preferably, the mass ratio of lumepone to polymeric material is 2:(6 to 8); even more preferably, the mass ratio of lumepone to polymeric material is 2:(6.5 to 7).

[0009] In some embodiments of the present invention, the molecular weight of the main material polylactide is 5,000 to 100,000 Daltons, preferably 10,000 to 80,000 Daltons, more preferably 10,000 to 50,000 Daltons, more preferably 20,000 to 30,000 Daltons, and even more preferably 25,000 Daltons.

[0010] In some embodiments of the present invention, the release regulator comprises 0% to 50% of the main material polylactide; preferably 0% to 40%; more preferably 0% to 35%; and even more preferably 0% to 30%.

[0011] In some embodiments of the present invention, the molar ratio of lactide to glycolide in the polylactide-glycol group of the release regulator is 50:50 to 95:5, and the molecular weight of the polylactide-glycol group is 5,000 to 100,000 Daltons; preferably, the molar ratio of lactide to glycolide is 50:50 to 85:15, and the molecular weight of the polylactide-glycol group is 5,000 to 90,000 Daltons; more preferably, the molar ratio of lactide to glycolide is 50:50 to 75:25, and the molecular weight of the polylactide-glycol group is 10,000 to 80,000 Daltons; even more preferably, the molar ratio of lactide to glycolide is 50:50 to 75:25, and the molecular weight of the polylactide-glycol group is 60,000 to 70,000 Daltons.

[0012] In some embodiments of the present invention, the molecular weight of the polylactide in the release regulator is 5,000 to 100,000 Daltons, preferably 5,000 to 80,000 Daltons, and more preferably 5,000 to 50,000 Daltons.

[0013] In some embodiments of the present invention, the release regulator is poly(lactic-co-glycolic acid) PLGA with a lactide to glycolide molar ratio of 50:50 to 85:15 and a molecular weight of 5000 to 90000 Daltons; preferably, the release regulator is poly(lactic-co-glycolic acid) PLGA with a lactide to glycolide molar ratio of 50:50 to 75:25 and a molecular weight of 10000 to 80000 Daltons; preferably, the release regulator is poly(lactic-co-glycolic acid) with a lactide to glycolide molar ratio of 75:25 and a molecular weight of 10000 to 80000 Daltons; preferably, the release regulator is poly(lactic-co-glycolic acid) with a lactide to glycolide molar ratio of 75:25 and a molecular weight of 60000 to 70000 Daltons.

[0014] In some embodiments of the present invention, the polymeric material is polylactide.

[0015] In some embodiments of the present invention, the polymeric material is a mixture of polylactide and polylactide glycolide, wherein the mass of polylactide glycolide is 20% to 50% of that of polylactide.

[0016] In some embodiments of the present invention, the salt of rumepiride is selected from rumepiride erucic acid salt, oleate salt, α-linolenic acid salt, palmitate salt, pearlate salt, undecenoate salt, hexadecanoate salt, laurate salt, stearate salt, adipate salt, and benzoate salt.

[0017] In some embodiments of the present invention, the long-acting sustained-release formulation of lumepirocin is selected from microspheres or subcutaneous implants.

[0018] A second aspect of the present invention provides a method for preparing lumepirocin long-acting sustained-release microspheres, comprising the following steps:

[0019] The polymer material and lumepimeperone or its salt are dissolved in a solvent, sterilized and filtered to obtain the oil phase, and kept at a controlled temperature of 2–35°C for later use. A 0.2–5% aqueous solution of polyvinyl alcohol (PVA) is prepared, sterilized and filtered to obtain the aqueous phase, and kept at a controlled temperature of 2–35°C for later use. The oil phase is added to the aqueous phase in a shearing machine to form a pre-emulsion, which is then stirred and evaporated. After filtration, the microspheres are washed with distilled water and freeze-dried to obtain lumepimeperone long-acting sustained-release microspheres.

[0020] In some embodiments of the method of the present invention, the polymer material and lumepiroline or its salt are dissolved in dichloromethane.

[0021] In some embodiments of the method of the present invention, the rotational speed of the shearing machine is 1000-8000 rpm.

[0022] In some embodiments of the method of the present invention, the colostrum is stirred and evaporated at 50-500 rpm, preferably at 100-200 rpm.

[0023] A third aspect of the present invention provides a method for preparing a long-acting sustained-release subcutaneous implant of lumepimeperone, comprising the following steps:

[0024] The polymer material is mixed with rumepiride or its salt, extruded, then drawn into fibers and granulated, and sterilized by irradiation to obtain rumepiride long-acting sustained-release subcutaneous implant.

[0025] In some embodiments of the method of the present invention, a twin-screw extruder is used for extrusion.

