Lumateperone sustained-release formulation composition and method for preparing the same

Abstract

This application discloses a sustained-release formulation composition of lumateperone, comprising lumateperone or a salt thereof and a polymer material. The mass ratio of lumateperone to the polymer material is 0.5:9.5 to 5:5, and the polymer material comprises a main material, polylactide, and a selectively present release modifier, the mass of which is 0% to 95% of the main material, polylactide, and the release modifier is a mixture of one or more selected from polylactide or poly(lactide-co-glycolide). The sustained-release formulation of the present invention can achieve a sustained-release effect from one week to three months, can improve patient compliance, and does not have a clear burst release in the early stages, does not have a release delay period, the release of the formulation is stable, and the safety and efficacy of drug release are ensured.

Description

Technical Field

[0001] The present invention relates to a lumateperone sustained-release pharmaceutical composition and a method for preparing the same.

Background Art

[0002] Schizophrenia is a common chronic disabling mental disorder that affects approximately 1% of people worldwide. Treatment with antipsychotic drugs is the main means of treating schizophrenia, but currently, the remission by drug treatment is limited, and various side effects always accompany during the treatment. In December 2019, the U.S. Food and Drug Administration approved the marketing of lumateperone, a new antipsychotic drug. This drug has a unique mechanism of action, good safety and tolerance, can effectively treat positive symptoms, and at the same time can improve the negative symptoms, depressive symptoms and social life functions of patients.

[0003] Lumateperone is a novel small molecule antipsychotic drug first developed by Bristol Myers Squibb and exclusively licensed to Intra-Cellular Therapies in 2005. It is the first newly created drug that selectively regulates 5-hydroxytryptamine (serotonin), dopamine (DA) and glutamate simultaneously. In December 2019, this drug was approved for marketing by the FDA in the United States and is used for the treatment of adult schizophrenia. In addition to being used for the treatment of schizophrenia, lumateperone has potential therapeutic effects on bipolar depression, behavioral disorders associated with dementia and Alzheimer's disease, insomnia and major depressive disorder (MDD), and at the same time has better tolerance and is less likely to cause side effects such as weight gain and abnormal blood lipid metabolism.

[0004] Currently, lumateperone tosylate capsules are on the market. This product is an oral preparation, and in order to maintain its blood drug concentration, it needs to be administered frequently every day, which reduces the medication adherence of patients.

[0005] CN115671057A discloses a lumateperone sustained-release microsphere formulation using poly(lactide-co-glycolide) (PLGA) polymer material to prepare the microspheres. However, these microspheres have several problems: i) the particle size distribution is narrow, causing the release behavior of the microspheres to be too concentrated, which is unfavorable for maintaining a stable blood drug concentration within the administration cycle; ii) there is a long delay period in the body, resulting in unstable release; and iii) the burst release in the early stages is too high. [Overview of the project]

[0006] In a first aspect of the present invention, a sustained-release lumateperone formulation composition is provided, comprising lumateperone or a salt thereof and a polymer material, wherein the mass ratio of lumateperone to the polymer material is 0.5:9.5 to 5:5, the polymer material comprises polylactide (PLA) as the main material and a selectively present release modifier, the mass of the release modifier being 0% to 95% of the polylactide as the main material, and the release modifier being a mixture of one or more types selected from polylactide or poly(lactide-co-glycolide).

[0007] In some embodiments of the present invention, the mass ratio of lumateperone to polymer material is 1:9 to 4:6, preferably 1.5:8.5 to 3:7, preferably 2:8 to 3:7, more preferably 2:(6 to 8), and even more preferably 2:(6.5 to 7).

[0008] In some embodiments of the present invention, the molecular weight of the polylactide main material is 5,000 to 100,000 daltons, preferably 10,000 to 80,000 daltons, more preferably 10,000 to 50,000 daltons, even more preferably 20,000 to 30,000 daltons, and even more preferably 25,000 daltons.

[0009] 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%, and even more preferably 0% to 30%.

