Lumepirone long-acting sustained-release preparation composition and preparation method thereof

Abstract

The invention discloses a lumepirone long-acting sustained-release preparation composition, which comprises lumepirone or a salt thereof and a high polymer material, the mass ratio of lumepirone to the high polymer material is 0.5: 9.5-5: 5, the high polymer material comprises a main material polylactide and an optional release regulator, the mass of the release regulator is 0-95% of that of the main material polylactide, and the mass of the release regulator is 0-95% of that of the main material polylactide. And the release regulator is selected from one or a mixture of more of polylactide or polylactide-glycolide. The long-acting sustained-release preparation disclosed by the invention can realize unequal sustained-release effects of 1 week to 3 months, can improve the compliance of a patient, has no obvious burst release and no release retardation period in the early stage, is stable in release, and ensures the safety and effectiveness of drug release.

Description

Lumiperone long-acting sustained-release preparation composition and preparation method thereof Technical Field

[0001] The present invention relates to a lumiperone long-acting sustained-release preparation composition and a preparation method thereof. Background Art

[0002] Schizophrenia is a common, chronic, and highly disabling mental disorder affecting approximately 1% of the world's population. Antipsychotic medication is the mainstay of treatment for schizophrenia, but current medications offer limited relief and are often associated with various adverse reactions. In December 2019, the U.S. Food and Drug Administration approved a new antipsychotic, lumateperone. This drug has a unique mechanism of action and is safe and well-tolerated. It effectively treats positive symptoms while also improving negative symptoms, depressive symptoms, and social functioning.

[0003] Lumiperone 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 and simultaneously regulates serotonin, dopamine (DA), and glutamate. In December 2019, the drug was approved by the FDA for the treatment of schizophrenia in adults in the United States. In addition to its use in the treatment of schizophrenia, lumiperone also has potential efficacy for bipolar depression, behavioral disorders associated with dementia and Alzheimer's disease, insomnia, and major depressive disorder (MDD). It also has better tolerability and is less likely to cause adverse reactions such as weight gain and dyslipidemia.

[0004] Currently on the market is Lumiperone toluenesulfonate capsules, which is an oral preparation that needs to be administered daily to maintain its blood concentration. Frequent administration results in poor medication compliance among patients.

[0005] CN115671057A discloses a long-acting sustained-release microsphere formulation of lumepirone, prepared using a poly(lactide-co-glycolide) (PLGA) polymer. However, these microspheres have the following issues: i) a narrow particle size distribution results in a concentrated release behavior, hindering the maintenance of a stable blood drug concentration over the dosing cycle; ii) a long hysteresis phase in the body, resulting in uneven release; and iii) an excessively high initial burst release.

[0006] SUMMARY OF THE INVENTION

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

[0008] In some embodiments of the present invention, the mass ratio of lumiperone to the polymer material is 1:9 to 4:6; preferably, the mass ratio of lumiperone to the polymer material is 1.5:8.5 to 3:7; preferably, the mass ratio of lumiperone to the polymer material is 2:8 to 3:7; more preferably, the mass ratio of lumiperone to the polymer material is 2:(6 to 8); more preferably, the mass ratio of lumiperone to the polymer 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 more preferably 25,000 Daltons.

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

[0011] In some embodiments of the present invention, the molar ratio of lactide to glycolide in the polylactide-glycolide in the release modifier is 50:50 to 95:5, and the molecular weight of the polylactide-glycolide is 5000 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-glycolide is 5000 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-glycolide is 10,000 to 80,000 Daltons; more preferably, the molar ratio of lactide to glycolide is 50:50 to 75:25, and the molecular weight of the polylactide-glycolide is 60,000 to 70,000 Daltons.

[0012] In some embodiments of the present invention, the molecular weight of the polylactide in the release modifier 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 modifier is poly(lactide-glycolide) PLGA having a molar ratio of lactide to glycolide of 50:50 to 85:15 and a molecular weight of 5,000 to 90,000 Daltons; preferably, the release modifier is poly(lactide-glycolide) PLGA having a molar ratio of lactide to glycolide of 50:50 to 75:25 and a molecular weight of 10,000 to 80,000 Daltons; preferably, the release modifier is poly(lactide-glycolide) having a molar ratio of lactide to glycolide of 75:25 and a molecular weight of 10,000 to 80,000 Daltons; preferably, the release modifier is poly(lactide-glycolide) having a molar ratio of lactide to glycolide of 75:25 and a molecular weight of 60,000 to 70,000 Daltons.

