Brexpiprazole injectable sustained-release particle preparation and preparation method thereof

Abstract

The invention provides a brexpiprazole injectable sustained-release microparticle preparation taking fatty glyceride as a carrier, and provides a preparation method of the brexpiprazole injectable sustained-release microparticle preparation. According to the invention, fatty glyceride and drugs are uniformly mixed and crushed by a simple method to prepare the injectable sustained-release microparticle preparation, and the injectable sustained-release microparticle preparation has good biocompatibility and stable sustained-release effect, is suitable for various administration modes such as subcutaneous injection, intramuscular injection and the like, and has a better application prospect.

Description

Technical Field

[0001] This invention relates to an injectable sustained-release microparticle formulation of epipiperazole, specifically an injectable sustained-release microparticle formulation of epipiperazole using fatty acid glycerides as a carrier material and its preparation method, belonging to the field of pharmaceutical preparations. Background Technology

[0002] Brexpiprazole (BRE), chemical name: 7-[4-(benzo[B]thiophene-4-1-piperazine)butoxy]-2(1H)-quinolinone, CAS number: 913611-97-9, molecular formula: C25H27N3O2S, molecular weight: 433.57, structural formula is shown below:

[0003] Epilippazole, jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Pharmaceutical Co., Ltd. of Japan, was approved by the U.S. Food and Drug Administration (FDA) in 2015 for adjunctive treatment of schizophrenia and major depressive disorder in adults. Epilippazole is an atypical antipsychotic, acting as a dopamine D2, 5-HT1A receptor agonist, and 5-HT2A receptor antagonist, regulating the monoamine neurotransmission system in the brain. Furthermore, in 2023, the FDA approved it for the treatment of agitation (AAD) caused by Alzheimer's disease.

[0004] Currently, there are no long-acting formulations of epipiperazole available on the market; they are mainly available as regular tablets, with strengths ranging from 0.25 to 4 mg per tablet, one tablet daily. However, due to significant individual differences among patients, coupled with complex conditions such as mood swings and somatization symptoms, medication adherence is generally poor, leading to frequent irregular medication use and thus affecting the full efficacy of the drug. Therefore, developing injectable extended-release formulations of epipiperazole is particularly important. This would not only help improve drug efficacy but also reduce the frequency of dosing, thereby significantly improving patient adherence.

[0005] Epilippazole itself is highly hydrophobic. In existing technologies, its dihydrate form is prepared as a suspension for subcutaneous injection, achieving a sustained-release effect of approximately one month (see CN104254530A). However, this preparation process involves complex purification steps and is time-consuming. To further improve patient medication adherence, this invention aims to develop formulations with longer sustained-release periods, such as one and a half months or even two months. These formulations do not require specific crystal forms; the anhydrous form of epilippazole can achieve a longer sustained-release effect, broadening its applicability.

[0006] Fatty acid glycerides are mainly derived from natural oils and fats, and are similar to lipids in the body, effectively reducing tissue irritation and not causing significant immune responses. Furthermore, fatty acid glycerides can be broken down and utilized in the body through normal metabolic pathways, generating glycerol and fatty acids. These products can further participate in energy metabolism or other biological processes, exhibiting good biocompatibility and biodegradability. Compared with traditional sustained-release carriers, fatty acid glycerides can better control the drug release rate and do not have significant toxicity accumulation issues.

[0007] However, for small molecule chemical drugs encapsulated within fatty acid glycerides, drug release is not only affected by the surface erosion of the carrier fatty acid glycerides, but more importantly, the differences in the physicochemical properties of different drugs lead to varying diffusion rates within the carrier, making their release patterns difficult to predict. Previously, we encapsulated colchicine and progesterone in tristearate glyceride microparticles, finding that the sustained-release time was less than one day for the former and only 3-4 days for the latter. However, when we encapsulated epilapiazole in fatty acid glyceride microparticles, we unexpectedly found that it could achieve a stable sustained release for at least two months. Furthermore, the preparation methods provided by this invention (solvent evaporation method, spray cooling solidification method, melt extrusion method, etc.) are relatively simple, can be carried out under conventional drug preparation conditions, and do not require complex chemical reactions or expensive equipment. This method has high operability and good batch-to-batch consistency during production.