[0026] In some embodiments of the method of the present invention, the extrusion parameters of the twin-screw extruder are as follows: feed temperature: 15-30℃, feed temperature: 35-40℃, mixing: 60-100℃, degassing: 80-100℃, extrusion: 50-80℃, die temperature: 50-60℃, extrusion speed: 80-120rpm, torque: 7-8N.cm.

[0027] In some embodiments of the method of the present invention, the extrusion parameters of the twin-screw extruder are as follows: feed temperature: room temperature, feed temperature: 35~40℃, mixing: 80~100℃, degassing: 100℃, extrusion: 80℃, die temperature: 60℃, extrusion speed: 100rpm, torque: 7~8N.cm.

[0028] In the context of this application, the term "molecular weight" refers to the weight-average molecular weight of a polymer.

[0029] The long-acting sustained-release formulation of this invention can achieve a sustained-release effect ranging from 1 week to 3 months, which can improve patient compliance. Furthermore, there is no obvious burst release in the early stage, no release lag period, and the formulation release is stable, ensuring the safety and effectiveness of drug release.

[0030] This invention uses emulsification technology to prepare microspheres, which can effectively control the particle size distribution and thus obtain a stable pharmacokinetic curve. Attached Figure Description

[0031] Figure 1 The pharmacokinetic curves of the microspheres in Examples 1, 2 and 3 on days 0-20 (25 or 60).

[0032] Figure 2 The pharmacokinetic curves of the microspheres in Examples 1, 2 and 3 on day 0-1 are shown.

[0033] Figure 3 The pharmacokinetic curves of the microspheres in Example 2 are shown from day 0 to 25.

[0034] Figure 4 The pharmacokinetic curves of the microspheres in Example 2 on day 0-1 are shown.

[0035] Figure 5 The pharmacokinetic curves of the microspheres of Example 3 and the subcutaneous implant of Example 4 are shown on days 0-60.

[0036] Figure 6 The pharmacokinetic curves of the microspheres of Examples 3 and 5 on days 0-60 (100).

[0037] Figure 7 The pharmacokinetic curves of the microspheres in Examples 3 and 5 on day 0-1 are shown. Example

[0038] The present invention will be further illustrated by the following embodiments. The embodiments 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 can make some non-essential improvements and adjustments, which still fall within the protection scope of the present invention.

[0039] Unless otherwise specified, all steps in the embodiments of the present invention are performed at room temperature. Room temperature refers to a temperature of 20℃±5℃.

[0040] Example 1

[0041] 0.7 g of lumepirozoline and 2.3 g of PLGA (lactide:glycolic acid = 50:50, carboxyl-terminated, molecular weight 40,000 Daltons) were dissolved in 10 mL of dichloromethane. The mixture was then added to 300 mL of 0.5% PVA aqueous solution under shearing conditions at 1000 rpm to form a primary emulsion. The emulsion was then stirred and evaporated at 200 rpm for 4 hours. After filtration, the microspheres were washed three times with distilled water and lyophilized to obtain lumepirozoline long-acting sustained-release microspheres. The microsphere particle size (D50) was measured to be 57 μm using a laser particle size analyzer.

[0042] Example 2

[0043] 0.7 g of lumepirozoline and 2.3 g of PLGA (lactide:glycolic acid = 75:25, ester-terminated, molecular weight 70,000 Daltons) were dissolved in 10 mL of dichloromethane. The solution was then added to 300 mL of 0.5% PVA aqueous solution under shearing conditions at 1000 rpm to form a primary emulsion. The emulsion was then stirred and evaporated at 200 rpm for 4 hours. After filtration, the microspheres were washed three times with distilled water and lyophilized to obtain lumepirozoline long-acting sustained-release microspheres. The particle size (D50) of the microspheres was measured to be 61 μm using a laser particle size analyzer.

[0044] Example 3

[0045] 0.7 g of lumepirozoline and 2.3 g of PLA (molecular weight 25,000 Daltons) were dissolved in 10 mL of dichloromethane. The solution was then added to 300 mL of 0.5% PVA aqueous solution under shearing conditions at 1000 rpm to form a primary emulsion. The emulsion was then stirred and evaporated at 200 rpm for 4 hours. After filtration, the microspheres were washed three times with distilled water and lyophilized to obtain long-acting sustained-release lumepirozoline microspheres. The microsphere particle size (D50) was measured to be 59 μm using a laser particle size analyzer.

[0046] Example 4

[0047] Pulverized 7g of lumepirozol and 23g of PLA (molecular weight 25,000 Daltons) and mixed well for later use.

[0048] A Thermo Fisher Pharma 11 twin-screw extruder was selected. The hot melt extruder was turned on and the following settings were set: feed temperature: room temperature; feed temperature: 35-40℃; mixing temperature: 80-100℃; degassing temperature: 100℃; extrusion temperature: 80℃; die temperature: 60℃; pressure: 60 bar; extrusion speed: 100 rpm; torque: 7-8 N.cm.