[0010] In some embodiments of the present invention, the molar ratio of lactide to glycoside in the poly(lactide-co-glycolide) in the release regulator is 50:50 to 95:5, the molecular weight of the poly(lactide-co-glycolide) is 5000 to 100000 daltons, preferably the molar ratio of lactide to glycoside is 50:50 to 85:15, and the molecular weight of the poly(lactide-co-glycolide) is 5 The molecular weight is 000 to 90000 daltons, more preferably the molar ratio of lactide to glycolide is 50:50 to 75:25, the molecular weight of the poly(lactide-co-glycolide) is 10000 to 80000 daltons, and even more preferably the molar ratio of lactide to glycolide is 50:50 to 75:25, the molecular weight of the poly(lactide-co-glycolide) is 60000 to 70000 daltons.

[0011] 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.

[0012] In some embodiments of the present invention, the release regulator is a poly(lactide-co-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 a poly(lactide-co-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 a poly(lactide-co-glycolide) having a molar ratio of lactide to glycolide of 75:25 and a molecular weight of 10,000 to 80,000 daltons, and preferably a poly(lactide-co-glycolide) having a molar ratio of lactide to glycolide of 75:25 and a molecular weight of 60,000 to 70,000 daltons.

[0013] In some embodiments of the present invention, the polymer material is polylactide.

[0014] In some embodiments of the present invention, the polymer material is a mixture of polylactide and poly(lactide-co-glycolide), where the mass of poly(lactide-co-glycolide) is 20-50% of that of polylactide.

[0015] In some embodiments of the present invention, the salt of lumateperone is selected from erucate, oleate, α-linolenate, palmitate, margarate (heptadecanate), undecylenate, hexadecanedioate, laurate, stearate, adipine, and benzoate of lumateperone.

[0016] In some embodiments of the present invention, the lumateperone sustained-release formulation is selected from microspheres or subcutaneous implants.

[0017] In a second aspect of the present invention, The present invention provides a method for preparing lumateperone sustained-release microspheres, comprising the steps of: dissolving a polymer material and lumateperone or a salt thereof in a solvent, sterilizing it, filtering it to obtain an oil phase, and preparing it for use under conditions where the temperature is controlled to 2 to 35°C; preparing a 0.2 to 5% aqueous solution of polyvinyl alcohol (PVA), sterilizing it, filtering it to obtain an aqueous phase, and preparing it for use under conditions where the temperature is controlled to 2 to 35°C; and adding the oil phase to the aqueous phase in a shearing machine and shearing it to obtain a pre-emulsion, then stirring to volatilize it, filtering it, washing the microspheres with distilled water, and freeze-drying it to obtain lumateperone sustained-release microspheres.

[0018] In some embodiments of the method of the present invention, a polymer material and lumateperone or a salt thereof are dissolved in dichloromethane.

[0019] In some embodiments of the method of the present invention, the rotational speed of the shearing machine is 1000 to 8000 rpm.

[0020] In some embodiments of the method of the present invention, the preliminary emulsion is stirred and volatilized under conditions of 50 to 500 rpm, preferably 100 to 200 rpm.

[0021] A third aspect of the present invention is: The present invention provides a method for preparing a lumateperone sustained-release subcutaneous implant, comprising the steps of uniformly mixing a polymer material and lumateperone or a salt thereof, extruding the mixture, drawing it into lines to form granules, sterilizing it by irradiation, and obtaining a lumateperone sustained-release subcutaneous implant.

[0022] In some embodiments of the method of the present invention, a twin-screw extruder is used to perform extrusion.

[0023] In some embodiments of the method of the present invention, the extrusion parameters of the twin-screw extruder are as follows: the feeding temperature is 15 to 30 °C, the propulsion temperature is 35 to 40 °C, the kneading temperature is 60 to 100 °C, the degassing temperature is 80 to 100 °C, the extrusion temperature is 50 to 80 °C, the die temperature is 50 to 60 °C, the extrusion speed is 80 to 120 rpm, and the torque is 7 to 8 N·cm.