[0008] The goal of developing an injectable sustained-release microparticle formulation of epipiperazole is to maintain effective blood drug concentrations over a prolonged period with a single dose. Simultaneously, injectability and stability are key performance indicators that require close monitoring during the development process. Therefore, our objective is to develop a technically feasible injectable formulation that ensures safe and stable drug release over an extended period, thereby significantly improving patient adherence. Summary of the Invention

[0009] The purpose of this invention is to provide an injectable sustained-release microparticle formulation of epipiperazole and a method for preparing the same. The injectable sustained-release microparticle formulation comprises sustained-release microparticles.

[0010] The sustained-release microparticles of the present invention, by weight, contain 20-99 parts of fatty acid glycerides and 1-80 parts of the active pharmaceutical ingredient. Preferably, they contain 40-90 parts of fatty acid glycerides and 10-60 parts of the active pharmaceutical ingredient.

[0011] Preferably, the active pharmaceutical ingredient is epipiperazole or a pharmaceutically acceptable salt thereof or a derivative of epipiperazole. Fatty acid glycerides suitable for the sustained-release formulations of the present invention include, but are not limited to: 1-monolaurate glyceride, 1,2-dilaurate glyceride, dilaurate glyceride (mixed), trilaurate glyceride, monotetrazole glyceride, 1,3-tetrazole diglyceride, tritetrazole triglyceride, 1-monomyristate glyceride, 2-monomyristate glyceride, 1,2-dimyristate glyceride, 1,3-dimyristate glyceride, trimyristate glyceride, monopentadecanate glyceride, 1,2-dipentadecanate glyceride, 1,3-dipentadecanate glyceride, deca-... Pentacosanyl triglyceride, 1-monopalmitoyl glyceride, 2-monopalmitoyl glyceride, monopalmitoyl glyceride (mixed), 1,2-dispalmitoyl glyceride, 1,3-dispalmitoyl glyceride, dipalmitoyl glyceride (mixed), tripalmitoyl glyceride, heptadecanyl glyceride, 1,2-heptadecanyl diglyceride, 1,3-heptadecanyl diglyceride, heptadecanyl triglyceride, 1-monostearyl glyceride, 2-monostearyl glyceride, monostearyl glyceride (mixed), 1,2-distearate glyceride, 1,3-distearate glyceride, tristearyl glyceride Esters, monononadecanoglyceride, 1,2-nonadecanoglyceride diglyceride, 1,3-nonadecanoglyceride diglyceride, monotetracosanoglyceride, 1,3-tetracosanoglyceride diglyceride, tetracosanoglyceride triglyceride, monobenzyl ... One or more combinations of glycerides, 1,3-stearic acid-2-laurate glycerides, 1,2-palmitoyl-3-stearic acid glycerides, 1,2-palmitoyl-3-myristate glycerides, 1,2-palmitoyl-3-pentadecanoyl glycerides, 1,3-palmitoyl-2-stearic acid glycerides, 1,3-palmitoyl-2-myristate glycerides, 1,2-myristoyl-3-palmitoyl glycerides, 1,2-myristate-3-laurate glycerides, 1,2-laurate-3-myristate glycerides, and 1,2-behenic acid-3-myristate glycerides.

[0012] In specific implementations, the present invention preferably uses one or more of tristearate, tris(2-methyl)hexane, or tripalmitate.

[0013] In a specific implementation, the fatty acid glyceride described in this invention is more preferably tristearate glyceride.

[0014] One embodiment of the present invention is an injectable sustained-release microparticle formulation of epipiperazole, comprising: (1) Epicipazole lipid microparticles, including the active pharmaceutical ingredient epicipazole and one or more fatty acid glycerides; (2) Aqueous carrier.

[0015] Preferably, the aqueous carrier contains one or more of the following: a suspending agent, a surfactant, a preservative, an antioxidant, water, physiological saline, a glucose solution, and a buffer solution.

[0016] More preferably, the aqueous carrier comprises one or more suspending agents, surfactants and / or preservatives, antioxidants and water.