[0049] Wire drawing and pelletizing: After extrusion, the wire is drawn into short rods of 3×30mm;

[0050] Irradiation: The short rod is sterilized by irradiation at 18 kGy to obtain lumepirocin subcutaneous implant.

[0051] Example 5

[0052] 0.7 g of lumepirozol, 1.725 g of PLA (molecular weight 25,000 Daltons), and 0.575 g of PLGA (lactide:glycol = 75:25, ester-terminated, molecular weight 70,000 Daltons) were dissolved in 10 mL of dichloromethane. The mixture was then added to 300 mL of 0.5% PVA aqueous solution at 1000 rpm to form a primary emulsion. The emulsion was then stirred and evaporated at 200 rpm for 4 hours. After filtration, the microspheres were washed three times with distilled water and lyophilized to obtain long-acting sustained-release lumepirozol microspheres.

[0053] Experimental Example 1

[0054] SD rats (n=4, female) were administered 10.5 mg / kg of the microspheres from Examples 1-3 and 5 via single intramuscular injection, respectively, and 10.5 mg / kg of the subcutaneous implant from Example 4 via subcutaneous implantation. The day of administration was designated as day 0. SD rats were administered the following doses at 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 5 h (or 4 h, 6 h), 8 h, 1 d, 2 d, and 3 h on the day of administration, respectively. Blood samples were collected on days d, 4 (or 5), 7, 8, 9, 11, 14 (or 13, 15), 17, 20, 25, 30, 35, and 40. Blood was then collected every 5 days based on the test results until complete release. 0.25 mL of blood was collected from the tail vein. Whole blood was temporarily stored on wet ice and centrifuged at 1500g for 10 min within 1 hour to separate the plasma (4℃). The collected plasma was stored at -80℃ for later analysis. After determining the plasma drug concentration following drug administration, a drug-time curve was fitted, and pharmacokinetic parameters were calculated. The results are as follows: Figure 1-7 As shown.

[0055] Combination Figure 1-4 It can be seen that the microspheres of Example 1 have an excessively high burst release in the early stage, the microspheres of Example 2 have a lag period of 4-5 days, while the microspheres of Example 3 have a longer release cycle and a significantly reduced burst release compared to Examples 1 and 2, and there is no lag period. This indicates that the microspheres of Example 3 can be used as a long-acting sustained-release formulation.

[0056] from Figure 5 It can be seen that there is no significant difference in the release cycle between the microspheres of Example 3 and the subcutaneous implant of Example 4. Furthermore, the release curve of the subcutaneous implant of Example 4 is smoother.

[0057] Combination Figure 6 and Figure 7 It can be seen that the microspheres of Example 5 have a longer release period than the microspheres of Example 3.

[0058] The methods and products described in this application have been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and products described herein without departing from the content, spirit, and scope of this application to achieve the technology of this application. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this application.

Claims

1. A long-acting sustained-release formulation composition of lumepirocin, characterized in that, The long-acting sustained-release formulation composition is selected from microspheres or subcutaneous implants, comprising lumepimeperone or its salts and a polymeric material, wherein the mass ratio of lumepimeperone to the polymeric material is 0.5:9.5 to 5:5, and the polymeric material comprises a main material, polylactide, and optionally a release modifier, wherein the mass of the release modifier is 0% to 95% of the main material, polylactide, and the release modifier is selected from one or more mixtures of polylactide or polylactide-glycolic acid; the molecular weight of the main material, polylactide, is 5000 to 100000 Daltons; the molar ratio of lactide to glycolide in the polylactide-glycolic acid in the release modifier is 50:50 to 95:5, and the molecular weight of the polylactide-glycolic acid is 5000 to 100000 Daltons; the molecular weight of the polylactide in the release modifier is 5000 to 100000 Daltons.

2. The long-acting sustained-release formulation composition of rumepiride according to claim 1, characterized in that, The mass ratio of lumepirocin to the polymer material is 1:9 to 4:

6.

3. The long-acting sustained-release formulation composition of rumepiride according to claim 1, characterized in that, The mass ratio of lumepiroline to the polymer material is 1.5:8.5~3:

7.

4. The long-acting sustained-release formulation composition of rumepiride according to any one of claims 1-3, characterized in that, The molecular weight of the main material, polylactide, is 10,000 to 80,000 Daltons.

5. The long-acting sustained-release formulation composition of rumepiride according to claim 4, characterized in that, The molecular weight of the main material, polylactide, is 10,000 to 50,000 Daltons.

6. The long-acting sustained-release formulation composition of rumepiride according to any one of claims 1-3, characterized in that, The mass of the release regulator is 0% to 50% of the main material, polylactide.