[0024] In some embodiments of the method of the present invention, the extrusion parameters of the twin-screw extruder are as follows: the feeding temperature is room temperature, the propulsion temperature is 35 to 40 °C, the kneading temperature is 80 to 100 °C, the degassing temperature is 100 °C, the extrusion temperature is 80 °C, the die temperature is 60 °C, the extrusion speed is 100 rpm, and the torque is 7 to 8 N·cm.

[0025] In the context of the present application, the term "molecular weight" refers to the weight-average molecular weight of the polymer.

[0026] The sustained-release formulation of the present invention can achieve a sustained-release effect from one week to three months, improve patient compliance, and has no obvious burst release and release lag period in the previous period. The release of the formulation is stable, ensuring the safety and effectiveness of drug release.

[0027] The present invention adopts an emulsification technique to prepare microspheres, can well control the particle size distribution, and further obtains a drug kinetic curve with stable release.

Brief Description of the Drawings

[0028] [Figure 1] Drug kinetic curves of the microspheres of Examples 1, 2 and 3 on the 0th to 20th (25th or 60th) day. [Figure 2] Drug kinetic curves of the microspheres of Examples 1, 2 and 3 on the 0th to 1st day. [Figure 3] Drug kinetic curve of the microspheres of Example 2 on the 0th to 25th day. [Figure 4] Drug kinetic curve of the microspheres of Example 2 on the 0th to 1st day. [Figure 5]These are the pharmacokinetic curves for the microspheres of Example 3 and the subcutaneous implants of Example 4 from day 0 to 60. [Figure 6] These are the pharmacokinetic curves of the microspheres from Examples 3 and 5 at days 0 to 60 (100). [Figure 7] These are the pharmacokinetic curves of the microspheres from Examples 3 and 5 from day 0 to day 1. [Examples]

[0029] The present invention will be further described below with reference to examples, but these examples are merely for illustrating the technical solutions of the present invention and are not intended to limit the scope of the invention. Those skilled in the art may make some non-essential improvements and modifications, and these improvements and modifications still fall within the scope of the present invention.

[0030] Unless otherwise specified, each step in the embodiments of this invention is performed at room temperature. Room temperature refers to a temperature of 20°C ± 5°C. Example 1

[0031] 0.7 g of lumateperone and 2.3 g of PLGA (lactide:glycolide = 50:50, capped with carboxyl groups, molecular weight 40,000 daltons) were dissolved in 10 mL of dichloromethane. This solution was then added to 300 mL of 0.5% PVA aqueous solution and sheared at a shearing machine speed of 1000 rpm to form a pre-emulsion. The mixture was then stirred at 200 rpm for 4 hours to volatilize, filtered, and the microspheres were washed three times with distilled water. The microspheres were then freeze-dried to obtain lumateperone sustained-release microspheres. The microsphere particle size (D50) measured by a laser particle size analyzer was 57 μm. Example 2

[0032] 0.7 g of lumateperone and 2.3 g of PLGA (lactide:glycolide = 75:25, capped with ester groups, molecular weight 70,000 daltons) were dissolved in 10 mL of dichloromethane. This solution was then added to 300 mL of 0.5% PVA aqueous solution and sheared at a shearing machine speed of 1000 rpm to form a pre-emulsion. The mixture was then stirred at 200 rpm for 4 hours to volatilize, filtered, and the microspheres were washed three times with distilled water. The microspheres were then freeze-dried to obtain lumateperone sustained-release microspheres. The microsphere particle size (D50) measured by a laser particle size analyzer was 61 μm. Example 3

[0033] 0.7 g of lumateperone and 2.3 g of PLA (molecular weight 25,000 daltons) were dissolved in 10 mL of dichloromethane. Under the conditions of a shearing machine rotation speed of 1000 rpm, the mixture was added to 300 mL of 0.5% PVA aqueous solution and sheared to form a pre-emulsion. After stirring at 200 rpm for 4 hours to volatilize, the mixture was filtered, the microspheres were washed three times with distilled water, and freeze-dried to obtain lumateperone sustained-release microspheres. The microsphere particle size (D50) measured by a laser particle size analyzer was 59 μm. Example 4

[0034] 7 g of lumateperone and 23 g of PLA (molecular weight 25,000 daltons) were ground and uniformly mixed for use.