[0017] In a specific implementation scheme, one of the preparation methods of the present invention includes the following steps: (1) Dissolve the carrier material fatty acid glycerides in an organic solvent to form an organic solution, and then add the active pharmaceutical ingredient, epipipazole, to ensure complete dissolution; (2) The organic solvent is evaporated, and solid lumps are precipitated. These are then ground and passed through a standard sieve to obtain lipid microparticles. (3) Preparation of aqueous carrier; (4) The lipid microparticles from step (2) are suspended in the aqueous carrier from step (3).

[0018] The organic reagents mentioned in step (1) include, but are not limited to, dichloromethane (DCM), chloroform, acetone, diethyl ether, methanol, ethanol, ethyl acetate, ethyl propionate, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and N-methyl-2-pyrrolidone (NMP).

[0019] Step (4) is preferably to mix water for injection, suspending agent, surfactant and / or preservative and antioxidant evenly, filter through a microporous membrane, and sterilize. Preferably, step (2) further includes the step of sealing vials after sterilization of lipid microparticles.

[0020] In the specific implementation plan, the mass percentage of epipiperazole to organic solvent is 2.4% to 21.6 wt%.

[0021] In a specific implementation plan, the preferred organic solvent for step (1) is dichloromethane.

[0022] In a specific implementation scheme, the second preparation method of the present invention includes the following steps: (1) After heating and melting fatty acid glycerides, add the active pharmaceutical ingredient epipipazole and stir until dissolved or mixed to prepare lipid microparticles; (2) Preparation of aqueous carrier; (3) Add lipid microparticles to the aqueous carrier described in step (2) and mix thoroughly to form a uniformly dispersed injectable formulation; Preferably, the lipid microparticle preparation step (1) is performed using a rotary disk atomization, spray cooling and solidification method, or melt extrusion method; Preferably, after preparing lipid microparticles in step (1), the process further includes sterilizing the lipid microparticles, filling them into a container, and then sealing them; the container is preferably a vial. Preferably, the step of preparing the aqueous carrier includes dissolving suspending agents, surfactants and / or preservatives, antioxidants, etc., in water for injection.

[0023] The formulations of this invention may also include other pharmaceutically acceptable excipients.

[0024] The excipients applicable to this invention account for 0.01% to 15% of the weight of the aqueous carrier. These excipients are one or more selected from suspending agents, surfactants, preservatives, antioxidants, water, physiological saline, glucose solution, and buffer solutions.

[0025] The suspending agent of the present invention may be selected from one or more combinations of sodium carboxymethyl cellulose (CMC-Na), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), sodium alginate, glycerin, gum arabic, xanthan gum, and gelatin, but is not limited to these suspending agents.

[0026] In specific implementation schemes, the present invention preferably uses one or more of sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), and methylcellulose (MC).

[0027] The suspending agent described in this application accounts for 0.2% to 10% of the weight of the aqueous carrier.

[0028] In a specific implementation, the present invention more preferably uses sodium carboxymethyl cellulose (CMC-Na), which accounts for 0.5% to 5% of the weight of the aqueous carrier.

[0029] The surfactant of the present invention may be selected from one or more combinations of phospholipids, HS15, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, polysorbate 20, polysorbate 80, dehydrated sorbate, polyoxyethylene dehydrated sorbate, sodium lauryl sulfate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil, and polyvinyl alcohol, but is not limited to these surfactants.

[0030] In specific implementation schemes, the present invention preferably uses phospholipids, poloxamer 124, poloxamer 188, polysorbate 20, and polysorbate 80.

[0031] Preferably, the surfactant accounts for 0.1% to 2% of the weight of the aqueous carrier.

[0032] In a specific implementation, the present invention more preferably uses poloxamer 188, which accounts for 0.25% to 1% of the weight of the aqueous carrier.

[0033] The preservatives of this invention can be selected from methylparaben, ethylparaben, propylparaben, butylparaben, benzoic acid, sodium benzoate, benzyl alcohol, sorbic acid, potassium sorbate, sodium sorbate, chlorobutanol, benzalkonium chloride, benzalkonium bromide, chlorhexidine acetate, hexadecyltrimethylammonium bromide, etc.

[0034] In a specific implementation scheme, the present invention preferably uses methylparaben, benzyl alcohol, and chlorobutanol, accounting for 0.01% to 2% of the weight of the aqueous carrier.