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

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

[0016] In some embodiments of the present invention, the salt of lumaperone is selected from erucate, oleate, α-linolenate, palmitate, perlenate, undecylenate, hexadecandioate, laurate, stearate, adipate, and benzoate of lumaperone.

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

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

[0019] The polymer material and lumepirone or its salt are dissolved in a solvent, sterilized and filtered to form the oil phase, and then the temperature is controlled between 2 and 35°C. A 0.2-5% aqueous solution of polyvinyl alcohol (PVA) is prepared, sterilized and filtered to form the aqueous phase, and the temperature is controlled between 2 and 35°C. The oil phase is added to the aqueous phase in a shearing machine to form colostrum, which is then stirred and evaporated. The microspheres are filtered, washed with distilled water, and lyophilized to obtain lumepirone long-acting sustained-release microspheres.

[0020] In some embodiments of the method of the present invention, the polymeric material and lumiperone or a salt thereof are dissolved in dichloromethane.

[0021] In some embodiments of the method of the present invention, the rotation 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 volatilized at 50-500 rpm, preferably the colostrum is stirred and volatilized at 100-200 rpm.

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

[0024] The polymer material and lumepirone or its salt are mixed evenly, extruded, then wire-drawn and granulated, and sterilized by irradiation to obtain the lumepirone long-acting sustained-release subcutaneous implant.

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

[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°C, propulsion temperature: 35-40°C, mixing: 60-100°C, degassing: 80-100°C, extrusion: 50-80°C, die: 50-60°C, 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, propulsion temperature: 35-40°C, mixing: 80-100°C, degassing: 100°C, extrusion: 80°C, die: 60°C, extrusion speed: 100 rpm, torque: 7-8 N.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 preparation of the present invention can achieve a sustained-release effect ranging from 1 week to 3 months, can improve patient compliance, and has no obvious burst release in the early stage and no release hysteresis period. The preparation releases smoothly, ensuring the safety and effectiveness of drug release.

[0030] The present invention adopts emulsification technology to prepare microspheres, which can well control the particle size distribution and thus obtain a stable release pharmacokinetic curve. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG1 shows the pharmacokinetic curves of the microspheres of Examples 1, 2 and 3 on days 0-20 (25 or 60).

[0032] FIG2 is the pharmacokinetic curves of the microspheres of Examples 1, 2 and 3 on day 0-1.

[0033] FIG3 is the pharmacokinetic curve of the microspheres of Example 2 on days 0-25.

[0034] FIG4 is a pharmacokinetic curve of the microspheres of Example 2 on day 0-1.

[0035] FIG5 shows the pharmacokinetic curves of the microspheres of Example 3 and the subcutaneous implant of Example 4 on days 0 to 60.

[0036] FIG6 is the pharmacokinetic curves of the microspheres of Examples 3 and 5 on days 0-60 (100).

[0037] FIG7 is the pharmacokinetic curves of the microspheres of Examples 3 and 5 on day 0-1. Example

[0038] The present invention is further described below through examples. The examples of the present invention are only used to illustrate the technical solutions of the present invention and are not used to limit the scope of the present invention. Those skilled in the art may make some non-essential improvements and adjustments, which still fall within the scope of protection of the present invention.

[0039] Unless otherwise specified, all steps in the embodiments of the present invention are carried out at room temperature, which refers to a temperature of 20°C ± 5°C.

[0040] Example 1

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

[0042] Example 2

[0043] 0.7g of lumepirone and 2.3g of PLGA (lactide:glycolide = 75:25, ester-terminated, molecular weight 70,000 Daltons) were dissolved in 10mL of dichloromethane. This was then added to 300mL of a 0.5% aqueous PVA solution at a shear speed of 1000rpm to form colostrum. The mixture was then stirred and evaporated at 200rpm for 4 hours, filtered, and the microspheres washed three times with distilled water and lyophilized to obtain lumepirone long-acting sustained-release microspheres. The particle size (D50) of the microspheres was measured by a laser particle size analyzer to be 61μm.

[0044] Example 3

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

[0046] Example 4

[0047] 7 g of lumepirone and 23 g of PLA (molecular weight 25,000 Daltons) were crushed and mixed for later use.