7. The long-acting sustained-release formulation composition of rumepiride according to claim 6, characterized in that, The mass of the release regulator is 0% to 40% of the main material, polylactide.

8. The long-acting sustained-release formulation composition of rumepiride according to claim 7, characterized in that, The mass of the release regulator is 0% to 30% of the main material, polylactide.

9. The long-acting sustained-release formulation composition of rumepiride according to any one of claims 1-3, characterized in that, The release regulator contains polylactide in a molar ratio of lactide to glycolide of 50:50 to 85:15, and the molecular weight of the polylactide is 5000 to 90000 Daltons.

10. The long-acting sustained-release formulation composition of rumepiride according to claim 9, characterized in that, The release regulator contains polylactide and glycolide in a molar ratio of lactide to glycolide of 50:50 to 75:25, and the molecular weight of the polylactide and glycolide is 10,000 to 80,000 Daltons.

11. The long-acting sustained-release formulation composition of rumepiride according to any one of claims 1-3, characterized in that, The molecular weight of the polylactide in the release regulator is 5,000 to 80,000 Daltons.

12. The long-acting sustained-release formulation composition of rumepiride according to claim 11, characterized in that, The molecular weight of the polylactide in the release regulator is 5,000 to 50,000 Daltons.

13. The long-acting sustained-release formulation composition of rumepiride according to any one of claims 1-3, characterized in that, The release regulator is polylactide-glycolic acid with a molar ratio of lactide to glycolide of 50:50 to 85:15 and a molecular weight of 5,000 to 90,000 Daltons.

14. The long-acting sustained-release formulation composition of rumepiride according to claim 13, characterized in that, The release regulator is polylactide-glycolic acid with a molar ratio of lactide to glycolide of 50:50 to 75:25 and a molecular weight of 10,000 to 80,000 Daltons.

15. The long-acting sustained-release formulation composition of rumepiride according to claim 14, characterized in that, The release regulator is polylactide-glycolic acid with a molar ratio of lactide to glycolide of 75:25 and a molecular weight of 10,000 to 80,000 Daltons.

16. The long-acting sustained-release formulation composition of rumepiride according to any one of claims 1-3, characterized in that, The polymeric material is polylactide; or, the polymeric material is a mixture of polylactide and polylactide glycolide, wherein the mass of the polylactide glycolide is 20% to 50% of the total mass of the polylactide.

17. The long-acting sustained-release formulation composition of rumepiride according to any one of claims 1-3, characterized in that, The salts of rumepiride are selected from rumepiride erucic acid salt, oleate salt, α-linolenic acid salt, palmitate salt, pearlate salt, undecenoate salt, hexadecanoate salt, laurate salt, stearate salt, adipate salt, and benzoate salt.

18. A method for preparing lumepone long-acting sustained-release microspheres according to any one of claims 1-17, comprising the following steps: The polymer material and the lumepirozon or its salt are dissolved in a solvent, sterilized and filtered to obtain the oil phase, and kept at a temperature of 2-35°C for later use; a 0.2-5% PVA aqueous solution is prepared, sterilized and filtered to obtain the aqueous phase, and kept at a temperature of 2-35°C for later use; the oil phase is added to the aqueous phase in a shearing machine to form a primary emulsion, then stirred and evaporated, filtered, the microspheres are washed with distilled water, and freeze-dried to obtain the lumepirozon long-acting sustained-release microspheres.

19. A method for preparing the long-acting sustained-release subcutaneous implant of rumepiride according to any one of claims 1-17, comprising the following steps: The polymer material and rumepiride or its salt are mixed, extruded, then drawn into fibers and granulated, and sterilized by irradiation to obtain the rumepiride long-acting sustained-release subcutaneous implant.

20. The method for preparing the long-acting sustained-release subcutaneous implant of lumepone according to claim 19, wherein the extrusion is performed using a twin-screw extruder.

21. The method for preparing the long-acting sustained-release subcutaneous implant of lumepirocin according to claim 20, wherein the extrusion parameters of the twin-screw extruder are as follows: feed temperature: 15~30℃, feed temperature: 35~40℃, mixing: 60~100℃, degassing: 80~100℃, extrusion: 50~80℃, die temperature: 50~60℃, extrusion speed: 80-120rpm, torque: 7~8 N.cm.

22. The method for preparing the long-acting sustained-release subcutaneous implant of lumepirocin according to claim 21, wherein the extrusion parameters of the twin-screw extruder are as follows: feed temperature: room temperature, feed temperature: 35~40℃, mixing: 80~100℃, degassing: 100℃, extrusion: 80℃, die: 60℃, extrusion speed: 100rpm, torque: 7~8 N.cm.

Images