[0035] In a specific implementation, benzyl alcohol is more preferably present in the present invention, accounting for 0.05% to 1% of the weight of the aqueous carrier.

[0036] The antioxidants of the present invention include any antioxidant known to stabilize epipiperazole compounds.

[0037] The antioxidants suitable for use in this invention include, but are not limited to, one or more combinations of sodium bisulfite, ascorbic acid, acetylcysteine, vitamin E, α-tocopherol, glutathione, sodium deoxythiamine, sodium nitrite sulfate, sodium thiobarbiturate, sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and tert-butylhydroquinone (TBHQ).

[0038] In a specific implementation scheme, the present invention preferably uses sodium bisulfite, α-tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) in an amount of 0.01% to 2% by weight of the aqueous carrier.

[0039] In a specific implementation scheme, the present invention preferably uses butylated hydroxytoluene (BHT), which accounts for 0.05% to 0.75% of the weight of the aqueous carrier. The epipiperazole injectable sustained-release microparticle formulation provided by the present invention has a simple process and is suitable for industrial production.

[0040] When using the product of this invention, the aqueous carrier needs to be injected into the lipid microparticles and vigorously shaken to obtain the product. The physical and chemical stability of the aqueous suspension needs to be maintained throughout its use.

[0041] This invention can be used via subcutaneous or intramuscular injection.

[0042] In addition, experimental verification has shown that the formulation described in this invention is well-adapted to patients and does not cause skin irritation at the injection site after administration.

[0043] The beneficial effects of this invention are mainly reflected in the following aspects: First, by using fatty acid glycerides as drug carriers, not only can the drug be released more sustainably than in existing technologies, but also a stable blood drug concentration can be maintained; second, the carrier is mainly derived from natural animal materials, which is highly safe and less likely to trigger immune rejection reactions, while also having good biocompatibility and degradability; finally, the preparation process of this invention is simple, which greatly reduces production costs and is conducive to industrial promotion. Attached Figure Description

[0044] Figure 1 Scanning electron microscope image of the ipilipazole lipid microparticles prepared in Example 3; (a) Full view, scale bar = 300 μm; (b) Surface view, scale bar = 50 μm; Figure 2 This is a pharmacokinetic (plasma concentration-time) curve of epilippazole raw material and epilippazole lipid microparticles administered subcutaneously in Experiment Example 1. Figure 3 This is a pharmacokinetic (blood concentration-time) curve of epilapiazole lipid microparticle subcutaneous administration in Experiment Example 2. Figure 4 This is a pharmacokinetic (blood concentration-time) curve of epilapiazole lipid microparticle subcutaneous administration in Experiment Example 3. Detailed Implementation

[0045] The following embodiments further illustrate the content of the present invention, but the present invention is not limited to the specific embodiments described. Furthermore, those skilled in the art can make equivalent substitutions, combinations, improvements, or modifications to the present invention based on its description, all of which are included within the scope of protection of the present invention.

[0046] Example 1 10% Epiliprazole Tristearate Microparticles 1 g of epilapiazole and 9 g of tristearate were dissolved in dichloromethane by sonication. The organic reagents were then evaporated to dryness, resulting in a solid mass. The mass was ground and passed through a standard sieve to collect lipid microparticles of 100–150 μm for further characterization.

[0047] The average particle size (D50) of the lipid microparticles was 131 μm, and the SPAN value (SPAN = (D90-D10) / D50) was 1.37.

[0048] Example 2 20% Epiliprazole Tristearate Microparticles 2 g of epipiperazole and 8 g of tristearate were placed in dichloromethane and sonicated until fully dissolved. The organic reagent was then evaporated to dryness, resulting in a solid mass. The mass was ground and passed through a standard sieve to collect lipid particles of 100–150 μm for further characterization.

[0049] The average particle size (D50) of the lipid microparticles was 128 μm, and the SPAN value (SPAN = (D90-D10) / D50) was 1.36.

[0050] Example 3 30% Epiliprazole Tristearate Microparticles 3 g of epipiperazole and 7 g of tristearate were placed in dichloromethane and sonicated until fully dissolved. The organic reagents were then evaporated to dryness, resulting in the precipitation of solid lumps. These lumps were ground and passed through a standard sieve to collect lipid particles of 100–150 μm for further characterization.