[0048] A Thermo Fisher Pharma 11 twin-screw extruder was used, and the hot melt extruder was turned on. The feed temperature was set to room temperature, the propulsion temperature was set to 35-40°C, the mixing temperature was set to 80-100°C, the degassing temperature was set to 100°C, the extrusion temperature was set to 80°C, the die temperature was set to 60°C, the pressure was set to 60 bar, the extrusion speed was set to 100 rpm, and the torque was set to 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 irradiated and sterilized under the condition of 18 kGy to obtain the lumepirone subcutaneous implant.

[0051] Example 5

[0052] 0.7 g of lumepirone, 1.725 g of PLA (molecular weight 25,000 Daltons), and 0.575 g of PLGA (lactide:glycolide = 75:25, ester-terminated, molecular weight 70,000 Daltons) were sequentially dissolved in 10 ml of dichloromethane. The mixture was then added to 300 mL of 0.5% PVA aqueous solution at a shear speed of 1000 rpm to form colostrum. The mixture was then stirred and evaporated at 200 rpm for 4 h, filtered, and the microspheres were washed three times with distilled water and freeze-dried to obtain lumepirone long-acting sustained-release microspheres.

[0053] Test Example 1

[0054] SD rats (n=4, female rats) were administered a single intramuscular injection of 10.5 mg / kg of microspheres of Examples 1-3 and 5, and a subcutaneous implant of 10.5 mg / kg of the subcutaneous implant of Example 4 was implanted subcutaneously. The day of administration was recorded as 0 day. SD rats were respectively administered before administration (0 h) and 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, 3 d, 4 d, 5 d, 6 d, 7 d, 8 d, 9 d, 10 d, 11 d, 12 d, 13 d, 14 d, 15 d, 16 d, 17 d, 18 d, 19 d, 20 d, 21 d, 22 d, 23 d, 24 d, 25 d, 26 d, 27 d, 28 d, 29 d, 30 d, 31 d, 32 d, 33 d, 34 d, 35 d, 36 d, 37 d, 38 d, 39 d, 40 d, 41 d, 42 d, 43 d, 44 d, 45 d, 46 d, 47 d, 48 d, 49 d, 50 d, 51 d, 52 d, 53 d, 54 d, Blood was collected on days 1, 4 (or 5), 7, 8, 9, 11, 14 (or 13, 15), 17, 20, 25, 30, 35, and 40. Thereafter, blood was collected every 5 days based on test results until complete release. 0.25 mL of blood was drawn from the tail vein. The collected whole blood was temporarily stored on wet ice and centrifuged at 1500 g for 10 minutes within 1 hour to separate the plasma (4°C). The collected plasma was stored in a -80°C refrigerator pending testing. Plasma concentrations of the post-dose plasma samples were measured, and drug-dose curves were fitted to calculate pharmacokinetic parameters. The results are shown in Figures 1-7.

[0055] From Figures 1-4 , it can be seen that the microspheres of Example 1 have an excessively high initial burst release, the microspheres of Example 2 have a hysteresis period of 4-5 days, and the microspheres of Example 3 have a longer release period and a significantly lower burst release than those of Examples 1 and 2, and there is no hysteresis period, indicating that the microspheres of Example 3 can be used as a long-acting sustained-release preparation.

[0056] As can be seen from Figure 5, there is no significant difference in the release period between the microspheres of Example 3 and the subcutaneous implant of Example 4. In addition, the release curve of the subcutaneous implant of Example 4 is smoother.

[0057] 6 and 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 of this application have been described through preferred embodiments. It is apparent to those skilled in the art that modifications, variations, and combinations of the methods and products described herein can be made without departing from the content, spirit, and scope of this application to implement the technology of this application. It is particularly important to note that all similar substitutions and modifications that would be obvious to those skilled in the art are deemed to be encompassed within the spirit, scope, and content of this application.

Claims

1. A lumiperone long-acting sustained-release preparation composition, characterized in that: The invention comprises lumiperone or its salt and a polymer material, wherein the mass ratio of lumiperone to the polymer material is 0.5:9.5 to 5:5, the polymer material comprises a main material polylactide and an optional release regulator, the mass of the release regulator is 0% to 95% of the main material polylactide, and the release regulator is selected from one or more mixtures of polylactide or polylactide glycolide.