[0035] Using a Thermo Fisher Pharma 11 twin-screw extruder, the hot melt extruder was started and the following settings were applied: feed temperature to room temperature, propulsion temperature to 35-40°C, mixing temperature to 80-100°C, degassing temperature to 100°C, extrusion temperature to 80°C, die temperature to 60°C, pressure to 60 bar, extrusion speed to 100 rpm, and torque to 7-8 N·cm.

[0036] For line drawing and granulation, after extrusion, the material is pulled and lined to form short rods of 3 x 30 mm. For radiation therapy, a short rod was sterilized by radiation under conditions of 18 kGy to obtain a Lumateperon subcutaneous implant. Example 5

[0037] 0.7 g of lumateperone, 1.725 g of PLA (molecular weight 25,000 daltons), and 0.575 g of PLGA (lactide:glycolide = 75:25, capped with ester groups, molecular weight 70,000 daltons) were sequentially added to 10 mL of dichloromethane and dissolved. Under conditions of a shearing machine rotation speed of 1000 rpm, the mixture was added to 300 mL of 0.5% PVA aqueous solution and sheared to obtain a pre-emulsion. After that, the mixture was stirred for 4 hours under conditions of 200 rpm to volatilize, filtered, and the microspheres were washed three times with distilled water. The microspheres were then freeze-dried to obtain lumateperone sustained-release microspheres. Test Example 1

[0038] SD rats (n=4, female rats) were used, and 10.5 mg / kg of the microspheres from Examples 1-3 and 5 were administered as a single intramuscular injection, while 10.5 mg / kg of the subcutaneous implant from Example 4 was implanted subcutaneously. The day of administration was designated as day 0, and observations were made before administration (0h) and on the day of administration 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 (or 5 d), and 7 d. Blood samples were collected from SD rats on days 8, 9, 11, 14 (or 13, 15), 17, 20, 25, 30, 35, and 40. Subsequently, depending on the detection results, blood samples were collected every 5 days until complete release. 0.25 mL of whole blood was collected from the tail vein, and the collected whole blood was temporarily stored on ice. Within 1 hour, the plasma (4°C) was separated by centrifugation at 1500 g for 10 minutes. The collected plasma was stored in a -80°C refrigerator for measurement. After measuring the blood drug concentration in the plasma samples after administration, the blood drug concentration-time curve was fitted, and pharmacokinetic parameters were calculated. The results are shown in Figures 1-7.

[0039] Figures 1-4 show that the microspheres of Example 1 had excessively high burst release in the early stages, and the microspheres of Example 2 had a delay period of 4-5 days. In contrast, the microspheres of Example 3 had a longer release period, significantly reduced burst release, and no delay period compared to Examples 1 and 2, indicating that the microspheres of Example 3 can be used as a sustained-release formulation.

[0040] Figure 5 shows that there is no significant difference in the release period 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.

[0041] By combining Figures 6 and 7, it can be seen that the microspheres of Example 5 have a longer release period than the microspheres of Example 3.

[0042] The methods and products of this application are illustrated by preferred embodiments, and it will be apparent to those skilled in the art that the technology of this application can be realized by modifying, appropriately changing, or combining the methods and products described herein without departing from the spirit and scope of this application. It should be particularly noted that all similar substitutions and modifications will be obvious to those skilled in the art and are all considered to be included in the spirit, scope and scope of this application.