[0051] The average particle size (D50) of the lipid microparticles was 117 μm, and the SPAN value (SPAN = (D90-D10) / D50) was 1.23.

[0052] Example 4 30% Epilapiazole Distearate Microparticles 3 g of epipiperazole and 7 g of distearate were placed in chloroform and sonicated until fully dissolved. The organic reagent was then evaporated to dryness, resulting in a solid mass. The mass was ground and passed through a standard sieve to collect lipid particles of 100–150 μm for further characterization.

[0053] The average particle size (D50) of the lipid microparticles is 125 μm, and the SPAN value (SPAN = (D90-D10) / D50) is 1.27.

[0054] Example 5 30% epipipeazole glyceryl monostearate microparticles 3 g of epipiperazole and 7 g of glyceryl monostearate were placed in chloroform and sonicated until fully dissolved. The organic reagent was then evaporated to dryness, resulting in a solid mass. The mass was ground and passed through a standard sieve to collect lipid microparticles of 100–150 μm for further characterization.

[0055] The average particle size (D50) of the lipid microparticles was 136 μm, and the SPAN value (SPAN = (D90-D10) / D50) was 1.39.

[0056] Example 6 50% Epilipazole Tristearate Microparticles 5 g of epipiperazole and 5 g of tristearate were placed in dichloromethane and sonicated until fully dissolved. The organic reagent was then evaporated to dryness, resulting in a solid mass. The mass was ground and passed through a standard sieve to collect lipid particles of 100-150 μm for further characterization.

[0057] The average particle size (D50) of the lipid microparticles was 133 μm, and the SPAN value (SPAN = (D90-D10) / D50) was 1.26.

[0058] Example 7 30% Epilapiazole Triamcinolone Glyceryl Particles 7 g of triglyceride triterpenoids was heated to 182°C in a container to melt, and 3 g of epiloperazole powder was added and stirred until dissolved. The resulting solution was cooled to 80°C, and then lipid microparticles were prepared by spray cooling solidification.

[0059] The average particle size (D50) of the lipid microparticles is 130 μm, and the SPAN value (SPAN = (D90-D10) / D50) is 1.34.

[0060] Example 8 30% Epilapiazole Tripalmitate Microparticles 7 g of tripalmitic acid glyceride was heated to 80°C in a container to melt it, and 3 g of epiperazole micro powder was added and stirred until uniform. Then, lipid microparticles were prepared by spray cooling and solidification.

[0061] The average particle size (D50) of the lipid microparticles was 122 μm, and the SPAN value (SPAN = (D90-D10) / D50) was 1.36.

[0062] Example 9 30% Epilapiazole Trilaurate Microparticles Take the prescribed amount of the drug and fatty acid glycerides (3 g: 7 g), put them into a hot melt extrusion instrument, set the hot melt temperature (182℃), heat and melt the mixture and extrude it, then extrude it through a sieve plate and quickly cool and solidify it to prepare a strip-shaped solid, and then crush it to make lipid microparticles.

[0063] The average particle size (D50) of the lipid microparticles was 134 μm, and the SPAN value (SPAN = (D90-D10) / D50) was 1.32.

[0064] Example 10 Preparation of aqueous carriers Example 10a 15 mg CMC-Na, 5 mg poloxamer 188, 0.5 mg benzyl alcohol and 0.5 mg BHT were added sequentially to water for injection, and after being fully dissolved and dispersed, the volume was adjusted to 1 mL to prepare the final aqueous carrier.

[0065] Example 10b 10 mg CMC-Na, 5 mg poloxamer 188, 0.5 mg benzyl alcohol and 0.5 mg BHT were added sequentially to water for injection, and after being fully dissolved and dispersed, the volume was adjusted to 1 mL to prepare the final aqueous carrier.

[0066] Example 10c 25 mg HPMC, 2.5 mg Tween 80, 1 mg methylparaben, and 1 mg α-tocopherol were added sequentially to water for injection, dissolved and dispersed thoroughly, and then brought to a final volume of 1 mL to obtain the final aqueous carrier.

[0067] Example 10d 10 mg of HPMC was added to water for injection, and after being fully dissolved and dispersed, the volume was adjusted to 1 mL to obtain the final aqueous carrier.