2. The lumiperone long-acting sustained-release preparation composition according to claim 1, characterized in that: The mass ratio of lumiperone to the polymer material is 1:9 to 4:6; preferably, the mass ratio of lumiperone to the polymer material is 1.5:8.5 to 3:

7.

3. The lumiperone long-acting sustained-release preparation composition according to claim 1 or 2, characterized in that: The molecular weight of the main material polylactide is 5000-100000 Daltons, preferably 10000-80000 Daltons, more preferably 10000-50000 Daltons.

4. The lumepirone long-acting sustained-release preparation composition according to any one of claims 1 to 3, characterized in that: The mass of the release regulator is 0% to 50% of the main material polylactide; preferably 0% to 40%; more preferably 0% to 30%.

5. The lumiperone long-acting sustained-release preparation composition according to any one of claims 1 to 4, characterized in that: The molar ratio of lactide to glycolide in the polylactide-glycolide in the release modifier is 50:50 to 95:5, and the molecular weight of the polylactide-glycolide is 5000 to 100000 Daltons; preferably, the molar ratio of lactide to glycolide is 50:50 to 85:15, and the molecular weight of the polylactide-glycolide is 5000 to 90000 Daltons; more preferably, the molar ratio of lactide to glycolide is 50:50 to 75:25, and the molecular weight of the polylactide-glycolide is 10000 to 80000 Daltons; The molecular weight of the polylactide in the release modifier is 5000 to 100000 Daltons, preferably 5000 to 80000 Daltons, more preferably 5000 to 50000 Daltons.

6. The lumiperone long-acting sustained-release preparation composition according to any one of claims 1 to 5, characterized in that: The release modifier is polylactide-glycolide with a molar ratio of lactide to glycolide of 50:50 to 85:15 and a molecular weight of 5000 to 90000 Daltons; preferably, the release modifier is polylactide-glycolide with a molar ratio of lactide to glycolide of 50:50 to 75:25 and a molecular weight of 10000 to 80000 Daltons; preferably, the release modifier is polylactide-glycolide with a molar ratio of lactide to glycolide of 75:25 and a molecular weight of 10000 to 80000 Daltons.

7. The lumepirone long-acting sustained-release preparation composition according to any one of claims 1 to 6, characterized in that: The polymer material is polylactide; or, the polymer material is a mixture of polylactide and polylactide glycolide, and the mass of the polylactide glycolide is 20% to 50% of the mass of the polylactide.

8. The lumiperone long-acting sustained-release preparation composition according to any one of claims 1 to 7, characterized in that: The salt of lumepirone is selected from erucate, oleate, α-linolenate, palmitate, pearlate, undecylenate, hexadecandioate, laurate, stearate, adipate and benzoate of lumepirone.

9. The lumepirone long-acting sustained-release preparation composition according to any one of claims 1 to 8, which is selected from microspheres or subcutaneous implants.

10. The method for preparing the lumepirone long-acting sustained-release microspheres according to claim 9, comprising the following steps: The polymer material and the lumepirone or its salt are dissolved in a solvent, sterilized and filtered as an oil phase, and the temperature is controlled to 2-35° C. for standby use; a 0.2-5% PVA aqueous solution is prepared, sterilized and filtered as a water phase, and the temperature is controlled to 2-35° C. for standby use; the oil phase is added to the water phase in a shearing machine to shear to form colostrum, and then stirred for volatilization, filtered, the microspheres are washed with distilled water, and freeze-dried to obtain the lumepirone long-acting sustained-release microspheres.

11. The method for preparing the lumepirone long-acting sustained-release subcutaneous implant according to claim 9, comprising the following steps: The polymer material and the lumepirone or its salt are mixed and evenly extruded, and then wire-cut and pelletized, and irradiated and sterilized to obtain the lumepirone long-acting sustained-release subcutaneous implant; Preferably, the extrusion is carried out using a twin-screw extruder; Preferably, the extrusion parameters of the twin-screw extruder are as follows: feed temperature: 15-30°C, propulsion temperature: 35-40°C, mixing: 60-100°C, degassing: 80-100°C, extrusion: 50-80°C, die: 50-60°C, extrusion speed: 80-120rpm, torque: 7-8N.cm; More preferably, the extrusion parameters of the twin-screw extruder are as follows: feed temperature: room temperature, propulsion temperature: 35-40°C, mixing: 80-100°C, degassing: 100°C, extrusion: 80°C, die: 60°C, extrusion speed: 100rpm, torque: 7-8N.cm.

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