Claims

1. A sustained-release lumateperone formulation composition comprising lumateperone or a salt thereof and a polymer material, wherein the mass ratio of lumateperone to the polymer material is 0.5:9.5 to 5:5, the polymer material comprises a main material polylactide and an optionally present release regulator, the mass of the release regulator is 0% to 95% of the main material polylactide, and the release regulator is a mixture of one or more types selected from polylactide or poly(lactide-co-glycolide).

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

7.

3. The lumateperone sustained-release formulation composition according to claim 1 or 2, characterized in that the molecular weight of the polylactide, the main material, is 5,000 to 100,000 daltons, preferably 10,000 to 80,000 daltons, and more preferably 10,000 to 50,000 daltons.

4. The lumateperone sustained-release formulation 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 polylactide of the main material, preferably 0% to 40%, and more preferably 0% to 30%.

5. In the release regulator, the molar ratio of lactide to glycolide in the poly(lactide-co-glycolide) is 50:50 to 95:5, and the molecular weight of the poly(lactide-co-glycolide) 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 poly(lactide-co-glycolide) 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 poly(lactide-co-glycolide) is 10,000 to 80,000 daltons. The lumateperone sustained-release formulation composition according to any one of claims 1 to 4, characterized in that 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.

6. The lumateperone sustained-release formulation composition according to any one of claims 1 to 5, characterized in that the release regulator is a poly(lactide-co-glycolide) 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 a poly(lactide-co-glycolide) 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, and preferably a poly(lactide-co-glycolide) having a molar ratio of lactide to glycolide of 75:25 and a molecular weight of 10,000 to 80,000 daltons.

7. The lumateperone sustained-release formulation composition according to any one of claims 1 to 6, characterized in that the polymer material is polylactide, or a mixture of polylactide and poly(lactide-coglycolide), and the mass of the poly(lactide-coglycolide) is 20 to 50% of the polylactide.

8. The lumateperone sustained-release formulation composition according to any one of claims 1 to 7, characterized in that the salt of lumateperone is selected from erucate, oleate, α-linolenate, palmitate, margarate, undecylenate, hexadecanedioate, laurate, stearate, adipine, and benzoate of lumateperone.

9. A sustained-release lumateperone formulation composition according to any one of claims 1 to 8, selected from microspheres or subcutaneous implants.

10. A method for preparing lumateperone sustained-release microspheres according to claim 9, comprising the steps of: dissolving the polymer material and the lumateperone or a salt thereof in a solvent, sterilizing and filtering to obtain an oil phase, and preparing it for use under conditions where the temperature is controlled to 2 to 35°C; preparing a 0.2 to 5% PVA aqueous solution, sterilizing and filtering to obtain an aqueous phase, and preparing it for use under conditions where the temperature is controlled to 2 to 35°C; and adding the oil phase to the aqueous phase in a shearing machine and shearing to obtain a pre-emulsion, then stirring to volatilize, filtering, washing the microspheres with distilled water, and freeze-drying to obtain the lumateperone sustained-release microspheres.

11. The steps include uniformly mixing the polymer material and the lumateperone or a salt thereof, extruding the mixture, drawing it into lines to form granules, sterilizing it by irradiation, and obtaining the lumateperone sustained-release subcutaneous implant. Preferably, a twin-screw extruder is used to perform the extrusion. Preferably, the extrusion parameters of the twin-screw extruder are: supply temperature of 15 to 30°C, propulsion temperature of 35 to 40°C, kneading temperature of 60 to 100°C, degassing temperature of 80 to 100°C, extrusion temperature of 50 to 80°C, die opening temperature of 50 to 60°C, extrusion speed of 80 to 120 rpm, and torque of 7 to 8 N·cm. The method for preparing a lumateperone sustained-release subcutaneous implant according to claim 9, wherein the extrusion parameters of the twin-screw extruder are: supply temperature at room temperature, propulsion temperature at 35 to 40°C, mixing at 80 to 100°C, degassing at 100°C, extrusion at 80°C, die opening at 60°C, extrusion speed at 100 rpm, and torque at 7 to 8 N·cm.

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