[0068] Example 10e Add 5 mg PVA and 5 mg poloxamer 188 to water for injection, dissolve and disperse them thoroughly, and then bring the volume to 1 mL to obtain the final aqueous carrier.

[0069] Example 10f 10 mg of MC was added to water for injection, and after being fully dissolved and dispersed, the volume was adjusted to 1 mL to obtain the final aqueous carrier.

[0070] Example 10g 9 mg PVP and 1 mg sodium bisulfite were added to water for injection, dissolved and dispersed thoroughly, and then brought to a final volume of 1 mL to obtain the final aqueous carrier.

[0071] Take 100 mg of the lipid microparticles prepared in Examples 1-9 and add them to 0.9 mL of the above-mentioned aqueous carrier (Examples 10a~10 g). Shake for 30 s to mix, then let stand before use. Observation showed that the above-mentioned aqueous carriers could all produce a homogeneous suspension suitable for injection. The following experimental examples used the aqueous carrier of Example 10a for testing.

[0072] Experimental Example 1 Pharmacokinetic Studies - Investigation of Active Pharmaceutical Ingredients and Formulations Lipid microparticles were prepared using tristearate (GTS) as a carrier material and compared with the pharmacokinetic properties of epipipeazole (BRE) active pharmaceutical ingredient in vivo.

[0073] (1) Grouping (dosage: 30 mg) BRE epilapiazole active pharmaceutical ingredient powder, ultrasonically dispersed in an aqueous carrier. The lipid microparticles, with a BRE:GTS ratio of 3:7, were selected from Example 3 and suspended in an aqueous carrier. (2) Steps: Healthy male SD rats, weighing 220±20 g, were selected and administered the drug subcutaneously after a 12-hour fast. Blood samples were collected at intervals (posterior ocular venous plexus sampling) over a period of 60 days. Samples were placed in polyethylene tubes pre-anticoagulated with heparin sodium and centrifuged at 6000 rpm for 5 min. The separated plasma was stored at -20 ℃ for analysis. After protein precipitation, the blood drug concentration was determined by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS / MS) to obtain pharmacokinetic curves. Data were analyzed using Phoenix software, and the results are shown in the table below. Table 2: Pharmacokinetic Data of Example 11

[0074] Table 2 and Figure 2 The results showed that the formulation using the carrier material had better pharmacokinetic characteristics and exhibited a smoother pharmacokinetic curve compared to the active pharmaceutical ingredient.

[0075] Experiment Example 2 Pharmacokinetic Study - Carrier Ratio Assessment As demonstrated in Experiment 1, glyceryl tristearate (GTS) exhibits a certain sustained-release effect. Therefore, this invention further investigates whether different proportions of the carrier material in the formulation will affect the sustained-release effect.

[0076] (1) Grouping (dosage: 30 mg) BRE:GTS = 1:9. The lipid microparticles were selected from Example 1 and suspended in an aqueous carrier. BRE:GTS=2:8. The lipid microparticles were selected from Example 2 and suspended in an aqueous carrier. The lipid microparticles, with a BRE:GTS ratio of 3:7, were selected from Example 3 and suspended in an aqueous carrier. (2) Steps: Healthy male SD rats, weighing 220±20 g, were selected and administered the drug subcutaneously after a 12-hour fast. Blood samples were collected at intervals (posterior ocular venous plexus sampling) over a period of 60 days. Samples were placed in polyethylene tubes pre-anticoagulated with heparin sodium and centrifuged at 6000 rpm for 5 min. The separated plasma was stored at -20 ℃ for analysis. After protein precipitation, the blood drug concentration was determined by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS / MS) to obtain pharmacokinetic curves. Data were analyzed using Phoenix software, and the results are shown in the table below. Table 3: Pharmacokinetic Data of Experimental Example 2

[0077] Table 3 and Figure 3 The results showed that, within a certain range, changes in the proportion of fatty acid glycerides added had no significant effect on its sustained-release performance, and all maintained a good sustained-release effect.

[0078] Experimental Example 3 Pharmacokinetic Study - Carrier Esterification Degree Three lipid materials—glyceryl monostearate (GMS), glyceryl distearate (GDS), and glyceryl tristearate (GTS)—were selected to investigate the effect of esterification degree on sustained-release efficacy. Furthermore, the proportion of fatty acid glycerides (GTS) was increased to further examine its sustained-release properties.

[0079] (1) Grouping (dosage: 30 mg) The lipid microparticles, with a BRE:GTS ratio of 3:7, were selected from Example 3 and suspended in an aqueous carrier. The lipid microparticles, with a BRE:GDS ratio of 3:7, were selected from Example 4 and suspended in an aqueous carrier. The lipid microparticles, with a BRE:GMS ratio of 3:7, were selected from Example 5 and suspended in an aqueous carrier. BRE:GTS = 5:5. The lipid microparticles were selected from Example 6 and suspended in an aqueous carrier. (2) Steps: Healthy male SD rats, weighing 220±20 g, were selected and administered the drug subcutaneously after a 12-hour fast. Blood samples were collected at intervals (posterior ocular venous plexus sampling) over a period of 60 days. Samples were placed in polyethylene tubes pre-anticoagulated with heparin sodium and centrifuged at 6000 rpm for 5 min. The separated plasma was stored at -20 ℃ for analysis. After protein precipitation, the blood drug concentration was determined by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS / MS) to obtain pharmacokinetic curves. Data were analyzed using Phoenix software, and the results are shown in the table below. Table 4: Pharmacokinetic Data of Experimental Example 3

[0080] Table 4 and Figure 4 The results showed that the degree of esterification of the carrier material was positively correlated with its sustained-release performance, with glyceryl tristearate exhibiting the best sustained-release characteristics. Furthermore, even when the proportion of glyceryl tristearate was reduced to 50%, it still maintained a good sustained-release effect.

Claims

1. An injectable sustained-release microparticle formulation of epipiperazole, characterized in that, It contains lipid microparticles, which, by weight, contain 20-99 parts of fatty acid glycerides and 1-80 parts of epipiperol.

2. The epipiperazole injectable sustained-release microparticle formulation according to claim 1, wherein the lipid microparticles comprise 40-90 parts of fatty acid glycerides and 10-60 parts of epipiperazole.

3. The epipiperazole injectable sustained-release microparticle formulation according to claim 1, wherein the fatty acid glycerides are selected from 1-monolaurate glyceride, 1,2-dilaurate glyceride, dilaurate glyceride (mixed), trilaurate glyceride, monotetrazole glyceride, 1,3-tetrazole diglyceride, tritetrazole triglyceride, 1-monomyocarbamate glyceride, 2-monomyocarbamate glyceride, 1,2-dimyristicin glyceride, 1,3-dimyristicin glyceride, trimyristicin glyceride, monopentadecanocarbamate glyceride, 1,2-dipentadecanocarbamate glyceride, 1,3-dipentadecanocarbamate glyceride, Pentadecanoic acid triglyceride, 1-monopalmitoyl glyceride, 2-monopalmitoyl glyceride, monopalmitoyl glyceride (mixed), 1,2-dispalmitoyl glyceride, 1,3-dispalmitoyl glyceride, dipalmitoyl glyceride (mixed), tripalmitoyl glyceride, heptadecanoyl glyceride, 1,2-heptadecanoyl diglyceride, 1,3-heptadecanoyl diglyceride, heptadecanoyl triglyceride, 1-monostearyl glyceride, 2-monostearyl glyceride, monostearyl glyceride (mixed), 1,2-distearate glyceride, 1,3-distearate glyceride, tristearyl glyceride, nonadecanoyl glyceride 1,2-Nondecanoic acid diglyceride, 1,3-Nondecanoic acid diglyceride, monocosanoic acid glyceride, 1,3-Cocanoic acid diglyceride, cocosanoic acid triglyceride, monobenzyl ... One or more combinations of 1,2-palmitoyl-3-stearyl glyceride, 1,2-palmitoyl-3-myristoyl glyceride, 1,2-palmitoyl-3-pentadecanoyl glyceride, 1,3-palmitoyl-2-stearyl glyceride, 1,3-palmitoyl-2-myristoyl glyceride, 1,2-myristoyl-3-palmitoyl glyceride, 1,2-myristoyl-3-laurate glyceride, 1,2-laurate-3-myristoyl glyceride, and 1,2-benzyl-3-myristoyl glyceride, preferably one or more of tristearate, tribenzyl-3-benzyl-3-olate, and tripalmitoyl glyceride.

4. The epipiperazole injectable sustained-release microparticle formulation according to claim 1, characterized in that, The lipid microparticles have an average particle size of 30-200 μm.

5. The epipiperazole injectable sustained-release microparticle formulation according to any one of claims 1-4, characterized in that, The formulation further comprises an aqueous carrier, the aqueous carrier comprising one or more pharmaceutically acceptable excipients selected from one or more of a self-suspending agent, a surfactant, a preservative, an antioxidant, water, physiological saline, a glucose solution, or a buffer solution.

6. The epipiperazole injectable sustained-release microparticle formulation according to claim 5, characterized in that, The suspending agent is selected from one or more combinations of sodium carboxymethyl cellulose (CMC-Na), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), sodium alginate, glycerin, gum arabic, xanthan gum, and gelatin. The content of the suspending agent in the aqueous carrier is 0.2% to 10% by weight. The surfactant is selected from phospholipids, HS15, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, polysorbate 20, polysorbate 80, dehydrated sorbitan ester, polyoxyethylene dehydrated sorbitan ester, sodium lauryl sulfate, etc. The antioxidant is selected from one or more combinations of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil, and polyvinyl alcohol, with a content of 0.1% to 2% by weight in the aqueous carrier; the antioxidant is selected from one or more combinations of sodium bisulfite, ascorbic acid, acetylcysteine, vitamin E, α-tocopherol, glutathione, sodium deoxythiamine, sodium nitrite sulfate, sodium thiobarbiturate, sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and tert-butylhydroquinone (TBHQ), with a content of 0.01% to 2% by weight in the aqueous carrier.

7. A method for preparing the epipiperazole injectable sustained-release microparticle formulation according to any one of claims 1-6, characterized in that... Includes the following steps: (1) After heating and melting fatty acid glycerides, add the active pharmaceutical ingredient epipipazole and stir until dissolved or mixed to prepare lipid microparticles; (2) Preparation of aqueous carrier; (3) Add lipid microparticles to the aqueous carrier described in step (2) and mix thoroughly to form a uniformly dispersed injectable formulation; The lipid microparticle preparation step (1) is performed using a rotary disk atomization, spray cooling and solidification method, or melt extrusion method. Step (1) after preparing lipid microparticles further includes sterilizing the lipid microparticles, filling them into a container, and then sealing them; the container is preferably a vial. The steps for preparing an aqueous carrier include dissolving suspending agents, surfactants and / or preservatives, antioxidants, etc., in water for injection.

8. A method for preparing the epipiperazole injectable sustained-release microparticle formulation according to any one of claims 1-6, characterized in that... Includes the following steps: (1) Epicipazole and fatty acid glycerides are fully dissolved in an organic reagent in a certain proportion, wherein the organic reagent is selected from dichloromethane and chloroform; (2) Rotate the above organic reagents to dryness and remove the precipitate; (3) Grind the precipitate and use a standard sieve to separate lipid particles of a certain size; (4) After preparing the aqueous carrier, add the lipid microparticles from step (3) and mix thoroughly to form a uniformly dispersed injectable formulation; The steps for preparing an aqueous carrier include dissolving suspending agents, surfactants and / or preservatives, antioxidants, etc., in water for injection.

9. A kit for an injectable sustained-release microparticle formulation of epipiperazole, comprising: (1) Lipid microparticles containing the epipiperazole according to any one of claims 1-6 or 7-8, sterilized; (2) Prepare an aqueous carrier, dispense and seal for later use; (3) The above (1) and (2) are packaged together and thoroughly mixed before use for subcutaneous or intramuscular injection. The steps for preparing an aqueous carrier include dissolving suspending agents, surfactants and / or preservatives, antioxidants, etc., in water for injection; The sterilization in step (1) is gamma radiation sterilization.

10. The use of the epipiperazole injectable sustained-release microparticle formulation according to any one of claims 1-6, the injectable sustained-release microparticle formulation prepared by the preparation method according to any one of claims 7 or 8, or the kit according to claim 9 in the preparation of drugs for treating schizophrenia, depression, borderline personality disorder, and Alzheimer's disease.

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